Medicine Update (Vol 28) 2018 PDF

Medicine Update 2018
DISCLAIMER
This book contains the views and opinions of a group of experts and does not represent the decisions or stated
policies of the Association of Physicians of India or Indian College of Physicians or Editors.
The authors/contributors are themselves responsible for obtaining appropriate permissions to reproduce data/
illustrations/figures/tables from other sources. The editors and publishers have accepted manuscripts in good
faith and on the condition that all authors have adhered to the highest standards of publication ethics.
Medicine is an ever changing science. As new data and drugs become available, treatment concepts and
recommendations are constantly changing. The editors and publishers have tried to ensure that the information
provided in this book is current and in keeping the present standard of care. Readers are, however, advised to cross
check full prescribing information with the product inserts provided by the drug manufacturers. References from
the web are provided for informational purposes only and do not constitute endorsement of any website.
© Copyright API 2018
All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic,
mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers/editor(s)/author(s).
ISBN: 978-81-935342-6-7
Printed in India
Published and exclusively distributed by EVANGEL PUBLISHING
Medicine Update 2018
Pritam Gupta MBBS MD (Gen Med) FICP FAMS

Head
Department of Medicine
Sunder Lal Jain Hospital
Ashok Vihar, New Delhi, India
President Elect and Chairman
Scientific Committee
APICON 2018
New Delhi, India

Dedicated to
My dear Mother and Father
(Late) Smt Prem Wati Gupta
and
(Late) Shri Babu Ram Ji Gupta
Who dedicated their whole life in bringing me up and
taught me all the values
My wife
Dr (Mrs) Sushma Gupta
Being so tolerant, cooperative and supportive to all my life
and
Dr Ankur Gupta, Dr Preeti Gupta, Parth Gupta
Dr Rajat Gupta, Dr Deepti Gupta, Ishan and Shanaya
Making me so proud of them

To all my
Teachers especially Professor C Prakash
and
Patients
Who have taught me medicine
CONTRIBUTORS
Aakash Aggarwal AKP Singh Anil Kumar Gupta

Senior Resident Professor Head
Department of Medicine Member Department of Transfusion Medicine
Shri Guru Ram Das Institute of Medical Heart Failure Society of America Sunder Lal Jain Hospital
Sciences and Research New Delhi, India
Amritsar, Punjab, India Alaka K Deshpande
Professor and Head Anil Kumar Virmani
Aarathy Kannan Department of Medicine Consultant and Physician
Physician and Diabetologist Sir JJ Hospital and Grant Medical College Kantilal Gandhi Memorial Hospital
Sundaram Arulrhaj Hospitals Mumbai, Maharashtra, India Jamshedpur, Jharkhand, India
Tuticorin, Tamil Nadu, India
Alok Gupta
Anish Kumar Gupta
Senior Professor
Abhishek Gupta Department of Medicine and Coordinator
North Delhi Nursing Home Pvt Ltd
Senior Resident Ashok Vihar, New Delhi, India
Medical Education
Department of Cardiology
Dr Sampurnanand Medical College
All India Institute of Medical Sciences Anita Jaiswal
Jodhpur, Rajasthan, India
New Delhi, India Senior DMO
Amal Kumar Banerjee Department of Medicine
Abhishek Pandey Consultant and Interventional Cardiologist Central Railway, India
Assistant Professor Institute of Cardiovascular Sciences
Department of Medicine Institute of Postgraduate Medical Ankur Bahl
Institute of Medical Sciences Education and Research and Seth Sukhlal Consultant
Banaras Hindu University Karnani Memorial Hospital Max Super Speciality Hospital
Varanasi, Uttar Pradesh, India Kolkata, West Bengal, India Saket, New Delhi, India
Ajay Aggarwal Amar R Pazare Anshul Kumar Jain

Endocrinologist Professor and Head Senior Consultant and Interventional
Department of Endocrinology Seth GS Medical College and KEM Hospital Cardiologist
Fortis Hospital Mumbai, Maharashtra, India Fortis Hospital and Jaipur Golden Hospital
Shalimar Bagh, New Delhi, India New Delhi, India
Amit Adhikary
Clinical Tutor
Ajay Kumar Anuj Maheshwari
Chairman Professor and Head
North Bengal Medical College
Administration and Grievance Department of General Medicine
Darjeeling, West Bengal, India
Medical Council of India BBD University
Lucknow, Uttar Pradesh, India
Ananda Bagchi
AK Chauhan Senior Consultant and Physician
Diabetocardiologist Dum Dum Specialised Hospital and ILS Anupam Dey
Chairman and Managing Director Hospital Associate Professor
Chauhan Sanjeevani Hospital Kolkata, West Bengal, India All India Institute of Medical Sciences
Bareilly, Uttar Pradesh, India Bhubaneswar, Odisha, India
Anil C Anand
Akhilesh Kumar Singh Academic Coordinator and Senior Consultant Anup K Das
Assistant Professor Department of Hepatology and Head
Department of Medicine Gastroenterology Department of Medicine
Sarojini Naidu Medical College Indraprastha Apollo Hospitals Assam Medical College and Hospital
Agra, Uttar Pradesh, India New Delhi, India Dibrugarh, Assam, India
viii Medicine Update 2018
A Pandey Asha N Shah BB Thakur

Associate Professor Unit Head Consultant Physician
Department of Medicine Department of Medicine Past President HSI and API
Sarojini Naidu Medical College and Hospital BJ Medical College Past Dean, ICP
Agra, Uttar Pradesh, India Ahmedabad, Gujarat, India Professor and Head
Aparna Agrawal Ashima Katyal SKMCH
Director and Professor Senior Resident Muzaffarpur, Bihar, India
Department of General Medicine Pandit Bhagwat Dayal Sharma
Lady Hardinge Medical College and Post Graduate Institute of Medical Sciences Bhupendra Gupta
Associated Hospitals Rohtak, Haryana, India Professor
Shaheed Bhagat Singh Marg North DMC Medical College and
New Delhi, India Ashish Chawla Hindu Rao Hospital
District Program Officer New Delhi, India
Apu Adhikary Revised National Tuberculosis Control
Faculty Program Bidita Khandelwal
North Bengal Medical College Ludhiana, Punjab, India Professor and Head
Kolkata, West Bengal, India Department of Medicine
Ashish Duggal
Sikkim Manipal Institute of Medical
Apurba Kumar Mukherjee Assistant Professor
Sciences
Head Department of Neurology
Sikkim Manipal University
Department of General Medicine and Govind Ballabh Pant Institute of
Gangtok, Sikkim, India
Endocrinology Postgraduate Medical Education and
RG Kar Medical College Research (Delhi University) Blessy Sehgal
Kolkata, West Bengal, India New Delhi, India Consultant Nephrologist
Department of Nephrology and Renal
Aradhna Sharma Ashish Gautam
Transplant
Assistant Professor Associate Professor
Sri Action Balaji Medical Institute
Department of Medicine Sarojini Naidu Medical College
New Delhi, India
Sawai Man Singh Hospital and Medical Agra, Uttar Pradesh, India
College Ashok Kumar BNBM Prasad
Jaipur, Rajasthan, India Associate Professor Professor and Head
Department of Medicine Department of Pulmonary Medicine
Aradhya Sekhar Bagchi Amrita Institute of Medical Sciences
Santosh Medical Dental College and
Medical College Kochi, Kerala, India
Hospital
Kolkata, West Bengal, India
Ghaziabad, Uttar Pradesh, India
BR Bansode
Arunkumar Ramachandrappa Head
Balvir Singh
Assistant Professor Department of Medicine
Professor
Department of General Medicine Babasaheb Ambedkar Memorial Hospital
Mahatma Gandhi Medical College and (Central Railway)
Sarojini Naidu Medical College
Research Institute Mumbai, Maharashtra, India
Agra, Uttar Pradesh, India
Puducherry, Tamil Nadu, India
BA Muruganathan Brij Mohan
Arun Shivaraman MM Chairman Fellow Diabetes India
Resident AG Hospital Active Member of National and
Institute of Neurology Tirupur, Tamil Nadu, India International Academic Bodies
Madras Medical College
Chennai, Tamil Nadu, India Bappaditya Kumar Chakravarthy DJK
Department of Cardiology GSL Medical College
Arup Kumar Kundu Medical College Rajahmundry, Andhra Pradesh, India
Professor Kolkata, West Bengal, India
Department of General Medicine and Chanchal Kumar Jana
In-Charge BB Rewari Professor
Division of Rheumatology Ex-Associate Professor Department of General Medicine
IQ City Medical College PGIMER and Dr RML Hospital RG Kar Medical College and Hospital
Durgapur, West Bengal, India New Delhi, India Kolkata, West Bengal, India
Contributors ix
DC Sharma Dipankar M Bhowmik G Prakash

Insititute of Endocrine and Diabetes Professor Associate Professor and Head
Srajan Hospital Department of Nephrology Department of Diabetology
Udaipur, Rajasthan, India All India Institute of Medical Sciences Government Mohan Kumaramangalam
New Delhi, India Medical College
Debasis Chakrabarti Salem, Tamil Nadu, India
Associate Professor
Department of Medicine Divya G Guhan R
North Bengal Medical College Senior Resident Resident
Siliguri, West Bengal, India Lourdes Hospital Institute of Neurology
Kochi, Kerala, India Madras Medical College
Deebanshu Gupta Chennai, Tamil Nadu, India
Postgraduate
Gaurab Bhaduri Gunja Jain
Department of General Medicine
Senior Resident Assistant Professor
Jawaharlal Nehru Medical College
Department of General Medicine Department of Medicine
KLE Univesity
RG Kar Medical College and Hospital Sawai Man Singh Medical College
Belgaum, Karnataka, India
Kolkata, West Bengal, India Jaipur, Rajasthan, India
Deepak Jain Gurinder Mohan
Associate Professor Geeta Kampani Professor and Head
Department of Medicine Consultant and Professor Department of Medicine
Pandit Bhagwat Dayal Sharma University of Department of General Medicine Shri Guru Ram Das Institute of Medical
Health Sciences VMMC and Safdarjung Hospital Sciences and Research
Rohtak, Haryana, India New Delhi, India Amritsar, Punjab, India
Deepak Sharma Gurleen Wander

Associate Consultant Ghan Shyam Pangtey Speciality Registrar
Department of Gastroenterology and Professor Queen Charlotte’s and Chelsea Hospital
Hepatology Department of Medicine Imperial College
Max Superspeciality Hospital Lady Hardinge Medical College NHS Trust London
New Delhi, India New Delhi, India United Kingdom
Devendra Prasad Singh Gurpreet Singh Wander

Professor and Head Girish Khurana Professor and Head
Department of Respiratory Medicine Senior Consultant Physician Department of Cardiology
Jawaharlal Nehru Medical College and Vidya Medicare Centre Dayanand Medical College and Hospital
Hospital Bahadurgarh, Haryana, India Hero DMC Heart Insititute
Bhagalpur, Bihar, India Ludhiana, Punjab, India
Girish Mathur Gurubax Singh
Deven Juneja Senior Consultant Sunder Lal Jain Hospital
Institute of Critical Care Medicine
JLN Medical College New Delhi, India
Max Superspeciality Hospital
Ajmer, Rajasthan, India
New Delhi, India Harbir Kaur Rao
Professor
Dinesh Khullar Girish MP Department of Medicine
Chairman and Head Professor Maharishi Markandeshwar Institute of
Department of Nephrology Department of Cardiology Medical Sciences and Research
Institute of Renal Sciences GB Pant Institute of Postgraduate Medical Ambala, Haryana, India
Max Superspeciality Hospital Education and Research
Saket, New Delhi, India New Delhi, India Harendra Kumar
Senior Consultant
Dipanjan Bandyopadhyay Hony National Professor of Medicine
Professor and Head G Loganathan Former Director (2012–2016)
Department of Medicine Adjunct Professor Indira Gandhi Institute of Cardiology
North Bengal Medical College Dr MGR Medical University Patna Medical College and Hospital
Darjeeling, West Bengal, India Chennai, Tamil Nadu, India Patna, Bihar, India
x Medicine Update 2018
Harpreet Singh Kashinath Padhiary Laxmi Kant Goyal

Assistant Professor Professor Assistant Professor
Maulana Azad Medical College and VIMSAR Department of Medicine
Associated LN Hospital Burla, Odisha, India SMS Medical College
New Delhi, India Jaipur, Rajasthan, India
Kirti Shetty
Harpreet Singh Associate Professor L Ilavarasi
Professor The Johns Hopkins University School of Consultant
Pandit Bhagwat Dayal Sharma University of Medicine Priya Nursing Home
Health Sciences Baltimore, Maryland, USA Chennai, Tamil Nadu, India
Rohtak, Haryana, India
L Santhosh Vivekanadan
KJ Shetty Surgical Consultant
Hem Shanker Sharma
Senior Consultant GL Hospital (Unit Mullai Srinivasam
Assistant Professor
Bangalore Baptist Hospital Hospitals Private Limited)
Bengaluru, Karnataka, India Salem, Tamil Nadu, India
JLN Medical College
Bhagalpur, Bihar, India
KK Pareek Madhulata Agarwal
Hitesh Sharma Senior Consultant Assistant Professor
Junior Resident Department of Medicine Department of Medicine
Department of Medicine Director Sawai Man Singh Hospital and Medical
Sawai Man Singh Hospital and College SN Pareek Memorial Hospital and College
Jaipur, Rajasthan, India Research Center Jaipur, Rajasthan, India
Kota, Rajasthan, India
HK Aggarwal Mangesh Tiwaskar
Shilpa Medical Research Centre
Senior Professor K Mugundhan
Mumbai, Maharashtra, India
Pandit Bhagwat Dayal Sharma University of Assistant Professor
Health Sciences Department of Neurology
Manikandan R
Rohtak, Haryana, India Government Mohan Kumaramangalam
PG DNB Medicine
Medical College Hospital
Sundaram Arulrhaj Hospitals
HK Chopra Salem, Tamil Nadu, India
Tuticorin, Tamil Nadu, India
Chief Cardiologist
Moolchand Medcity K Nagesh Manish Bamrotiya
New Delhi, India Senior Consultant National Consultant
Physician and Director National AIDS Control Organisation
Indira Maisnam Nagesh Hospital New Delhi, India
Consultant Endocrinologist Hassan, Karnataka, India
Department of Endocrinology Manish Bansal
RG Kar Medical College Associate Director
KN Manohar
Kolkata, West Bengal, India Cardiology
Consultant Physician
Manipal Hospital Medanta—The Medicity
Jahnvi Dhar Gurugram, Haryana, India
Bengaluru, Karnataka, India
Maulana Azad Medical College Man Mohan Mehndiratta
New Delhi, India K Tewary Professor
Professor and Head Department of Neurology
Jayant Kumar Panda Department of Medicine Govind Ballabh Pant Institute of
Department of Medicine SK Medical College Postgraduate Medical Education and
SCB Medical College Muzaffarpur, Bihar, India Research (Delhi University)
Cuttack, Odisha, India New Delhi, India
Lakshmi Narasimhan Ranganathan
Jugal Kishor Sharma Professor and Director Manoranjan Behera
Medical Director and Senior Consultant Institute of Neurology Assistant Professor
Central Delhi Diabetes Centre Madras Medical College Nagesh Hospital, Channarayapatna
New Delhi, India Chennai, Tamil Nadu, India Hassan, Karnataka, India
Contributors xi
Mathew Thomas Munish Prabhakar Niteen D Karnik

Professor Senior Consultant Professor and Head
Department of Medicine Department of Medicine Department of Medicine
KIMS Hospital, Anayara PO Private Hospital LTMMC and LTMG Hospital
Trivandrum, Kerala, India India Mumbai, Maharashtra, India
Mayank Gupta NK Singh

Nagendra Boopathy Senguttuvan
Senior Resident Director
Assistant Professor
Department of Medicine Diabetes and Heart Research Centre
Sri Ramachandra Medical College and
SMS Medical College Dhanbad, Jharkhand, India
Research Institute
Jaipur, Rajasthan, India Chennai, Tamil Nadu, India N Rajkanna
Senior Resident
Meghna Gupta
Naman Mukhi Department of Nephrology
Adesh Institute of Medical Sciences and
Senior Resident All India Institute of Medical Sciences
Research
Pandit Bhagwat Dayal Sharma New Delhi, India
Bathinda, Punjab, India
Postgraduate Institute of Medical
Sciences N Subramanian
Minal Mohit Assistant Professor and Consultant
Consultant Velammal Medical College and
Manipal Hospital Research Institute, Madurai
Jaipur, Rajasthan, India Narayan G Deogaonkar
Consultant Rheumatologist
Consultant Physician
Tirunelveli, Tamil Nadu, India
Mohanjeet Kaur Deogaonkar Hospital
Consultant Physician Nashik, Maharashtra, India Omender Singh
Shree Raghunath Hospital Institute of Critical Care Medicine
Ludhiana, Punjab, India Narendra Pal Jain Max Superspeciality Hospital
Professor New Delhi, India
Mohit D Gupta Department of Internal Medicine
Professor Dayanand Medical College and Hospital Onkar Awadhiya
Department of Cardiology Ludhiana, Punjab, India Junior Resident
GB Pant Institute of Postgraduate Medical Bhopal Memorial Hospital and
Education and Research Neeraj Kumar Research Centre
New Delhi, India Resident Bhopal, Madhya Pradesh, India
Pandit Bhagwat Dayal Sharma University of
Mohit Goyal OP Sharma
Health Sciences
Rheumatologist Senior Consultant
Udaipur, Rajasthan, India Department of Geriatric Medicine
Indraprastha Apollo Hospitals
Nidhi Raina New Delhi, India
Mridul Chaturvedi
Senior Resident
Professor
Department of Pathology Paluru Vijayachari
Government Medical College and Hospital Director
Chandigarh, India Regional Medical Research Centre (ICMR)
Port Blair, Andaman and Nicobar Islands,
Niraj Nirmal Pandey India
Mrinal Kanti Roy
Department of General Medicine Senior Resident
Pankaj Kumar
Calcutta National Medical College and Department of Cardiovascular Radiology
Senior Consultant
Hospital and Endovascular Interventions
Fortis Hospital
Kolkata, West Bengal, India All India Institute of Medical Sciences
Shalimar Bagh, New Delhi, India
New Delhi, India
Mugundhan Krishnan Paramjeet Singh
Associate Professor Nirupam Prakash Associate Professor
Institute of Neurology Consultant Physician Department of Medicine
Madras Medical College Central Government Health Scheme Government Medical College
Chennai, Tamil Nadu, India Lucknow, Uttar Pradesh, India Haldwani, Uttarakhand, India
xii Medicine Update 2018
Piyush Jain Prashasti Gupta Punit L Jain

Associate Professor IIIrd Year Postgraduate Student Consultant Hematologist
Department of Medicine Department of General Medicine Global Hospitals
PGIMER and Dr RML Hospital Lady Hardinge Medical College and Mumbai, Maharashtra, India
New Delhi, India Associated Hospitals
Shaheed Bhagat Singh Marg Ragini Ghalaut
PK Agrawal New Delhi, India Assistant Professor
General Physician Blood Transfusion Department
Sir Ganga Ram Hospital Prem Parkash Gupta Bhagat Phool Singh Government Medical
New Delhi, India Professor
College
Department of Respiratory Medicine
Sonipat, Haryana, India
PK Maheshwari Postgraduate Institute of Medical Sciences
Professor and Head Rohtak, Haryana, India Rahul Chauda
Pritam Gupta Resident
Head Department of Medicine
Department of Medicine Pandit Bhagwat Dayal Sharma University of
PK Sasidharan Sunder Lal Jain Hospital Health Sciences
Professor and Head Ashok Vihar, New Delhi, India Rohtak, Haryana, India
Government Medical College Priya Bhate Rajat Gupta
Former Dean, Department of Medicine Assistant Professor Resident
University of Calicut Department of Medicine Department of Medicine
Kozhikode, Kerala, India Seth GSMC and KEM Hospital Dr Sampurnanand Medical College
Mumbai, Maharashtra, India Jodhpur, Rajasthan, India
Prabhleen Kaur
Priya Jagia Rajeev Chawla
Junior Resident
Professor
Department of Pulmonary Medicine Director
Department of Cardiovascular Radiology
Government Medical College North Delhi Diabetes Centre
and Endovascular Interventions
Patiala, Punjab, India New Delhi, India
All India Institute of Medical Sciences
Prabuddha Mukhopadhyay New Delhi, India
Rajeev Gupta
Assistant Professor PS Ghalaut Additional Director and Senior Consultant
Vivekananda Institute of Medical Sciences Director and Professor Department of Internal Medicine
Kolkata, West Bengal, India Bhagat Phool Singh Government Medical Orlando Regional Medical Centre
College Florida, USA
Pramod Kumar Sinha
Sonipat, Haryana, India
Associate Professor Rajeev Mohan Kaushik
Department of Medicine PS Shankar Professor
Anugrah Narayan Magadh Medical Emeritus Professor Department of Medicine
College and Hospital Department of Medicine Himalayan Institute of Medical Sciences
Gaya, Bihar, India Rajiv Gandhi University of Health Sciences Swami Rama Himalayan University
KBN Institute of Medical Sciences Dehradun, Uttarakhand, India
Prasanta Kumar Bhattacharya Kalaburagi, Karnataka, India
Professor and Head
Department of General Medicine
Rajeev Raina
Puneet Rijhwani
North Eastern Indira Gandhi Regional Professor
Professor and Head
Institute of Health and Medical Sciences Department of Medicine
Departmen of Medicine
Shillong, Meghalaya, India Indira Gandhi Medical College
Mahatma Gandhi University of Medical
Sciences and Technology Shimla, Himachal Pradesh, India
Prashant Prakash Jaipur, Rajasthan, India
Associate Professor and Head Rajesh Aggarwal
Superspeciality Division of Pulmonary Puneet Saxena Senior Consultant
Medicine Professor Department of Nephrology and Renal
Deptartment of Medicine Department of Medicine Transplant
Sarojini Naidu Medical College Sawai Man Singh Hospital and Medical College Sri Balaji Action Medical Institute
Agra, Uttar Pradesh, India Jaipur, Rajasthan, India New Delhi, India
Contributors xiii
Rajesh Kumar Jha Ravindra Kumar Das R Sajith Kumar

Professor and Head Assistant Professor Professor and Head
Department of General Medicine Department of Medicine Department of Infectious Diseases, and
Sri Aurobindo Medical College and Darbhanga Medical College Department of Medical Education
Postgraduate Institute Laheriasarai, Bihar, India Government Medical College
Indore, Madhya Pradesh, India Kottayam, Kerala, India
Ravi R Kasliwal
Rajesh Rajput
Chairman Sagar Dembla
Senior Professor and Head
Clinical and Preventive Cardiology Department of General Medicine
Department of Endocrinology
Medanta—The Medicity Sri Aurobindo Medical College and
Postgraduate Institute of Medical Sciences
Gurugram, Haryana, India Postgraduate Institute
Indore, Madhya Pradesh, India
Rajesh Shankar Iyer Revati R Iyer
Consultant Consultant Gynecologist and Obstetrician Sagar Gupta
Department of Neurology Ambika Clinic Department of Nephrology
KG Hospital and Postgraduate Medical Navi Mumbai, Maharashtra, India Institute of Renal Sciences
Institute Max Superspeciality Hospital
Coimbatore, Tamil Nadu, India Richa Singh Agnihotri Saket, New Delhi, India
Research Fellow
Rajesh Upadhyay
Diabetes and Heart Research Center
Director and Head Sameer Gulati
Dhanbad, Jharkhand, India Associate Professor
Department of Gastroenterology and
Hepatology Department of Medicine
Max Superspeciality Hospital
Richie Gupta VMMC and Safdarjung Hospital
Senior Consultant and Head New Delhi, India
New Delhi, India
Fortis Hospital
Rajib Ratna Chaudhary Shalimar Bagh, New Delhi, India
Sameer Kumar
Professor and Head
Senior Resident
Department of Medicine Rishu Bhanot
Department of Cardiology
Rohilkhand Medical College and Hospital Senior Resident
GB Pant Institute of Postgraduate Medical
Bareilly, Uttar Pradesh, India Department of Internal Medicine
Education and Research
Dayanand Medical College and Hospital
Rajinder Singh Gupta New Delhi, India
Ludhiana, Punjab, India
Professor
Department of Medicine Samman Verma
Rommel Singh
Maharishi Markandeshwar Institute of Postgraduate Institute of Medical
Assistant Professor
Medical Sciences and Research Education and Research
Government Medical College
Ambala, Haryana, India Chandigarh, India
Patiala, Punjab, India
Raman Sharma
Senior Professor Roopak Wadhwa Sandeep Garg
Department of Medicine Department of Endocrinology Professor
SMS Medical College Fortis Hospital Department of Medicine
Jaipur, Rajasthan, India Shalimar Bagh, New Delhi, India Maulana Azad Medical College
New Delhi, India
Ram Prakash Pandey
R Rajasekar
Junior Resident S Anita Nambiar
Consultant
Department of Medicine Consultant and Physician
Physician and Diabetologist
Sarojini Naidu Medical College Varma Hospital
Heart and Diabetes Therapy Center
Agra, Uttar Pradesh, India Tripunithura, Kerala, India
Kumbakonam, Tamil Nadu, India
Ranjeet Kaur
Associate Professor RR Singh Sanjay Dash
Department of Medicine Head CMO and Head
Shri Guru Ram Das Institute of Medical Department of Cardiac Lab and Pacing Unit Department of Medicine
Sciences and Research Raghvendra Hospital and Heart Center Nehru Shatabdi Central Hospital
Amritsar, Punjab, India Jhansi, Uttar Pradesh, India Talcher, Odisha, India
xiv Medicine Update 2018
Sanjay Kumar Agarwal Shaurya Mehta Sidhartha Das

Professor and Head Resident Dean and Principal
Department of Nephrology Department of Medicine SCB Medical College and Hospital
All India Institute of Medical Sciences Dr DY Patil Medical College Cuttack, Odisha, India
New Delhi, India Navi Mumbai, Maharashtra, India
Smita Thakur
Sanjiv Maheshwari Sher Singh Dariya GP Partner
Senior Professor Junior Specialist Eightlands Surgery
Department of Medicine Department of Medicine Dewsbury Health Centre
JLN Medical College Sawai Man Singh Hospital and Medical West Yorkshire, United Kingdom
Ajmer, Rajasthan, India College
Jaipur, Rajasthan, India SM Mustafa Zaman
Santanu Guha Senior Resident
Professor and Head Shibendu Ghosh Department of Cardiology
Department of Cardiology Associate Professor GB Pant Institute of Postgraduate Medical
Medical College Department of Medicine Education and Research
Kolkata, West Bengal, India RIMS, Raipur, Chhattisgarh, India New Delhi, India
Santosh Kumar Swain Shipra Kunwar SN Narasingan

Assistant Professor Professor and Head Managing Director
Department of Medicine Department of Obstetrics and Gynecology SNN Specialities Clinic
SCB Medical College Era’s Lucknow Medical College Chennai, Tamil Nadu, India
Cuttack, Odisha, India Lucknow, Uttar Pradesh, India
Sonia Arora
Saroj Kumar Tripathy Shraddha Ranjan
Consultant Diet and Nutrition
Senior Resident
Assistant Professor Kishori Ram Hospital and Diabetes Care
Cardiology
Department of Medicine Center and Pragma Hospital
Medanta—The Medicity
SCB Medical College Bathinda, Punjab, India
Gurugram, Haryana, India
Cuttack, Odisha, India
Shrikant Chaudhary SP Yoganna
Saumitra Ray JLN Medical College
Founder Chairman
Interventional Cardiologist Suyog Hospital
Ajmer, Rajasthan, India
Vivekananda Institute of Medical Sciences Mysuru, Karnataka, India
Kolkata, West Bengal, India Shubha Laxmi Margekar
Associate Professor S Ramakrishnan
Saurabh Srivastava Department of Medicine Professor
Professor Lady Hardinge Medical College and SSK Department of Cardiology
Department of Medicine Hospital All India Institute of Medical Sciences
School of Medical Sciences and Research New Delhi, India New Delhi, India
Sharda University
Greater Noida, Uttar Pradesh, India Shyamashis Das S Ramnathan Iyer
Consultant Rheumatologist Consultant Physician
Shalini Jaggi Institute of Neurosciences Godrej Memorial Hospital
Consultant Diabetologist and Head Kolkata, West Bengal, India Mumbai, Maharashtra, India
Dr Mohans’ Diabetes Specialities Centre
New Delhi, India Shyam Sundar Srikant Kumar Dhar
Professor Associate Professor
Shankha S Sen Department of Medicine Department of Medicine
Consultant Physician Institute of Medical Sciences IMS and SUM Hospital
Neotia Gatewel Hospital Banaras Hindu University Bhubaneswar, Odisha, India
Siliguri, West Bengal, India Varanasi, Uttar Pradesh, India
Sriprasad Mohanty
Shantanu Kumar Kar Siddharth Chopra Associate Professor
Director Intern Department of Medicine
IMS and SUM Hospital, S ‘O’A University Government Medical College SCB Medical College
Bhubaneswar, Odisha, India Patiala, Punjab, India Cuttack, Odisha, India
Contributors xv
SS Lakshmanan Sunil Gupta TP Singh

Senior Consultant Managing Director Professor
Priya Nursing Home Sunil’s Diabetes Care and Research Centre Department of Medicine
Chennai, Tamil Nadu, India Pvt Ltd Sarojini Naidu Medical College
Nagpur, Maharashtra, India Agra, Uttar Pradesh, India
Subrahmanya Murti V
Postgraduate Student Sunil Mahavar Trupti H Trivedi
Department of General Medicine Associate Professor Associate Professor
North Eastern Indira Gandhi Regional Department of Medicine In-Charge Medical ICU
Institute of Health and Medical Sciences SMS Medical College LTM Medical College and General Hospital
Shillong, Meghalaya, India Jaipur, Rajasthan, India Mumbai, Maharashtra, India
Sunita Aggarwal Tuhin Santra

Sudhir Mehta
Professor RMO
Senior Professor
Department of Medicine Department of General Medicine
Maulana Azad Medical College Midnapore Medical College
SMS Medical College
New Delhi, India Midnapore, West Bengal, India
Jaipur, Rajasthan, India
SV Ramana Murty Umashankar US

Sudhir Varma PG Resident
Senior Consultant Professor
Department of General Medicine Department of General Medicine
Sadbhavna Medical and Heart Institute VMMC and Safdarjung Hospital
Patiala, Punjab, India Academic Director (PG Education)
GSL Medical College New Delhi, India
Suhas Erande Rajahmundry, Andhra Pradesh, India

Vaibhav Agnihotri
Consultant Research Fellow
Tanuja Pravin Manohar
Pune Municipal Corporation Diabetes and Heart Research Center
Associate Professor
Pune, Maharashtra, India Dhanbad, Jharkhand, India
Department of Medicine, NKP Salve
Institute of Medical Sciences and VA Kothiwale
Sujata Mangla
Research Center Professor
Senior Consultant
Nagpur, Maharashtra, India Department of General Medicine
Ashok Vihar, New Delhi, India Jawaharlal Nehru Medical College
Tanu Shweta Pandey KLE University
Consultant Physician Belgaum, Karnataka, India
Sujoy Sarkar Internal Medicine
Assistant Professor Los Angeles, USA
Venkata Pradeep Babu K
DNB Resident
Calcutta National Medical College and Tarun Kumar Dutta Medical Oncology
Hospital Professor Rajiv Gandhi Cancer Institute and
Kolkata, West Bengal, India Department of General Medicine Research Center
Mahatma Gandhi Medical College and New Delhi, India
Suman Singh Research Institute
Consultant Puducherry, Tamil Nadu, India Venkataraman Nagrajan
National AIDS Control Organisation Senior Consultant and Neurologist
New Delhi, India Thamil Pavai N Chairman, National Neuroscience
Assistant Professor Research and Task Force
Sundaram Arulrhaj Institute of Neurology Indian Council of Medical Research
Chairman Madras Medical College Government of India
Sundaram Arulrhaj Hospitals Chennai, Tamil Nadu, India Ministry of Health
Tuticorin, Tamil Nadu, India New Delhi, India
Tony Kadavanu
Sundeep Mishra Assistant Professor Venugopal Margekar
Professor Department of General Medicine Senior Resident
Department of Cardiology Mahatma Gandhi Medical College and Department of Medicine
All India Institute of Medical Sciences Research Institute All India Institute of Medical Sciences
New Delhi, India Puducherry, Tamil Nadu, India Raipur, Chattisgarh, India
xvi Medicine Update 2018
Vijay Negalur Viplav N Deogaonkar VK Katyal

Dr Negalur’s Diabetes and Thyroid Deogaonkar Hospital Senior Professor and Unit Head
Specialities Center Nashik, Maharashtra, India Department of Medicine
Mumbai, Maharashtra, India Pandit Bhagwat Dayal Sharma
Virendra Kumar Goyal Postgraduate Institute of Medical
Vijay Prakash Hawa Head Sciences
Senior Resident Department of General Medicine Rohtak, Haryana, India
Department of Medicine North Eastern Indira Gandhi Regional
JLN Medical College Institute of Health and Medical Sciences V Palaniappen
Ajmer, Rajasthan, India Shillong, Meghalaya, India Managing Director
Dr V Palaniyappen’s Diabetes Specialities
Vinay Rampal Vishal Chopra Centre and Sri Sakthi Vinayakar
Government Medical College Associate Professor Multispeciality Hospital
Jammu, Jammu and Kashmir, India Department of Pulmonary Medicine Dindigul, Tamil Nadu, India
Government Medical College
Vineet Talwar Patiala, Punjab, India V Shankar
Co-Director Professor and Head
Department of Medical Oncology Vitull K Gupta Department of Neurology
Rajiv Gandhi Cancer Institute and Professor and Unit Head Sri Ramachandra Medical College
Research Center Department of Medicine Chennai, Tamil Nadu, India
New Delhi, India Adesh Institute of Medical Sciences and
Research
Vinodh Kumar A Consultant
PG DNB Medicine Kishori Ram Hospital and Diabetes Care
Sundaram Arulrhaj Hospitals Centre
Tuticorin, Tamil Nadu, India Bathinda, Punjab, India
FOREWORD
The prestigious conference ‘APICON 2018’ is going to be held in the last week of February, 2018
at Bengaluru, the city of digital technology. This Annual Scientific Program is much awaited by
students, teachers and practitioners with equal zeal and enthusiasm. The proceedings of this
Scientific Program are compiled in the form of a book titled Medicine Update. This year the Medicine
Update is edited by the President Elect, Dr Pritam Gupta, a very senior practitioner of medicine in
North India. The theme chosen by Dr Pritam Gupta is Dawn of New Era in Medicine which truly reflects
the spirit and advancement in the field of medicine.
Dr Pritam Gupta has been successful in getting the contributions from the doctors all over the country and they
are all experts in their own field and have command over the subject matter. This book has covered all the newer
advancements in the field of diagnosis and management of diseases. The book covers the global context of medicine
and has also been very successful being relevant to the Indian context. This book is a multiauthored compilation so
there is a variation in the style of presentation and conveying the message. However, the Editor—Dr Pritam Gupta and
his team of editorial board have tried to present the data in a precise and uniform pattern. Moreover, these publications
of API have a very useful supplementary role to the Textbook of Medicine which is published once in three years.
We are grateful to the authors for having spared their valuable time and expertise by contributing to this book. Dr
Pritam Gupta deserves our thanks and appreciation for having compiled the book which provides a concise, easy-to-
read and knowledge for gearing up the clinicians of India for practice of medicine in future as well. The book is appealing
to the eye, the style and formatting are easy-to-read and the language is simple and easy to understand. I am sure this
effort of Dr Pritam Gupta will find place on the desk of all doctors who can lay their hands on this useful compilation for
ready reference, and learning the new trend, and thought in changing medicine. These topics will be discussed by the
masters during the forthcoming APICON by themselves in person. So, you will have an opportunity to interact with them
to clarify your doubts from the book. Before I close, I am inspired to quote Swami Vivekananda
Education is the manifestation of the perfection already in man.
Yash Pal Munjal

Medical Director, Banarsidas Chandiwala Institute of Medical Sciences
Director, Physicians Research Foundation
Past Editor-in-Chief, API Textbook of Medicine
Past Dean, Indian College of Physicians
Past President, Association of Physicians of India
PREFACE
Change is the law of nature and so is with the medical science. The whole perception of the medicine has changed.
Many early impressions, personal experiences, options, dogmas and axons of the past years have been challenged and
proven to be wrong in the present era of evidence-based medicine. Modern imaging has transformed the approach to
anatomy. Molecular biology and genetics can predict various diseases, which can occur in future. Interventions have
blurred the boundary between the physicians and surgeons. Robots are conducting various surgeries and targeted
interventions. Target therapy is being done for cancers, and is a part of protocol. Today we are living in digital world.
Moreover, the society and media have easy access to Internet and the expectations of the patients are too high from the
treating doctors. Therefore, it is essential for the treating physicians to update themselves with the latest developments
in the field of medicine. With that view I have kept the theme of my scientific program as “Dawn of a New Era in Medicine”.
For a good doctor, three things are essential, i.e. competence, communication and compassion. Competence, i.e.
skill is achieved through conferences, literatures, journals, books and Internet. Conference provides a means of updating
knowledge in the context of changing scenarios of Medical Sciences. There is one-to-one interaction between the
attendees and the experts, and they can exchange and share their views. APICON is a multidisciplinary conference,
where all disciplines of medicine are being discussed at one common platform. Medicine Update 2018 a very popular
book read by postgraduate students and internists, which contain the preceding of APICON-2018. It contains common
topics, clinical problems and approach and management of various disorders, especially in Indian context. The intention
is not to replace textbooks or journals but to complement them.
This book contains 159 chapters in 17 sections written by the experts in their fields meant for Indian population. The
emphasis has been laid on clinical approach to medical problems, case-based discussions and algorithmic approach to
various diseases. I am sure that this book will be very handy and useful not only for postgraduates but also as a reference
guide for busy practicing physicians.
I do hope you find the book stimulating for, in the words of Alan Bennett, “A book is a device to ignite the
imagination”. The book belongs as much to the reader as it does to me as the editor. I have enjoyed editing this. I hope
you enjoy reading this.
Pritam Gupta MBBS MD (Gen Med) FICP FAMS

Head
Ashok Vihar, New Delhi, India
President Elect and Chairman
Scientific Committee
APICON 2018
ACKNOWLEDGMENTS
I would like to acknowledge the contribution of the galaxy of eminent academicians, physicians and experts from India
and abroad in contributing the chapters. At times due to limitations of time, I pushed them hards and would like to
apologize for the same.
I am extremely thankful to Dr YP Munjal, my mentor, a role model for guidance who has been helping at every step
for preparing a good scientific program and editing this book. His commitment to academics and passion to achieve
perfection in scientific pursuits, whether it is a session, guidelines or book has been guiding us to move a step forward.
Whenever I needed his help even at midnight, he was ever fresh and encouraging me for the whole year. Drs Siddharth
N Shah and BB Thakur deserve the special thanks for inspiring me to bring out a good scientific program and the book,
Medicine Update 2018.
Drs Ghan Shyam Pangtey and Anupam Prakash made my job easy for free papers and poster presentation. Our past
president Drs Rajesh Upadhyay, Shashank Joshi, Sandhya Kamath, A Muruganathan were always helping me time to
time in preparing scientific program. Dr BR Bansode, President of API, an ever smiling personality, helped me a lot and
was always inspiring me.
Scientific committee members Drs NK Soni, Rita Sood, Sandeep Garg and Sekhar Chakraborty were instrumental in
finalizing the scientific program. Drs RM Chhabra, MPS Chawla, AK Agarwal, RK Singal and JR Chugh were kind enough
in providing their valuable opinion and guidance for the publication of this book.
Drs Rohini Handa, Jyotirmoy Pal, Girish Mathur, GS Wander and KK Pareek were very generous in discussing the
scientific material and program. My heartfelt thanks to Dr Milind Y Nadkar, Editor-in-chief, JAPI, and Dr Mangesh
Tiwaskar, Secretory, API, who had always been a great support to me and guiding regularly. I would like to pay thanks to
whole staff of API Headquarter especially Mrs Sunita Shukla and other for their support.
For every success, there is always a lady behind it; she is Dr Sushma Gupta, my beloved wife. She had always been
cooperative, tolerant and source of inspiration to me. Drs Ankur Gupta and Rajat Gupta my sons had been a great
support of help for me, especially in planning and execution of this project including the publication of Medicine Update
2018.
I thank my all well wishers, friends and staff of Sunder Lal Jain Hospital especially Dr Sunil Mangla, who had been
looking after the patients in my absence.
Organizing committee members from Bengaluru, Dr P Chandrasekhra and their team-mates were always generous
and cooperative during the whole year. My special thanks to them.
I would like to thank the team of Evangel Publishing, especially Mr Tarun Duneja (Director) and Mr Mohit Bhargava
(Production Head), for printing this book in time.
Scientific committee of APICON-2018 is grateful to unconditional educational grant from Mankind Pharma, USV
Pharma, Merck Ltd, Abbott Pharma, Dr Reddy’s Laboratories Ltd, Novo Nordisk, Aristo Pharma, Sun Pharma, Alkem
Pharmaceuticals, Maxcare and Sanetra Pharma, etc.
I thank Mr Tapas Thakur my secretary and other members of staff especially, Mr Devender Kumar, without their help
it was not possible for me to bring out the scientific program and Medicine Update 2018 in time.
CONTENTS
SECTION 1 HYPERTENSION
1. Pitfalls in Hypertension Management..........................................................................................................3
K Tewary
Errors in Examination 3
Diagnostic Errors 3
Treatment Errors 4
Errors by Patients 4
2. Ambulatory Blood Pressure Monitoring in Clinical Practice.....................................................................6

Narayan G Deogaonkar, Viplav N Deogaonkar
3. Azilsartan: A New Baby in Old Horizon...................................................................................................... 17

BA Muruganathan
Evolution of the Angiotensin II Receptor Blockers 17
Angiotensin Receptor Blockers: Beyond Blood Pressure Lowering Effects 18
Tolerability 18
Direct AT1R Effects of Azilsartan 19
Azilsartan: Potent AT1 Receptor Binding 19
Azilsartan: Pleiotropic Effects Beyond BP Lowering 19
Azilsartan: Potential Effect in Cardio-Renal Protection 20
Summary of the Unique Features of Azilsartan 22
4. Hypertension and Menopause.................................................................................................................... 24

Anuj Maheshwari, Shipra Kunwar
Role of Oxidative Stress and Vasoconstrictors 24
Hypertension: The Key Risk Factor during Menopause 26
How should It be Treated? 27
5. Renovascular Hypertension: Current Status............................................................................................. 28

Puneet Rijhwani
Pathogenesis 28
Renovascular Hypertension: Major Causes 28
Diagnosis 29
Medical Management 30
xxiv Medicine Update 2018
Surgical Revascularization 31
Angioplasty 31
6. Diuretics for Hypertension: Review and Update...................................................................................... 33

R Rajasekar
Effect of Low Dose Diuretic 33
Types of Diuretics 33
Potassium-Sparing Common Combination Diuretics 35
Combination of Diuretic with Anti-HT Drugs 35
7. High Altitude Systemic Hypertension: Unraveling the Mystery........................................................... 36

VA Kothiwale, Deebanshu Gupta
Effects of High Altitude on Cardiovascular System 36
Need for Definition of HASH – and Its Prevalence 36
Pathophysiology of Hash 38
Role of Endothelin 1 40
Ageing, High Altitude and Blood Pressure-A Complex Relationship 41
Blood Pressure Changes with Aging 41
How BP Behaves with Aging in People Chronically Exposed to High Altitude 42
Importance of Recognizing Hash 42
Diagnosis of HASH 42
Treatment of HASH 42
8. Management of Isolated Systolic Hypertension: Current Concepts.................................................... 44

Girish Mathur, Shrikant Chaudhary
Prevalence and Risk Factor 44
Classification of ISH 45
Evaluation of ISH 45
Management of Hypertension 45
Benefits of Treatment of ISH 48
Interventional Trial Concerning ISH 48
Smaller Studies on ISH 48
9. Blood Pressure Control with Changing Time............................................................................................ 50

BR Bansode
Management of Hypertension 50
JNC 1974 to 2003 (1 to 7) 51
Conclusion and Perspectives 54
Contents xxv
10. Management of Hypertension in Diabetes............................................................................................... 55

BB Thakur, Smita Thakur
Hypertension 55
Pharmacologic Treatment 58
Gestational Diabetes 61
11. Grey Areas in Diagnosis and Management of Hypertension................................................................. 67

Anita Jaiswal
Rule of Halves 67
Types of Blood Pressure Instruments 70
SECTION 2 CARDIOLOGY
12. Atherosclerosis: Can We Tame it?................................................................................................................ 75
Harendra Kumar
Methods are Carotid Intima-Media Thickness (CIMT) 75
Cholesterol Absorption Inhibitor 77
13. Cardiac Cachexia............................................................................................................................................ 80

AKP Singh
Pathophysiology 80
Anabolic Failure 80
Catabolic Activation 80
Insulin Resistance 80
Skeletal Muscle 81
14. Is Intervention Still Relevant in Stable CAD?............................................................................................ 82

Santanu Guha, Bappaditya Kumar
Management of Stable Coronary Artery Disease 82
Indications for PCI 83
Improvement in Survival with PCI 83
Relief of Angina 83
Patients without Clear Indications for Intervention 84
15. Newer Oral Anticoagulants in Clinical Practice........................................................................................ 86

Anshul Kumar Jain
Comparison of NOACs with VKA 86
xxvi Medicine Update 2018
16. Dual Antiplatelet Therapy: How Long?...................................................................................................... 90

Sameer Kumar, Girish MP, Mohit D Gupta
What is the Debate? 90
Risk Stratification 90
Short-term versus Long Term DAPT: The Evidence So Far 91
Duration of Dual Antiplatelet Therapy in Cases of Stable Coronary Artery Disease (CAD) After PCI 91
Duration of Dual Antiplatelet Therapy in Patients Presenting with Acute Coronary Syndrome (ACS) 92
Duration of DAPT in Patients Undergoing CABG 93
Elective Noncardiac Surgery in Patients Treated with DAPT and PCI 93
Switch Over Between Antiplatelets 94
Special Circumstances 94
17. Newer Biomarkers in Heart Failure............................................................................................................. 97

Saumitra Ray
Diagnosis 97
Other Biomarkers 98
Biomarkers of HFpEF 98
18. Coronary Microvascular Dysfunction: An Update................................................................................. 100

SM Mustafa Zaman
Risk Factors and Pathophysiology 100
Diagnosis 102
Clinical Profile 102
Treatment of Coronary Microvascular Dysfunction 104
19. How did Fractional Flow Reserve Change My Clinical Decisions? Case-based Discussions.......... 110
Fractional Flow Reserve 110
Characteristics of FFR 110
Functional PCI 111
Deferred PCI 112
Assessment of Serial Lesions 112
20. Mega Trials in Cardiology........................................................................................................................... 115

Sundeep Mishra
Hypertension Trials 115
Secondary Prevention of CAD 116
Hope Trial 116
Arrhythmia 117
Contents xxvii
Heart Failure 117

Diabetes Mellitus 118
21. Rheumatic Valvular Heart Disease............................................................................................................ 121

RR Singh
Signs and Symptoms 121
Mitral Stenosis 122
Mitral Stenosis with Close-up on Mitral Valve 122
Medical Treatment 124
Surgical Treatment 124
22. Advances in Management of Pulmonary Arterial Hypertension........................................................ 125

Abhishek Gupta, S Ramakrishnan
Current Epidemiology 125
Management of PAH 125
Newly Approved Medications for PAH 126
Combination Therapy 127
Nonpharmacological Options 128
Stem Cell Therapy 128
Lung Transplantation 128
23. Infective Endocarditis: An Update............................................................................................................ 129

Sudhir Varma, Samman Verma, Rommel Singh
Changing Epidemiological Profile 129
Diagnostic Issues 129
Antimicrobial Therapy 129
Complications 130
Indications for Surgery 131
Prevention 132
24. Pregnancy and Heart Disease.................................................................................................................... 133

Gurleen Wander, Gurpreet Singh Wander
Physiological Changes in Pregnancy 133
Peripartum Cardiomyopathy 134
Rheumatic Heart Disease 135
Prosthetic Heart Valves 135
Aortic Dissection 135
Congenital Heart Disease 136
General Principles of Management 136
Intrapartum 136
xxviii Medicine Update 2018
25. A Review of Cardiorenal Syndrome.......................................................................................................... 138

Gurinder Mohan, Ranjeet Kaur, Aakash Aggarwal
Pathophysiology 139
Biomarkers in Cardiorenal Syndrome 140
Management 141
26. Heart Failure with Reduced Ejection Fraction: Treatment Strategy................................................... 144
Amal Kumar Banerjee
Classifiction 144
Diagnosis 145
Pharmacologic Treatment 147
Nonsurgical Device Treatment 147
Mechanical Circulatory Support and Heart Transplantation 148
Heart Failure and Comorbidities 149
Arrhythmias and Conductance Disturbances 149
Monitoring 149
27. Pulmonary Embolism: Focus on New Drugs........................................................................................... 151

VK Katyal, Ashima Katyal, Naman Mukhi
Pathophysiology 151
Clinical Presentations 151
Diagnosis 152
Management of Acute Pulmonary Embolism 153
28. Echocardiographic Navigation of AF from Irregular Pulse to Slurring of the Speech:

Relevant at All Stages in India and the Real World................................................................................ 157
HK Chopra, Ravi R Kasliwal, Manish Bansal, Shraddha Ranjan
Echocardiographic Navigation in AF Management 158
SECTION 3 DIABETES
29. ADA Standards of Care: An Update........................................................................................................... 173
Abhishek Pandey
Section Changes 173
Staging of Type 1 Diabetes 174
Pharmacologic Therapy for Diabetes 175
30. Can Medical Care Change the Natural History of T2DM: Turning Fiction into Reality?.................. 181
Rajesh Rajput
Contents xxix
31. Are all Gliptins the Same: How to Decide and Choose?........................................................................ 186
Harbir Kaur Rao, Rajinder Singh Gupta
Pathogenesis of Type 2 Diabetes Mellitus 186
Ideal Antihyperglycemic Drug 187
Dipeptidyl Pepitidase-4 Inhibitors 187
Efficacy 188
Safety 189
32. Diabetes and Inflammation ....................................................................................................................... 191

Jugal Kishor Sharma, Girish Khurana
Link Between Diabetes and Inflammation 191
Clinical Implications of Inflammation in Type-2 Diabetes 195
Clinical Benefits Based on Inflammatory Theory 195
Drugs Related to the Endoplasmic Reticulum Stress Theory 195
33. Pollution and Diabetes: Is there a Link?................................................................................................... 198

Brij Mohan
Persistent Organic Pollutants 198
Air Pollutants Sources 200
34. Musculoskeletal Manifestations of Diabetes Mellitus.......................................................................... 203

S Anita Nambiar, Divya G
Limited Joint Mobility/ Rosenbloom Syndrome 203
Adhesive Capsulitis of the Shoulder 204
Dupuytren’s Contracture/Disease 204
Hyperostosis 204
Carpal Tunnel Syndrome 204
Flexor Tenosynovitis 205
Neuroarthropathy (Charcot’s Joints) 205
Diabetic Amyotrophy 205
Osteoporosis 205
Diabetic Muscle Infarction 205
Reflex Sympathetic Dystrophy 206
35. How to Hold the HOLD?.............................................................................................................................. 207

NK Singh, Vaibhav Agnihotri, Richa Singh Agnihotri
Prevalence 207
Peculiarities of HOLD in India 207
Mechanistic Characteristics 208
xxx Medicine Update 2018
Behavioral Modification 208

Physical Activity 209
Getting Rid of Persistent Organic Pollutants 209
Pharmacological Interventions 210
36. Dyslipidemia Management: Newer Avenues.......................................................................................... 211

Nirupam Prakash
CETP Inhibitors 214
37. Metformin versus Insulin in Treatment of Gestational Diabetes Mellitus......................................... 217

Sandeep Garg, Onkar Awadhiya, Sunita Aggarwal
Mechanism of Diabetes in pregnancy 217
Diagnosis of GDM 217
Glycemic Targets in GDM 218
Treatment Modalities of GDM 218
Comparison of Insulin versus Metformin in GDM 219
38. Early Initiation of Insulin Therapy in Diabetes Mellitus........................................................................ 221

Rajesh Kumar Jha, Sagar Dembla
Concept and Evolution of Basal Insulin 221
Role of Insulin in Treatment of Type 2 Diabetes Mellitus 222
Benefits of Insulin Therapy in Diabetes Mellitus 222
Barriers to Basal Insulin in Type 2 Diabetes Mellitus 222
How to Start Insulin? 223
39. Diabetic Complications in Indian Scenario: An Update........................................................................ 225

Sidhartha Das, Santosh Kumar Swain, Saroj Kumar Tripathy
Diabetes in India 225
Complications in Type 2 DM 226
Macrovascular Complications 226
Type 2 DM and Metabolic Syndrome 229
Microvascular Complications in Type 2 DM 229
Diabetic Retinopathy 230
Diabetic Neuropathy and Diabetic Foot 230
Other Complications in Type-2 DM 232
40. GLP-1 Analogs: Benefits Beyond Glycemic Control............................................................................... 238

Rajeev Chawla, Shalini Jaggi
GLP-1 Analogs 239
Glycemic Efficacy of GLP-1 Receptor Agonists 241
Contents xxxi
Extra Glycemic Benefits of GLP-1 Analogs 241

Weight Loss Associated with the Use of GLP-1 Receptor Agonists 242
Side Effects and Associated Risks of GLP-1 Receptor Agonists 243
41. Gliptins versus Sulfonylureas: Which is Better?...................................................................................... 247

V Palaniappen
Importance of Glycemic Control in Curbing the Diabetes Burden 247
DM in Elderly Recommendation 259
Negative is not Absolutely Negative in SU Usage 261
Points in Favor of SU 261
42. Metformin—the Molecule of the Decade: Old is Gold.......................................................................... 262

Sanjay Dash
History 262
Mechanism of Action 262
Role of Metformin in T2DM 263
Metformin and Body Weight 263
Cancer Biology 264
Adverse Drug Reactions and Contraindications 264
43. A Decade of RCTs in Diabetes: Clinical Implications.............................................................................. 266

Suhas Erande
Prelude 266
2007: What Did We Know? DCCT EDIC UKPDS 266
2008: Tighter Glucose Control (?More Benefits) 266
Impact of Recent CVOT in Diabetes on Practice 267
Centrality of RCTS in Clinical Practice 267
Importance of Clinical Practice Guidelines 268
Factors which Influence Physician Practice 268
Have RCTS in Diabetes Helped Clinical Practice in Last Decade? 269
44. Insulin Pumps in India ................................................................................................................................ 270

Narendra Pal Jain, Rishu Bhanot
Insulin Pumps in Type 2 in India 270
Types 271
Indications for an Insulin Pump 271
Current Scenario of Insulin Pumps in India 272
xxxii Medicine Update 2018
45. Newer Insulins and Art of Insulin Therapy.............................................................................................. 273

Mangesh Tiwaskar
Science of Insulin Therapy: The Need 273
Insulins at a Glance 274
Modes of Insulin Delivery 275
Initiating Insulin Therapy 275
Overcoming the Psychological Barriers to Insulin Therapy 277
46. Individualization of Diabetes Care............................................................................................................ 281

KK Pareek, Girish Mathur
Treatment Approaches for T2 Diabetes 281
Patient–Centered Approach 246
Implementation Strategies 284
Other Considerations 284
Therapeutic Patient Education 285
47. Diabetes and Immunity.............................................................................................................................. 286

Apurba Kumar Mukherjee, Indira Maisnam
Immunity in the Pathogenesis of Diabetes Mellitus 286
Defective Immune Response in Diabetes Mellitus 288
48. Novel Therapeutic Approaches to Preserve Beta Cell Function in Diabetes Mellitus..................... 290
Vijay Negalur
Pancreatic Beta Cell Mass Function in Diabetes 290
Therapeutic Approaches to Preserve Beta Cell Function in T1D 291
Tumor Necrosis Factor-Α (TNF-Α) Agonist 293
Therapeutic Approaches to Preserve Beta Cell Function in T2D 293
49. Management of Diabetes in Resource Crunch Countries..................................................................... 299

G Prakash
Prevalence 299
Challenges and the Way Ahead Epidemiological Data 299
Screening 299
Diabetes Management 300
Diabetes Education 300
Pharmacologic Management: Oral Antidiabetic Drugs 300
50. Exercise Prescription for Lifestyle Diseases: A Cornerstone................................................................ 302

Anil Kumar Virmani
Lifestyle Diseases 302
Contents xxxiii
51. Nonhigh–Density Lipoprotein Cholesterol: Primary Target for Lipid Lowering.............................. 305
SN Narasingan
Non-HDL-C as an Indicator of ASCVD Risk 305
Other Advantages of Non-HDL-C 307
SECTION 4 ENDOCRINOLOGY
52. Growth Hormone Replacement Therapy: Current Recommendations.............................................. 313
Minal Mohit
Differences Between COGHD and AOGHD 314
Consequences of Untreated GHD 314
Metabolic Complications 314
Osteopenia/Osteoporosis 314
Quality of Life 315
Transitional Care of GHD 315
Diagnosis of GHD in Adults 315
Factors Affecting GH Dosing 316
Dosing Strategies 317
Safety Issues with GH Replacement Therapy 318
Unapproved Uses of GH in Adults 319
53. Vitamin D Therapy: Hope or Hype............................................................................................................ 326

PK Sasidharan
Vitamin D Basic Facts 326
Landmark Study on Vitamin D Deficiency 326
Reasons for Widespread Deficiency of Vitamin D 327
54. Approach to a Patient with Short Stature............................................................................................... 333

Indira Maisnam
Physiology of Normal Growth 333
Patterns of Normal Growth 333
Diagnostic Approach to a Child with Short Stature 334
55. Logical Approach to Thyroid Nodule........................................................................................................ 337

KJ Shetty, KN Manohar
Clinical Presentation 337
Management 338
xxxiv Medicine Update 2018
56. Primary Hypoparathyroidism and its Management.............................................................................. 341

Ajay Aggarwal, Roopak Wadhwa
Epidemiology 341
Pathophysiology 341
Signs and Symptoms 342
Investigations 342
Treatment 342
57. A New Look at Testosterone Therapy in Aging Males........................................................................... 344

DC Sharma
Changes in Reproductive Hormones with Age 344
Effects of Decrease in Testosterone 344
Suggested Approach 345
58. Lipohypertrophy Secondary to Insulin Injection Therapy................................................................... 347

Sunil Gupta
Prevalence 347
Definition of Lipohypertrophy 347
Causes of Lipohypertrophy 347
Diagnosis 348
Clinical Consequences of Lipohypertrophy 348
Management 350
SECTION 5 NEUROLOGY
59. Headache: Headache for Physician........................................................................................................... 355
Gurubax Singh
Every Head has its Own Headache 355
First Severe Headache 355
Chronic Daily Headache 356
Headache in Elderly 357
Status Migranosus 357
Menstrual Migraine 357
Headache with Comorbidities 357
60. Approach to Multiple Cranial Nerve Palsy............................................................................................... 359

K Mugundhan
Intrinsic vs Extrinsic Brainstem Lesions 359
Contents xxxv
61. Nocturia: Evaluation and Management................................................................................................... 363

Anish Kumar Gupta
Pathophysiology 363
Treatment 365
Multidisciplinary Management 366
62. Neuromyelitis Optica: A Physician’s Perspective.................................................................................... 367

Mrinal Kanti Roy, Sujoy Sarkar
Epidemiology 367
63. First Seizure: Should or Should not be Treated?.................................................................................... 371

PK Maheshwari, A Pandey, Akhilesh Kumar Singh
Importance of Multiple Seizures 371
Is There any Role of Antiepileptic Drug Prophylaxis? 371
When to Initiate Antiepileptic Drugs? 372
Seizure Recurrence 372
Approach to a Case of First Seizure 373
Management of First Seizure 374
64. An Overview and Practical Clinical Hints in the Diagnosis of Temporal Lobe Epilepsy.................. 376
Venkataraman Nagrajan
Definition 376
Etiology 376
Pathology 376
Pathophysiology 376
Clinical Features 377
International Classifciation of the CPS 377
Seizure Phenomena 377
Eeg Phenomenon in TLE or CPS 378
Imaging Studies CT vs MRI 378
Differential Diagnosis 378
Management 379
Prognosis 379
65. Changing Scenario in Management of Status Epilepticus................................................................... 380

Rajesh Shankar Iyer
Changing Definitions and Classification 380
New Terminologies 381
xxxvi Medicine Update 2018
Super-refractory Status Epilepticus 382

Treatment of Super-refractory SE: An Update 382
66. Present Status of Thrombolysis in Acute Ischemic Stroke: Indian Scenario..................................... 386
V Shankar
Rates of Thrombolysis 386
Thrombolysis Outcomes 386
Thrombolysis Dosage 387
Sonothrombolysis 387
Tenecteplase 387
Telestroke 387
Complications and Other Observations 387
Intraarterial TPA 388
Thrombolysis and Endovascular Therapy 388
67. Immunomodulation in Neurological Disorders..................................................................................... 389

Man Mohan Mehndiratta, Ashish Duggal
Central Nervous System Disorders 389
Immunotherapy for MS Relapses 389
Disease-modifying Immunotherapy for MS 392
Myelin Oligodendrocyte Glycoprotein (MOG) Associated Demyelination 394
Acute Disseminated Encephalomyelitis 395
Primary Angiitis of CNS 398
Disease Affecting the Peripheral Nervous System 398
68. Vertigo: Clinical Approach and Management........................................................................................ 404

Lakshmi Narasimhan Ranganathan, Thamil Pavai N,
Guhan R, Arun Shivaraman MM, Mugundhan Krishnan
Treatment of Vertigo 410
SECTION 6 GASTROENTEROLOGY/HEPATOLOGY
69. Acute Upper Gastrointestinal Bleeding .................................................................................................. 415
Rajesh Upadhyay, Deepak Sharma
Etiology 415
Risk Factors 415
Management 416
Contents xxxvii
Medical Therapy 417

Endoscopic Therapy 417
Surgical Treatment 418
Angiographic Therapy 418
Prevention of Re-bleed 419
70. Acute Pancreatitis........................................................................................................................................ 421

G Loganathan, L Santhosh Vivekanadan
Etiopathogenesis 421
Clinical Features, Diagnosis and Severity Prediction 423
Management 426
Beyond the Early Phase 428
Prevention 432
71. The Gut Microbiota: A Forgotten Organ.................................................................................................. 436

Balvir Singh, Ram Prakash Pandey, Mridul Chaturvedi, TP Singh, Ashish Gautam
Composition of Gut Microbiota 436
Humans as Microbial Depots 436
Emergence of Microbiota 436
Gut Microbiota as an Organ 437
Link Between Gut Flora and Diseases 438
Future Hopes for Various Diseases 438
72. Nonalcoholic Fatty Liver Disease: Is it Really Benign?........................................................................... 442

AK Chauhan
NAFLD is a Progressive Condition 442
Role of Metabolic Risk Factors in Disease Progression 443
Pathophysiologic Link of Metabolic Risk Factors with HCC 443
Extrahepatic Complications of Nafld 444
73. Glucose Metabolism Disorders in Chronic Liver Disease...................................................................... 446

Aparna Agrawal, Prashasti Gupta
Role of Liver in Carbohydrate Metabolism 446
Glucose Metabolism in Diseased Liver 446
Mechanism of IR and GMD in CLD 446
Mechanism of LD in DM 447
Burden of GMD and IR in CLD and of LD in DM 447
Correlation of GMD with Etiology and Severity of CLD and Risk Factors of DM 447
Clinical Presentation of GMD in CLD 447
xxxviii Medicine Update 2018
Implications of GMD on Complications of CLD 448

Diagnosis and Monitoring 448
Treatment of GMD in CLD 448
Results of Our Study 449
74. Hepatorenal Syndrome: Clinical Considerations................................................................................... 451

Definition 451
Epidemiology 451
Pathophysiology 451
Precipitating Factors 452
Diagnosis 453
Diagnostic Criteria for Hepatorenal Syndrome 453
Preventive Measures 453
Biomarkers in HRS 453
Treatment 453
75. Cirrhosis of Liver: Beyond Beta-blockers and Diuretics........................................................................ 456

Anup K Das
Variceal Hemorrhage 456
Hepatorenal Syndrome (HRS) 457
Spontaneous Bacterial Peritonitis (SBP) 457
76. Hepatitis B: Are We Moving Ahead Towards Cure?................................................................................ 463

Anil C Anand
Epidemiology of HBV in India 463
The Virus 464
Immunopathogenesis 464
Natural History of HBV Infection 464
Management of Chronic HBV Infection and Innovative Approaches 465
Newer Drugs and Innovative Approaches 465
77. HIV/Hepatitis Coinfections......................................................................................................................... 469

PK Agrawal
Epidemiology 469
Pathogenesis 469
Treatment 470
Contents xxxix
78. Fecal Microbiota Transplantation: Current Indications and Methods............................................... 472

L Ilavarasi, SS Lakshmanan
Fecal Microbiota Transplantation Techniques 472
Donor Selection 472
History to be Obtained from the Donor 474
Stool Evaluvation 474
Donor Blood Screening 474
Donor Stool Preparation: European Consensus 2017 474
Routes of Administration of FMT 474
Colonoscopy Guided 474
Upper GI Endoscopy Guidance 474
Clostridium Difficle Infections 474
Inflammatory Bowel Disease 475
Irritable Bowel Syndrome 475
FMT in Obesity/Insulin Resistance and Diabetes 475
FMT in Neurological Diseases 475
Current and Future Directions 475
SECTION 7 RESPIRATORY SYSTEM

79. Clinical Approach to a Patient of Dyspnea.............................................................................................. 481
Alok Gupta, Rajat Gupta
Mechanism 481
Causes of Dyspnea 482
Assessment Of Dyspnea 487
History Taking 489
Physical Examination 489
Laboratory Studies 490
Advanced Studies 491
Management 493
80. Syndrome Z................................................................................................................................................... 495

Devendra Prasad Singh
OSA and Hypertension 495
Obesity 495
xl Medicine Update 2018
Insulin Resistance 495

Pathophysiology of Syndrome Z 495
Diagnosis of Syndrome Z 497
OSA: Clinical Features 497
OSAs and Hypertension 497
Lifestyle Modifications 498
81. Asthma COPD Overlap Syndrome............................................................................................................. 500

Kashinath Padhiary
Definition 500
Incidence 500
Pathogenesis 501
Contributing Factors 501
Diagnosis 501
Prognosis 502
Treatment 502
82. Global Warming and its Health Impact.................................................................................................... 504

PS Shankar
Health Impact 504
Surface Temperature 504
El Nino 505
Ozone 505
Diseases 505
Future 506
83. ARDS: Recognition and Management...................................................................................................... 508

Niteen D Karnik, Priya Bhate
Recognition 508
Diagnosis 508
Management 508
84. Clinical Approach to Solitary Pulmonary Nodule.................................................................................. 514

BNBM Prasad
Defnition 514
Causes 514
Prevalence 515
Approach to Diagnosis 515
Management 521
Contents xli
85. Challenges in the Management of CAP................................................................................................... 525

Prashant Prakash, Akhilesh Kumar Singh
Definition of CAP 525
Epidemiology and Etiology 525
Diagnosis of CAP 525
Role of Microbiological Investigations in CAP 526
General Investigations and Risk Stratification Required in Patients with CAP 528
Antimicrobial Therapy in CAP 529
86. Air Pollution and its Health Impact........................................................................................................... 533

Vishal Chopra, Prabhleen Kaur, Siddharth Chopra
Mechanisms Leading to Health Effects 533
Types of Pollutants 534
Effects of Air Pollution on Different Organs 534
SECTION 8 INFECTIONS
87. Infections Causing Cancer.......................................................................................................................... 539
Anupam Dey
Pathogenesis 539
International Agency for Research on Cancer (WHO) Classification 539
Mechanisms by which Common Agents Cause Cancers 540
Detection and Proving Association of the Infectious Agent in Cancer 540
88. Transfusion Transmitted Infection............................................................................................................ 543

Apu Adhikary, Tuhin Santra
Human Immunodeficiency Virus 543
Hepatitis B virus 544
Hepatitis C virus 544
Malaria 544
Syphilis 544
Human T-Lymphotropic Virus I and II 544
Cytomegalovirus 545
Epstein–Barr virus 545
West Nile Virus 545
Parvovirus B19 545
Arboviruses 545
Bacterial infections 545
xlii Medicine Update 2018
Other Infectious Agents 546

Pathogen Inactivation Technology 546
Donor Screening Questionnaire 546
89. Arboviral Infections: Is Effective Vaccination a Possible Solution?.................................................... 547

Ashok Kumar, Shubha Laxmi Margekar, Venugopal Margekar
Transmission 547
Clinical Findings and Epidemiology 548
Vaccination 548
Yellow Fever Vaccine 549
Japanese Encephalitis 549
Dengue Vaccine 550
Chikungunya Vaccine 551
Kyasanur Forest Disease 551
Crimean Congo Hemorrhagic Fever Virus 552
90. MDR-TB and XDR-TB: What are the Options? ......................................................................................... 553
Bidita Khandelwal
Epidemiology 553
Defining MDR-, Pre-XDR- and XDR-TB 553
Management Options in M/XDR-TB 553
Regimes 554
Newer Drugs Options 554
High-Dose Isoniazid 555
Duration of Treatment M/XDR-TB 555
Surgical Options 555
91. Acute Encephalitis: Indian Scenario......................................................................................................... 556

Debasis Chakrabarti, Shankha S Sen
Etiology 556
Epidemiology 556
92. Tropical Fever: A Case-based Approach................................................................................................... 562

Manoranjan Behera, Sidhartha Das, Jayant Kumar Panda
Specific Infections 564
Investigation Strategy 566
Treatment Strategy 566
Contents xliii
93. Vivax Malaria: No Longer Benign!............................................................................................................. 570

K Nagesh
Epidemiology 570
Malaria Parasite 571
Vivax Malaria 571
Malignant Behavior of Plasmodium Vivax 572
Pathophysiology 573
Clinical Classifications 573
Management 574
Treatment of Malaria in Pregnancy 574
Clinical Malaria 575
94. Newer Modalities in Diagnosis of Tuberculosis...................................................................................... 576

Prem Parkash Gupta
Direct Sputum Smear Microscopic Examination 576
Culture-Based Methods for the Diagnosis of Tuberculosis 576
Rapid Detection of Drug Resistance: In-house Methods 577
Colorimetric Redox Indicator Methods 578
Diagnosis of TB Based on DNA Tools 578
Latent Tuberculous Infection Diagnosis 580
95. Resurgence of Yellow Fever: A Great Challenge..................................................................................... 583

Rajib Ratna Chaudhary
Transmission of Yellow Fever Virus 583
Pathogenesis 584
Laboratory Finding 584
Treatment and Prevention 585
Prognosis 585
96. Complicated Dengue................................................................................................................................... 586

Rajeev Gupta
Introduction to Dengue 586
Hepatic Complications 587
xliv Medicine Update 2018
97. Scrub Typhus: Need for Alert..................................................................................................................... 588

Raman Sharma, Sunil Mahavar, Mayank Gupta
Etiology 588
Epidemiology and Transmission 588
Clinical Manifestations 589
Diagnosis 590
Treatment 590
Prevention 591
98. Pyrexia of Unknown Origin: Current Concept........................................................................................ 592

SV Ramana Murty, Chakravarthy DJK
Epidemiology 592
99. Approach to a Patient of Meningitis......................................................................................................... 600

Sanjiv Maheshwari, Vijay Prakash Hawa
Examination 601
Investigation 602
CSF Examination 602
Other Laboratory Studies 603
Neuroimaging 603
Treatment 603
100. Leptospirosis: What We Should Know?.................................................................................................... 604

Shantanu Kumar Kar, Paluru Vijayachari, Jayant Kumar Panda
Epidemiology 604
Diagnosis 605
Treatment and Prevention 606
101. Kala-azar Elimination in India.................................................................................................................... 607

Shyam Sundar
102. Sickle Cell Crisis: How to go Forward?...................................................................................................... 610

Srikant Kumar Dhar
How to Diagnose? 610
How to Manage? 610
Principles of Management 611
Analgesia 611
Contents xlv
Fluid Replacement 611

Treatment of Acute Chest Syndrome 611
Recommendations for Vaccination 613
103. Do Not Rash When Fever Coincides with Rash....................................................................................... 614

Sriprasad Mohanty
Approach to Diagnosis 614
Viral hemorrhagic Fevers 615
104. Disseminated Intravascular Coagulation: Management Updates...................................................... 617

Puneet Saxena, Aradhna Sharma, Madhulata Agarwal, Sher Singh Dariya, Hitesh Sharma
Pathogenesis 617
Diagnosis 618
Treatment 620
105. Adult Immunization: Current Scenario in India...................................................................................... 622

Prasanta Kumar Bhattacharya, Subrahmanya Murti V
Hepatitis B Vaccine 622
Hepatitis A Vaccine 624
Diphtheria, Pertussis and Tetanus Vaccines 624
Measles, Mumps and Rubella Vaccine 624
Varicella and Zoster (Shingles) Vaccines 624
Pneumococcal Vaccine 625
Meningococcal Vaccine 625
Haemophilus Influenzae Vaccine 626
Human Papilloma Virus Vaccine 626
Influenza Vaccine 626
Japanese Encephalitis Vaccine 626
Yellow Fever Vaccine 626
Cholera Vaccine 626
Typhoid Vaccine 626
Newer Vaccines 627
106. H1N1 Influenza: 9 Years’ Journey in Gujarat............................................................................................ 629

Asha N Shah
History of Reassortment Events in the Evolution of the 2009 Influenza A (H1N1) Virus 629
Government of India Guidelines on Categorization of Seasonal Influenza A H1N1 Cases
(Revised on 11-2-2015) 630
Cytokine Storm in Young 632
xlvi Medicine Update 2018
107. Ebola............................................................................................................................................................... 636

Rajeev Raina, Nidhi Raina
Background 636
Transmission 636
Clinical Symptoms 638
Diagnosis 639
Treatment and Vaccines 639
Lessons Learnt 639
SECTION 9 HUMAN IMMUNODEFICIENCY VIRUS

108. 90-90-90 Strategy in HIV Epidemic........................................................................................................... 645
R Sajith Kumar
Treatment Target 645
Reaching Target 1 648
Ending the AIDS Epidemic 650
109. ART in HIV Infection: State-of-the-Art...................................................................................................... 652

BB Rewari, Manish Bamrotiya, Suman Singh
Antiretroviral Therapy for HIV Infection 652
Goals of Antiretroviral Therapy 652
Clinical Pharmacology of Commonly used ARV Drugs 653
Considerations before Initiation of ART 654
Recommended Choice of First Line Regimen 656
Monitoring of Patients on ART 656
Treatment Failure: When to Change and What to Change 658
110. Opportunistic Infections in HIV: Changing Scenario............................................................................. 660

Amar R Pazare
Common Opportunistic Infections in HIV-infected Patients in the Past 660
111. Neurological Manifestations of HIV.......................................................................................................... 663

Dipanjan Bandyopadhyay, Amit Adhikary
Acute Seroconversion Illness 663
Direct Viral Invasion 663
Myelopathy due to HIV 663
Contents xlvii
Peripheral Neuropathy 664

Opportunistic Infections Affecting the CNS 664
Progressive Multifocal Leukoencephalopathy 666
HIV Associated Malignancies Affecting the CNS 666
Neurological Disease Arising from ART 666
112. Cardiopulmonary Manifestations of HIV................................................................................................. 667

Alaka K Deshpande
Pericardial Disease 667
Cardiotoxic Drugs 668
Coronary Artery Disease 668
Pulmonary Manifestations 669
Bacterial Infections 669
Fungal Infections 670
Malignant Neoplasms 670
113. Immune Reconstitution Inflammatory Syndrome................................................................................. 671

Vinay Rampal
Background 671
Definition 671
Clinical Factors Associated with the Development of IRIS 672
Mycobacterium Tuberculosis IRIS 673
Atypical Mycobacterial IRIS 674
Cytomegalovirus Infection IRIS 674
Varicella Zoster Virus Infection IRIS 675
Cryptococcus Neoformans Infection IRIS 675
Other Etiologies 676
SECTION 10 INTENSIVE CARE UNIT

114. Critical Care Toxicology: Update 2018...................................................................................................... 681
Omender Singh, Deven Juneja
Initial Resuscitation and Management 681
Laboratory Investigations 682
Decontamination 682
Enhanced Elimination 682
xlviii Medicine Update 2018
115. Hypoglycemia in ICU................................................................................................................................... 684

Sundaram Arulrhaj, Aarathy Kannan, Manikandan R, Vinodh Kumar A
Classification of Hypoglycemia 684
Pathogenesis of Hypoglycemia in ICU 684
Acute Coronary Syndrome 690
116. Biomarkers in Sepsis.................................................................................................................................... 695

Virendra Kumar Goyal, Mohit Goyal
C-reactive Protein 697
Biomarker Combinations 698
Statement of UNMET Need 698
117. Early and Empiric Antibiotics in Sepsis: Current Controversy............................................................. 700

Trupti H Trivedi
Future Therapy 703
118. Arterial Blood Gas Analysis: Simple Steps for Understanding............................................................ 705
Ravindra Kumar Das
Collection of Blood Samples and Transportation 705
Method of Analyisis 705
Case History/Provisional Diagnosis 710
119. Superbugs in ICU and the Need for Antibiotic Stewardship................................................................ 716
Pankaj Kumar
120. Perioperative Management in Diabetes.................................................................................................. 720

Pramod Kumar Sinha
Risks of Poor Diabetic Control 720
Factors Causing Adverse Outcome 720
Metabolic Response to Surgery and Anesthesia and the Effect of Diabetes 721
Principles and Target of Perioperative Management 721
Preoperative Measures 721
Intraoperative Management 722
Measures During Surgery 722
Postoperative Managemant 724
121. Hospital Acquired Infections...................................................................................................................... 725

Piyush Jain
Nosocomial Pneumonia 725
Diagnosis 726
Contents xlix
Causative Organisms 726

Treatment 726
Preventive Measures 727
Nosocomial Urinary Tract Infections 727
Diagnosis 727
Treatment 727
Catheter Related Blood Stream Infection 728
Diagnosis 728
Treatment 728
Nosocomial Surgical Site and Soft Tissue Infection 728
Management 729
SECTION 11 TOXICOLOGY
122. Clinical Approach to Patient of Coma...................................................................................................... 733
Geeta Kampani, Umashankar US, Munish Prabhakar
Etiology and Pathogenesis 733
Assessment of COMA 733
History 733
General Physical Examination 733
Neurologic Examination 734
Brainstem Reflexes 735
Respiratory Patterns 735
Investigations 735
Prognosis 736
123. Common Poisoning and Management.................................................................................................... 737

Saurabh Srivastava
Aluminium Phosphide Poisoning (Celphos Poisoning) 737
Mechanism of Toxicity 737
Clinical Features of Intoxication 737
Organophosphate Poisoning 738
Mechanism of Toxicity 738
Management 739
Corrosive Poisoning 739
Mechanism of Injury 739
l Medicine Update 2018

Management 740
Rodenticides 740
Zinc Phosphide 740
Anticoagulants 740
Kerosene Oil 740
Management 740
Benzodiazepines 740
Management 741
124. Management of Snake Bite in India.......................................................................................................... 742

Shibendu Ghosh, Prabuddha Mukhopadhyay
Snake Bite Prevention and Occupational Risk 744
Preventative Measures 744
Diagnosis Phase 744
General Signs and Symptoms of Viperine Envenomation 744
Late-onset Envenoming 747
Diagnosis Phase: Investigations 747
Management of Snake Bite in General 747
Handling Tourniquets 748
ASV Administration Criteria 748
Prevention of ASV Reactions: Prophylactic Regimes 749
Neurotoxic Envenomation 751
Recovery Phase 751
AntiHemostatic Maximum ASV Dosage Guidance 752
SECTION 12 HEMATOLOGY/ONCOLOGY
125. Stem Cell Therapy in Various Diseases: Dawn of a New Era................................................................. 759
Sunita Aggarwal, Jahnvi Dhar, Sandeep Garg
Stem Cell 759
Methods for Stem Cells Transplantation 759
Hematopoietic Stem Cell Transplantation (HSCT) 759
Scope of Stem Cell Therapy in India 761
Contents li
126. Basics of Hematopoietic Stem Cell Transplant: Autologous and Allogeneic.................................... 763
Punit L Jain
Principles of HSCT 763
127. Clinical Approach to Patient with Purpuric Spot.................................................................................... 767

Chanchal Kumar Jana, Gaurab Bhaduri
Pathophysiology 767
Causes of Nonpalpable Purpura 767
Causes of Palpable Purpura 768
Clinical Approach to Purpuric Spots 768
Case Studies 768
Diagnosis: Henoch–Schönlein Purpura 768
Diagnosis: Purpura Fulminans 769
Management of Some Common Causes of Purpura 769
128. Thrombocytosis: Clinical Approach.......................................................................................................... 772

Sudhir Mehta, Laxmi Kant Goyal, Shaurya Mehta, Gunja Jain
Regulation of Thrombopoiesis 772
Causes of Thrombocytosis 773
Treatment 776
129. Macrophage Activation Syndrome.........................................................................................................7778

Tarun Kumar Dutta, Tony Kadavanu, Arunkumar Ramachandrappa
Epidemiology 778
Etiopathogenesis and Triggers 778
Laboratory Features 779
Diagnostic Criteria 781
Further Approach 781
Management 781
Biologicals 782
130. Hemotransfusion Therapy: Boon or Bane?.............................................................................................. 784

Anil Kumar Gupta
Hemotherapy: A Precious Tool for Humans 784
Hemotherapy, Inherent Risks 785
lii Medicine Update 2018
131. Idiopathic CD4 Lymphocytopenia............................................................................................................ 788

Bhupendra Gupta, Harpreet Singh
Pathogenesis 788
Clinical Manifestations 788
Infections 788
Evaluation 789
Diagnosis 789
Treatment 790
Other Treatment Modalities 790
Prognosis 790
132. Hepatocellular Carcinoma: Surveillance, Diagnosis and Management............................................. 791

Kirti Shetty
Background 791
Surveillance Strategy 791
Target Population 791
Tests 791
Diagnosis 792
Tissue Diagnosis 792
Staging 792
Treatment 792
Surgical Therapies for HCC 793
133. Approach to a Patient with Polycythemia............................................................................................... 795

Mathew Thomas
Introduction, Definitions and Classification 795
Mechanisms 795
Major Causes of Polycythemia 796
Initial Evaluation of Patients with Polycythemia 796
Physical Examination 797
Systemic Examination 797
Laboratory Investigations 797
Further Diagnostic Approach 797
Further Evaluation 797
Diagnosis of Polycythemia Vera 798
Treatment of Polycythemia Vera 798
Management of Secondary Polycythemia 800
Contents liii
134. Immunotherapy: A New Weapon in Cancer Treatment........................................................................ 801

Vineet Talwar, Venkata Pradeep Babu K
Oncolytic Viruses in Immunotherapy 801
Vaccines in Immunotherapy 802
Adoptive Cell Therapy 802
Immune Check Point Blockade 802
135. Metronomic Chemotherapy in Metastatic Malignancies: A New Concept....................................... 805

Ankur Bahl
Metronomic Chemotherapy Versus Conventional Chemotherapy 805
Angiogenesis–Chemotherapy Model 806
Activation of Immunity 806
Rational of Various Drugs Used in Metronomic Chemotherapy 806
Metronomic Chemotherapy in Adult Cancers 807
Toxicity of Metronomic Chemotherapy 807
SECTION 13 RHEUMATOLOGY
136. Asymptomatic Hyperuricemia: What to Do?........................................................................................... 811
Arup Kumar Kundu, Shyamashis Das
Epidemiology 811
Definitions 811
Why Hyperuricemia Occurs? 811
Clinical Consequences of Persistent Hyperuricemia 812
Evaluation of Patients with Asymptomatic Hyperuricemia 813
When to Treat Asymptomatic Hyperuricemia? 813
137. Polyarteritis Nodosa: An Enigma............................................................................................................... 815

Ghan Shyam Pangtey, Paramjeet Singh
Case Vignette 815
Introduction 816
Epidemiology 817
Laboratory Evaluation and Imaging 818
Prognosis 818
Management 819
liv Medicine Update 2018
138. Chikungunya Arthritis................................................................................................................................. 821

Harpreet Singh, Neeraj Kumar
139. Clinical Approach to a Patient with Vasculitis......................................................................................... 825

N Subramanian
Pathogenesis 825
Classification 825
Investigations 827
Management 827
Practical Points 828
140. Osteoporosis Screening, Prevention, and Treatment............................................................................ 830

Tanu Shweta Pandey
Osteopenia 830
SECTION 14 NEPHROLOGY
141. Recipient and Donor Selection for Renal Transplantation in India: Current Status........................ 837
Sanjay Kumar Agarwal
Advantages of Renal Transplant over Maintenance Dialysis 837
Contraindication of Renal Transplantation 837
Recipient Evaluation 837
Donor Evaluation 839
142. Rituximab: Panacea of Glomerular Diseases.......................................................................................... 842

Dipankar M Bhowmik, N Rajkanna
Primary Glomerular Diseases 843
Glomerular Diseases that Cause Nephrotic Syndrome: Immune Complex 843
Secondary Glomerular Diseases 844
Adverse Effects of Rituximab 844
143. ABO-Incompatible Kidney Transplantation............................................................................................ 846

Dinesh Khullar, Sagar Gupta
Historical Perspective 846
ABO Antigens and Blood Groups 847
Pathogenesis 847
Accommodation 847
Contents lv
Techniques of Desensitization 847

Complications 848
144. Prevention and Management of Diabetic Kidney Disease................................................................... 849

Pritam Gupta, Rajesh Aggarwal, Blessy Sehgal
Spectrum of Renal Involvement in Diabetes Mellitus (Type 2) 849
Risk Factors for the Development of Diabetic Nephropathy 849
Management of Microalbuminuria in Diabetes 851
Screening for Diabetic Kidney Disease 851
Other Biochemical Markers 851
Natural History of Type I Diabetic Nephropathy 851
Treatment Target 851
What is Optimal Target HBA1C? 852
Blood Pressure Control 852
Blockade of Renin Angiotensin System 852
Treatment of Dyslipidemia in Diabetic Nephropathy 853
Emerging and Future Therapies 853
145. Anemia in Chronic Kidney Disease: Management................................................................................. 854

HK Aggarwal, Deepak Jain, Rahul Chauda
Anemia in Chronic Kidney Disease: Management 854
Diagnosis and Evaluation 854
Treatment 854
Erythropoiesis Stimulating Agents 855
Blood Transfusion 856
Other Therapies 856
Option in Future 857
SECTION 15 GERIATRICS AND GENETIC

146. Geriatric Teaching Indian Relevance........................................................................................................ 861
OP Sharma
Ageing 861
Medical Infrastructure 862
Geriatrics Services 862
Need v/s Availability 863
Need Based Solutions 863
lvi Medicine Update 2018
147. Therapeutic Uses of Human Endothelial Progenitor Cells................................................................... 865

Ananda Bagchi, Aradhya Sekhar Bagchi
Isolation of EPC 866
Therapeutic Uses of EPC 866
EPCs and Cardiovascular Risk factors 866
EPC and Atherosclerotic Cardiovascular Disease 867
EPCs and Cardiovascular Trials 868
Effect of Cardiac Drugs on EPCs 868
ACE Inhibitors and Angiotensin II Receptor Blockers 868
CD34 Antibody Coated Stents 868
Uses of EPCs in Diabetes Mellitus 869
Role of EPCs in Tumor Growth 869
Role EPCs in Endometriosis 869
Uses of EPCs in Wound Healing 869
Uses of EPCs in Peripheral Arterial Obstructive Disease 870
148. Management of Gender Dysphoric Persons, Sex Change Surgeries

and Our (Indian) Experience...................................................................................................................... 872
Richie Gupta, Rajat Gupta
149. Anemia in Elderly: Experience at a Large Tertiary Center..................................................................... 876

PS Ghalaut, Ragini Ghalaut
Classification of Anemia 876
Diagnosis of a Case with Anemia in Elderly 878
Investigations in Anemia in Elderly 878
Management of Anemia in Elderly 880
Indications of Blood Transfusion 881
SECTION 16 SOCIAL ISSUES

150. Medical Ethics............................................................................................................................................... 885
Hem Shanker Sharma
Theories of Medical Ethics 885
Governing Bodies and Rules 887
Contents lvii
151. Soul and Spiritual Health............................................................................................................................ 888

SP Yoganna
Origin and Evolution of Universe—Matter and Energy theory (Big Bang Theory) 888
Natural Principles of Universe 888
Human is a Manifestation of Universal Energy 889
Human Being is the Miniature of the Universe 889
Human Being is Holistic 889
PreProgrammed Evolution and Human Body Functions 890
Life Energies 894
Soul (Atma) 895
Ways of Acquiring Spiritual Energy 897
God and God Men 898
What is Spiritual Health? 899
Diagnostic Approach 899
152. Cooking Oils: Which to Use?....................................................................................................................... 901

Sonia Arora, Vitull K Gupta, Meghna Gupta
Composition of Fats 901
Trans Fatty Acids or Partially Hydrogenated Fatty Acids 902
What are Cooking Oils? 903
Choosing the Right Oil 904
Why Blends are Needed? 905
153. IT Solution in Regulation of Medical Education and Medical Practice.............................................. 906

Ajay Kumar
SECTION 17 MISCELLANEOUS
154. Changing Trends in Medicine: Past, Present and Future...................................................................... 909
Pritam Gupta, Ghan Shyam Pangtey, Sujata Mangla
Medicine Before the 20th Century 909
Medicine in the 20th Century 911
Medical Science and Technology in 21st Century 913
Future Medical Inventions 915
lviii Medicine Update 2018
155. Isoniazid Preventive Therapy: Operational Guidelines......................................................................... 918

Mohanjeet Kaur, Ashish Chawla
TB and HIV 918
HIV-TB Collaborative Activities 918
Single Window Services 918
Isoniazid Preventive Therapy 919
Why INH for IPT? 920
Evaluation of the Patients (Before Starting IPT) 920
Regimen Plan for IPT 920
Concomitant Use of IPT with ART 920
Can Co-Trimoxazole be Dispensed with IPT? 920
Drug Resistance with IPT 921
156. Hypnotherapy in Medical Disorders......................................................................................................... 922

Rajeev Mohan Kaushik
Areas of the Brain Affected by Hypnosis 922
Physiological Effects of Hypnosis 923
Factors Affecting Therapeutic Response 923
Types of Hypnosis 923
Applications of Hypnotherapy in Medical Disorders 924
Hypnoanalysis 925
Prospects 925
157. An Approach to Recurrent Falls in the Elderly........................................................................................ 926

S Ramnathan Iyer, Revati R Iyer
158. Ultrasonography in Critically Ill Patients................................................................................................. 929

Sameer Gulati, Bhupendra Gupta
Equipment 929
Procedure: Lung Ultrasonography 929
Procedure: Compression Ultrasonography for Deep Vein Thrombosis 931
Procedure: Bedside Ocular Ultrasound 931
Procedure: Focussed Echocardiography 932
Procedure: Screening Abdominal Ultrasonography 933
Ultrasonography in Trauma 933
Advantages and Limitations 934
Contents lix
159. Imaging Parameters in Pulmonary Thromboembolism....................................................................... 935

Priya Jagia, Niraj Nirmal Pandey
Diagnosis of Pulmonary Embolism and Deep Venous Thrombosis 935
Imaging Modalities 935
Assessment of Pulmonary Embolism Severity and Prognostication 937
Diagnostic Algorithm in a Patient of Suspected PE 939
Index........................................................................................................................................................... 941
SECTION
1
Hypertension
Pitfalls in Hypertension Management High Altitude Systemic Hypertension:
K Tewary Unraveling the Mystery
Ambulatory Blood Pressure Monitoring
in Clinical Practice Management of Isolated Systolic Hypertension:
Narayan G Deogaonkar, Viplav N Deogaonkar Current Concepts
Azilsartan: A New Baby in Old Horizon
BA Muruganathan Blood Pressure Control with Changing Time
BR Bansode
Hypertension and Menopause
Anuj Maheshwari, Shipra Kunwar Management of Hypertension in Diabetes
Renovascular Hypertension: Current Status
Puneet Rijhwani Grey Areas in Diagnosis and
Management of Hypertension
Diuretics for Hypertension: Review and Update
Anita Jaiswal
R Rajasekar
CHAPTER
1
Pitfalls in Hypertension Management
K Tewary
Hypertension is one of the most commonly encountered TABLE 1: Average changes in blood pressure associated with
cardiovascular disease (CVD) in the outpatient depart common activities*
ment (OPD). It is a silent killer associated with high Change in blood pressure, mm Hg
morbidity and mortality. More than 1 billion people Activity Systolic Diastolic
suffer from hypertension worldwide. Although it looks Attending a meeting +20.2 +15.0
very simple to diagnose and treat hypertension, a lot of Working +16.0 +13.0
practical challenges are there in real life management of Commuting +14.0 +9.2
hypertension. Following types of errors are commonly Walking +12.0 +5.5
seen in routine management of hypertension. Dressing +11.5 +9.7
1. Errors in examination Doing chores +10.7 +6.7
2. Diagnostic errors Talking on telephone +9.5 +7.2
3. Treatment errors Eating +8.8 +9.6
4. Patient errors (Compliance Issues) Talking +6.7 +6.7
Doing desk work +5.9 +5.3
ERRORS IN EXAMINATION Reading +1.9 +2.2
In countries like India where crowded OPDs are very Doing business (at home) +1.6 +3.2
common, it is not unusual to see that clinicians do not Watcing television +0.3 +1.1
have sufficient time to discuss patient’s history. Many Sleeping –10.0 –7.6
important points such as quantitative assessment of *Changes are shown relative to BP while relaxing
salt intake, calorie intake and daily exercise time are
missed. These points help to provide overall assessment 10–15 minute physical and mental rest. As shown in
of patient. Modest education and encouragement to the Table 1 many mild physical activities can increase
patient can help the patient to control BP and multiple blood pressure significantly. Patient should avoid
other risk factors. smoking or drinking tea/coffee just before blood
pressure measurement. Crossing the legs is known to
DIAGNOSTIC ERRORS increase systolic blood pressure by 2–8 mm Hg. Patients
It is important to prepare and relax the patient in proper arm should not be hanging in air and resting at the
position before measurement of blood pressure. Patient heart level. No tight clothing should constrict the arm
should be in either supine or sitting position with minimum while BP measurement. The BP cuff should remain to
4 SECTION 1: Hypertension
the level of heart. American Heart Association (AHA) and Indian hypertension guidelines recommend
publishes guidelines for blood pressure measurement usage of either indapamide or chlorthalidone,
recommends that the bladder length and width (the whenever diuretics are required to control BP.
inflatable portion of the cuff ) should be 80% and 40% Combined Use of 2 RAAS (renin angiotensin aldos
respectively, of arm circumference (Table 1). terone system) blockers : in ONTARGET study,
Korotkoff V is the commonly recommended combined use of telmisartan and ramipril did not
measuring point except in pregnant patients as It is provide any extra-cardiovascular benefits while
associated with less interobserver variations and It is increasing risk of adverse events such as diarrhea,
easier to detect by most observers. Korotkoff IV is on hypotension and renal impairment. Similarly in
average 8 mm Hg above the invasively measured diastolic ALTITUDE trial, addition of aliskiren to ACEI or ARB
blood pressure. Korotkoff V is on average 2 mm Hg above in diabetic nephropathy patients did not provide
the invasively measured diastolic blood pressure. cardiovascular benefits and increased risk of non-
fatal stroke, renal complications, hyperkalemia
TREATMENT ERRORS and hypotension. Based on these studies, US-FDA
Targeting low BP goal in elderly: Previously, low BP and other regulatory agencies have advised not to
levels (< 130/80 mmHg or < 120/80 mm Hg) were combine two RAAS blockers in same patients.
recommended in elderly population. Such low levels
can lead to falls and fractures in elderly population
ERRORS BY PATIENTS
As hypertension requires a lifelong disease, patient
who have high prevalence of osteoporosis. As per
compliance is an important issue in long-term therapy.
recent JNC-8 guidelines, ESC (European Society
Various studies have shown that compliance to anti-
of Cardiology) and ASH (American Society of
hypertensive therapy is around 20–70%. Sudden
Hypertension) guidelines, BP targets in elderly (age
withdrawal of antihypertensive drugs can lead to
> 60 years or 80 years) should be < 150/80 mm Hg. In
serious complications due to shoot up in BP. Fixed dose
some selected elderly patients, BP targets of < 140/90
combination (FDCs) of different antihypertensive drugs
mm Hg can be tried, if it is tolerated well by patients
can help to improve patient compliance. Use of FDCs
without adverse events.
can also minimize adverse effects of different drugs,
Selection of wrong drugs for management of
e.g. when ARBs/ACE inhibitors are used as FDCs with
hypertension : Drugs such as atenolol and
thiazide diuretics, there is reduced risk of imbalance in
hydrochlorothiazide are still very commonly used in
serum potassium (either hypokalemia or hyperkalemia).
India and other developing countries despite lack of
Similarly, use of CCBs (calcium-channel blockers) with
evidence of cardiovascular benefits in randomized ARBs can reduce the risk of CCB-induced pedal edema.
clinical trials. In a meta-analysis published in Lancet Proper patient education regarding compliance to
in 2004 (which included data from 5 clinical trials of therapy is essential.
atenolol comparing it with other antihypertensives;
total 17671 patients were followed up for mean 4–6 BIBLIOGRAPHY
years), atenolol significantly increased risk of stroke, 1. 2013 ESH/ESC Guidelines for the management of arterial
all-cause mortality and cardiovascular mortality. 2013 hypertension. The Task Force for the management of arterial
Indian guidelines for hypertension recommended hypertension of the European Society of Hypertension (ESH)
and of the European Society of Cardiology (ESC). European
to use newer (3rd generation) beta-blockers in
Heart Journal. 2013;34:2159-219.
hypertension in young patients. In ACCOMPLISH 2. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH
trial, HCTZ was shown to be inferior to amlodipine Fixed-dose combinations improve medication compliance:
for cardiovascular risk reduction. So, NICE guidelines a meta-analysis. Am J Med. 2007;120(8):713-9.
CHAPTER 1: Pitfalls in Hypertension Management 5
3. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in 6. Littlejohn TW, Majul CR, Olvera R, Seeber M, Kobe M,
hypertension: is it a wise choice? Lancet. 2004;364(9446): Guthrie R, Oigman W; Study Investigators. Results of
1684-9. treatment with telmisartan-amlodipine in hypertensive
4. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, patients. J Clin Hypertens (Greenwich). 2009;11(4):207-13.
Hester A, Gupte J, Gatlin M, Velazquez EJ. Benazepril plus 7. Weber MA, Schiffrin, EL, Whilte WB, et al. Clinical Practice
amlodipine or hydrochlorothiazide for hypertension in high- Guidelines for the Management of Hypertension in the
risk patients. ACCOMPLISH Trial Investigators. N Engl J Med. Community. A Statement by the American Society of
2008;359(23):2417-28. Hypertension and the International Society of Hypertension.
5. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based The Journal of Clinical Hypertension. 2014;16(1):14-26.
guideline for the management of high blood pressure 8. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both
in adults: report from the panel members appointed in patients at high risk for vascular events. N Engl J Med.
to the Eighth Joint National Committee (JNC 8). JAMA. 2008;358(15):1547-59.
2014;311:507-20.
CHAPTER
2
Ambulatory Blood Pressure
Monitoring in Clinical Practice
Narayan G Deogaonkar, Viplav N Deogaonkar
INTRODUCTION
Hypertension (HTN) is a significant global health
problem, responsible for 7.5 million deaths each year
worldwide. 1 It is a common cardiovascular disease
(CVD) risk factor, usually diagnosed and treated based
on blood pressure readings obtained in the clinic setting.
Traditionally, BP in the office or clinic has been assessed
with the auscultatory technique, which was introduced
into clinical medicine at the beginning of the twentieth
Fig. 1: Factors involved in 24-hour blood pressure (BP) variability
century, and which has survived to this day in clinical (Mancia G. Journal of Cardiovascular
practice. Although the technique is inherently accurate, Pharmacology. 1990;16(6):S1-S6)
it is dependent on observer attention to detail, which
is often lacking, and it provides only a momentary progressively gaining recognition as the gold standard for
measurement of BP, usually under circumstances diagnosing hypertension.
that can influence the level of BP being measured. To
overcome these serious methodological problems, Blood Pressure Variability (Fig. 1)
techniques for obtaining automated profiles of BP over Blood pressure (BP) measurements are highly variable.
24 hours and measures of BP in the home setting have Measured blood pressure varies due to a various factors
been developed. such as measurement technique, accuracy of equipment,
Five decades ago, Kain et al. 2 demonstrated the and multiple patient factors such as anxiety. Even though
benefits of ambulatory blood pressure monitoring these factors are controlled, blood pressure is subject to
(ABPM), and the attractive possibility of measuring blood biological variation (circadian variation) from beat-to-
pressure during patients’ daily activities. ABP monitoring beat, minute-to-minute, and day-to-day.
was developed initially to study the circadian changes The circadian blood pressure profile is similar in both
in BP and to determine the influence of BP-lowering normotensive and essential hypertensives (mild-severe).
drugs on the 24-h profile. ABPM gives information on The profile is deranged only in malignant hypertension,
circadian variations in blood pressure, and documents complicated hypertension, and some secondary
blood pressure responses to different behaviors. ABPM is hypertension which are characterized by the reduction
CHAPTER 2: Ambulatory Blood Pressure Monitoring in Clinical Practice 7
or loss of nocturnal hypotension. 3 In hypertensive daytime average (reverse dippers). Other important
patients, 24-h blood pressure (BP) variability (V) shows parameters of blood pressure assessment facilitated by
a positive relationship with organ damage, organ ambulatory blood pressure monitoring are the morning
damage progression and cardiovascular morbidity. 4 surge, when blood pressure increases rapidly from
Understanding the extent of BP variability is very nighttime levels to daytime levels, and blood pressure
important since it impacts diagnosis of hypertension, variability.7
clinical management of elevated BP and number of drugs The advantages of ABPM stated in comprehensive
prescribed to achieve ‘‘BP control’’.5 reviews are briefly summarized as follows:
The technique of ambulatory blood pressure Gives a larger number of readings than office blood
monitor ing is impor tant in the diagnosis and pressure measurement

management of hypertension. Blood pressure variability Provides a profile of blood pressure behavior in the
on 24-hour ABPM is generally reported using two patient’s usual daily environment
metrics, day-night standard deviation which captures Allows identification of white-coat and masked
the variability a patient experiences around their mean hypertension phenomena

daytime and nighttime blood pressure, and average real Demonstrates noctural hypertension
variability which captures variability in blood pressure Assesses blood pressure variability over the 24-h
between successive measurements.6 period

Assesses the 24-h efficacy of antihypertensive medi
Fundamentals of Ambulatory BP cation

Monitoring Is a stronger predictor of cardiovascular morbidity
An alternative to traditional measurement, automated and mortality than office measurement.

office BP measurement is the mean of multiple BP
readings recorded with a fully automated device with the ABPM as Diagnostic Tool
patient resting quietly, alone, in the office/clinic. It has Suspected White-Coat HTN
several advantages over manual BP, especially in routine The term ‘‘white-coat’’ has been given to this type of
clinical practice, by virtually eliminating office-induced hypertension on the assumption that the differences
increases in BP, improving accuracy and minimizing between clinic and ambulatory blood pressures are
observer error. due to the white-coat effect; that is, the rise in blood
The circadian cycle can be divided into various pressure that often occurs when blood pressure is
periods: assessments at different times permit evaluation measured by a doctor or nurse. The wide interest in
of circadian variation in blood pressure. Night-time white-coat hypertension is appropriate, as identification
blood pressure is one of the most important measures of individuals in whom blood pressure is raised only
of this circadian variation. Normally during sleep, blood temporarily as an emotional reaction to the clinical
pressure decreases (‘dips’) such that sleep average blood environment may prevent unnecessary treatment of
pressure is lower than average awake blood pressure. The people whose blood pressure is normal during routine
‘normal’ dip is considered 10–20%. Individuals who dip daily life. However, the significance of white-coat
<10% are said be nondippers. Nocturnal hypertension hypertension is still beleaguered by a series of problems
and non-dipping pattern are strongly associated with that have produced misconceptions, misnomers, and
increased cardiovascular morbidity and mortality. misunderstandings.
Around 70% of individuals show reduced blood pressure With the prevalence of white-coat hypertension
at night (i.e. show dipping ≥10%), and about 30% have in the community being significantly high (20–25%),
non-dipping patterns, when blood pressure remains it is important to make an accurate diagnosis, which
similar to daytime average, or occasionally rises above can best be achieved by having 24-h ABPM and/or
home BP monitoring (HBPM) done before prescribing events including death. Nondipping is common in
antihypertensive drug therapy (ESH 2014 guidelines). diabetic patients and may reach a prevalence of ~30%.
For diagnosis of nondipping, it is important to relate
Masked Hypertension nighttime readings with the patient’s’ diary to confirm
Masked hypertension is the phenomenon whereby their reliability. A decrease in heart rate, which is typical
certain individuals who are not on antihypertensive in sleep time, may indicate that the patient was asleep.
medication show non-elevated blood pressure in a Extreme fall of 0–20% in BP during sleep time is known
clinical setting but show high blood pressure when out as extreme dipping. This pattern is not necessarily
of the office, typically assessed by ambulatory blood benign, since it may be associated with mild cognitive
pressure monitoring: approximately 15–30% of adults impairment in the elderly.
with non-elevated office blood pressure have masked
hypertension. Since masked hypertension is associated Prediction of CV Events
with increased risks of cardiovascular morbidity and Blood pressure (BP) is an established prognostic factor
mortality, clinic readings may therefore underestimate for cardiovascular disease. But, are all BP values created
an individual’s cardiovascular risk. Antihypertensive equal? Multiple cross-sectional and cohort studies
treatment may be warranted in patients with masked have demonstrated that home (BP measured regularly
hypertension, but there are currently no randomized trials at rest by the patient at home) and ambulatory (BP
that have evaluated this strategy, and the best method to measured automatically regardless of activity or time
identify people with masked hypertension has not been of day) BP readings are superior to traditional office BP
established. There is a substantial diagnostic overlap values in predicting end-organ damage and incident
between prehypertension and masked hypertension. cardiovascular disease. Home BP fails to provide
overnight readings, which correlate highly with disease
Night-time Blood Pressure: ‘‘Dippers’’ Versus events, and it is also subject to selection bias. Ambulatory
‘‘Nondippers’’ (Table 1) blood pressure (ABP) has long been recognized as
The possibility of noninvasive measurement of blood a superior predictor of cardiovascular disease and
pressure at night and during sleep by ambulatory mortality, independent of clinic measurements.8-10
monitoring devices has stimulated interest in the No matter the level of office BP, it is the out-of-office
pathophysiological significance of night-time blood BP that best predicts events by 17–39% (home BP) and
pressure. Physiologically, BP falls by >10% during 17–31% (ABPM) per 10 mm Hg increase in systolic BP.11,12
nighttime (asleep). When BP falls by <10% during Diagnostic and predictive accuracy of blood pressure
nighttime, it is defined as nondipping. screening methods with consideration of rescreening
Nocturnal nondipping is associated with increased intervals: a systematic review for the U.S. Preventive
risk of stroke, end-organ damage, and cardiovascular Services Task Force.
TABLE 1: Blood pressure patterns that can be determined by means of ABPM and other methods (N Engl J Med. 2006;354:2368-74)
Variable Ambulatory blood-pressure Clinical blood-pressure Home blood-pressure
monitoring monitoring monitoring
zz True, or mean, blood pressure Yes Questionable Yes
zz Diurnal blood pressure rhythm Yes No No
—— Dipping status Yes No No
—— Morning surge Yes No Questionable
zz Blood pressure variability Yes No Questionable
zz Duration of drug effects Yes No Yes
Studies have reported that ABP measurements However, unlike ABPM it does not allow the assessment of
give better prediction of clinical outcomes compared BP during sleep or at work or the quantification of short-
with conventional clinic or office blood pressure term BP variability. In addition, the recommendation to
measurements.13,14 measure BP at home may induce anxiety that leads to
The first involved 1542 subjects of Ohasama, Japan, excessive measurements and treatment changes made
who were followed up for a mean of 6.2 years. ABP on the basis of erroneous measurements. HBPM should
measurements better predicted mortality than did be used in conjunction with ABPM as a complementary
casual blood pressure measurements. In another study method of BP assessment. When there is a concordance
of 808 older participants (aged over 60 years) with between the methods, HBPM may be appropriate for
isolated systolic hypertension followed up for a mean long-term follow-up of treated HTN patients.
of 4.4 years, ambulatory systolic blood pressure was a
significantly better predictor of cardiovascular events ABPM Guiding Management of HTN
than conventional blood pressure measurement. ‘‘Smooth’’ or uniform blood pressure control is an
There are several potential explanations for the better obvious goal of antihypertensive therapy, but it is
prognostication afforded by out-of-office BP levels. First, difficult to measure by the traditional clinic blood
both methods include a larger number of readings, thus pressure measurements. Ambulatory blood pressure
increasing their reliability and reproducibility compared monitoring, therefore, is used increasingly to evaluate
with office readings. Second, both home BP and ABPM new antihypertensive drugs and to assess the adequacy
are able to diagnose white coat hypertension (high office of treatment. This application is based on the assumption
BP, normal ambulatory BP) and masked hypertension that treatment must be continuously adequate and
(normal office BP < high ambulatory BP). By identifying that more frequent blood pressure measurements
these two conditions, home BP and ABPM allow more during treatment, particularly at different times and
accurate determination of overall BP burden and its during various types of activity or mental states, may
associated risk. Third, ABPM, but not home BP, is able to lead to a more accurate assessment than infrequent
quantify BP during sleep. Sleep BP is marginally better measurements in the clinic.
than daytime BP in the prediction of hypertension- Progressive decrease in sleep BP in nondipping
related outcomes. Moreover, reverse dippers have patients reduces cardiovascular morbidity and mortality
increased cardiovascular risk compared with all other and therefore should be a therapeutic target. Achieving
types of circadian BP patterns. There is also increased this target requires proper patient evaluation by 24-h
risk among non-dippers (compared to dippers) and ABPM. Bedtime treatment will be clearly indicated in
perhaps a protective effect from extreme dipping. patients with a nondipping pattern, whereas in extreme
dippers evening dosing should be avoided. ABPM may
Comparison of Ambulatory BP Measurements also identify patients with morning BP surge. Several
with Home Measurements studies showed an association between morning BP
Home BP monitoring (HBPM) offers an attractive surge and cardiovascular morbidity and mortality.18-20
alternative to 24-h ABPM. Several studies have reported Drugs that are given once daily in the morning but
that target organ damage and cardiovascular outcomes do not provide adequate BP control during the night
are more strongly correlated with HBPM than with clinic and early morning may be less protective than drugs
BP measurements.15-17 HBPM provides measurements providing 24-h BP control. Pareek et al (J Am Coll Cardiol
over a much longer period, is cheaper, more widely 2016;67:379–89) showed that Treatment with low-dose
available, more convenient for patients (particularly for chlorthalidone, 6.25 mg daily, significantly reduced
repeated measurements), and has been shown to improve mean 24-h ABP as well as daytime and nighttime BP.
patients’ compliance with treatment and HTN control. Due to its short duration of action, no significant 24-h
ABP reduction was seen with HCTZ, 12.5 mg daily, which TABLE 2: Thresholds of hypertension diagnosis based on ABPM
merely converted sustained hypertension into masked 24-h average ≥130/80 mm Hg
hypertension. Awake (daytime) average ≥135/85 mm Hg
The threshold values in NICE 2003 guidelines, the Asleep (night-time) average ≥120/70 mm Hg
JNC 7 2007 guideline, the ESH/ESC 2013 guidelines and (ESH guidelines)
the results of outcome studies have contributed to the
definition of consensus values summarized in following
TABLE 3: Additional information derived from ABPM
Table 2.
Compelling indications
Additional Information Derived from ABPM Identifying white-coat hypertension phenomena
ABPM may help to identify secondary HTN. Lack of zz White-coat hypertension in untreated individuals
nocturnal fall in BP may suggest the existence of sleep zz White-coat effect in treated or untreated individuals
apnea. Performing ABPM is indicated in all patients with zz False resistant hypertension due to white-coat effet in treated
individuals
resistant HTN to exclude white coat effect as a cause of
Identifying masked hypertension phenomena
apparent resistance. Data derived from 24-h ABPM can
zz Masked hypertension in untreated individuals
be useful to diagnose the cause of syncope. It is useful
zz Masked uncontrolled hypertension in treated individuals
to document fluctuating BP in patients with orthostatic
Identifying anbnormal 24-h BP patients
hypotension, autonomic failure, or asymptomatic
postprandial hypotension (Table 3).
zz Daytime dipping/post-prandial hypotension
ABPM can be useful both in monitoring the acute zz Nocturnal hypertension
effects of ischemic and hemorrhagic stroke and in zz Dipping status/isolated nocturnal hypertension
predicting outcome in stroke survivors. A frequent Assessment of treatment
finding in stroke patients is the loss of nocturnal BP zz Assessing 24-h BP control

dipping, which may lead to worse target organ damage zz Identifying true resistant hypertension
and facilitate recurrent stroke. Moreover, BP recorded Additional indications
during sleep or in the early morning is more predictive zz Assessing morning hypertension and morning BP surge
of first or recurring stroke events than daytime SBP, zz Screening and follow-up of obstructive sleep apnea
especially in the elderly.21 Conventional BP recordings zz Assessing increased BP variability
may, therefore, be inadequate to precisely identify these zz Assessing hypertension in children and adolescents
changes in BP over 24 hours. zz Assessing hypertension in pregnancy
zz Assessing hypertension in the elderly
ABPM in Diabetes Patients zz Assessing hypertension in high-risk patients
ABPM is particularly useful in diabetic patients zz Identifying ambulatory hypotension
for characterizing the nocturnal profile, because a zz Identifying BP patterns in Parkinson’s disease
nondipping or hypertensive nocturnal BP pattern is more zz Assessing endocrine hypertension
common in diabetic patients and is a strong predictor of
future cardiovascular events. inaccurate, attention to methodological detail is of little
relevance. The most popular validation protocol is the
Use of Ambulatory Blood Pressure European Society of Hypertension International Protocol
Monitor (Figs 2A to D) (ESH-IP). Separate validation is required in specific
Device Validation populations, such as children and adolescents, pregnant
A n a c c u ra t e d e v i c e i s f u n d a m e n t a l t o a l l B P women and the elderly, and in certain diseases, such as
measurements; if the device used to measure BP is obesity and arrhythmias. All ABPM monitors measure
the day and night, and set without the readings being
displayed to the patient. Although ABPM occurs while
individuals go about their normal daily activities, they
are asked to keep their arm still while the cuff is inflating,
and to avoid excessive motion, which is associated
with unobtainable or artifactual readings. At the end
of the recording period, the readings are downloaded
into a computer for processing. Individuals can fill out
a diary during the monitoring period to document any
symptoms, awakening and sleeping times, naps, periods
of stress, timing of meals, and medication ingestion.22
Average BP values (over 24 h, daytime, and night-
A B time) are undoubtedly the most important parameters
obtained from ABPM recordings, based on outcome
data. However, a large number of additional indices with
promising clinical evidence may be derived from ABPM
recordings.
ABPM and Assessment of Treatment

(Figs 3 and 4)
Ambulatory blood-pressure monitoring is not commonly
used in routine clinical practice for evaluating the
response to antihypertensive treatment, mainly because
of the high cost and the inconvenience of performing
multiple ambulatory blood-pressure recordings.
C D However, changes in ambulatory blood pressure correlate
Figs 2A to D: Multiple ambulatory devices
more closely than do changes in clinic blood pressure
with the regression of left ventricular hypertrophy during
antihypertensive treatment.23
BP and pulse rate and most provide measurements not
ABPM should be performed in patients in whom
only for SBP and DBP but also for mean BP and pulse
BP tends to be unstable and highly variable with
pressure. office or clinic BP measurement or with home BP
In the 1960s, a manually inflated device was monitoring. Unstable BP may also be an indication
introduced that could take blood pressure readings on that antihypertensive treatment is being ineffective and
an ambulatory basis throughout the day. ABPM will demonstrate both the efficacy of treatment
At present, ambulatory monitors are fully automated, and the smoothness of BP reduction.
utilize the oscillometric technique to estimate blood ABPM also provides a better assessment of the
pressure, and are typically used to obtain blood pressure response to treatment than does clinic BP; the efficacy
readings for a 24-hour period. Ambulatory monitors of treatment without the white-coat effect can be
are compact, typically worn on a belt or in a pouch, and ascertained, excessive drug effect and the occurrence of
connected to a sphygmomanometer cuff on the upper symptoms can be determined, the duration of BP control
arm by a tube. The monitors are usually programmed over the 24-h period and the consequences of missed
to obtain readings every 15–30 minutes throughout doses on BP can be demonstrated.
Fig. 3: Clinically blood pressure followed by 24-hour ambulatory blood pressure monitor device
Fig. 4: Clinically blood pressure followed by home blood pressure monitoring

ABPM is particularly useful in pregnancy for detecting pressure measurement has been reported, causing a
white-coat and nocturnal hypertension. ABPM is higher prevalence of white-coat phenomenon.31
particularly helpful in hypertensive patients who for
various considerations are regarded as being at high risk Patients with Atrial Fibrillation
of cardiovascular disease. BP measurement in patients with atrial fibrillation is less
An example of an ABP report and its interpretation is precise as this type of arrhythmia is accompanied by
shown in Figure 5. increased beat-to-beat BP variability due to variations in
ventricular filling time, stroke volume, and contractility.
Position of ABPM in Hypertension Unfortunately, published evidence regarding the role of
Guidelines (Table 4) ABPM in patients with arrhythmias and, specifically in
ABPM has an increasingly defined and appropriate patients with atrial fibrillation, is scarce. Inspite of these
position within some, but not all, guidelines. limitations, and although larger trials in patients on atrial
NICE, CHEP and NHFA guidelines recommend that fibrillation are needed, there is no reason at present to
ABPM is useful to exclude white-coat hypertension. exclude such patients from ABPM procedures.32
However, the guidelines of the American Joint National
Committee (JNC) 8 did not mention either ABPM or Children and Adolescents
HBPM based on the fact that these techniques have not In children and adolescents, ABPM is indicated for
been evaluated by randomized controlled trials.24 suspected white-coat hypertension, evaluation and
follow-up of primary and secondary hypertension or
Challenges in using ABPM in conditions with associated risk of arterial hypertension,
Special Population such as diabetes mellitus, chronic pyelonephritis, chronic
Obese Patients renal failure and autosomal dominant polycystic kidney
Obesity is a well-established major risk factor for disease because it shows better correlation with the
hypertension with higher prevalence in specific development of target organ damages than office blood
population groups. In obese persons some technical pressure measurement (Degree of Recommendation IIa
difficulties, such as miscuffing may be present but – Evidence Level C). Only a few ABPM devices have been
these should not prevent them from undergoing this validated for use in children. Applicability, however,
investigation. is promising, and there have been reports of good
In such cases, conically shaped cuffs might be used, precision and reproducibility. The success percentage
when available. In patients with very obese arms in whom in obtaining measurements increases with age. The
ABPM cannot be performed, ABPM carried out with the primary limitation to its use in children and adolescents
cuff placed on the forearm may be the only means of is the lack of normative pediatric values.32
obtaining a 24-h recording, with an instruction that the
wrist must be kept at heart level during measurement, Elderly Patients
although this possibility requires further investigation.30 ABPM can provide valuable clinical support for
In obese patients with arm circumference above 20.5 suspected orthostatic, postprandial, drug-related
inches or short arms, the examination is contraindicated, and situational arterial hypotension, as well as for
because ABPM devices do not have appropriate cuffs evaluation of patients with dysautonomia and syncope
(Degree of Recommendation III – Evidence Level D). (Degree of Recommendation IIa – Evidence Level D). In
It should also be emphasized that in obese patients, elderly individuals with isolated systolic hypertension,
particularly those with visceral fat distribution, an ABPM is useful to rule out white-coat effect (Degree
increased frequency of alert reactions to casual blood of Recommendation IIa – Evidence Level A). Some
Ambulatory blood pressure report

Patient name: M J Bond ID: 007
Clinic BP
Scan start date 29/08/2011 Clinic SEP/DEP 140/90 suggests
San start time 12:08 Total readins 56 hypertension
Scan end date 30/08/2011 Successful readings 52
Scan end time 13:37 Percent successful 93 OK if >85%
SBP: Grade 2
Summary
hypertension
Min Mean Max STD BP load (>20%) ≥148 mm Hg
Systolic 125 151 183 13.4 94%
Diastolic 71 90 115 11.9 57%
Heart rate 54 79 94 9.5 DBP: Grade 1
Day summary 6:00 to 22:00 hypertension
≥84 mm Hg
Min Mean Max STD BP load (>20%)
Systolic 125 152 176 12.2 91%
Diastolic 73 91 111 10.9 65%
Heart rate 54 71 90 8.7
Night summary 22:00 to 6:00
Min Mean Max STD BP load
Night SBP Systolic 129 146 183 14.7 100%
dipping Diastolic 71 96 115 135 70%
abnormal
Heart rate 57 69 94 11.1 Night DBP
% Night SBP dip 3.9% % Night DBP dip 5.5% dipping
(>10%) (>10%) abnormal
Awake summary 7:00 to 1:30
Systolic 132 155 183 11 100%
Diastolic 75 92 115 11 55%
Heart rate 55 73 94 9
Asleep summary 1:30 to 7:00
Systolic 125 134 143 5 100%
Asleep SBP
dipping Diastolic 71 76 85 5 55%
normal Heart rate 54 60 67 5 Asleep DBP
% Night SBP dip 14% % Night DBP dip 28% dipping
(>10%) (>10%) normal
Interpretation: Patient ABP day, night, awak, asleep BP, BP load values are
all above hypertension grade 1 threshold (shown in red). While night summary
suggests nondipping (<10%) this is due to very late sleep onset. The nocturnal
dipping based on awake and asleep values are satisfactory (>10%)
Conslusion: Confirmed grade 1 hypertension
Fig. 5: ABP report and its interpretation

Source: Australian Family Physician. 2011;40(11).
TABLE 4: Indication of ABPM in hypertension guidelines

Guideline Year Indication
25
The National Heart Foundation of Australia (NHFA) 2016 If clinic BP is 140/90 mm Hg or hypertension is suspected, ABPM
and/or home monitoring should be offered to confirm BP level
Canadian Hypertension Education Program (CHEP)26 2015 If clinic BP is 140/90 mm Hg or hypertension is suspected, ABPM
and/or home monitoring should be offered to confirm BP level
Japanese Society of Hypertension (JSH)27 2014 zz For the difficult decision in treatment strategy using home or
office BP
zz For patients with BP 125 to 135/80 to 84 mm Hg at home
zz For patients with increased BP variability at home
zz For patients concerned with short-time BP variability
European Society of Hypertension (ESH)28 2013 zz Marked discordance between office BP and home BP
zz Assessment of dipping status
zz Suspicion of nocturnal hypertension or absence of dipping,
such as in patients with sleep apnea, CKD, or diabetes mellitus

zz Assessment of BP variability
National Institute for Health and Care Excellence (NICE)29 2011 If clinic BP is ≥140/90 mm Hg, offer ABPM to confirm the diagnosis
of hypertension
limitations must be emphasized in this age group. Age- antihypertensive treatments and should be included in
related arterial stiffening underestimates blood pressure studies designed to compare the effects of various drugs.
measurement obtained by the oscillometric method Night-time blood pressure can be assessed only with
and thus, ABPM is subject to errors in the presence of ambulatory blood-pressure monitoring, and evidence
pseudo-hypertension.32 suggests that a failure of blood pressure to decrease at
night may be associated with an adverse prognosis.
Pregnant Women
Ambulatory blood pressure monitoring during pregnancy REFERENCES
has been used to identify white-coat hypertension, whose 1. Peterson CG, Miyashita Y. Front Pediatr. 2017 Jun 30;5:153.
prevalence is similar in both pregnant and nonpregnant doi: 10.3389/fped.2017.00153. eCollection 2017. The Use
women. Its identification is critical, however, during of Ambulatory Blood Pressure Monitoring As Standard of
pregnancy to prevent unnecessary treatment that Care in Pediatrics.
2. Kain HK, Hinman AT, Sokolow M. Arterial blood pressure
could be potentially harmful to the fetus (Degree of
measurements with a portable recorder in hypertensive
Recommendation IIa – Evidence Level B).32
patients. I. Variability and correlation with “casual”
pressures. Circulation. 1964;30:882-92.
CONCLUSION 3. Mancia G. Journal of cardiovascular pharmacology.
Ambulatory blood-pressure monitoring is currently used 1990;16(6):S1-S6.
only in the minority of patients with hypertension, but 4. Sega R, et al. Hypertension. 2002;39(2):710-4.
its use is gradually increasing. It can be regarded as the 5. Musini V, et al. PLoS ONE 2009;4(5):e5673-e5677.
gold standard for the prediction of risk related to blood 6. Shimbo D, et al. Ann Intern Med. 2015;163(9):691-700.
7. Turner JR, Viera AJ, Shimbo D. Ambulatory Blood Pressure
pressure, since prognostic studies have shown that
Monitoring in Clinical Practice: A Review, The American
it predicts clinical outcome better than conventional
Journal of Medicine 2014.
blood-pressure measurements. Though expensive 8. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S,
in comparison to other BP measuring methods, the et al. Superiority of ambulatory over clinic blood pressure
diagnosis of white-coat hypertension may reduce the measurement in predicting mortality the Dublin outcome
cost of treatment. It is also invaluable for assessing study. Hypertension. 2005;46:156-61.
9. Perloff D, Sokolow M, Cowan R. The prognostic value of 21. Gorostidi M, Sobrino J, Segura J, Sierra C, de la Sierra A,
ambulatory blood pressures. JAMA. 1983;249:2792-8. Hernańdez del Rey R, et al. Spanish Society of Hypertension
10. Verdecchia P, Schillaci G, Reboldi G, Franklin SS, Porcellati C. ABPM Registry investigators. Ambulatory blood pressure
Different prognostic impact of 24 hour mean blood pressure monitoring in hypertensive patients with high cardiovascular
and pulse pressure on stroke and coronary artery disease in risk: a cross-sectional analysis ofa 20 000-patient database
essential hypertension. Circulation. 2001;103:2579-84. in Spain. J Hypertens. 2007;25:977-84.
11. Ann Intern Med. 2015;162(3):192-204. doi: 10.7326/M14- 22. O’Brien E, Parati G, Stergiou G, et al. European Society of
1539. Hypertension Working Group on Blood Pressure Monitoring.
12. Piper MA, Evans CV, Burda BU, Margolis KL, O’Connor E, J Hyper tens. 2013;31(9):1731-68. doi: 10.1097/
Whitlock EP. HJH.0b013e328363e964.
13. Imai Y. Prognostic significance of ambulatory blood 23. Mancia G, Zanchetti A, Agabiti-Rosei E, et al. Ambulatory
pressure. Blood Press Monit. 1999;4:249-56. blood pressure is superior to clinic blood pressure in
14. Staessen J, Thijs L, Fagard R, et al. Predicting cardiovascular predicting treatment-induced regression of left ventricular
risk using conventional vs ambulatory blood pressure hypertrophy. Circulation 1997;95:1464-70. [Erratum,
in older patients with systolic hyper tension. JAMA. Circulation 1997;96:1065.
24. James PA, Oparil S, Carter BL, et al. 2014 evidence-based
1999;282:539-46.
guideline for the management of high blood pressure in adults:
15. Ohkubo T, Imai Y, Tsuji I, et al. Home blood pressure
Report from the panel members appointed to the Eighth Joint
measurement has a stronger predictive power for mortality
National Committee (JNC 8). JAMA. 2014;311:507-20.
than does screening blood pressure measurement: a
25. Gabb GM, Mangoni AA, Anderson CS, et al. Guideline
population-based observation in Ohasama, Japan. J
for the diagnosis and management of hypertension in
Hypertens. 1998;16:971-5.
adults–2016. Med J Aust. 2016;205:85-9.
16. Stergiou GS, Argyraki KK, Moyssakis I, et al. Home blood
26. Gelfer M, Dawes M, Kaczorowski J, et al. Diagnosing
pressure is as reliable as ambulatory blood pressure in
hyper tension: Evidence suppor ting the 2015 reco
predicting target-organ damage in hypertension. Am J
mmendations of the Canadian hypertension education
Hypertens. 2007;20:616-21.
program. Can Fam Physician. 2015;61:957-61.
17. Niiranen TJ, Hänninen MR, Johansson J, Reunanen A, Jula
27. Shimamoto K, Ando K, Fujita T, et al. The Japanese Society of
AM. Home-measured blood pressure is a stronger predictor Hypertension guidelines for the management of hypertension
of cardiovascular risk than office blood pressure: the Finn- (JSH 2014). Hypertens Res. 2014;37:253-387.
Home study. Hypertension. 2010;55:1346-51. 28. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC
18. Kario K, Pickering TG, Umeda Y, et al. Morning surge guidelines for the management of arterial hypertension:
in blood pressure as a predictor of silent and clinical The task force for the management of arterial hypertension
cerebrovascular disease in elderly hypertensives: a of the European Society of Hypertension (ESH) and of
prospective study. Circulation. 2003;107:1401-06. the European Society of Cardiology (ESC). J Hypertens.
19. Kario K, Yano Y, Matsuo T, Hoshide S, Eguchi K, Shimada K. 2013;31:1281-357.
Additional impact of morning haemostatic risk factors and 29. National Institute for Health and Care Excellence (NICE).
morning blood pressure surge on stroke risk in older Japanese Hypertension in adults: diagnosis and management 2011.
hypertensive patients. Eur Heart J. 2011;32:574-80. https://www.nice.org.uk/guidance/cg127. Accessed
20. Metoki H, Ohkubo T, Kikuya M, et al. Prognostic significance 21, 2017.
for stroke of a morning pressor surge and a nocturnal 30. Parati G, et al. Journal of Hypertension 2014;32:1359-66.
blood pressure decline: the Ohasama study. Hypertension. 31. Katalin M, et al. Acta Medica Marisiensis. 2016;62(3):350-5.
2006;47:149-54. 32. Parati G, et al. Journal of Hypertension. 2014,32:1359-66.
CHAPTER
3
Azilsartan: A New Baby in Old Horizon
BA Muruganathan
INTRODUCTION ARBs are chemically heterogenous, which render

The prime goal in the management of hypertension them unique pharmacological characteristics. Losartan
is targeted blood pressure reduction, so to reduce contains an imidazole with Cl and COOH substituents,
the risk of development of short-term and long-term Valsartan is different with the absence of a nitrogen
cardiovascular outcomes. containing heteroc ycle. Eprosartan has a large
As per the direction of the current guideline substituent on the imidazole ring, whereas olmesartan
recommendations, the target blood pressure goals are more closely resembles to losartan, Irbesartan has
being to achieve < 140/90 mm Hg, and a more stringent < a cyclopentyl ring incorporated instead of the Cl.
130/80 mm Hg for hypertension associated with diabetes Candesartan and azilsartan substitute benzimidazole,
and CKD. unlike telmisartan which contains benzimidazole
Several class of drugs are available for the treatment with a second benzimidazole attached. In telmisartan,
of hypertension, namely, angiotensin II receptor blockers tetrazole is replaced witha carboxyl group, whereas the
(ARBs), angiotensin converting enzyme inhibitors most recently introduced angiotensin receptor Blocker,
(ACE-I), diuretics, beta – adrenergic blockers, alpha Azilsartan, is chemically characterized with a unique
adrenergic blockers, calcium chanel blockers (CCBs). modification, biphenyl-5-oxo-1,2,4-oxadiazole, which
renders higher lipophilicity and bioavailability (Table 1).
EVOLUTION OF THE ANGIOTENSIN II Lipophilicity is a novel ability of drugs to penetrate
RECEPTOR BLOCKERS (ARBs) across the cell membranes, it decides a drugs’ pharma
Most of the ARBs used in clinical practice possess a cological profile such as absorption, tissue penetration,
molecular structure like Losartan–the first marketed absorption across specific tissue compartments and
ARB. These molecules are known to possess unique blood brain barrier. Prodrug lipophilicity, wherever
pharmacokinetic properties, critical for binding to AT1R feasible, is critical for absorption, whereas active
and may become fundamentally important for achieving molecular lipophilicity forms a fundamental basis for
a distinct pharmacological profile—oral bioavailability, distribution within the body. These molecular variations
binding affinity, dissociation rates, inverse agonism, and across ARBs are responsible for differential efficacy,
several other non- AT1 R mediated effects.1,2 safety and duration of action.
TABLE 1: Pharmacokinetic profile of azilsartan in comparison to other available angiotensin II receptor blockers
Parameters Azilsartan Losartan Telmisartan Olmesartn Valsartan Irbesartan Candesartan Eprosartan

medoxomil
F (%) 60 33 42–58 26 10–35 60–38 15 13

(bioavailability
Active Yes Yes No Yes No No Yes No

metabolite
Tmax (hr) 1.5–3 I (metabolite, No 1–3 2–4 1.5–2 3–4 1–2

3–4)
t ½ (hr) 11 I (metabolite, Only 11% 12–18 6 11–15 3.5–4 5–9

6–9) biotransformed (metabolite, (metabolite,
8–13) 3–11)
Primary Cytochrome CYP-2C9 and Conjugation De- Unknown CYP 2C9 O-demethyla- Glucoronide
metabolic P450 (CYP) 3A4 eserifictation tion conjugation
pathway 2C9
Elimination 55 feces, 35 renal, 60 >97 biliary 8–12 renal and 10 renal, 20 renal, 33 renal and 67 7 renal and
(%) 42 urine, hepatic hepatic >80 80 hepatic hepatic 90 hepatic
15 hepatic
unchanged
Interactions No 10% decrease in 6–20% decrease No ~50% No No Delayed

with food bioavailability in bioavailability decrease absorption
in AUC (NS)
(NS)
Dose in No initial Initial dosage Use with No change in No No change No change in No change in
chronic liver dose caution dose change in in dose* dose* dose
disease adjustment dose*
Dose in No initial No change in No change in No change in No No change No change in No change in

chronic kidney dose dose dose dose change in in dose dose dose
disease adjustment dose
ANGIOTENSIN RECEPTOR drugs for clinical effects beyond blood pressure control,
BLOCKERS: BEYOND BLOOD PRESSURE potentially counteracting cardiac hypertrophy, cardiac
fibrosis and insulin resistance, along with enhanced
LOWERING EFFECTS
renoprotection and atherosclerotic plaque stabilization.
ARBs could decelerate the progression of diabetic
nephropathy, independently of their BP lowering effect.
ARBs may be more effective clinical utility over other class TOLERABILITY
of drugs in reducing proteinuria in patients with diabetic Azilsartan at dosages of 20, 40 or 80 mg once daily,
nephropathy despite similarly induced reductions in are, in general favorably tolerated by adults, for the
BP. AT1R blockade may help to modulate diabetes- management of hypertension, over a period of up to 24
induced vascular remodeling, probably independently weeks, as indicated by the results of three RCTs. Studies
of BP lowering. Very high affinity and slow dissociation suggested that the tolerability profile of azilsartan was
from the angiotensin 1 receptor (AT1R) combined with like that of placebo in the two 6-week trials, the most
its inverse agonistic properties make them promising frequently encountered adverse events were headache
CHAPTER 3: Azilsartan: A New Baby in Old Horizon 19
and dizziness. Increase in serum creatinine of ≥50% angiotensin (1–7) which acts on the Mas receptors
above baseline was observed in ≤1.1% of patients, which (present in cardiac muscles) resulting into vasodilatation,
was reversible upon discontinuation. No elevations in antihypertrophy thus cardioprotection with BP
serum potassium levels (>6.0 mmol/L) was detected in lowering. Azilsartan even reduces levels of 20-HETE (a
any of the study participants.1,2 prostaglandin metabolite) thus leading to vasodilatation,
BP lowering and renoprotection. Azilsartan reduces
DIRECT AT1R EFFECTS OF AZILSARTAN expression of NHE3 sodium transporter in proximal
Azilsartan possesses a very high selectivity 39,000 times tubules and improves salt sensitivity.
greater for the AT1 receptor than for the AT2 receptor. Azilsartan, could likely be the very potent AT1
It also depicted a potent ability to inhibit the binding receptor blocker known till date, due to strong binding
of angiotensin II to human AT1 receptors (IC50 values properties, which allows it tooffer 24-hour BP lowering
>30–1000-fold lower for azilsartan compared to other effect; this seems to be significantly more than maximum
ARBs including telmisartan, olmesartan, valsartan and approved doses of other ARBs such as olmesartan,
irbesartan. Time course studies of the ability of different valsartan, and candesartan; however, it remains to be
ARBs to persistently block angiotensin II binding to AT1 determined whether azilsartan will offer further clinical
receptors after drug washout have also indicated that benefits beyond those afforded by its robust ability to
azilsartan dissociates from AT1 receptors more slowly inhibit the renin angiotensin system and lower BP.
than other ARBs including olmesartan, telmisartan, and
valsartan. As azilsartan bound tightly to and dissociated AZILSARTAN: PLEIOTROPIC EFFECTS
slowly from AT1 receptors compared with conventional BEYOND BP LOWERING
ARBs, azilsartan is expected to be a desirable ARB,as it Several recent preclinical studies indicated that azilsartan
not only shows superior BP control compared with other may have beneficial effects on cellular mechanisms
ARBs but also improves insulin resistance in preclinical related of morbid cardiometabolic processes, through
studies. Study even demonstrated that azilsartan induces actions mediated beyond just blockade of AT1 receptors
stronger inverse agonism than candesartan, and this and/or reduction in BP.4
ability of azilsartan may be associated with its unique Azilsartan, when compared with conventional ARB,
moiety, a 5- oxo-1,2,4-oxadiazole, in place of a tetrazole including candesartan, valsartan or olmesartan, in a
ring.3,4 study that compared the efficacy and tolerability of
azilsartan to candesartan, 622 Japanese patients with
AZILSARTAN: POTENT AT grade I-II essential hypertension were included. Blood
1 RECEPTOR BINDING reduction was superior with azilsartan medoxomil,
Major International and Indian guidelines on compared with candesartan. Similarly, azilsartan was
hypertension recommended ARB as a 1st line treatment found to be more effective than candesartan for its effect
for hypertension. Azilsartan a long-acting and more on ambulatory blood pressure at 14 weeks, particular
potent ARB provides a 24-hour potent and sustained improvements in diastolic and systolic BP over a 24-h
antihypertensive effect, which plays a role in its greater period. Azilsartan indicated to possess maximal pressor
blood pressure lowering efficacy. Novel Sartan azilsartan, effect of angiotensin II by approximately 90% when the
angiotensin receptor blocker approved in US and Europe, drug reaches peak plasma concentration. Twenty-four
is now available in India. Multimodal action azilsartan hours after administration, azilsartan lowers the pressor
acts on the RAS system at AT1 receptor, thus selectively effect by approximately 60 percentage.
and competitively inhibiting angiotensin II and resulting In another study, azilsartan 40–80 mg were compared
into vasodilatation and sodium/fluid excretion and with valsartan 320 mg during 24 weeks of treatment. At
lowering BP. Azilsartan increases levels of the metabolite the end of the study, 24-h mean SBP was reduced by 14.9,
15.3 and 11.3 mm Hg, respectively; p < 0.001 for both rationale behind use of renin-angiotensin system (RAS)
doses of azilsartan vs valsartan. blockers as antihypertensive therapy for protection
Azilsartan has also been compared in a clinical trial against hypertensive-based organ damage. However,
with olmesartan, one of the most potent available ARB RAS blockers have been perceived as unfavorable
until the launch of azilsartan. The study that included for the treatment of salt-sensitive hypertension. The
1,275 patients diagnosed of hypertension, with baseline antihypertensive effects of RAS blockers seem to be
24-h mean ambulatory systolic BP ≥ 130 and ≤ 170 mm attenuated under high salt loading in hypertensive
Hg (mean 146 mm Hg). Six weeks after treatment, as patients. Interestingly, RAS blockers have even been
anticipated, there wasa dose-dependent reduction in reported to enhance salt sensitivity. The analyses of renal
24-h mean SBP across all azilsartan groups. Azilsartan 80 tubular sodium transporters showed that azilsartan
mg provided superior reductions in 24-h mean SBP than reduced the expression of protein NHE3 (but not at the
olmesartan 40 mg (treatment difference -2.1 mm Hg; 95% transcriptional level) and did not alter protein expression
CI -4.0 to -0.1 mm Hg; p = 0.038).5 of the downstream transporters NKCC2, NCC, or ENaC.
Results of a pooled analysis of 3821 patients, derived Such, decreased NHE3 expression resulted in natriuresis.
from three different RCTs comparing the effects of These findings indicate that azilsartan (which strongly
azilsartan (40 and 80 mg), olmesartan (40 mg), valsartan blocks the effect of angiotensin II) reduces NHE3
(320 mg), and placebo on changes in ABPM and in-clinic expression and thereby, improves salt sensitivity.7
blood pressure (BP) among patients with hypertension
and prediabetes mellitus or T2DM suggested that AZILSARTAN: POTENTIAL EFFECT IN
azilsartan 80 mg/day lowers SBP by a significantly greater
CARDIORENAL PROTECTION
magnitude than olmesartan or valsartan at maximally
Data from seven randomized, double-blind, controlled
approved doses in patients with prediabetes mellitus and
trials indicate that azilsartan lowers BP in 3672 patients
T2DM.6
with mild, moderate or severe hypertension. Several
Preclinical studies are suggestive that treatment with
azilsartan completely antagonized the elevation of BP preclinical studies and in vitro experiments show that
induced due to ANG II, reduced the progression of cardiac azilsartan has shown beneficial effects on cellular
hypertrophy, attenuated kidney damage, and increased mechanisms of cardiovascular disease and possible
ANG (1–7) and EET/DHET ratio while diminishing 20- action on insulin sensitivity. In one of the preclinical
HETE levels. Increased ANG (1–7) and EETs levels point studies conducted on obese insulin-resistant mice fed a
towards novel therapeutic mechanisms contributing high fat diet, with left ventricular pressure overload after
towards antihypertensive and antihypertrophic actions aortic banding, the addition of azilsartan was associated
of azilsartan treatment and their relative role compared with a reduction in left ventricular wall thickness and
to AT1R blockade may depend on the underlying cardiac plasminogen activator inhibitor- 1 (PAI-1),
pathophysiology in each case of hypertension.7 as well as with an increase in cardiac output. After
Salt sensitivity was found in 51% of patients with myocardial infarction (MI), overexpression of PAI-1 in
hypertension and 26% of normotensive individuals. the heart may lead to negative left ventricular modelling
Such patients may have a greater tendency to manifest and heart failure. Inhibition of the AT1 receptor may
cardiovascular and renal events compared to non-salt- potentially blunt expression of the PAI-1 protein in the
sensitive patients, and present with a 3-fold higher wall of the aorta, subsequently reducing the threat of
incidence of cardiovascular events, again associated with atherosclerosis, a significant cause of morbidity and
increased mortality independent of blood pressure. The mortality globally.
Guidelines Recommendations on TABLE 2: ACE- I and ARBs should not be used or used with caution
in certain circumstances
Management of Hypertension Secondary
ACE inhibitors (ACE- I) Angiotensin receptor
to Renal Impairment blockers (ARBs)
European Society of Cardiology (ESC) Hypertension To use with zz Women planning to zz Women planning to
Management Guidelines 2016 caution conceive conceive
zz Bilateral renal artery zz Bilateral Renal Artery
An angiotensin receptor blocker (ARB), where
stenosis Stenosis
tolerated, should be included as first-line therapy in zz Drugs which cause zz Drugs which cause
view of the evidence of superior protective effects hyperkalemia Hyperkalemia

zz Angioedema to ACE-I
against development and progression of nephropathy
ARBs are particularly useful in reducing left Do avoid use zz Pregnancy zz Allergy to ACE-I or ARB
ventricular hypertrophy, microalbuminuria and zz History of allergy zz Pregnancy
to ACE-I or ARB zz Cough with use of ARB
proteinuria, preserving renal function and delaying zz Cough due to ACE-I
progression towards advanced stage of renal disease.
In most patients, the ACE inhibitor or ARB can be

Eighth Joint National Committee JNC VIII

continued if:
CKD: Antihypertension treatment regimen should
—— GFR decline over 4 months is <30% from baseline
include an either ACE inhibitors (ACE-I) or
value (B);
angiontensin receptor blockers (ARBs)
—— Serum potassium is ≤5.5 mEq/L
In individual >18 years with CKD, initial (or add-on)
ACE- I and ARBs should not be used or used with
antihypertensive treatment should include an ACEI
caution in certain circumstances, as Table 2.
or ARB to improve kidney disease outcomes. This
may apply to all CKD patients with hypertension In accordance to US FDA approved prescribing
secondary to diabetic kidney disease (DKD) information, dose adjustment is not required in patients
with mild-to-severe renal impairment or end-stage
American Society of Hypertension/International renal disease (ESRD). A possible explanation for this
Society of Hypertension (ASH/ISH) is that azilsartan is metabolized into two primary
Hypertension and chronic kidney disease (CKD): First metabolites M-I and M-II, both M-I and M-II of which
Drug-ARB or ACE inhibitor. are pharmacological inactive. Following an oral dose of
14
C-labeled azilsartan, approximately 55% of radioactivity
Indian Guidelines of Hypertension could be traced in feces and approximately 42% in urine,
Reduction of proteinuria can be achieved by effective with approximately 15% of the dose excreted in urine in
blood pressure control specially with use of ACE azilsartan form. As per data available on Cmax and AUC
inhibitors and angiotensin II receptor blockers (ARBs). of azilsartan are not significantly affected by mild to
moderate renal impairment.
Recommendations from the Kidney Disease The exposure to candesartan is slightly increased
Outcomes Quality Initiative (KDOQI) Guidelines for with mild to moderate renal impairment and almost
Treatment of Hypertension Associated with Chronic doubles in patients with severe renal impairment
Kidney Disease and those individuals undergoing hemodialysis. C max
ACE inhibitors and ARBs can be used safely in most and AUC of Eprosartan increase by 30–50% and by
patients with CKD. 70–90% with moderate to severe renal impairment.
Pharmacokinetics of irbesartan are unaffected in patients in these patients; where calcium channel blockers
with renal impairment or in patients on hemodialysis. (CCBs) are contraindicated due to their severe adverse
Irbesartan is not excreted by hemodialysis and no effects. Thus, switching to azilsartan might improve
dosage adjustment is required insuch patients. The the long-term prognosis of hemodialysis patients.
plasma concentrations and AUCs of losartan and Strong antihypertensive effects of azilsartan stems
EXP3174 are increased by 50–90% in patients with from a combination of ARB class-effect and stronger
mild or moderate renal insufficiency, and the renal suppression of the sympathetic nervous system. It was
clearance is reduced by 55–85% for both losartan and noted that, switching from olmesartan to azilsartan did
EXP3174 in such patients. The serum concentrations not modify serum sodium or serum potassium levels.
of olmesartan were prominently increased in patients There were no cardiovascular events during 9-month
with renal insufficiency, as compared to subjects with follow-up after switching to azilsartan.
normal renal function. Consistent with the virtual lack
of renal elimination of telmisartan, dose adjustment is SUMMARY OF THE UNIQUE FEATURES
not necessary in patients with reduced renal function. OF AZILSARTAN
Telmisartan by hemofiltration is not eliminated from Azilsartan produces greater affinity for AT1 receptor
blood. The exposure to valsartan (measured by AUC) blockade compared to several other angiotensin
apparently does not correlate to renal function in II receptor antagonists, including valsartan and
patients with different degrees of renal impairment. olmesartan
Consequently, no dose adjustment may be necessary in Azilsartan is known to demonstrate pleiotropic
patients with mild-to-moderate renal dysfunction.
cardioprotective effects, independent of its blood
The mortality rate for hemodialysis patients is 20%
pressure lowering effect.
during the first year of treatment and advances up to70% Pharmacokinetic profile permits for use as once-
post five years of treatment. Cardiovascular disease is
daily oral administration regime, making it a patient
high pervasive and a leading cause of morbidity and
compliant therapy.
mortality in hemodialysis patients, since hemodialysis
Efficacious in reducing 24-h mean systolic blood
patients possess several risk factors. It has been reported
pressure (SBP) compared to maximum approved
that treatment with antihypertensive drugs should be
dosages of olmesartan or valsartan
considered for patients on dialysis to reduce the very
Generally, well tolerated, most common adverse
high cardiovascular morbidity and mortality rate in
effects being headache and dizziness.
this population group. Measurement of blood pressure
is critical in hemodialysis patients, because disparate
REFERENCES
reading is obtained based on the timing, location,
1. Michel MC, et al. A systematic comparison of the properties
frequency, and technique of BP measurement. Azilsartan of clinically used Angiotensin II Type 1 receptor antagonists.
is a new ARB, and may help to reduce cardiac mortality Pharmacol Rev. 2013;65:809-48.
rates in hemodialysis patients. 2. Perry CM. Azilsartan Medoxomil. A Review of its Use in
Research indicates that switching from olmesartan to Hypertension. Clin Drug Investig. 2012;32(9):621-39.
azilsartan significantly decreased home-measured BP in 3. Miura S, et al. Unique binding behavior of the recently
approved angiotensin II receptor blocker azilsartan
hemodialysis patients with left ventricular hypertrophy
compared with that of candesartan. Hypertens Res.
(LVH). Switching did not alter serum potassium levels.
2013;36(2):134-9.
It is also reported that renin angiotensin blockade is not 4. Kurtz TW, et al. Differential pharmacology and benefit/risk
associated with hyperkalemia in patients on dialysis. of azilsartan compared to other sartans. Vascular Health
Azilsartan seemed to be useful for blood pressure control and Risk Management. 2012;8:133-43.
5. Barrios V, et al. Azilsartan medoxomil in the treatment of 7. Hatanaka M, et al. Azilsartan Improves Salt Sensitivity
hypertension: the definitive angiotensin receptor blocker?. by Modulating the Proximal Tubular Na+–H+ Exchanger-3
Expert Opin. Pharmacother. 2013;14(16):2249-61. in Mice. PLoS ONE 2016;11(1):e0147786.doi:10.1371/
6. White WB, et al. Effects of azilsartan medoxomil compared journal. pone.0147786.
with olmesar tan and valsar tan on ambulator y and 8. Carroll MA, et al. Azilsartan Is Associated with Increased
clinic blood pressure in patients with type 2 diabetes Circulating Angiotensin-(1–7) Levels and Reduced
and prediabetes. Journal of Hypertension. 2016;34: Renovascular 20-HETE Levels. American Journal of
788-97. Hypertension. 2014;1-8. doi:10.1093/ajh/hpu201.
CHAPTER
4
Hypertension and Menopause
Anuj Maheshwari, Shipra Kunwar
Hypertension is the most common chronic disease activation of rennin–angiotensin (RA) pathway which
and the most important risk for cardiovascular disease. could be genetic in origin as rennin angiotensin gene
According to WHO report (2012) one in every three polymorphisms have been seen in women, or could be
adult above the age of 25 years in the world is suffering because of increase in plasma renin activity.
from hypertension. .With increasing age, there is an Postmenopausal women have a rise in endothelin
increase in blood pressure for both men as well as levels. The loss of sex hormones or a change in estrogen to
women. However, after menopause the increase in androgen ratio can be responsible for this rise. Although,
blood pressure is almost abrupt with premenopausal the activation of RA axis may also be responsible.
women having an incidence of hypertension of 1.5% as Whatever, the cause elevated endothelin levels do
compared to postmenopausal women having incidence contribute to oxidative stress (Fig. 1).
of 41%. In 1976, the Framingham investigators reported
a 2.6-fold higher incidence of cardiovascular events in
age-matched postmenopausal women compared with
premenopausal women.
Besides the increase in prevalence of hypertension
after menopause the pattern of hypertension is also
different in women with lesser fall of BP during night
hours leading to more target organ complications, also
the control of blood pressure may not be as effective
in females as compared to males even with the same
medication. This protective effect of sex hormones is not
clear completely, in fact it is multifactorial.
ROLE OF OXIDATIVE STRESS

AND VASOCONSTRICTORS
Estrogen has been shown to increase expression of
superoxide dismutase and inhibit NADPH oxidase
activity, thereby reducing oxidative stress. There is Fig. 1: Mechanism of hypertension in menopausal women
CHAPTER 4: Hypertension and Menopause 25
Loss of estrogen at any age contributes to endothelial Is Postmenopausal Hypertension

dysfunction, which is common in individuals with Preventable?
hyper tension. Women w ith premature ovar ian From the above discussion, one may come to the
failure exhibit reduced brachial FMD (Flow Mediated conclusion that supplementing estrogen may lead to
Vasodilatation). Altered FMD is prognostic of coronary protection against hypertension and cardiovascular
artery disease risk factors, including hypertension. disease. This was initially suppor ted by some
Inflammation has been shown to increase BP. Menopause observational studies but later had been disapproved by
is associated with increase in c-reaction protein. There randomized controlled trials.
have been report that levels of TNF α and 11-6 correlated Hormone therapy (HT) is currently not recommended
well with insulin resistance and hyperglycemia in women for coronary protection in women of any age. Initiation
with polycystic ovary. Arachidonic acid is converted to of HT by women ages 50–59 years or by those within
epoxy eicosalrenoic acids by epoxygenases or 20-HETE 10 years of menopause to treat typical menopausal
by omega-hydroxylase. There are preliminary report in symptoms does not seem to increase the risk of CHD
postmenopausal rat model that suggest that 20-HETE events. However, there is emerging evidence that the
may be contributing to postmenopausal hypertension. initiation of ET in early post menopause may reduce
coronary artery disease and CHD risk.
Sympathetic Overactivity
It is also seen in postmenopausal women. Increased Endothelial Dysfunction
body weight leads to increased sympathetic activity E n d o t h e l i a l d y s f u n c t i o n o c c u r s w i t h re d u c e d
and increased leptin level, which further activates vasodialators modulating tone of blood vessels
melanocortin 4 receptors causing a rise in blood pressure. contributing hypertension and atherosclerosis. This
Aging also causes an increase in insulin resistance and may be one of the possible mechanism through which
metabolic syndrome thereby increasing leptin levels estrogen deficiency causes hypertension. One unit
reduction in flow mediated dialation (FMD) increases
and leading to increased prevalence of cardiovascular
the risk of hypertension by 16%. This can be measured by
disease in postmenopausal women.
high resolution ultrasound. Flow mediated dialation in
postmenopausal women declined most when compared
Role of Obesity and Fat Distribution
with men (P<0.01) and premenopausal women
Menopausal women are three times more likely to
(P<0.001). Endothelium dependent vasodialation mostly
develop obesity. The fat distribution also changes
mediated by acetylcholine, decreases with advancing
after menopause with increase in abdominal fat rather
age in hypertensive women as compared to lesser
than subcutaneous fat. Weight that accumulates in
decline in premenopausal females and males. On other
the abdomen is associated with higher incidence of hand, endothelium independent vasodialation with
cardiovascular disease than weight that is accumulated nitropruside has not been shown to affected by age
in the lower body. or gender. Importantly in normotensive women, age
related endothelial dysfunction has been seen only after
Depression and Anxiety menopause. After oophorectomy, otherwise healthy
Women also tend to have higher anxiety and depression. women face acute shortage of estrogen which causes
This form of chronic mental stress may lead to loss of endothelium dependent vasodialation due to
development of hypertension. Individuals with bipolar lack of nitric oxide (NO). Estrogen therapy improves
disorder have an increased risk of hypertension. This it, not only after oophorectomy but also in case of
shows that anxiety and depression may be linked to natural menopause. However, in a larger number of
development of hypertension. postmenopausal females, hormone replacement therapy
improves flow mediated dialation (FMD) only in those reduces bioavailability of nitric oxide, which is
women who do not have cardiovascular risk factors. responsible for salt sensitivity of systolic blood pressure
in otherwise healthy postmenopausal females who are
Arterial Stiffness not taking hormone replacement therapy. Estradiol
Though, few investigators did not find gender variation reduces salt sensitivity of BP in postmenopausal females.
in arterial wall properties with advancing age. In Low sodium diet has been found to benefit both in
females, it has been found coinciding with menopause. experimental as well as in real world too. Exercise
Postmenopausal women shows higher carotid-femoral also plays a positive role in reducing hypertension in
pulse wave velocity and larger common carotid artery association with low sodium diet.
diameters reflecting greater arterial stiffness which is self
explanatory of high rise of systolic pressure even after Genetic Factors
adjusting it for age, body mass index and smoking. Hypertension is a polygenetic disorder contributing
30–50% blood pressure variability among individuals.
Renin-angiotensin System Human hypertension has been studied for gender
Renin-angiotensin system (RAS) regulates blood specific associations with polymorphisms of component
pressure, fluid and electrolytes. Estradiol is conspicuous of RAS, aldosterone synthase and nitric oxide synthase.
of reducing activity of angiotensin 1-converting enzyme Menopause only provides a trigger in females having
(ACE) by AT1 receptor expression in vessels and kidney. higher probability of being hypertensive for genetic
Thus it gives cardiovascular protection by controlling reasons. Polymorphic genes regulating sodium
component of RAS. Role of RAS in hypertension of
absorption, like adducin-1 have been associated with
postmenopausal women is not very clear. Two years
blood pressure and hypertension. Gene environment
of estrogen therapy could not correlate blood pressure
interaction is shown in BMI and salt intake also. Gender
with plasma rennin activity in a placebo controlled
specific contribution of estrogen to hypertension is
study. Plasma rennin activity increased on oral but
genetic factor.
not on transdermal administration of estradiol. In fact,
Hereditary hypogonadotrophic ovarian failure
some studies has shown decreased activity also. Ovaries
is caused by inactivation of mutations occurring in
start producing prorenin in response to gonadotropin,
follicular stimulating hormone receptor (FSHR) gene
thus it regulates prorenin and rennin activity. Effect
which is also linked to essential hypertension in women.
of estrogen on prorenin and rennin seems complex
Gene-gender and gene-environment interactions have
and antihypertensive drugs which inhibit the RAS,
significant impact on hypertension in women where
complicate it further.
menopause is simply an environmental trigger.
Salt Sensitivity
Postmenopausal women are more salt sensitive. It is
HYPERTENSION: THE KEY RISK
caused by lack of vasodilation of the renal circulation FACTOR DURING MENOPAUSE
that occurs possibly due to less availability of nitric oxide Plenty of evidences are there, estrogen level before
(NO), more vasoconstrictor response to angiotensin menopause does not allow atherosclerosis to progress.
II or sometimes there may be diminution of l-arginine In this way, high estrogen level protects women from
conversion to nitric oxide in vascular endothelium hypertension and CV risks. Certain risk factors like
of kidney. It increases with age in both the genders. smoking, insulin resistance and diabetes withdraws this
Postmenopausal women are more salt sensitive than estrogen mediated cardiovascular protection in women.
premenopausal women. It is also seen in surgical Young women with estrogen deficiency have more
menopause. Presence of asymmetrical dimethyl-L- than seven fold higher risk of cardiovascular diseases
arginine with increased level of NO synthase antagonist due to development of coronary artery sclerosis. As
CHAPTER 4: Hypertension and Menopause 27
endogenous estrogen level declines with increasing achieve goal. Among diabetics only 21% achieved goal.
age especially after 40 years when reaching close to These results were due to inadequate treatment as most
menopause, they develop atherosclerosis with fibrous of the women were taking only one antihypertensive
cap formation. Carotid intima media thickness remains medication. Multidrug therapy may be necessary at
an important tool to diagnose subclinical atherosclerosis this age of women which should be added to life style
especially in women before menopause having multiple modifications like low sodium diet and exercise.
risk factors for coronary artery disease. After menopause,
atherosclerosis gets more extensive with inflammation CONCLUSION
and calcification of vessel wall. Cardiovascular events Hypertension in postmenopausal age group is significant
mostly occur in women after 63 years of age. In presence medical problem responsible for adverse cardiovascular
of advanced atherosclerotic disease, significantly outcomes. It is multifactorial. In spite of being good
decreased expression of estrogen receptor alters vascular compliance in women, level of hypertension control is
wall biology. Although estrogen dilates endothelium not better. There should be strategies to increase public
of vessel wall in healthy condition but its replacement awareness for hypertension and its adverse outcomes in
has serious side effects in diseased atherosclerotic postmenopausal women.
vascular wall. It activates inflammation and produces
vasoconstrictive factors, which makes atherosclerotic BIBLIOGRAPHY
plaque unstable. Early adverse CV events have been 1. Coylewright M, Reckelhoff JF, Ouyang P. Menopause and
observed after hormone therapy in randomized trials. hypertension an age-old debate. Hypertension. 2008;Part
II;952-9.
HOW SHOULD IT BE TREATED? 2. Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza
S, Munusamy S, Smith G, Stec DE. Obesity-induced
Cardiovascular risk assessment should be first thing to hypertension: role of sympathetic nervous system, leptin,
do, while managing hypertension in postmenopausal and mela- nocortins. J Biol Chem. 2010;285(23):17271-6.
women. Most of the women develop hypertension in 3. h t t p : / / w w w . e u r o . w h o . i n t / e n / h e a l t h - t o p i c s /
their lifetime. Those who become hypertensive in their noncommunicable-diseases/diabetes/news/news/
early life, carry high cardiovascular adverse event risk. 2012/5/world-health-statistics-2012-report-increase-of-
In women, prevalence rises steeply after middle age. hypertension-and-diabetes accessed on 26/9/2017.
4. Kurtz EG, Ridker PM, Rose LM, Cook NR, Everett BM,
One third perimenopausal women free of cardiovascular
Buring JE, Rexrode KM. Oral postmenopausal hormone
disease develope hypertension in next ten years. The therapy, C-reactive protein, and cardiovascular outcomes.
50% of the women at high normal blood pressure Menopause. 2011;18:23-9.
become hypertensive in five years. Women with clear cut 5. Maheshwari A , Maheshwari B. Hyper tension and
hypertension at baseline have higher CV risks followed menopause. Hypertension J. 2017;3(1):23-6.
by women at high normal compared with normotensive. 6. Mass AHEM, Franke HR. Women’s health in menopause
with a focus on hypertension. Netherlands Heart Journal.
Sy s t o l i c hy p e r t e n s i o n i s p re d i c t o r o f a d v e r s e
2009;17(2):68-72.
cardiovascular events in those older than 50. Treatment 7. Rossi R, Nuzzo A, Origliani G, Modena MG. Prognostic role
of systolic hypertension avoids stroke, myocardial of flow-mediated dilation and cardiac risk factors in post-
infarction, CHF and death. Lifestyle modifications like menopausal women. J Am Coll Cardiol. 2008;51:997-1002.
low sodium diets decreases blood pressure. Strategies to 8. The 2012 Hormone Therapy Position Statement of The North
delay the development of hypertension in women can be American Menopause Society Menopause. 2012;19(3):257-
71. doi: 10.1097/gme.0b013e31824b970a
of larger public health benefit. Most of the women keep
9. Xing D, Nozell S, Chen YF, Hage F, Oparil S. Estrogen and
their blood pressure high despite treatment. Many of the
mechanisms of vascular protection. Arterioscler Thromb
women in postmenopausal age group are not recognized Vasc Biol. 2009;29(3):289-95.
and treated or treated inadequately. In a study, only 52% 10. Yanes LL, Reckelhoff JF. Postmenopausal hypertension
were found to receive medication but only 36% could Am J Hypertens. 2011;24(7):740-9.
CHAPTER
5
Renovascular Hypertension: Current Status
Puneet Rijhwani
Renovascular hypertension (RVHT) is a repercussion of the most common cause of RVHT in children. Specially
the unusual relation between anatomically axiomatic significant is a study from south Asia that reported 87%
arterial occlusive disease and increased blood pressure. of the patients of renovascular hypertension to be due to
arteritis.
PATHOGENESIS
A low perfusion pressure that is created by constriction Age-related Demographics
of arteries is the main indicator of pathogenesis and Patients less than 30 years or more than 50 years are more
is sensed by the juxtaglomerular cells, located on the disposed to the onset of RVHT. Systemic hypertension is
afferent arteriole wall which act as baroreceptors, less frequent in children than in adults, but nevertheless
resulting in renin secretion. The biochemistry involves the incidence of hypertension in this group is around
the conversion of angiotensinogen to angiotensin I which 1–5%. Approximately 5–25% of cases of secondary
is done by the secreted renin. Angiotensin I is converted hypertension in children is attributed to renovascular
to angiotensin II in the lungs, a process mediated by disease.
Angiotensin Converting Enzyme (ACE).
Angiotensin II causes constriction of both efferent Sex-related Demographics
and afferent arterioles, but because of the smaller basal Younger women and older men are more susceptible to
diameter of the efferent arteriole, the increase in efferent
RVHT. Atherosclerotic disease is the most common cause
resistance is more significant than afferent resistance
(Fig. 1). Angiotensin II–causes release of vasodilatory
nitric oxide and prostaglandins that further reduces
afferent vasoconstriction. Angiotensin II also reduces the
surface area available for filtration through constriction
of the glomerular mesangium.
RENOVASCULAR HYPERTENSION:
MAJOR CAUSES
Epidemiology
Role of Arteritis
A number of reports from Asia have zeroed down upon
arteritis, either Takayasu’s arteritis or aortoarteritis, as Fig. 1: Control of intrarenal hemodynamics and RAAS
CHAPTER 5: Renovascular Hypertension: Current Status 29
of RVHT in older people and it mainly affects the proximal failure having eGFR <30 mL/min/1.72 m 2. Another
one-third of the main renal artery. While younger women noninvasive alternative is Duplex ultrasonography but
develop RVHT mainly due to fibromuscular disease is technically complicated and relies on the skills of the
which affects the distal 2/3rd of the renal arteries and its operator.
branches. Duplex ultrasound is extensively available and
makes a sound assessment of both functional and
Clinical Presentation anatomical aspects of stenosed renal artery and is quite
Headache seems to be the most common symptom of accurate in diagnosis in the setting of renal failure when
RVHT. Others include changes in visual acuity, vomiting, other tests are contraindicated or inconclusive. The
altered mental status, seizures, coma, encephalopathy, conventional color Doppler echocardiography is outrun
hyperexcitability, hyperirritability. Some present with by Galactose-based echocardiography-enhanced duplex
congestive heart failure symptoms. Failure to thrive is ultrasound that produces accurate images of the renal
a common presentation in young children with RVHT. artery.
Oliguric renal failure is also seen in some patients. Whether gadolinium-enhanced magnetic reso
nance angiography may be used an alternative to
Clinical Clues conventional angiography or as screening test, remains
Patients having ≥2 of the below mentioned clinical clues, to be established. Apart from limited availability, the
indicating RVHT, need to be thoroughly investigated: drawbacks of this investigation include:
Patients aged >55 or <30 years with acute onset or Segmental and accessory renal arteries are not
deterioration of hypertension control properly visualized

Hypertension resistant to ≥3 drugs Stenosis is commonly overestimated
Presence of an abdominal bruit Threat of nephrogenic systemic fibrosis in renal
ACE inhibitor or ARB associated increase in serum failure patients having eGFR <30 mL/min/1.72 m2
creatinine level ≥30% Costly.
Other atherosclerotic vascular disease, specifically in In the backdrop of a well documented and confirmed
smokers or having dyslipidemia anatomical stenosis, the following evidences might be
Hypertensive surges landing in recurrent pulmonary given for functionally significant stenosis
edema. >70% of the lumen area showing stenosis
> 21 mm Hg pressure gradient across the stenosed
DIAGNOSIS area
The appropriate test for diagnosing RVHT depends Lateralization of plasma renin activity in renal vein
majorly on the underlying clinical presentation (e.g. Doppler ultrasound indicating high arterial resistance
presenting with renal failure) and the locally available index

expert radiologists. Gold standard is selective renal Delayed accumulation and excretion of contrast on
angiography. IVP*
Alternative imaging techniques are CT angiography Renal blood flow is impaired on captopril renogram*
and MR angiography; as these are less invasive and *contraindicated in patients having eGFR < 30 mL/
commonly available, disadvantage is lower sensitivity min/1.72 m2).
and specificity, especially in suspected fibromuscular
dysplasia with middle or distal renal artery involvement Treatment
in which they might be falsely negative. Also, the risk Preservation of renal function and achieving good BP
of gadolinium-induced dermatofibrosis renders MR control is the main purpose of treatment in patients
angiography contraindicated in patients with renal having renal artery stenosis (Table 1). Currently, there
TABLE 1: Factors determining patient selection for revascu Points not Favoring Positive Response
larization
Post Revascularization
Atherosclerosis induced renal Aortic dissection
artery stenosis BP less than140/90 mm Hg on less than 3 anti
Fibromuscular disease Aortic endograft obstructing hypertensive drug regimen
zz Medial fibroplasia the renal artery Renal parameters are normal
zz Perimedial fibroplasia
zz Intimal fibroplasia
Unilateral contracted kidney (length <7.5 cm)
zz Medial hyperplasia
There is clinical evidence or history of cholesterol
Arterial embolus embolization
Other medical disorders: On Doppler ultrasonography renal resistive index is
zz Hypercoagulable state with
>80 mm Hg
renal infarction More than 1 gm/day proteinuria
zz Takayasu’s arteritis
zz Radiation induced fibrosis

Patient hypertensive for >10 years
Extrinsic fibrous band Tumor compressing the renal Stenosis of renal artery <70%
artery, e.g. pheochromocytoma
Renal trauma Polyarteritis nodosa
zz Page kidney (perirenal
MEDICAL MANAGEMENT
fibrosis) The treatment of renal artery stenosis primarily relies on
zz Segmental renal infarction
zz Arterial dissection
medical management. Angiotensin converting enzyme
inhibitors, ARBs and Calcium channel blockers are
convincing in blood pressure control in unilateral RAS
is an ongoing debate regarding management of patients
and may result in reducing the speed of progression of
with renal artery stenosis, both in terms of methods used
disease (class I, level B).
for revascularization and whether it is actually beneficial
Published data from many clinical trials call for
practically. In cases where target blood pressure control
cannot be reached or there is evident deterioration of augmentation of antihypertensive therapy and checking
renal function, strong recommendation is in favor of additional risk factors (good glycemic control, smoking
revascularization. cessation, use of aspirin, statins, etc.).
The major threat of drugs used nowadays resides
Points Favoring Expected Positive in the deterioration of renal function, especially when
Response Post Revascularization using an ACE inhibitor or ARB, which are useful
Recurrent “flash” pulmonary edema antihypertensives in 86–92% patients of RVHT, usually
Resistant hypertension despite patient on three drug when combined with a calcium channel blocker and a
regimen diuretic. Angiotensin converting enzyme inhibitors and
Unexplained, progressive deterioration of renal ARBs are generally tolerated well, with only around 5%
parameters requiring the drug to be discontinued during the initial
Acute, reversible increase in serum creatinine if on 3 months. More than 30% decrease in eGFR (or >0.5
ACE inhibitor or ARB drugs mg/dL increase in S. creatinine) may be indicative of
Requirement of dialysis recently in a patient suspected considering renal revascularization.
to be having ischemic nephropathy Bilateral RAS or renal artery stenosis in a single
On Doppler ultrasonography renal resistive index is functional kidney is a contraindication for using ACEI or
<80 mm Hg ARB.
CHAPTER 5: Renovascular Hypertension: Current Status 31
There is evidence that diuretics of thiazide group between 10% and 30%, which varied as per the type of
and other hypertensives like hydralazine, beta-blockers stenosis as well as the time duration of follow-up.
are also effective in controlling BP in patients with renal As per the latest ESC guidelines for the treatment
artery stenosis. of peripheral artery disease, in patients considered for
angioplasty, it is recommended that stenting should
SURGICAL REVASCULARIZATION be done in ostial atherosclerotic RAS (Class I, LOE
As the number of angioplasty procedures is on the rise B). Angioplasty, preferably with stenting, may be
so surgical revascularization is rarely used nowadays. conducted in cases who are symptomatic and have >60%
For technical and anatomic reasons, bypass procedures stenosis of renal artery resulting from atherosclerosis;
from nonaortic donor regions (hepatic, mesenteric, endovascular therapy of RAS to be considered to be
celiac, or splenic artery) are commonly used now a appropriate in patients with poor renal function. Balloon
days as compared to the renal endarterectomy and the angioplasty along with or without stenting, may be
aortic-renal bypass. Surgical modality may be indicated considered in RAS patients with unexplained repeated
for patients going for repair of the aorta, patients with congestive heart failure or sudden pulmonary edema
complicated anatomy of the renal arteries, or after and preserved systolic left ventricular function.
unsuccessful endovascular procedure (class IIb, level C).
A meta analysis of forty seven retrospective or Summary of Current Thinking on
nonrandomized studies was done. It compared the
Renovascular Hypertension
results in patients treated surgically verses patients
Altogether it is apparent that advances in medical
treated by endovascular procedures. In terms of technical
therapy, vascular imaging and endovascular procedures
success rates the outcomes were same, had better long-
have change d the s cenar io of management of
term control of blood pressure and renal function,
renovascular hypertension. Many cases presenting
with a slightly high perioperative mortality in surgical
simply as new-onset hypertension with normal renal
revascularization group (mainly because of concomitant
function can be treated with existing antihypertensive
aortic surgery).
medication, usually including drugs that act upon the
ANGIOPLASTY renin-angiotensin system. Renovascular disease being
an important predictor of cardiovascular risk requires
The preferred treatment modality is renal percutaneous
transluminal angioplasty (RPTA) when the cause of intensive therapy to reduce this risk by including aspirin,
RVHT is fibromuscular dysplasia. The restenosis rate is statins, tobacco cessation, glycemic and weight control,
around 5–11% at the end of one year postprocedure. in addition to blood pressure control. For patients with
Treatment of atherosclerotic renal artery disease by complex disease, deteriorating renal function, or those
this procedure is controversial, as trials conducted have who fail to respond to antihypertensive medications,
not shown significant clinical benefits. further diagnostic workup with a commitment to
T h e o re t i c a l l y a n g i o p l a s t y p l u s s t e n t i n g i s restoring renal perfusion may be required.
advantageous, especially when done at sites having high
tendency for restenosis. Four years follow-up study, BIBLIOGRAPHY
which was the widely studied experience published was 1. Abela R, Ivanova S, Lidder S, et al. An analysis
comparing open surgical and endovascular treatment of
from Durros et al. Patients were treated with a particular,
atherosclerotic renal artery stenosis. Eur J Vasc Endovasc
early renal artery stent. These patients documented a Surg. 2009;38:666-75.
significant control in blood pressure, a slight decrease 2. Black HR, Elliot WJ. Hypertension. A Companion to
in antihypertensive drugs required for BP control, and Braunwald’s Heart Disease. Second Edition. Elsevier
the overall mortality rate was 26%. Rate of restenosis was Saunders. 2013;8:69-79.
3. Durros G, Jaff M, Mathiak L, et al. Multicenter Palmaz stent 7. Rocha-Singh KJ, Eisenhauer AC, Textor SC, et al. American
renal artery stenosis revascularization registry report: Heart Association Atherosclerotic Peripheral Vascular
four-year follow–up of 1068 successful patients. Catheter Disease Symposium recommendations. Circulation
Cardiovasc Interv. 2002;55:182-8. 2008;118:2873-8.
4. Dworkin LD, Cooper CJ. Renal-Artery Stenosis. N Engl J Med. 8. Rosenthal J, Arlart I, Franz HE. Renovascular Hypertention.
2009;361:1972-8. In Rosenthal, Julian. Arterial Hypertension: Pathogenesis,
5. Gregory YH, John E. (2007-06-28). Comprehensive Diagnosis, and Therapy. Springer. 2012. pp. 201–202.
Hypertension. Elsevier Health Sciences. p. 101. ISBN ISBN 978-1-4612-5657-1.
9780323070676. 9. Safian RD, Textor SC. Renal artery stenosis. N Engl J Med
6. Hypertension Canada’s 2016 Canadian Hypertension 2001;344:431-42.
Education Program Guidelines for Blood Pressure 10. Stable patients with atherosclerotic renal artery stenosis
Measurement, Diagnosis, Assessment of Risk, should be treated first with medical management. Plouin
Prevention, and Treatment of Hypertension. Can J Cardiol. PF. Am J Kidney Dis 2003;42:851-7.
2016;32(5):569-88.
CHAPTER
6
Diuretics for Hypertension:
Review and Update
R Rajasekar
EFFECT OF LOW DOSE DIURETIC Organic anions transporters help in concentration

Many trials have shown low doses of diuretics are of thiazides in tubular lumen—finally → Delivered to
effective and safe in mild-to-moderate hypertension secretory regions of PCT
(HT). Hydrochlorothiazide (HCTZ) -12.5, Chlorthalidone Mostly, Onset of action thiazides is 2–3 hours with
(CTD) 12.5 and bendroflurazide 1.25 mg are effective little natriuretic effect beyond 6 hours
antihypertensives. CTD is more potent than HCTZ, as The metabolism, bioavailability and plama half life
many studies have shown. The low dose of HCTZ and are vaiable among thiazides. Bioavailability and Plasma
CTD have an advantage of less metabolic side effects. half life are vital as they decide the dose and frequency
Diuretics differ in molecular structure and site of of dosing.
action within the nephron. Though diuretics differ in Usually, a thiazide type diuretic acting on DCT (Distal
molecular structure the terminology thiazides include convoluted tubule) is started as an anti-HT. Though
all diuretics primarily acting in distal convoluted tuble. CTD and indapamide are structurally different they are
The site of action determines its efficacy and inhibiting thiazides like. If serum creatinine exceeding 1.5 mg/dL
reabsorbtion of sodium at different segments of renal a loop diuretic is used. Metalazone is also a thiazide like
tubular system thereby producing diuresis. The diuretics diuretic. A potassium sparring diuretic acting at DCT is
acting on proximal tubule are seldom used. to reduce hypokalemia. Potassium-sparing diuretic are
The pharmacokinetic effects of thiazides differ after weak.
oral absorption and they are distributed in the body
either equally or greater than body weight. Thiazides TYPES OF DIURETICS
are mainly bound to plasma proteins, thereby limiting HCTZ: About 12.5 mg as low as 6.25 to maximum 25
filtration by the glomerulus. This in turn trap the diuretic mg. Monotherapy/combination therapy (ACE/ARB/
in vascular space and make it available to secretary CCB) low dose of HCTZ prevents adverse metabolic
sites of proximal tubular cells of kidney. Organic anion lipid effects. Though it induces potassium loss/
transporters also help by concentrating thiazides in hypokalemia. It can be prevented by simultaneous
tubular lumen. prescription of ACE inhibitors/ARBs.
In a nutshell, Chlorthazide is lipid insoluble and so large doses
Thiazides → Trapped in vascular space are used to achieve the levels enough to reach the
(Bound to plasma proteins) real site of action. But hydrochlorthiazide has better
bioavalability—about 60–70% is absorbed and food cardiac preload and output. Long-term phase
intake hastens absorption. Some thiazides undergo is less reliably predicted. The continous
extensive metabolism and some remain unchanged antihypertensive of many thiazides is overall
and excreted almost intact in urine. reduction of systemic resistance. Though the
In HT patients 50% reduction of absorption is exact mechanism is less clear but CTD does not
observed so even after a year. It is not elusive about thiazide
CTD: 12.5 mg—prescribed in systolic hypertension exerting vasodilation or a reverse autoregulation
of SHEP study of elders. The dose can be increased property. Moreover, it is presumed. Thiazides
to 25 mg and is considered as good as alternative to may cause structural membrane changes and
CCB/ACE inhibitor in ALLHAT study But the risk of ion gradients. Another explanation is constant
diabetes and hypokalemia have to be checked. prescription of thiazides may keep a normal state
Bendroflurazide: It is also effective thiazide 24 hours of volume contraction, thus creating a downward
action-Dose—1.25 mg per day, and ameloride, transfer in vascular resistance.
potassium sparing diuretic is less effective. Diuretic tolerance: L ong and short-term
Indapamide: A modified thiazide. A lipid neutral adaptations are mainly due to have a protective
and standard thiagide. A vasodilating thiazide 2.5 effect on intravascular volume. Short-term
mg once daily. Now sustained release 1.5 mg is the tolerance is due to post-dosing of antinatruresis
standard dose. Potassium fall, blood glucose hikes initiated by reduction of extracellular fluid
and uric acid hikes are to be kept in mind. It induces volume. Renin angiotensin aldosterone and
regression LVH and is infact better than enalapril. sympathetic nervous system activation and
Loop diuretics for HT: suppression of secretion of atrial natriuretic
1. Frusemide is short acting and should not be peptide and renal prostaglandin are responsible
given and is not a fit routine antihypertensive for short-term tolerance. Dietary Sodium
drug, moreover, it has to be given twice a day. markedly influences post dose sodium retention.
Most thiazides have half life of 8–12 hours, so So dietary sodium restriction leads to negative
once daily dosing is possible. The thiazides CTD sodium balance and increases therapeutic
is long acting with half life of 50–60 hours due to response to thiazides. A continuous dietary
its extensive volume distribution. Almost 99% of sodium intake negativates this beneficial effect.
CTD is bound to erythrocyte cabonic anhydrase Long-term diuretic adaptation or breaking
and the drug has a strong inhibition action effect are due to return of sodium chloride to
than other thiazides. Thus, the marked binding electroneural level. A continous volume clearing
of chlorthalidone into erythrocyte carbonic seems to initiate prolonged activation of RAAS
anhydrase aptly by forming a tissue reservoir, resulting in circulating angiotensin 2 levels,
allowing constant CTD release back into plasma thereby promoting increased proximal sodium
thereby it exerts its effect beneficially. So this reabsorption, limiting final delivery of sodium
depot effect of CT has an advantage of once daily to distal region. The other volume independent
dosing. mechanism are uptitration of sodium
Pharmacodynamics: The hemodynamics of transporters downstream from primary region
thiazides are of two phases i.e. short- and long- of diuretic action and structural enlargement of
term phase. The first phase of reduction of blood distal Nephrons.
pressure is due to reduction of extracellular Tolerance is achieved by higher dosing or
fluid and plasma volume resulting in reduced combinations such as thiazide and loop diuretic
CHAPTER 6: Diuretics for Hypertension: Review and Update 35
to exert synergistic effect. But one has to be Excessive dietary sodium intake, real impairment,
careful of high doses and combinations to avoid food, NSAID may all cause resistance to natriuretic and
renal injury and electrolyte abnormalities. anti-HT action of diuretics.
Torsemide: It is tree of metabolic and lipid side
2.
effect but used in subdiuretic dose i.e. 2.5 mg or ABBREVIATIONS
even at a higher dose 5–10 mg being natriurectic DBP, Diastolic blood pressure
with risk of metabolic changes. SBP, Systolic blood pressure
ACEI, Angiotensin converting enzyme inhibitor
POTASSIUM-SPARING COMMON ARB, Angiotensin receptor blocker
COMBINATION DIURETICS BB, Beta-blocker
Though it is slightly costly, the diuretic induced CCB, Calcium channel blocker
hypokalemia and hypomagnesemia is prevented. DHP, Dihydro pyridine
By combination, risk of sudden cardiac death (SCD) CAD, Caronary artery disease
is reduced. Fixed dose combination of triamterene/ HT, Hypertension
ameloride with HCTZ is used. RAAS, Renin angiotensin aldosterone system
NSAID, Nonsteroidal anti inflammatory drugs
COMBINATION OF DIURETIC DM, Diabetes mellitus
WITH ANTI-HT DRUGS
Diuretic can be combined with all anti-HT (ACEs/ARBs/ BIBLIOGRAPHY
1. Ernst ME, Pharm D, Moser M. Use of diuretics in patients
beta-blockers) combination of ACE inhibitors, diuretics
with hypertension. N Engl J Med. 2009;361:2153-64.
can prevent hypokalemia. Combination of Indapamide 2. Kaplan NM. Kaplan’s Clinical Hypertension. (10th ed.).
with ACE inhibitors is ideal in elderly. Philadelphia, PA:Lippincott Williams & Wilkins. 2009.
3. Katritsis DG, Gersh BJ, Camm AJ. Clinical Cardiology
CONCLUSION Current Practice Guidelines (1st ed.). Oxford, UK: Oxford
Though metabolic side effects are like new onset of DM University Press. 2014.
4. Levine GN. Cardiology Secrets (4th ed.). Philadelphia,
especially at high doses. A low dose is ideal as an initial
United States: Elsevier-Health Sciences. 2013.
treatment especially in elders. It helps to reduce stroke/ 5. Opie L, Gersh B. Drugs for the Heart. (8th ed.). Philadelphia,
CAD in elderly thereby reducing mortality in mild-to- PA: Elsevier Saunders. 2013.
moderate HT.
CHAPTER
7
High Altitude Systemic Hypertension:
Unraveling the Mystery
INTRODUCTION Coronary heart disease and arrhythmias

Cerebral vascular disease.
Twenty-seven percent of earth’s surface is made of
mountainous region which accounts for approximately The minimally studied among the HAI is the commonly
39.5 million km2 of area. occurring High Altitude Systemic Hypertension (HASH).
High altitude (HA) is defined as an area 2500 meters
above sea level and its population is estimated to be EFFECTS OF HIGH ALTITUDE ON
around 98 million and if we add nearly 70 million visitors CARDIOVASCULAR SYSTEM
travelling to high altitude every year for recreational
Definition of HA
purposes and jobs it adds up to nearly 168 million people.
According to Rimoldi and co-workers, HA can be termed
Comparable to the rate of increase of HA tourism
as any upward descent from sea level at which oxygen
worldwide, India does not lag behind and HA tourism
– hemoglobin saturation falls below 90% - at moderate
continues to be on the rise in India also. Mountainous
latitude and this corresponds well to an altitude of 2500
terrains are inherently dangerous and all mountaineering
m.
human activities involve rigorous exercise in a definitive
To maintain adequate oxygenation of different
environment where the additive effect of the following
systems in body, HA induced hypoxemia induces a series
factors are noted:
Falling barometric pressure
of changes in cardiovascular and pulmonary circulation
Ambient hypoxia
(Fig. 1).
Temperature - humidity
These complex interactions in cardiovascular and
Enhanced effect of solar radiation
pulmonary circulation, heart rate, peripheral vascular
Increase in wind speed.
resistance, etc. and other changes in response to
hypoxemia of HA leads to HASH (High Altitude Systemic
All of above trigger a series of important physiological
Hypertension) which vary depending on acute or chronic
responses and consequently evoke a set of health/
exposure to HA and are tabulated below in Table 1.
medical problems known as High Altitude Illness (HAI)
such as
High altitude pulmonary edema
NEED FOR DEFINITION OF HASH –
High altitude cerebral edema
AND ITS PREVALENCE
Acute mountain sickness Exposure of healthy humans to hypoxia at HA leads
Chronic mountain sickness to pulmonary hypertension and changes in renin-
CHAPTER 7: High Altitude Systemic Hypertension: Unraveling the Mystery 37
Fig. 1: Effects of hypoxemia of high altitude on systemic and pulmonary circulation
TABLE 1 : Acute and chronic effects of hypoxia

Acute exposure Chronic exposure
Heart rate (HR) Increase in HR corresponds to enhanced High resting HR
sympathetic activity and subsequent vagal Further increase with increment in altitude.
withdrawal.
Peripheral Hypoxia either directly, or through its metabolic Total sympathetic activity is seen to increase with increasing
vascular effects, leads to vasodilatation in most vascular altitude and hypoxia and hence increasing peripheral vascular
resistance beds, consequently sympathetic tone needs resistance.
to be increased so as to reduce exaggerated
vasodilatation and hypotension.
Circulation During the very early exposure to HA, hypoxic Acclimatization associated with continued exposure to high altitude
vasodilatation scores over sympathetic leads to rise in oxygen level of the blood via:
vasoconstriction in the systemic circulation and zz Reduced plasma volume leading to rise in hemotocrit, and
net effect being either same or slight reduction in zz Exaggerated erytropoiesis causing increased red cell mass.
systemic blood pressure.

Coronary To compensate for hypoxemia induced reduced After 2 weeks at 3100 m, due to acclimatization there is increase in
circulation oxygen content of blood, there is rapid resting oxygen level of arterial blood and correspondingly a reduction in
myocardial flow due to dilatation of coronaries coronary blood flow. To maintain effective myocardial oxygenation
which maintains cardiac function upto 4500 meters there is increase in myocardial oxygen extraction per unit volume
above sea level. of blood.
Heart An increase in heart rate is an indicator of increased Stroke volume is decreased and maximal cardiac output falls –
cardiac activity which is compensated by decreased maximal rate of oxygen consumption remains reduced. Stroke
stroke volume on 1st day. Diastolic dysfunction is volume reduction is caused by reduced LV dimensions and filling
compensated for by an enhanced atrial contraction. pressures due to decreased plasma volume by 20% which is
mediated by:
zz Increased release of atrial natriuretic peptide.
zz Decreased synthesis of aldosterone.
zz By fluid shift from extracellular to intracellular compartment.
Contd...
Contd...
Acute exposure Chronic exposure

Systemic blood Increased adrenergic drive and functional Acclimatization caused increased sympathetic activity and decrease
pressure sympatholysis effects PVR which correlates with in tissue hypoxia and consequently reduced vasodilation leading to
HASH at HA. At HA, immediately there may be a gradual rise in both systolic and diastolic BP.
slight fall in BP, which starts rising in next few hours.
Ambulatory Ambulatory BP measurements show a diurnal zz Increase in ambulatory BP persists during prolonged altitude
blood pressure rhythm with marked rise in BP during the day exposure
accompanied by reduced nocturnal dipping in the zz Involves the day-time ABP values but is particularly pronounced
BP values. for the night-time ones, with a consequent reduction of the

nocturnal dipping phenomenon at the higher altitude.
Gaseous At HA, alveolar-arterial difference for oxygen is At HA, decreased driving pressure for oxygen from alveolar gas into
diffusion higher than would be predicted from measured arterial blood is insufficient to fully oxygenate blood as it passes
ventilation-perfusion inequality. through pulmonary capillary.
With more altitude-more sustained stay, exercise induced cardiac
output increases and blood spends less time at gas exchanging
surface (diffusion limitation).
Blood Initially at HA, hemoglobin concentration rises due As hemoglobin production-concentration rises, there is increased
to fall in plasma volume due to dehydration. Later, coagulability abd viscocity of blood and hence increased risk
hypoxia stimulates JGA of kidney for increased of stroke and venous thromboembolism. Neither aspirin nor
erythropoietin. So, hemoglobin production- venesection reduces incidence of venous arterial thrombosis.
concentration rises.
angiotensin system, elevated sympathetic activity and Association of HASH with deletion allele of angio
association of deletion allele of ACE gene leads to HASH. tensin-converting enzyme (ACE) gene
H A S H i s d e f i n e d a s p re s e n c e o f s u s t a i n e d
hypertension (>150/90 mm Hg, as per JNC criteria) in Role of Sympathetic Activation
low landers at HA (>2500 m). HASH can be categorized Role of ANS in controlling HR-CO is well established
as a type of secondary hypertension wherein prolonged Sensing of acute hypoxemia by peripheral-medullary
stay at high altitude acts as predisposing factor and chemoreceptors activates sympathetic nervous
thereby leads to long term morbidity, mortality caused system as reflected by increase in concentration of
by its effects on the human physiology. Exercise of any epinephrine- norepinephrine which leads to hypoxia
form or duration including daily activities at HA leads to induced tachycardia and hypertension.
further increase in systemic BP. Duplain et al, Rowell et al postulated that hypoxia
Prevalence of HASH is reported to be 28–62% in induced sympathetic activation is a defense mechanism
different studies. by which an increased cardiac output ensures proper
Interestingly, migratory population showed higher oxygen supply to critical organs.
prevalence compared to natives born there. Those exposed to chronic hypoxia also show
enhanced sympathetic activity as demonstrated by

PATHOPHYSIOLOGY OF HASH isotope dilution method and nor adrenaline spill
Seems multifactorial: over rate which indirectly determines systemic
Sympathetic activation sympathetic nervous system activity.
Role of increased er ythropoiesis and raised Nine Danish low landers who were healthy when they
hematocrit migrated from sea level to HA of 5620 m, underwent

Role of endothelial dysfunction measurement of systemic and skeletal muscle nor
Fig. 2: After 9 weeks of stay at 5260 m, arterial blood pressure (BP) measurements and systemic and 2-leg vascular conductance (VC)
compared with readings taken after 6–9 months of returning to sea level
Source: Adapted from Calbet JAL. Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans.
The Journal of Physiology. 2003;551(Pt 1):379-86.
adrenaline spill over after a week which proved the have been reset at a higher set point as seen in sleep
above hypotheis (Fig. 2). apnea syndrome patients.
Calbert et al showed 3.8 fold increase in whole body At HA, 15–20% fall in blood volume in circulation
nor adrenaline release. Compared to sea level, this occurs which leads to fall in cardiac filling pressures
observed sympathetic over activity was accompanied by and consequently reduced stimulation of low
decreased systemic vascular conductance and increased pressure baroreceptors. This nullifies negative
systemic blood pressure as shown in the above graph. feedback and leads to more sympathetic activation.
This approves the hypotheis that SNS plays significant Other factors which increased SNS activity responsible
role in pathogenesis of hypoxia induced hypertension. for HASH are:

Comparing the level of increased noradrenaline —— Enhanced viscocity of blood
release in response to chronic hypoxemia, vascular —— Fall in production of nitric oxide (NO)
conductance decreased only by 1/3rd which was far —— Increasing Hb (enhanced erythropoiesis) causing
less than the quantum of NA spill over. This postulates more NO scavenging.
that some hypoxia induced vasodilatory mechanism So, chronic hypoxia causes increased systemic arterial
blunts the action of NA and vascular smooth muscle pressure and massive activation of the sympathetic
response to vasoconstrictors in chronic hypoxia. nervous system in healthy humans, despite improved
We can postulate that severely increased sympathetic arterial O2 content with acclimatization.
activity, resting BP in response to prolonged
hypoxia in healthy humans have definitive clinical Role of Increased Erythropoiesis
implications. Despite marked rise in blood pressure and Raised Hematocrit
at HA continued increase in noradrenaline spillover As discussed above, though sympathetic stimulation
occurred at HA and it should have blunted further seems to be the primary reason for pressor response to
sympathetic activation through stimulation of HA, other mechanisms may be involved, many of which
baroreceptors. This physiological phenomenon can were investigated in HIGHCARE-HIMALAYA study.
only be explained if we presume that baro receptors During high altitude permanence, hematocrit levels
increased as a consequence of plasma-volume depletion

and later by hypoxic stimulation of erythropoiesis. In
turn an increased hematocrit leads to increased blood
viscocity, which increase peripheral vascular resistance
with subsequent increased blood pressure levels .
Relative importance of blood viscocity in the
determination of BP has been emphasized by the
evidence from studies in polycythemic patients
presenting with hypertension in whom decrease in blood
viscocity without altering blood volume (Isovolumic
hemodilution) causes discrenible fall in both clinic and Fig. 3: Renin-angiotensin-aldosterone system
ambulatory 24 hr blood pressure readings.
plays an important role in pathogenesis of hypertension
Role of Endothelial Dysfunction (Fig. 3).
In many high altitude illnesses other than HASH, role Molecular studies of hypertension concentrating on
of endothelial dysfunction as an etiology has been RAAS have identified a number of polymorphic proteins
well substantiated. Ultrasonographic and clinical in this system with their corresponding genetic loci.
determinants of endothelial dysfunction are: A substantial fraction of human blood pressure
Intimal media thickness (IMT)
variation is genetically determined. It is postulated
Flow mediated dilatation (FMO)
that hypertension-susceptibility genes insinuate in a
Intra-arterial ultrasonography (IAU)
definitive environment only.
Yanemandra Uday et al. in their research study There are two alleles in the ACE gene locus:
to define role of ED in HASH, found that endothelial 1. One with a deletion (D) allele
markers (SICAM and VICAM ) were increased in subjects
2. Other with an insertion (I) allele of 287 base pairs
with HASH compared to controls with comparative
within intron 16.
length of stay at high altitude. Following mechanisms
Those individuals with D allele are known to be
were postulated:
associated with increased ACE activity and those with I
Secondary to inherent effect of atherosclerosis.
allele have less ACE activity.
Effect of HA on unmasking underlying ED.
The association of the ACE D allele with systemic
Flow Mediated Dialatation (FMO) was also studied
hypertension has been shown in previous studies.
in a group of patients and it was found to be impaired in
A study was done by Ratan Kumar et al. to test
HASH patients.
the hypothesis on soldiers being posted at HA to test
ROLE OF ENDOTHELIN 1 whether they were potentially at greater susceptibility
of developing HASH and whether ACE gene I or D
An increase in Endothelin 1 level may also contribute to
polymorphism can be used as a genetic marker to
vasoconstriction-HASH.
identify such soldiers. 46 age matched healthy normal
Association of HASH with Deletion Allele male volunteers who had never been to high altitude and
of Angiotensin-Converting Enzyme (ACE) none was taking any antihypertensive medication were
Gene recruited in the study.
Renin-Angiotensin-Aldosterone system (RAAS) the Out of 46 volunteers 28 were normotensive and 18
primary regulator of plasma Na reabsorption by kidney, developed HASH.
Also, frequency of the ACE D allele was higher in AGEING, HIGH ALTITUDE AND BLOOD
volunteers who developed systemic hypertension at PRESSURE-A COMPLEX RELATIONSHIP
higher altitude i.e. HASH.
Advancing age promote to development of hypertension
Thereby a positive correlation of ACE D allele (which
by stiffening of large vessels, enhanced atherosclerosis,
is responsible for elevated ACE activity) was found with
impairment of arterial baroreflex and renal dysfunction.
HASH.
Evidence is less clear on whether to what extent,
In earlier study by the same authors and others, no
combined effect of advancing age and chronic hypoxia
significant association between ACE D allele and HASH
on exposure to high altitude for prolonged periods
was observed in various Indian populations (Gorkha,
influences the blood pressure (Fig. 4).
Sikh, Assamese, Dogras, Jats, Kumaonis and Yadavas)
Nowadays a very significant elderly low lander
when studied at plains (Kumar et al. 2001).
population migrates to high altitude for prolonged
S o t h e i n t e ra c t i o n b e t w e e n t h e g e n e s a n d
the environment plays very significant role in the periods of stay.
development of systemic hypertension at high altitude.
Thus presence of ACE D allele as a genetic factor
BLOOD PRESSURE CHANGES WITH
not expressed fully in previous enviorment predisposes AGING
a population to have elevated blood pressure when Lewington et al. 2002 indicated that aging is associated
exposed to a new enviorment such as HIGH ALTITUDE. with progressive increase in BP levels.
Fig. 4: Effects of aging and altitude in BP regulation

Abbreviations: CO, cardiac output; CV, cardiovascular; DBP, diastolic blood pressure; ET-1, endothelin-1; HA, high altitude; HIF-1: hypoxia
inducible factor-1; HR, heart rate; NO, nitric oxide; PP, pulse pressure; RAAS, renin angiotensin aldosterone system; SBP, systolic blood
pressure; SDB: sleep disordered breathing.
Source: Adapted from “Aging, high altitude, and blood pressure: A complex relationship” by Parati et al. High altitude medicine and biology.
2015;16:97-109.
Arterial system in youth is designed to receive spurts (PWVR) among dippers compared to higher ratios
of blood from LV to distribute this as steady flow through among nondippers.
peripheral capillaries. Factors of optical efficiency of Higher red cell distribution width (a phenomenon
vascular - ventricular interaction include: directly proportional to adverse cardiovascular
Greater distensibility of proximal than distal aorta outcomes) in nondippers compared to dippers.
Dispersion of peripheral reflecting sites Increased levels of asymmetric dimethyl arginine-
Location of heart in upper thorax (an indicator of oxidative stress) among non-
Inverse relationship between HR and body length. dippers compared to dippers.
As aorta ages it stiffens, aortic PWV (Pulse Wave Enhanced levels of mean platelet volume – an
Velocity) increases and tuning between LV and arterial indicator of platelet activation is higher among
tree is progressively lost. nondippers than dippers.
Exposure to high altitude is associated with
progressive reduction in central-peripheral pulse DIAGNOSIS OF HASH
pressure.
No set guidelines at present
Potential mechanisms of this include:
Diagnosis on the basis of JNC guidelines for
Reduction in stroke volume associated with hypoxia
diagnosing hypertension at sea level but the duration
triggered tachycardia
Increase in diastolic BP levels which is caused by
of stay at high altitude (>2500 m) should be for more
than 3 months in a person who was previously a low
an increase in vascular tone with increase in central
lander.
sympathetic stimulation of peripheral vasculature
Compared to conventional BP readings which
leading to increased PVR.
underestimate the BP effects of HA, ambulatory BP
HOW BP BEHAVES WITH AGING IN readings were found to be superior.
PEOPLE CHRONICALLY EXPOSED TO Absence of nocturnal dip in the BP due to increased
symphathetic activation attributed to exaggerated
HIGH ALTITUDE
reduction in SpO2 during sleep at high altitude is one
Course of vascular aging is different in subjects on
of the earliest markers of HASH.
exposure to chronic hypoxia at high altitude.
In various cross sectional studies when BP levels
were assessed as a function of age, highlanders exhibited
TREATMENT OF HASH
higher increase in BP levels with age as compared to low Being a new entity no set guidelines are available.
landers i.e. systolic BP of 0.75 vs 0.32 mm Hg/year and Based on the promising research following treatment
diastolic 0.32 vs 0.08 mm Hg. modalities are proposed.
IMPORTANCE OF RECOGNIZING HASH Role of Beta Blockers

HASH patients have elevated night time BP recordings Vasodilating beta blockers have shown good results in
as documented by various studies otherwise termed as controlling BP at high altitude.
nondippers.
According to long term observational studies, Role of Other Antihypertensives
compared to dippers, nondippers have worse outcomes Antihypertensive effects of Telmisartan observed at
of cardiovascular events. the sea level was preserved at an altitude of upto 3400
Following mechanisms have been documented: M but disappeared as the altitude increased to 5400
There is enhanced arterial stiffness in nondippers M. This is explained by suppression of RAAS at high
which is proved by low pulse wave velocity ratios altitude >5400 M. (High Care Himalaya Study)
TABLE 2: Role of carvedilol and nebivolol hemotocrit and hormonal realignments occuring in
Carvedilol Nebivolol subjects with conventional risk factors can predispose
Nonselective beta-adrenergic Competitive and selective beta1- them to HASH.
and alpha1-adrenergic receptor antagonist. The thin line dividing the rise in BP due to
blocking agent.
At high altitude carvedilol At high altitude nebivolol lost acclimatization and that due to pathologic process
fully maintains the BP- some of the antihypertensive causing morbidities needs to be defined.
lowering effect achieved at effect seen at sea level. De escalation to lower altitude can reverse the
sea level.
Does not have much effect Nightime BP reduction more than
pathology with re occurrence on re induction to high
on nocturnal dipping. that during day at high altitude. altitude.
Worse tolerability (quantified At HA, better exercise tolerability CCB, ACE inhibitors/ARB’s, Beta blockers alone or
by side effects score), and of a and performance.
in combination are effective drugs for treatment of
more pronounced reduction
in exercise capacity at HA. HASH in various studies but definitive guidelines
or evidence is still awaited in literature terming or
Administration of Telmisartan at high altitude was coining an ideal agent for treatment of HASH.
well tolerated with no negative impact on SpO2 and no
impact on exercise tolerance. BIBLIOGRAPHY
When we look at pressor response at HA if antihy- 1. Bilo, Grzegorz & Caldara, Gianluca & Styczkiewicz et al.
pertensives like RAS blocking drugs along with Effects of selective and nonselective beta-blockade on
24-h ambulatory blood pressure under hypobaric hypoxia at
calcium channel blocking agents are combined,
altitude. Journal of hypertension. 2010;29:380-7.
BP lowering effect was similar at HA as at sea level
2. Bilo, Grzegorz and Villafuerte, Francisco & Faini A, et
without much adverse effects and intolerance al. Ambulatory blood pressure in untreated and treated
although they were uable to abolish HA exposure hypertensive patients at high altitude: The high altitude
pressor response (Table 2). cardiovascular research-andes study. Hypertension.
Combined treatment with CCB (Nifedipine) and ARB 2015;65:1266-72.
(Telmisartan): 3. Calbet JAL. Chronic hypoxia increases blood pressure and
noradrenaline spillover in healthy humans. The Journal of
—— Effective and safe at HA with BP values that
Physiology. 2003;551(Pt 1):379-86.
remained lower compared to subjects receiving 4. Kumar R, Pasha MQ, Khan AP, Gupta V, Grover S, Norboo
placebo. T, et al. Association of high-altitude systemic hypertension
—— Subjects on above combination of drugs, showed with the deletion allele-of the angiotensin converting
higher values of SPO2 postulated to be nifedipine enzyme (ACE) gene. International journal of biometeorology.
induced vasodilatory effects on pulmonary 2003;48:10-4.
5. Louis Hofstetter, Urs Scherrer, Stefano F. Rimoldi. Going to
circulation with enhanced ventilation-perfusion
high altitude with heart disease. Cardiovascular Medicine.
ratio. 2017;20(04):87-95.
6. Norboo T, Stobdan T, Tsering N, Angchuk N, Tsering P,
CONCLUSION: CARRY HOME MESSAGES Ahmed I, et al. Prevalence of hypertension at high altitude:
HASH can be termed as a type of secondary hyper cross-sectional survey in Ladakh, Northern India 2007-
tension due to prolonged exposure to high altitude. 2011. BMJ Open 2015;5:e007026.
It can be considered as an extended by product of 7. Parati G, Ochoa JE, Torlasco C, Salvi P, Lombardi C, Bilo
G. Aging, high altitude, and blood pressure: a complex
physiologic continuum of acclimatization response
relationship. High Altitude Medicine & Biology. 2015;16:97-
to hypoxemic enviorment. 109.
Sympathetic stimulation, endothelial dysfunction, 8. Peter Bärtsch, Simon J, Gibbs R. Effect of altitude on the
role of D allele of ACE gene, role of increased heart and the lungs. Circulation. 2007;116;2191-202.
CHAPTER
8
Management of Isolated Systolic
Hypertension: Current Concepts
Over the last few years a paradigm shift has occurred TABLE 1: Blood pressure
about elevation of diastolic blood pressure to our Category Blood pressure (mm Hg)
current knowledge that an elevation of systolic or rather Systolic Diastolic
combination of higher systolic and lower diastolic Optimal <120 <80
pressure (i.e. widening of pulse pressure) are the major Normal <130 <85
determinants of cardiovascular risk. The “J” shape curve High normal 130–139 85–89
of hypertension causing complications suggest same ISH
trends. Nowadays systolic hypertension is considered Stage I 140–159 <90
important prognostic factor in elderly rather than only Stage II 160–179 <90
age related phenomenon as it was considered previously. Stage III >180 <90
Patients with isolated systolic hypertension (ISH)
are definitely at high risk for developing cerebral and Systolic hypertension can be divided into three
coronary artery diseases and CHF as well. subtypes:
Chicago Heart Association based on these researches 1. Isolated Systolic Hypertension in Young (ISHY):
found that adults with ISH are at high risk of dying from ISH in young adults (typically 15–25 years of age).
ISH, women are at more risk than men although ISH is 2. Systolic Diastolic Hypertension in Middle Age:
more prevalent in men. Typically occurs in 30–50 years of age and also have
Elevated systolic hypertension in young individual elevated diastolic BP.
was considered previously as “spurious” or “pseudo”, 3. Isolated Systolic Hypertension in Elderly: Occurs
due to white coat hypertension or other causes. Newer after the age of 55 years.
studies have shown that these patients are at increased
risk of cardiovascular complications and so they should PREVALENCE AND RISK FACTOR
be carefully investigated and early treatment is warranted According to National Health and Nutrition Examination
in them. Survey III, ISH is most prevalent type of hypertension
As per WHO and JNC8 guidelines ISH is now defined above the age of 60 years. There is high variable data
as BP >140/<90 (Table 1). available regarding prevalence of ISH in different studies
CHAPTER 8: Management of Isolated Systolic Hypertension: Current Concepts 45
ranging from 6% to 30%. Aging is the most important risk nocturia, leg cramps, epistaxis, palpitation are presenting
factor in old. In young, it’s prevalence is estimated much features. Headache, blurring of vision are present in both
less than elderly. Obesity, smoking, low education level, subtypes of ISH.
male sex, alcohol, Stress are major risk factors.
EVALUATION OF ISH
Etiology As otherwise also every effort should be made to
In elderly people age related atherosclerosis and find identifiable cause of secondary hypertension,
stiffening of major arteries are main cause of ISH. other cardiovascular risk factors, end organ damage,
In young, etiology is unknown, genetic factors known life style risk factors like sedentary life style,
may play a role. It has been recently suggested that obesity, smoking, excessive alcohol consumption, etc.
angiotensin gene expression may be altered in ISH. Thorough assessment of all peripheral pulses, both
Hyperthyroidism, hyperaldosteronism, renal disease, optic fundi, thyroid status, cardiac, pulmonary, renal
renal artery stenosis, drug induced (corticosteroids, and neurological findings are mist as base line clinical
NSAIDs) may be other causes. evaluation.
The desirable investigations are as under:
Pathophysiology Urine analysis–for proteinuria,
Atherosclerosis due to endothelial dysfunction together Complete blood count–for unexplained anemia,
with vascular remodelling and fibrosis decrease arterial Serum creatinine–for kidney function,
elasticity and increase arterial stiffness. Pulse wave Serum uric acid–for hyperuricemia,
velocity is faster through stiff vessel, so the usual Serum electrolytes–for Conn’s syndrome,
reflection of pressure wave back from periphery occurs in Blood sugar–for diabetes,
mid systole rather than diastole augmenting the already Lipid profile–for dyslipidemia,
elevated systolic pressure and removing a major support Thyroid function test–for hyperthyroidism,
for the diastolic pressure, probably that’s why there is A m b u l a t o r y B P m o n i t o r i n g – f o r w h i t e c o a t
isolated systolic hypertension in elderly.
hypertension,
The increased systolic pressure leads to ventricular ECG–for left ventricular hypertrophy,
remodelling, fibrosis and impaired diastolic relaxation
Chest X-ray–for cardiomegaly,
subsequently leading to left ventricular hypertrophy,
Echocardiography–for chamber enlargement,
heart failure, coronary artery disease and aortic
USG abdomen–for kidney size and corticomedullary
aneurysm.
differentiation,
In young, atherosclerosis is less likely, sympathetic
CT abdomen and chest–for pheochromocytoma,
nervous system involvement is more likely as young
Carotid color Doppler–for atherosclerosis,
patient are usually associated with increased cardiac
Renal Doppler–for renal arterial stenosis.
output and tachycardia. There is evidence of renin
angiotensin aldosterone pathway over activity in young
MANAGEMENT OF HYPERTENSION
patients with ISH.
JNC8 Recommendations
CLASSIFICATION OF ISH Recommendation 1
Clinical Presentation In the general population aged ≥60 years,
Most patients are asymptomatic. An obese, active Start pharmacologic treatment to lower blood
smoker person, highly anxious with complaints of effort pressure to a goal SBP <150 mm Hg and goal DBP <90
intolerance is the usual presentation in young. In elderly, mm Hg.
Corollary Recommendation (Table 2) TABLE 2: Blood pressure goal

If pharmacologic treatment achieved lower SBP (e.g. BP goal JNC-7 JNC-8 ASH/ISH
<140 mm Hg) and treatment is well tolerated without Age<60 <140/90 <140/90 <140/90
adverse effects Age 60–70 <140/90 <150/90 <140/90
Treatment does not need to be adjusted. Age 80+ 140/90 <150/90 <150/90
Diabetes <130/80 <140/90 <140/90
Recommendation 2 and 3 CKD <130/80 <140/90 <140/90
In the general population aged <60 years,
Abbreviation: ASH, American Society of Hypertension; ISH, International
Start pharmacologic treatment to lower BP to a goal Society of Hypertension.
DBP <90 mm Hg.
Start pharmacologic treatment to lower BP to a goal This applies to all CKD patients with hypertension
SBP <140 mm Hg. regardless of race or diabetes status.
Recommendation 4 Recommendation 9
In the population aged 18 years with CKD, If goal BP is not reached within a month of treatment.
Start pharmacologic treatment to lower BP at SBP Increase the dose of the initial drug or add a second
140 mm Hg or DBP 90 mm Hg, and drug from one of the classes in recommendation 6
Treat to goal SBP <140 mm Hg and goal DBP <90 mm (thiazide-type diuretic, CCB, ACEI, or ARB).
Hg. Physician should continue to assess and adjust
treatment until goal BP is reached.
Recommendation 5 If goal BP is not reached with two drugs, add and
In the population aged 18 years with diabetes, titrate a 3rd one.
Start pharmacologic treatment to lower BP at SBP
Do not use an ACEI and an ARB together in the same
140 mm Hg or DBP 90 mm Hg, and patient.
Treat to a goal SBP <140 mm Hg and goal DBP <90
If goal BP cannot be reached using only the drugs in
mm Hg recommendation 6, because of a contraindication or
the need to use more than 3 drugs to reach goal BP.
Recommendation 6
Antihypertensive drugs from other classes can be
In the general nonblack population, including those with
used.
diabetes,
Referral to a hypertension specialist may be indicated
Start antihypertensive treatment should include a
for patients.
thiazide-type diuretic, CCBs, ACE inhibitors, or ARBs.
In whom goal BP cannot be attained using the above
Recommendation 7 strategy.
In the general black population, including those with For the management of complicated patients.
diabetes,
Initial antihypertensive treatment should include a Treatment of ISH
thiazide-type diuretic or CCB. Treatment of ISH starts with lifestyle modification
followed by drug therapy.
Recommendation 8
In the population aged18 years with CKD, Nonpharmacological Treatment
Initial (or add-on) antihypertensive treatment should Weight reduction-keep body weight within normal
include an ACEI or ARB to improve kidney outcomes. BMI range.
Salt restricted diet-moderate degree of daily salt should be useful in ISH. This is also shown in Systolic
intake should not be more then 2.4 gm or NaCl 6 gm/ Hypertension in Elderly Patients (SHEP) trial.
day which may lead to reduction in systolic BP by 2–8
mm Hg. Diuretics
Ad o p t i n g D A S H (d i e t a r y a p p ro a c h t o s t o p The current joint national committee guidelines
hypertension) meaning thereby the diet rich in fruits, recommend thiazide diuretics as initial therapy in most
vegetables, low saturated and total fat and high in patients with isolated systolic hypertension on the basis of
fiber content. their efficacy of reducing blood pressure, cardiovascular
Stopping tobacco by all means is must in managing complications and their low cost. These usually require
ISH. combination with other group antihypertensive drugs.
Moderation of alcohol consumption to not more than NSAIDs use may lead to reduced potency of thiazide
30 mL/day is effective in decreasing ISH upto 4 mm and lead to uncontrolled hypertension.
2011 British hypertension guidelines emphasize
Hg.
the use of thiazide like diuretics such as chlorthalidone
Physical exercise—Regular exercise like walking.
(12.5–25 mg once daily), in preference to conventional
Stress management—Stress management by yoga,
thiazide diuretics like hydrochlorthiazide, if there is high
pranayama and meditation may help in reducing
risk of heart failure. In presence of serum creatinine >2
stressful life.
mg/dL loop diuretics are of choice but metolazone also
Low caffeine—Caffeine is supposed to cause
act at low GFR.
temporary hypertension.
Elderly patients are prone to orthostatic hypotension,
Pharmacological Treatment dehydration, dyselectrolytemia and hypokelimia due to
Drug therapy recommendations: diuretics.
Lifestyle changes must always precede pharmaco
Calcium Channel Blockers
therapy as this may decrease the need for medication.
They can be labelled as ‘broad spectrum
The pharmacotherapy must be tailor made according
antihypertensives’ as they are effective as a single drug
to the patient’s cardiovascular profile and end organ
in almost 60% of patients in all demographic groups and
damage.
all grade of hypertension. Amlodipine is the only calcium
The general approach should be ‘start low – go slow’
channel blocker with established safety in patients with
to achieve the pharmacological effect.
severe heart failure.
To improve compliance long acting drugs should be
used. Angiotensin Converting Enzyme Inhibitors

Possible drug interactions should be kept in mind.
Hypertensive patients with high renin show maximum
Always avoid diastolic BP <55 mm Hg in older
response to ACE inhibitors. They are now increasingly
patients with ISH. being used in mild to moderate hypertension and are
Orthostatic hypotension should always be looked
agent of choice in diabetes with proteinuria and left
for and all care must be taken to avoid this at least in ventricular dysfunction. Chronic chough is common
diabetics and immobile patients. with them.
Drugs should be cost effective.
Angiotensin 2 Receptor Blockers

Classes of Antihypertensives which Data indicates that ARBs can improve cardiovascular
are Most Useful in ISH outcome in patients with hypertension. A remarkable
According to pathophysiology, agents which decrease feature is there safety and tolerability. The ISH substudy
total peripheral resistance and decrease arterial stiffness of LIFE demonstrated that losartan confers more
cardiovascular benefit over atenolol at the same level of study performed in Chinese ISH patients where active
BP control. treatment with nitrendipine significantly reduced the
following endpoint phenomenon:
b Blockers Total stroke—38%
These drugs are specially effective in patients with Stroke mortality—58%
increased sympathetic features like tachycardia, acts by All cause mortality—39%
reducing heart rate and cardiac output. Inhibit release of Cardiovascular mortality—39%
renin so effective in patients with elevated plasma renin Fatal and nonfatal cerebrovascular events—37%
activity such as young white patients. Bisoprolol and Intervention as a Goal in Hypertension Treatment
Nevibilol are beta blockers with less side effects and once (INSIGHT) Study which was performed in hypertensive
daily dose. patients with at least one additional risk factors such
Combination therapy: Most of the patients require as hyperlipidemia or diabetes mellitus. Though this
dual or even triple therapy to control ISH. The preferred study was not deliberately designed to investigate ISH
combinations are treatment, but it contained a subgroup of patients with
Diuretic and ACEI, defined ISH which were analyzed separately. Treatment
Diuretic and ARB, consisted of nifedipine (in the GITS form: Adalat-OROS)
Dihydropyridine CCB and ACEI, v/s hydrochlorothiazide. This subgroup was found to be
As per Avoiding Cardiovascular Events through more responsive than those with ‘ordinary’ hypertension
Combination Therapy in patients Living with Systolic to nifedipine–GITS. Interestingly, in these study patients
Hypertension (ACCOMPLISH) trial, the last combination with ISH whose DBP significantly decreased with
is more beneficial. increasing therapy were smokers with evidence of
Newer drugs: atherosclerosis.
Eplerenone: A newer aldosterone antagonist with very Both types of treatment (calcium antagonist v/s
low incidence of gynecomastia. diuretic) caused a significant and sustained reduction
Nitrates: Considered as potent drug by some experts in blood pressure (in particular SBP) and a significant
as new agent to treat ISH. reduction of the relevant endpoint parameters, such as
stroke and MI.
The ISH substudy of Losartan Intervention For
BENEFITS OF TREATMENT OF ISH
Endpoint reduction (LIFE) study compared Losartan
Multiple interventional trails like STOP-1 and STOP-
with atenolol and demonstrated that losartan reduced
2 clearly demonstrated the role of treating ISH in
the risk of stroke and CV death to greater degree than
preventing stroke and coronary artery disease.
atenolol.
Angiotensin II receptor antagonist telmisartan
INTERVENTIONAL TRIAL in isolated systolic hypertension (ARAMIS) studies
CONCERNING ISH demonstrated that Telmisartan (20–80 mg) produce
Systolic hypertension in the elderly (SHEP) showed significant reduction in SBP.
beneficial effect of treating elderly patients with Valsartan in isolated systolic hypertension (VALISH)
hypertension. showed a significant effect on ISH.
Systolic hypertension in Europe (SYST-EUR) showed
a significant reduction (by 42%) in incidence of stroke and SMALLER STUDIES ON ISH
vascular dementia (by 50%) by nitrendipine treatment. ACE inhibitors like Lisinopril, Enalpril, Periondopril are
Systolic hypertension in China (SYST-China) trial also suitable for blood pressure control in ISH patients
having the design quiet similar to that of the SYST-EUR and favorably influence cardiovascular risk factors.
BIBLIOGRAPHY Nutrition Examination Survey. Journal of hypertension.

1. Dennis Kasper, Anthony Fauci, et al. Harrison’s principle 2010;28(1):15.
of internal medicine, 19th edition. Hypertensive vascular 4. Lawes CM, Vander Hoorn S, Rodgers A. Global burden
disease. 2015;1611:1627. of blood-pressure-related disease, 2001. The Lancet.
2. Franklin SS, Pio JR, Wong ND, Larson MG, Leip EP, Vasan 2008;371(9623): 1513-8.
RS, Levy D. Predictors of new-onset diastolic and systolic 5. McEniery CM, Wallace S, Maki-Petaja K, McDonnell B,
hypertension. Circulation. 2005;111(9):1121-7. Sharman JE, Retallick C, Franklin SS, Brown MJ, Lloyd RC,
3. Grebla RC, Rodriguez CJ, Borrell LN, Pickering TG. Prevalence Cockcroft JR, Wilkinson IB. Increased stroke volume and
and determinants of isolated systolic hypertension among aortic stiffness contribute to isolated systolic hypertension
young adults: the 1999–2004 US National Health and in young adults. Hypertension. 2005;46(1):221-6.
CHAPTER
9
Blood Pressure Control with Changing Time
BR Bansode
In 1578–1657 William Harvey described that blood Charles Friedberg’s in 1949 in his book “Diseases of
flows through the arteries i.e “Circulation of Blood” in Heart” stated that, people with mild benign hypertension
his book “D-e Motu Cordis”. Stephen Hales measured (blood pressure up to 210/100) need not be treated. Over
blood pressure for the first time in 1733. Fredrick next decade more evidence accumulated from various
Akbar Mohamed (1849–1884) reported for the first studies and Framingham heart study stated that benign
time that blood pressure can be elevated without hypertension can result in death and cardiovascular
kidney disease. Scipione Riva-Rocci 1896 invented the morbidity. The National Institutes of Health carried
cuff base sphygmomanometer which could help the out various studies on hypertensive populations and
clinician to measure blood pressure in his clinic. In determined that African Americans had a higher burden
1905, Nikolai Korotkoff introduced the korotkoff sounds of hypertension and its complications.
that are heard when the artery is auscultated with the
stethoscope during gradual deflation of the BP cuff of the MANAGEMENT OF HYPERTENSION
sphygmomanometer. Historically, hypertension was called ‘hard pulse disease’
In 1911, Eberhard Frank described term essential and reducing the quantity of blood by blood letting or
hypertension, when BP elevated without any cause. application of leeches was advocated by the emperor of
Physician from Mayo clinic in 1928 describe the term China, Cornelius as well as by scholars like Celsius, Galan
malignant hypertension when BP is very high, with and Hippocrates.
severe retinopathy and adequate renal function, which In the early and mid 20th century, different therapies
resulted in invariable death due to stroke, heart failure or were used for the treatment of hypertension, but very
renal failure in one year. few were effective. Strict sodium restriction (rice diet),
Frankling D Rooseveslt, the then President of America sympathectomy and pyrogen therapy were but some
was found to have blood pressure of 240/140, which was of the modalities used. In 1900, first chemical used
declared normal by his treating physician. The very next for treating hypertension was sodium thiocynate but
day, he succumbed to a stroke (hemorrhage)! was discarded due to its many side effects. In second
In 1931 John Hay, Professor of Medicine from Liver world war and post war hydralazine and reserpine were
pool University and in 1947 Paul Dudley White concluded reasonably effective in controlling the hypertension.
that hypertension is a compensatory mechanism and Major breakthrough was achieved in 1950 with
declared that it should not be tampered with. discovery of diuretics which was well tolerated and
CHAPTER 9: Blood Pressure Control with Changing Time 51
very effective. Chlorthiazide (Diuril) was derived from TABLE 1: Blood pressure goals for hypertension control, JNC 1 –
antibiotic sulphanilamide and available for clinical use JNC 7
from 1958. Report number Committee BP goal (mm Hg) Examples of
The first sponsored trial on hypertension was carried (Year of chair seminal studies/
publication) influential
out comparing hydrochlorothiazide + reserpine + reports
hydralazine verses placebo. This trial was stopped 1 (1977) Marvin DBP <90 8
early due to placebo group having significantly more Moser
complications of hypertension than the treatment group. 2 (1980) Iqbal Krishan zz DBP <90 9
In 1975, the Lashkar special public health award was zz DBP 90–100
for individuals
bestowed upon the team that developed Chlorthiazide.
with moderate
In 1972–1994 with therapy of hypertension there was or severe
significant reduction (50%) in stroke, ischemic heart hypertension
disease and heart failure. 3 (1984) Harriet DBP < 90 10–14
In 1960, British physician James W Black developed Dustan
beta-blockers which were used for angina for which 4 (1988) Aram BP <140/90 15–17
Chobanian
he received the Nobel Prize in 1988. Calcium channel
blockers were discovered next and found to be more 5 (1993) Ray Gifford BP < 140/90 18, 19
effective. In 1977 ACE (Captopril) and more recently ARB 6 (1997) Sheldon BP < 140/90 20–24
Shepsz and “Lower if
were added to the armamentarium. The modern era of tolerated”
treating hypertension was more effective and many trials 7 (2003) Aram zz P < 140/90
B 25, 26
were carried out in clinical practice. zz <130/80 in
Between 1977 and 2003, under the direction patients with
of National Institutes of Health, the Joint National JNC 1 based on limited Clinical Trail Data recommended that, all
Committee on Detection, Evaluation and Treatment persons with diastolic blood pressure more than 105 mm/Hg to be
of high blood pressure (JNC) issued 7 reports. The treated with anti hypertension Drug Therapy, while DBP 90/104 mm/
Hg recommended on individual basis with other risk factors.
JNC 8 guidelines were in process for several years and
the National Institute of Health subsequently made TABLE 2: JNC 2 classification of hypertension
the decision to withdraw from issuing guidelines. The
Classification Diastolic blood pressure (mm Hg)
responsibility for issuing the hypertension guidelines
Stratum 1 (mild) 90–104
was transferred to the American Heart Association (AHA)
Stratum 2 (moderate) 105–114
and American college of cardiology (ACC). Without
Stratum 3 (severe) > 115
the endorsement of AHA and NIH, JNC 8 committee
members issued guidelines for treating hypertension Step care approach. Thiazide diuretic and adding the other drugs, the
blood pressure should be controlled.
which is based on clinical trials carried out in the past.
The impact of guidelines the 1950 and 1996 age
JNC 1974 TO 2003 (1 TO 7) (TABLES 1 TO 6) adjusted mortality rates for stroke and CVS disease in
The JNC define hypertension and management based on USA decrease by 60–70% and the public awareness about
newer understanding pathophysiology of hypertension. the hypertension was increased.
The purpose of this review of JNC-1 to JNC-8 is keeping WHO/ISH also recommended a step-wise approach
track the changing recommendations for hypertension to drug therapy starting with diuretics, similar to the
management over time and to realise the dynamic nature JNC. However, subsequent WHO/ISH reports expanded
of the process of developing treatment guidelines. JNC, the recommendation for an starting drug therapy with
European and Canadian reports represent consensus any one of 5 different classes of anti hypertensive agents
document written by panel of experts.
TABLE 3: JNC 3 and JNC 4 classification of hypertension TABLE 6: JNC 7 classification of hypertension
Classification BP range (mm Hg) Classification Systolic BP (mm Hg) Diastolic BP (mm Hg)
Diastolic Normal <120 AND < 80
Prehypertension 120–139 OR 80–89
Normal BP < 85
Stage 1 hypertension 140–159 OR 90–99
High normal BP 85–89
Stage 2 hypertension >160 OR >110
Mild hypertension 90–104
New clear and concise guidelines for clinician achieving goal blood
Moderate hypertension 105–114 pressure 140/90 mm/Hg and goal blood pressure 130/80 mm/Hg in
Severe hypertension >115 DM, CKD. Thiazide type diuretics recommended as first choice. Two
drugs required to achieve goal blood pressure or blood pressure 20/10
Systolic, when diastolic BP <90 mm/Hg above the goal.
Normal BP <140
Borderline isolated systolic hypertension 140–159 TABLE 7: NICE guidelines blood pressure
Isolated systolic hypertension >160 Step 1 A (for patients aged <55 years) or
C* (for patients aged _55 years and all black people of
Defining therapeutic goals on the basis of diastolic blood pressure. African or Caribbean descent)
Nonpharmacological treatment for DBP 90–94 mm/Hg should be
advised. Step 2 A + C*
Step 3 A+C+D
TABLE 4: JNC 5 classification of hypertension Step 4 Resistant hypertension A + C + D + further diuretic† (or
_ blocker or _ blocker if further diuretic treatment is not
Classification Systolic BP (mm Hg) Diastolic BP (mm Hg) tolerated or is contraindicated or ineffective) Consider
Normal <130 < 85 seeking specialist advice
High normal 130–139 86–89 Abbreviations: Key A, Angiotensin converting enzyme inhibitor or
angiotensin II receptor blocker; C, Calcium channel blocker;
Hypertension 90–104 D, Thiazide-like diuretic
Stage 1 (mild) 140–159 90–99 * Calcium channel blocker preferred, but consider thiazide-like
diuretics in people with oedema or high risk of heart failure
Stage 2 (moderate) 160–179 100–109
† Consider low dose spironolactone or higher doses of thiazide-like
Stage 3 (severe) 180–209 110–119 diuretic
Stage 4 (very severe) >210 >120 If blood pressure measured in the clinic is 140/90 mm Hg or higher:
zz Take a second measurement during the consultation
Advise drug therapy for SBP 140/149 and DBP 90/94 mm/Hg with life zz If the second measurement is substantially different from the first,
style modification and also had target organ damage. Diuretic beta take a third measurement
blocker may be used as first choice. The Goal BP 140/90 mm/Hg for zz Record the lower of the last two measurements as the clinic blood
initiation of treatment. pressure (Updated recommendation)
TABLE 5: JNC 6 classification of hypertension (diuretics, ACE inhibitor, beta blockers, calcium-channel
blocker or alpha-blocker).
Classification Systolic BP (mm Hg) Diastolic BP (mm Hg)
Between 1950 and 1996 in the United States, the
Optimal <120 AND < 80
age-adjusted mortality rates for cardiovascular disease
Normal <130 AND < 85
and cerebrovascular accidents declined by 70% and
High normal 130–139 OR 86–89
60% respectively. These trends began about 1–2 decades
Hypertension
before the JNC 1. Between 1999 and 2009, the relative
Stage 1 140–159 OR 90–99
rates of death attributed to cardiovascular disease and
Stage 2 160 – 179 OR 100–109
cerebrovascular accidents declined by 33% and 37%
Stage 3 180–209 OR ≥110
respectively. This data represents the impact that the
Use risk stratification as part of treatment. High normal BP > 140/90
mm of Hg treatment should be initiated with beta blocker or diuretics.
guidelines have had on outcomes (Tables 7 and 8).
The compelling indication the specific drugs should be given e.g. These guidelines encorporate the atherosclerotic
Diabetes, CCF, systolic dysfunction, myocardial infarction and chronic cardiovascular risk calculator and reduce the cut off of
renal disease.
hypertension to 130 mm Hg and 80 mm Hg for systolic
CHAPTER 9: Blood Pressure Control with Changing Time 53
TABLE 8: The Indian guidelines blood pressure classification (Age 18 and above)
Category SBP (mm Hg) DBP (mm Hg)
Optimal < 120 AND < 80
Normal <130 AND < 85
High normal 130–139 85–89
Hypertension
Stage 1 140–159 90–99
Stage 2 160–179 100–109
Stage 3 >180 >110
Isolated systolic hypertension
Grade I 140–159 <90
Grade II >160 <90
TABLE 9: ACC/AHA guidelines for high blood pressure in adults: November 2017
BP category Systolic BP Diastolic BP Treatment or follow-up
Normal <120 mm Hg <80 mm Hg Evaluate yearly; encourage healthy lifestyle changes to maintain normal BP
Elevated 120–129 mm Hg <80 mm Hg Recommend healthy lifestyle changes and reassess in 3–6 months
Hypertension: Stage 1 130–139 mm Hg 80–89 mm Hg Assess the 10-year risk for heart disease and strok using the atherosclerotic
cardiovascular disease (ASCVD) risk calculator
zz If risk is less than 10%, start with healthy lifestyle recommendations and
reassess in 3–6 months

zz If risk is greater than 10% or the patient has known clinical cardiovascular
disease (CVD) diabetes mellitus, or chronic kidney disease, recommend

lifestyle changes and BP-lowering medication 91 medication); reassess in 1
month for effectiveness of medication therapy
—— If goal met after 1 month, reassess in 3–6 months
—— If goal is not met after 1 month, consider different medication or titration
—— Continue monthly follow-up until control is achieved
Hypertension: Stage 2 >140 mm Hg >90 mm Hg Recommend healthy lifestyle changes and BP-lowering medication (2
medications of different classes); reassess in 1 month for effectiveness
zz If goal is met after 1 month, reassess in 3–6 months
zz If goal is not met after 1 month, consider different medications or titration
zz Continue monthly follow-up until control is achieved
and diastolic blood pressure respectively. The targets for opinions regarding hypertension management.
blood pressure control have also been reduced to 130 The goal would be resolution by an evidence based
mm Hg and 80 mm Hg for systolic and diastolic blood approach rather than by consensus statements. This
pressure respectively. This may represent the evolution would require collaboration with funding agencies.
of blood pressure management or may represent the The association of hypertension with other cardio
adhearance of evidence based approach to a fault. The vascular disease risk factors has been established
jury is still out on the practicality of these guidelines since decades. In a recent editorial, Peterson et al.
(Tables 7 and 8). suggested an integrated approach for prevention,
detection, evaluation and treatment of overall
Improving the Impact of Guidelines cardiovascular disease to have a greater impact than
(Table 9) discrete guidelines targeted for each individual risk
The following additional strategies could be considered to factor.
improve the impact of guidelines for hypertension: From a clinical and practical perspective, the primary
Research strategies might be recommended by hurdles to hypertension control may be related to the
guideline committes to resolve differences of inadequate implementation of recommendations by
both health care providers and patients rather than recommendations by different groups highlights the
the guidelines themselves. The guidelines do not difficulty of translating science into policy especially while
devote attension to strategies for overcoming these remaining patient centric. Conflicting recommendations
barriers in implementation. Addressing these issues tend to confuse the health care providers and patients
will require collaboration with disciplines and patient alike with a potentially to challenge the credibility of all
groups that have historically never been involved in recommendations. This will remain a major challenge to
guideline formation. all professional groups in the time to come.
Finally, guidelines currently serve an important
educational function and should not be considered as BIBLIOGRAPHY
rigid rules for action. They serve the healthcare provider 1. Hypertension Detection and Follow-up Program Cooperative
Group. The effect of treatment on mortality in “mild”
to make informed clinical decisions and judgments
hypertension. N Engl J Med. 1983;307:976-80.
regarding the treatment of individual patients. 2. Joint National Committee on Detection, Evaluation,
and Treatment of High Blood Pressure. Report of the
CONCLUSION AND PERSPECTIVES Joint National Committee on Detection, Evaluation, and
In conclusion, guidelines are consensus statements Treatment of High Blood Pressure: a cooperative study.
JAMA. 1977;237:255-61.
developed by panels of experts in the field. Without a
3. Joint National Committee on Detection, Evaluation, and
doubt institution of guidelines for hypertension have Treatment of High Blood Pressure. The 1980 report of
contributed to improved blood pressure control and the Joint National Committee on Detection, Evaluation,
reduced death rates attributable to cardiovascular and Treatment of High Blood Pressure. Arch Intern Med.
diseases over the past few decades. As expected, 1980;140:1280-5.
guidelines change over time, based on new information 4. Joint National Committee on Detection, Evaluation, and
Treatment of High Blood Pressure. The 1984 report of
and research and also on the basis of development
the Joint National Committee on Detection, Evaluation,
and availability of effective antihypertensive agents. and Treatment of High Blood Pressure. Arch Intern Med.
Nevertheless, the rates of uncontrolled hypertension 1984;144:1045-57.
and cardiovascular diseases remain unacceptably high, 5. Joint National Committee on Detection, Evaluation, and
constituting the leading cause of mortality in the United Treatment of High Blood Pressure. The 1988 report of
the Joint National Committee on Detection, Evaluation,
States, accounting for approximately 34% of all deaths
and Treatment of High Blood Pressure. Arch Intern Med.
annually. 1988;148:1023-38.
The lengthy delay in producing a revision of 6. Joint National Committee on Detection, Evaluation, and
JNC 7 guidelines reflects a vulnerability of the guideline Treatment of High Blood Pressure. The fifth report of the
process. Compared to the NIH’s involvement in directing Joint National Committee on Detection, Evaluation, and
the JNC reports, European and Canadian guidelines Treatment of High Blood Pressure (JNC V). Arch Intern Med.
1993;153:154-83.
have been directed by professional societies rather
7. Peterson ED, Gaziano M, Greenland P. Recommendations
than by a funding agency. Europeans and Canadians for treating hypertension: What are the right goals and
approaches have, therefore been more pragmatic purposes? JAMA Published online Dec 18, 2013.
than the JNC reports in their approach, with a regular 8. Tanner L. Panel shifts blood pressure goal Milwaukee
frequency of reports and flexibility in changing earlier Journal Sentinel, Dec 19,2013;p3A.
9. WHO Expert Committee: Arterial hypertension. Technical
recommendations with emphasis on implementation
Report Series No. 628 Geneva. World Health Organization.
strategies. The recent decision by NHLBI to transfer the 1978.
responsibility for guideline development to the AHA 10. Working Group on Hypertension in the Elderly Statement on
and ACC is a reasonable step. The current variation in hypertension in the elderly. JAMA. 1986;256:70-4.
CHAPTER
10
Management of Hypertension in Diabetes
INTRODUCTION According to review on “The Global Burden of

The definition of hypertension has always been an Hypertension”, the estimated prevalence of hypertension
issue of debate and controversies. In the last decade, (in people aged 20 years and older) in India in 2000 was
hypertension was defined as a blood pressure (BP) 20.6% among males and 20.9% among females and is
reading of 140/90 mm Hg or higher, but the updated projected to increase to 22.9% and 23.6% respectively by
guideline classifies hypertension as BP reading of 2025.
130/80 mm Hg or higher. It’s a complex cardiovascular
disorder rather than just blood pressure values with HYPERTENSION
many causes that result in both functional and structural Normal: Less than 120/80 mm Hg
changes in the heart and vascular system with the Elevated: Systolic between 120–129 and diastolic ≤ 80
presence or absence of risk factors, early disease mm Hg
markers, target-organ damage and different physiologic Stage 1: Systolic between 130–139 or diastolic between
abnormalities in the cardiovascular system and other 80–89 mm Hg
organs. Hypertension is strongly associated with ASCVD, Stage 2: Systolic between ≥140 mm Hg or diastolic ≥
death, disability, and microvascular complications and 90 mm Hg
its management to target reduces the risk of ASCVD
events, heart failure, and microvascular complications Hypertension in Diabetics: The Deadly
in people with diabetes.1-3 High blood pressure is the Combination
biggest single cause of death worldwide through heart The timing and presentation of hypertension differs
attack, stroke and kidney diseases. The situation in our between type 1 and type 2 diabetes. In type 1 diabetes,
country requires more attention as with modernization, hypertension develops after several years of disease and
we are trading healthy traditional diets for fatty foods, usually reflects the development of diabetic nephropathy.
physical jobs for desk bound ones and calm rural life In type 2 diabetes, hypertension may be present at
for stressful city life leading to rapid increase in the the time of diagnosis or even before the development
prevalence of hypertension. Thus, after being referred to of hyperglycemia. The prevalence of hypertension in
as the Diabetes Capital, India is also slated to become the diabetic population depends on type and duration
“Hypertension Capital” in the world. of diabetes, age, sex, race/ethnicity, BMI, history of
TABLE 1: BP patterns based on office and out-of-office measure diuretics should be continued or not. Support stockings
ments may be helpful in orthostatic hypertensive patients.11
BP category Office/Clinic/ Home/Nonhealthcare/ Compared to patients without diabetes, hypertension
Healthcare setting Ambulatory BP monitoring
is characterized by an earlier onset of systolic
setting
hypertension and ISH is more prevalent at any age.12
Normotensive No hypertension No hypertension
The coexistence of hypertension and type 2 diabetes
Sustained Hypertension Hypertension
hypertension
is more common in women and the systolic BP is
higher in women compared to men.12 The clustering
Masked No hypertension Hypertension
hypertension of hypertension, glucose intolerance or frank type 2
Whitecoat Hypertension No hypertension diabetes, hyperlipidemia, central obesity and insulin
hypertension resistance has been documented in several populations
including Indians.13
glycemic control, and the presence of kidney disease
and other factors.4,5 The overall prevalence is estimated Hypertension in Diabetes: Complications
to be 1.5–3 times higher than that of no diabetic age- Extensive epidemiological evidences indicate that
matched groups. Regardless of age 80% of adults with diabetes mellitus along with dyslipidemia, obesity and
diabetes mellitus have hypertension.6 Before we come hypertension greatly increases the risk of development
to a definitive diagnosis of hypertension, we should and progression of atherosclerotic cardiovascular
consider and exclude masked hypertension, white-coat disease (ASCVD) resulting in a higher incidence of
hypertension and pseudo-hypertension (Table 1). coronary heart disease, heart failure, peripheral artery
Identification and exclusion of these conditions with disease, stroke, etc. with increased risk of morbidity
and mortality.14 Compared to the general population,
home blood pressure monitors helps in avoiding over-
people with diabetes face two to four fold increased
treatment of white-coat hypertension which is not at
risk of cardiovascular disease (CVD). 15 Concomitant
risk of elevated ASCVD and timely treatment of masked
hypertension triples the already high risk of coronary
hypertension to avoid complications. 7 Most of the
artery disease (CAD), doubles total mortality and stroke
evidences of benefits of management of hypertension
risk and may be responsible for up to 75% of all CVD
in diabetes are based on office measurement of blood
events.15 Similarly, hypertension significantly accelerates
pressure except for ACCORD trial.
the progression of diabetic nephropathy, retinopathy,
Orthostatic hypotension in type 2 diabetes is and neuropathy.16,17 Systolic blood pressure is a stronger
commonly found due to Diabetic autonomic neuropathy predictor than diastolic blood pressure for both CVD and
or volume depletion,8 and may be further exacerbated renal complications.
by antihypertensive medications. It’s a decrease in
systolic blood pressure of 20 mmHg or diastolic blood Hypertension in Diabetes: The Goal Blood
pressure of 10 mm Hg in comparison to the blood Pressure?
pressure in sitting or supine position 9 within 3 min How far the blood pressure should be lowered in
of standing and it increases the risk of mortality and people with diabetes? The primary goal of therapy
heart failure.10 It is important to assess for symptoms of of hypertension should be effective control of BP in
orthostatic hypotension to decide the blood pressure order to prevent, reverse or delay the progression of
goal and the most appropriate antihypertensive agent complications and thus reduce the overall risk of an
with its dose to minimize adverse effects of therapy. It individual without adversely affecting the quality of life.
also helps about the timing of antihypertensive drugs There is a continuous relationship between the level of
(to change to night dose) and whether a-blockers and blood pressure and the risk of complications. Starting at
CHAPTER 10: Management of Hypertension in Diabetes 57
115/75 mm Hg, CVD risk doubles with each increment only 28–36% of diabetic hypertensive patients have their
of 20/10 mm Hg throughout the blood pressure range. blood pressure control to target, primarily because of
There are robust data that supports that pharmacologic poor control of systolic blood pressure. Similar level of
treatment of blood pressure in patients with diabetes inadequate blood pressure control have been noted in
reduces the risks of ASCVD, heart failure, retinopathy type 1 diabetic population.37, 38 It’s a matter great concern
and albuminuria18-23 by decreasing both macrovascular that only around 4–10% of diabetic patients meet the
and microvascular complications. In the HOT study combined goals for blood pressure, LDL cholesterol and
Diabetic patients with the lowest target DBP had a glycated hemoglobin [HbA1c].
significantly lower risk of CAD. 24 The findings of The Disease, patient and clinician factors contribute
United Kingdom Prospective Diabetes Study (UKPDS) to poor blood pressure control in diabetics also. The
was also in conformity with HOT trial that a tight control isolated systolic blood pressure is more difficult to
of BP (average achieved: 144/82 mm Hg) in diabetic control. Clinician inertia—the failure to increase the
patients conferred a substantial reduction in the risk dose or number of medications for patients who do not
of CAD compared to a less tight control of BP (average achieve therapeutic goal is an important contributor to
achieved:25 154/87 mm Hg). poor control of blood pressure. Inadequate knowledge
Large benefits are seen when multiple risk factors of control of hypertension as the most cost-effective
are addressed simultaneously.20 Due to improvement intervention to prevent CVD may be another reason and
in control of blood pressure ASCVD morbidity and time pressure during short office visits with complicated
mortality have decreased substantially in people with patients with diabetes may also be a strong reason for
diabetes since 1990.26-28 Clinical trials using a variety of clinician inertia.
antihypertensive agents have demonstrated that even
modest reduction in blood pressure of just 9–11 mm Hypertension in Diabetes: Treatment
Hg systolic and 2–9 mm Hg diastolic decreases CVD Strategies
events by 34–69% and microvascular complications The basic paradigm for achieving blood pressure goal in
(retinopathy and nephropathy) by 26–46% within just people with diabetes has not changed appreciably from
2–5 years.29-32 that recommended by JNC 7. However, physicians should
The patients and clinicians should discuss and make adopt a more integrated, patient-centered management
a shared decision to determine individual blood pressure of hypertension especially in diabetics by treating the
targets with the understanding that the benefits and risks intricacies of each patient profile including their total
of intensive blood pressure targets are uncertain and CVD risk rather than focusing on the disease in isolation.
may vary across patients (Table 2). Although there are no well-controlled studies on lifestyle
changes in the treatment of hypertension in individuals
Goal: BP with diabetes, studies in nondiabetic individuals have
Hypertension with diabetes mellitus ≤130/80 mm Hg. shown antihypertensive effects similar to pharmacologic
Hypertension with diabetes mellitus and CKD: monotherapy by limiting salt intake to < 2.4 g/day,
≤130/80 mm Hg. reducing excess body weight through caloric restriction;
Hypertension and stable CVD or ≥10% 10-year adopting the Dietary Approaches to Stop Hypertension
ASCVD risk: ≤130/80 mm Hg. (DASH) eating plan, increasing consumption of fruits
and vegetables (8–10 servings per day), and low-fat
Hypertension in Diabetes: Status of dairy products (2–3 servings per day); avoiding excessive
Control alcohol consumption (no more than 2 servings per day
Over all control of vascular risk factors is inadequate in men and no more than 1 serving per day in women),
in people with diabetes. In community-based studies reducing sedentary time, increasing physical activities,
TABLE 2: Randomized controlled trials of intensive vs. standard hypertension treatment strategies
Clinical trial Population Intensive Standard Outcomes
ACCORD BP 4,733 participants with T2D Systolic blood pressure Systolic blood pressure zz No benefit in primary end point:
aged 40–79 years with prior target: <120 mm Hg target: 130–140 mm Hg composite of nonfatal MI, nonfatal
evidence of CVD or multiple Achieved (mean) Achieved (mean) stroke, and CVD death
cardiovascular risk factors systolic/ diastolic: systolic/ diastolic: zz Stroke risk reduced 41% with
119.3/64.4 mm Hg 133.5/70.5 mm Hg intensive control, not sustained

through follow-up beyond the
period of active treatment
zz Adverse events more common in
intensive group, particularly elevated

serum creatinine and electrolyte
abnormalities
Advance BP33 11,140 participants with T2D Intervention: a Control: placebo zz Intervention reduced risk of primary
aged 55 years and older with single-pill, fixed- Achieved (mean) composite end point of major
prior evidence of CVD or dose combination systolic/diastolic: macrovascular and microvascular
multiple cardiovascular risk of perindopril and 141.6/75.2 mm Hg events (9%), death from any cause
factors indapamide Achieved (14%), and death from CVD (18%)
(mean) systolic/ zz 6-year observational follow-up
diastolic: 136/73 mm found reduction in risk of death in

Hg intervention group attenuated but
still significant34
HOT35 18,790 participants, including Diastolic blood Diastolic blood pressure zz In the overall trial, there was no
1,501 with diabetes pressure target: ≤ 90 mm Hg cardiovascular benefit with more
target: ≤ 80 mm Hg intensive targets
zz In the subpopulation with diabetes,
an intensive diastolic target was

associated with a significantly
reduced risk (51%) of CVD events
SPRINT36 9,361 participants without Systolic blood pressure Systolic blood pressure zz Intensive systolic blood pressure
diabetes target: <120 mm Hg target: < 140 mm Hg target lowered risk of the primary
Achieved (mean): Achieved (mean): 136.2 composite outcome 25% (MI, acute
121.4 mm Hg mm Hg coronary syndrome, stroke, heart
failure, and death due to CVD)
zz Intensive target reduced risk of
death 27%
zz Intensive therapy increased risks of
electrolyte abnormalities and acute

kidney injury
Abbreviations: CVD, cardiovascular disease; T2D, type 2 diabetes
smoking cessation and engaging in yoga-meditation. (systolic blood pressure 130–139 mm Hg or diastolic
Management of obstructive sleep apnea in diabetes has blood pressure 80–89 mm Hg), hence all patients should
also been found to reduce blood pressure.39 Lifestyle be counseled regarding life style modifications (Tables 3
management not only lowers blood pressure but also and 4).
enhances the effectiveness of some antihypertensive
medications, positively affects glycemic and lipid control PHARMACOLOGIC TREATMENT
with positive effect on cardiovascular events and helps Over the past decade, the goals of treatment have
prevent or delay progression of Stage 1 hypertension gradually shifted from optimal lowering of blood pressure
TABLE 3: Lifestyle modification

Modification Potential reduction in
systolic/diastoic blood pressure (mm Hg)
10-lb weight loss 7/6
American Heart Association 11.4/5.5
Dietary Approaches to Stop Hypertension Diet
Restriction of alcohol consumption 3.9/2.4
Men: ≤ 2 drinks/day
Women: ≤ 1 drink/day
Exercise: 30–60 minutes/day, 4–7 days/week 4.9/3.7
Restriction of dietary sodium to < 2.4 g/day 3.4/1.9
TABLE 4: Lifestyle modification: Nonpharmacological intervention and its dose40-47*

Nonpharmacologic intervention Dose
Healthy diet: DASH dietary pattern Diet rich in fruits, vegetables, whole grains, and low-fat dairy products with reduced
content of saturated and total fat
Weight loss: Optimization of weight/body fat zz Ideal body weight is best goal, but aim for at least 1 kg body weight reduction for
most overweight adults
zz Expect about 1 mm Hg for every 1 kg reduction in body weight
↓ Sodium intake <1500 mg/day is optimal goal, but aim for at least 1000 mg/day reduction in most
adults
↑ Potassium intake 3500–5000 mg/day, preferably by consumption of a diet rich in potassium
Physical activity: Add aerobic exercises zz 90–150 min/week
zz 65–75% heart rate reserve
Physical activity: Dynamic resistance training zz 90–150 min/week

zz 50–80% heart rate reserve, 1 rep maximum
zz 6 exercises, 3 sets/exercise, 10 repetitions/set
Physical activity: Isometric resistance training zz 4 × 2 min (hand grip), 1 minute of rest between exercises, 30–40% maximum
voluntary contraction, 3 sessions/week
zz 8–10/week
↓ Alcohol consumption For those who drink alcohol, the recommended daily consumption is no more than 2
drinks for men and 1 drink for women
*Type, dose, and expected impact on BP in adults with a normal BP and with hypertension
to patient’s overall well being, control of associated risk48 Class of Antihypertensive Medications
factors and protection from future target organ damage. Clinical trials involving large number of patients with both
Choice of an antihypertensive agent is influenced by diabetes and hypertension have demonstrated reduction
age, concomitant risk factors, presence of target organ in CVD events and microvascular complications with all
damage, other co-existing diseases, socioeconomic most all classes of drugs like diuretics. ACE inhibitors,
issues, and availability of the drug and past experience angiotensin receptor blockers (ARBs), dihydropyridine
of the physician. Due to a greater seasonal variation of (DHP) and nondihydropyridine (non DHP) calcium
temperatures in India, marginal alterations in dosages of channel blockers (CCBs), etc. β-blockers are preferred
drugs may be needed from time to time. in post infarct patients or in those with heart failure or
unstable angina but not as a first line drug in hypertension RAS blocker (direct renin inhibitors) on interaction of
without cardiac problem. Quality of life factors like renin/prorenin with its receptor may be potentially
impotence with diuretics and masking of hypoglycemia useful in patients with diabetes mellitus as a second drug
with β-blockers might be an important factor to deicide or in combination with other drugs. DRI has been found
the therapy. to be cardio and reno protective in some of the trials.
In metabolic syndrome, lifestyle modification with Kidney function test along with assessment of serum
an emphasis on improving insulin sensitivity by means potassium levels is needed regularly if ACE inhibitors,
of dietary modification, weight reduction and exercise is ARBs or diuretics are being used.
the foundation of treatment. Given the modest efficacy In a large scale trial in hypertension with diabetes with
of lifestyle modifications and the importance of prompt single-pill combinations which assessed cardiovascular
blood pressure control, in diabetics with blood pressure and renal outcomes, the Avoiding Cardiovascular Events
≥130/80 antihypertensive drug treatment should be Through Combination Therapy in Patients Living With
initiated with a treatment goal of <130/80 mm Hg. Initial Systolic Hypertension (ACCOMPLISH), in patients with
first-line therapy for stage 1 hypertension includes high risk of cardiovascular events (60% with diabetes)
ACE inhibitors or ARB or CCBs. Two first-line drugs of demonstrated a decrease in morbidity and mortality with
different classes are recommended in patients with stage the ACE inhibitor benazepril plus the dihydropyridine
2 hypertension and those with average BP of 20/10 mm CCB amlodipine versus benazepril and the thiazide-
Hg above the BP target. Titration and/or addition of other like diuretic hydrochlorothiazide in spite of similar
blood pressure drug/drugs should be made at the earliest blood pressure reduction in both.53-55 The other studies
appropriate time to achieve blood pressure targets. like SHIELD and STITCH trials have also observed
In case if the target blood pressure is still not achieved, a better control and achievement of target BP with
a thiazide like diuretic should be added to those with an combination therapy in diabetic hypertensives. Fixed-
estimated glomerular filtration rate (GFR) ≥ 50 mL/min dose antihypertensive drug combination may improve
per 1.73 m2 and a loop diuretic for those with an estimated patient adherence as well as effectiveness in lowering
GFR < 50 mL/min per 1.73 m2. Outcome trials of people blood pressure. The results resembles the benefit that was
with type 1 and type 2 diabetes and established diabetic achieved with a similar ACE inhibitor/calcium antagonist
kidney disease (including urinary albumin excretion ≥ therapy in the ASCOT trial.56 In a recent trial in patients
300 mg/g creatinine) have demonstrated that an ACE with type 2 diabetes and microalbuminuria, Irbesartan
inhibitor or ARB at maximum doses slows the progression has been found to be renoprotective independent of
of kidney disease in comparison to placebo.49,50 Patients its blood pressure lowering effect. The use of both ACE
with any level of albumanria (urinary albumin excretion inhibitors and ARBs in combination is not recommended
≥ 30 mg/g creatinine)51 should be given an ACE inhibitor given the lack of added ASCVD benefit and increased
or ARB as primary antihypertensive agent. In patients rate of adverse events namely, hyperkalemia, syncope,
without albuminuria other antihypertensive agents and acute kidney injury.57
are similar to ACE inhibitors and ARBs.52 Most diabetic Because these patients are at such high cardiovascular
hypertensive patients require a combination of two to risk, they require an integrated intervention that also
three antihypertensive agents to lower blood pressure includes optimal achievement of goals for glycemic
to target and patients with concomitant chronic kidney control (glycated hemoglobin [HbA1 c] <7% and pre-
disease may even require more number of drugs. prandial capillary plasma glucose 70–130 mg/dL,
We may also like to add drugs such as aldosterone normal lipid levels, and inhibition of platelet aggregation
receptor blockers (particularly recommended in obese (therapy with low-dose aspirin 75–162 mg/day). All
diabetic patients and resistant hypertension), a different diabetes patients should be on a statin, with other drugs
sub class of CCBs or alpha-blockers. Addition of another added, if necessary, to bring the LDL to <70 mg/dL,
triglycerides <150 mg/dL, and high-density lipoprotein damage including cardiovascular and renal diseases a
cholesterol >40 mg/dL in men and >45 mg/dL in women. lower blood pressure targets (i.e. 140/90 mm Hg) may
We should ascertain that potassium level is <5 mEq/L, be advisable to avoid the progression of these diseases
with lifestyle modifications or adjustment of drug during pregnancy.
therapy, as it is found to decrease the cardiovascular risk. Methyldopa, labetalol, hydralazine and long-
acting nifedipine, clonidine, and prazosin are known
Bed Time Dose to be effective and safe antihypertensive drugs in
Evidence suggests an association between absence pregnancy. ACE inhibitors, ARBs, or spironolactone
of nocturnal blood pressure dipping and ASCVD is contraindicated in pregnancy, as they may cause
events. Significantly reduced cardiovascular events was fetal damage. Diuretic use during pregnancy has been
observed by shifting one antihypertensive medication to associated with restricted maternal plasma volume
bedtime.58,59 Its desirable to give at least one drug in the which might reduce uteroplacental perfusion66 however
evening to them who require multiple drugs. they may be used during late-stage pregnancy if needed
for volume control. Those patients with gestational
Monitoring hypertension who had preeclampsia should have their
Self-management is very important aspect of diabetes blood pressures observed for 72 h in the hospital and
care for both diabetes and hypertension and home blood for 7–10 days’ postpartum.63 Long-term follow-up is
pressure monitoring is essential and it’s as reliable as 24-h recommended for these women, as they have increased
ambulatory blood pressure monitoring and correlates lifetime cardiovascular risk.
better with ASCVD risk than office measurements. 60
Home blood pressures improves patient medication Hypertension in Diabetes: Resistant
adherence61 and cardiovascular risk reduction62 so the
Hypertension
updated guideline emphasizes patients to monitor their
Mineralocorticoid receptor antagonists (MRAs) are
own BP for hypertension diagnosis, treatment, and
effective for management of resistant hypertension in type
management.
2 diabetics and they may be added to the existing drugs
GESTATIONAL DIABETES like a renin-angiotensin system (RAS) inhibitor, diuretic,
and CCB. They reduce sympathetic nerve activity, reduce
The women with gestational hypertension of systolic
blood pressure, ≤ 160 mm Hg or diastolic blood pressure, albuminuria and have added cardiovascular benefits.67-69
≤ 105 mm Hg without the evidence of end-organ However, caution should be applied as they are known to
damage should not be treated with antihypertensive increase the risk of hyperkalemic episodes if added to an
medications, as there is no benefit vis a vis potential ACE inhibitor or ARB which can be managed with dietary
risks of therapy.63 There is no evidence to treat mild to potassium restriction, potassium-wasting diuretics, or
moderate preexisting hypertension in terms of reducing potassium binders.70
the risk of preeclampsia, preterm birth, fetal death, size
of infants in relation to gestational-age. 64 Low-dose Hypertension in Diabetes: Older Adults
aspirin is recommended to start at 12 weeks of gestation In older adults (Aged ≥ 65 years) diabetes and aging leads
for pregnant women at high risk of preeclampsia.65 Blood to arterial stiffness with increase in systolic and decrease
pressure between 120 and 160 mm Hg systolic and 80 in diastolic blood pressure. Systolic blood pressure
and 105 mm Hg diastolic is desirable for women who should be our main target of management in them which
need antihypertensive therapy. Lower blood pressure is difficult to achieve due to arterial stiffness and there
levels may cause impaired fetal growth. In pregnant are chances of iatrogenic complications like volume
women with hypertension and evidence of end-organ depletion, hypoglycemia and orthostatic hypotension.
When considering pharmacological treatment in benefit by lowering blood pressure to target. There
older adults with diabetes we should be careful regarding is robust data that supports targeting blood pressure
drug selection, their doses and earliest sign of side effects reduction to at least 140/90 in most adults with diabetes.
as β-blockers may mask signs of hypoglycemia, drugs In selected patients on an individual basis with high
may increase orthostatic hypotension, and diuretics cardiovascular disease risk lower blood pressure targets
can enhance the volume depletion. Medicine-taking may be beneficial if they can be achieved without
behaviors may be affected in the older aged group due to undue burden and side effects. ACE inhibitors, ARBs,
mental status like cognitive dysfunction. dihydropyridine CCBs and thiazide-like diuretics have
The therapeutic strategy for those who are fit should shown to improve clinical outcomes and are preferred
be similar to that in younger individuals with a blood for blood pressure control. If the target blood pressure
pressure target of 130/80 mm Hg.71 We should initiate goal is not achieved with the initial dose of first-line
therapy with a single agent in the elderly, those with high drug, increases in doses or the addition of a second drug
CVD risk, or patients with a history of hypotension or from a different group are recommended. Regardless
drug-associated side effects. ACE inhibitors, angiotensin of the initial drug treatment In addition to lifestyle
receptor blockers (ARBs), thiazide-like diuretics, or modifications multiple drugs (many will require three
dihydropyridine calcium channel blockers are the drug or more) are often needed to attain blood pressure goal
of choice. Multiple-drug therapy is generally required to of ≤ 130/80 mm Hg. Achievement of the target blood
achieve blood pressure targets. We should be cautious pressure may be more important than the particular
when initiating antihypertensive pharmacotherapy drug regimen used. In patients with albuminuria an ACE
with 2 drugs in older patients because hypotension or inhibitor or ARB should be the initial antihypertensive
orthostatic hypotension may develop. Simultaneously therapy. In patients treated with an ACE inhibitor, ARB or
administering more than 1 renin-angiotensin system diuretic serum/estimated glomerular filtration rate and
blocker should be avoided. serum potassium levels should be monitored frequently.
In those with loss of autonomy and major functional Treatment decisions should, of course be, individualized
limitations, higher systolic blood pressure goals should on the basis of clinical characteristics of the patient
be considered and treatment should be modified in including comorbidities, expected benefit of reduction
the presence of low supine systolic blood pressure or in ASCVD, heart failure, retinopathy and progression of
presence of orthostatic hypotension. diabetic kidney disease and risk of adverse events as well
In older people with impaired vascular compliance as tolerability, personal preference and cost especially for
and pulse pressure of 60 mm Hg we should be careful in poor patients. Less expensive fixed-dose combinations
reducing the systolic pressure against the risk of lowering of many drugs are available with better compliance.
diastolic pressure below 65–70 mm Hg as lowering Effective behavioral and motivational strategies are
of diastolic pressure below 65–70 mm Hg in this age recommended to promote lifestyle modification along
increases the risk for coronary heart disease, mortality, with integrating home-based monitoring and telehealth
and other adverse cardiovascular outcomes. interventions. Outcome may improve with quality
improvement strategies at the health care system
CONCLUSION provider and patient level.
Hypertension is one of the most important modifiable
risk factor for the macrovascular and microvascular REFERENCES
1. Chobanian AV, Bakris GL, Black HR, et al. National Heart,
complications of diabetes. Large numbers of studies
Lung, and Blood Institute Joint National Committee on
with multiple classes of antihypertensive medications in Prevention, Detection, Evaluation, and Treatment of High
patients of diabetes have demonstrated improvement in Blood Pressure; National High Blood Pressure Education
a range of outcome of cardiovascular and microvascular Program Coordinating Committee. The Seventh Report of
the Joint National Committee on Prevention, Detection, 15. Sowers JR, Epstein M, Frolich ED. Diabetes, hypertension,
Evaluation, and Treatment of High Blood Pressure: the JNC and cardiovascular disease: an update. Hypertension.
7 report. JAMA. 2003;289:2560-72. 2001;37:1053-9.
2. Adamsson Eryd S, Gudbj örnsdottir S, Manhem K, et al. 16. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. Diabetic
Blood pressure and complications in individuals with type 2 retinopathy. Diabetes Care. 2004;27:2540-53.
diabetes and no previous cardiovascular disease: national 17. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes
population based cohort study. BMJ. 2016;354:i4070. C, Ionescu-Tirgoviste C, Witte DR, Fuller JH. Vascular
3. Forouzanfar MH, Liu P, Roth GA, et al. Global burden of risk factors and diabetic neuropathy. N Engl J Med.
hypertension and systolic blood pressure of at least 110 to 2005;352:341-50.
115 mm Hg, 1990-2015. JAMA. 2017;317:165-82. 18. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel
4. de Ferranti SD, de Boer IH, Fonseca V, et al. Type 1 diabetes A. Blood pressure lowering in type 2 diabetes: a systematic
mellitus and cardiovascular disease: a scientific statement review and metaanalysis. JAMA. 2015;313:603-15.
from the American Heart Association and American 19. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure
Diabetes Association. Circulation. 2014;130:1110-30. lowering for prevention of cardiovascular disease and
5. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney death: a systematic review and metaanalysis. Lancet.
disease: a report from an ADA Consensus Conference. 2016;387:957-67.
Diabetes Care. 2014;37:2864-83. 20. Brunström M, Carlberg B. Effect of antihypertensive
6. Centers for Disease Control and Prevention. National treatment at different blood pressure levels in patients with
Diabetes Statistics Report: Estimates of Diabetes and Its diabetes mellitus: systematic review and meta-analyses.
BMJ. 2016;352:i717.
Burden in the United States. Atlanta, GA: US Department of
21. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood
Health and Human Services; 2014.
pressure targets in subjects with type 2 diabetes mellitus/
7. Stergiou GS, Asayama K, Thijs L, et al. Prognosis of white-
impaired fasting glucose: observations from traditional and
coat and masked hypertension: International Database
Bayesian random effects meta-analyses of randomized
of Home blood pressure in relation to Cardiovascular
trials. Circulation. 2011;123:2799-810.
Outcome. Hypertension. 2014;63:675-82.
22. Thomopoulos C, Parati G, Zanchetti A. Effects of blood-
8. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic
pressure-lowering treatment on outcome incidence in
neuropathy: a position statement by the American Diabetes
hypertension: 10 – Should blood pressure management
Association. Diabetes Care. 2017;40:136-54.
differ in hypertensive patients with and without diabetes
9. Freeman R, Wieling W, Axelrod FB, et al. Consensus
mellitus? Overview and meta-analyses of randomized trials.
statement on the definition of orthostatic hypotension,
J Hypertens. 2017;35:922-44.
neurally mediated syncope and the postural tachycardia
23. Xie X, Atkins E, Lv J, et al. Effects of intensive blood
syndrome. Auton Neurosci. 2011;161:46-8. pressure lowering on cardiovascular and renal outcomes:
10. Fleg JL, Evans GW, Margolis KL, et al. Orthostatic hypotension updated systematic review and meta-analysis. Lancet.
in the ACCORD (Action to Control Cardiovascular Risk in 2016;387:435-43.
Diabetes) blood pressure trial: prevalence, incidence, and 24. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt
prognostic significance. Hypertension. 2016;68:888-95. D, Menard J, et. al for HOT Study group. Effects of intensive
11. Briasoulis A, Silver A, Yano Y, Bakris GL. Orthostatic blood pressure lowering and low-dose aspirin in patients with
hypotension associated with baroreceptor dysfunction: hypertension: Principle results of the Hypertension Optimal
treatment approaches. J Clin Hypertens (Greenwich). Treatment (HOT) randomized trial. Lancet. 1998;351:1755-
2014;16:141-8. 62.
12. UK Prospective Diabetes Study Group: Tight blood pressure 25. UK Prospective Diabetes Study Group. Tight blood pressure
control and risk of macrovascular and microvascular control and risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 38. BMJ. complications in type 2 diabetes: UKPDS 38. BMJ.
1999;318(7175):29. 1998;317:703-13.
13. Eriksson H, Welim L, Wilhelmsen L, Larsson B, Ohlson 26. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore
LO, Svardsudd K, Tibblin G: Metabolic disturbances in G, Gregg EW. Achievement of goals in U.S. diabetes care,
hypertension: results from the population study: “Men born 1999-2010. N Engl J Med. 2013;368:1613-24.
in 1913.” J Int Med. 1992;232:389-95. 27. Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations
14. Ruilope LM. Proteinuria and renal function. Blood Pressure. of kidney disease among US adults with diabetes, 1988-
1993;2(Suppl.1):55-8. 2014. JAMA. 2016;316:602-10.
28. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease 38. Zgibor JC, Wilson RR, Orchard TJ. Has control of
in U.S. deaths from coronary disease, 1980-2000. N Engl J hypercholesterolemia and hypertension in type 1 diabetes
Med. 2007;356:2388-98. improved over time? Diabetes Care. 2005;28:521-6.
29. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, 39. ShawJE, Punjabi NM, Naughton MT, et al. The effect of
Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie treatment of obstructive sleep apnea on glycemic control in
G, Oberman A, Rutan GH, Stamler J. Effect of diuretic-based type 2 diabetes. Am J Respir Crit Care Med. 2016;194:486-
antihypertensive treatment on cardiovascular disease risk 92.
in older diabetic patients with isolated systolic hypertension. 40. Appel LJ, Champagne CM, Harsha DW, et al. Writing Group
JAMA. 1996;276:1886-92. of the PREMIER Collaborative Research Group. Effects of
30. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, comprehensive lifestyle modification on blood pressure
Antikainen R, Bulpitt CJ, Fletcher AE, Forette F, Goldhaber control: main results of the PREMIER clinical trial. JAMA.
A, Palatini P, Sarti C, Fagard R. Effects of calcium-channel 2003;289(16):2083-93.
blockade in older patients with diabetes and systolic 41. Appel LJ, Moore TJ, Obarzanek E, et al. For the DASH
hypertension. N Engl J Med. 1999;340:67784. Collaborative Research Group. A clinical trial of the effects
31. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt of dietary patterns on blood pressure. N Engl J Med.
D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. 1997;336(16):1117-24.
Effects of intensive blood pressure lowering and low-dose 42. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM.
aspirin in patients with hypertension: principal results of the Influence of weight reduction on blood pressure: a meta-
Hypertension Optimal Treatment randomized trial. Lancet. analysis of randomized controlled trials. Hypertension.
1998;351:1755-62, 2003;42(5):878-84.
32. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of 43. Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio
aggressive blood pressure control in normotensive type 2 FP, Meerpohl JJ. Ef fect of lower sodium intake on
diabetics on albuminuria, retinopathy, and strokes. Kidney health: systematic review and metaanalyses. BMJ.
Int. 2002;61:1086-97. 2013;346:f1326.
33. Patel A, MacMahon S, Chalmers J, et al. ADVANCE 44. Whelton PK, He J, Cutler JA, et al. Effects of oral potassium
Collaborative Group. Effects of a fixed combination on blood pressure: meta-analysis of randomized controlled
of perindopril and indapamide on macrovascular and clinical trials. JAMA. 1997;277(20):1624-32.
microvascular outcomes in patients with type 2 diabetes 45. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on
mellitus (the ADVANCE trial): a randomised controlled trial. blood pressure: a meta-analysis of randomized, controlled
Lancet. 2007;370:829-40. trials. Ann Intern Med. 2002;136(7):493-503.
34. Zoungas S, Chalmers J, Neal B, et al. ADVANCE-ON 46. Inder JD, Carlson DJ, Dieberg G, McFarlane JR, Hess NC,
Collaborative Group. Follow-up of blood-pressure lowering Smart NA. Isometric exercise training for blood pressure
and glucose control in type 2 diabetes. N Engl J Med. management: a systematic review and meta-analysis to
2014;371:1392-406. optimize benefit. Hypertens Res. 2016;39(2):88-94.
35. Hansson L, Zanchetti A, Carruthers SG, et al. HOT Study 47. Roerecke M, Kaczorowski J, Tobe SW, Gmel G, Hasan OSM,
Group. Effects of intensive blood pressure lowering and low- Rehm J. The effect of a reduction in alcohol consumption
dose aspirin in patients with hypertension: principal results on blood pressure: a systematic review and meta-analysis.
of the Hypertension Optimal Treatment (HOT) randomised Lancet Public Health. 2017;2(2):e108-e20.
trial. Lancet. 1998;351:1755-62. 48. Gavras H, Gavras I. On the JNC V report. A different point of
36. Wright JT Jr, Williamson JD, Whelton PK, et al. SPRINT view. Am J Hypertens. 1994;7:288-93.
Research Group. A randomized trial of intensive 49. Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL
versus standard blood-pressure control. N Engl J Med. Study Investigators. Effects of losartan on renal and
2015;373:2103-16. cardiovascular outcomes in patients with type 2 diabetes
37. Maahs DM, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea and nephropathy. N Engl J Med. 2001;345:861-9.
D, Hokanson J, Ehrlich J, Garg S, Eckel RH, Rewers MJ. 50. Lewis EJ, Hunsicker LG, ClarkeWR, et al. Collaborative Study
Hypertension prevalence, awareness, treatment, and control Group. Renoprotective effect of the angiotensin-receptor
in an adult type 1 diabetes population and a comparable antagonist irbesartan in patients with nephropathy due to
general population. Diabetes Care. 2005;28:301-6. type 2 diabetes. N Engl J Med. 2001;345:851-60.
51. Palmer SC, Mavridis D, Navarese E, et al. Comparative Associazioni (PAMELA) study. Circulation. 2005;111:1777-
efficacy and safety of blood pressure lowering agents in 83.
adults with diabetes and kidney disease: a network meta- 61. Omboni S, Gazzola T, Carabelli G, Parati G. Clinical
analysis. Lancet. 2015;385:2047-56. usefulness and cost effectiveness of home blood pressure
52. Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes telemonitoring: meta-analysis of randomized controlled
mellitus as a compelling indication for use of renin studies. J Hypertens. 2013;31:455-67; discussion 467-8.
angiotensin system blockers: systematic review and meta- 62. DeAlleaume L, Parnes B, Zittleman L, et al. Success in the
analysis of randomized trials. BMJ. 2016;352:i438. Achieving Cardiovascular Excellence in Colorado (A CARE)
53. Weber MA, Bakris GL, Jamerson K, et al. ACCOMPLISH home blood pressure monitoring program: a report from
Investigators. Cardiovascular events during differing the Shared Networks of Colorado Ambulatory Practices
hypertension therapies in patients with diabetes. J Am Coll and Partners (SNOCAP). J Am Board Fam Med. 2015;28:
Cardiol. 2010;56:77-85. 548-55.
54. Jamerson K, Weber MA, Bakris GL, et al. ACCOMPLISH 63. American College of Obstetricians and Gynecologists;
Trial Investigators. Benazepril plus amlodipine or Task Force on Hypertension in Pregnancy. Hypertension in
hydrochlorothiazide for hypertension in high-risk patients. N pregnancy. Report of the American College of Obstetricians
Engl J Med. 2008;359:2417-28. and Gynecologists’ Task Force on Hyper tension in
55. Jamerson KA. Avoiding Cardiovascular events through Pregnancy. Obstet Gynecol. 2013;122:1122-31.
Combination therapy in Patients Living with Systolic 64. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy
Hypertension Trial (ACCOMPLISH): the first hypertension for mild to moderate hypertension during pregnancy.
trial comparing the effects of two fixed-dose combination Cochrane Database Syst Rev. 2014;6:CD002252.
therapy regimens on cardiovascular events. J Clin Hypertens 65. LeFevre ML. US Preventive Services Task Force. Low-
(Greenwich). 2003;5(4 Suppl. 3):29-35. Cross Ref Medline. dose aspirin use for the prevention of morbidity and
56. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, mortality from preeclampsia: US Preventive Services
Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes Task Force recommendation statement. Ann Intern Med.
GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J. ASCOT 2014;161:819-26.
Investigators. Prevention of cardiovascular events with an 66. Sibai BM. Treatment of hypertension in pregnant women. N
antihypertensive regimen of amlodipine adding perindopril Engl J Med, 1996;335:257-65.
as required versus atenolol adding bendroflumethiazide as 67. Williams B, MacDonald TM, Morant S, et al. British Hyper
required, in the Anglo-Scandinavian Cardiac Outcomes Trial- tension Society’s PATHWAY Studies Group. Spironolactone
Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre versus placebo, bisoprolol, and doxazosin to determine
randomised controlled trial. Lancet. 2005;366:895-906. the optimal treatment for drug-resistant hypertension
Cross Ref Medline Web of Science. (PATHWAY-2): a randomised, double-blind, crossover trial.
57. Makani H, Bangalore S, Desouza KA, Shah A, Messerli Lancet. 2015;386: 2059-68.
FH. Efficacy and safety of dual blockade of the renin- 68. Filippatos G, Anker SD, Böhm M, et al. A randomized
angiotensin system: meta-analysis of randomised trials. controlled study of finerenone vs. eplerenone in patients
BMJ. 2013;346:f360. with worsening chronic heart failure and diabetes mellitus
58. Hermida RC, Ayala DE, Moj ón A, Fernández JR. Influence and/or chronic kidney disease. Eur Heart J. 2016;37:2105-
of time of day of blood pressure lowering treatment on 14.
cardiovascular risk in hypertensive patients with type 2 69. Bomback AS, Klemmer PJ. Mineralocorticoid receptor
diabetes. Diabetes Care. 2011;34:1270-6. blockade in chronic kidney disease. Blood Purif. 2012;33:
59. H e r m i d a RC , Ay a l a D E , M o j ´ o n A , Fe r n ´ a n d e z 119-24.
JR. Bedtime dosing of antihypertensive medications 70. Bakris GL, Pitt B, Weir MR, et al. AMETHYSTDN Investigators.
reduces cardiovascular risk in CKD. J Am Soc Nephrol. Effect of patiromer on serum potassium level in patients with
2011;22:2313-21. hyperkalemia and diabetic kidney disease: the AMETHYST-
60. Sega R, Facchetti R, Bombelli M, et al. Prognostic value DN randomized clinical trial [published correction appears
of ambulatory and home blood pressures compared with in JAMA 2015. JAMA. 2015;314:731.
office blood pressure in the general population: follow- 71. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/
up results from the Pressioni Arteriose Monitorate e Loro AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA
guideline for the prevention, detection, evaluation, and BIBLIOGRAPHY

management of high blood pressure in adults: a report 1. American College of Cardiology/American Heart Association
of the American College of Cardiology/American Heart Task Force on Clinical Practice Guidelines 2017 for the
Association Task Force on Clinical Practice Guidelines Prevention, Detection, Evaluation and Management of High
[published online ahead of print November 13, 2017]. Blood Pressure in Adults.
Hypertension. doi: 10.1161/HYP.0000000000000065. 2. Thakur BB. Management of Hypertension in Diabetes.
Medicine Update. 2010;20:407-12.
CHAPTER
11
Grey Areas in Diagnosis and
Management of Hypertension
Anita Jaiswal
Hypertension is only a marker of the bigger problem. Stroke

Hypertension is a multiorgan systemic disease. Cerebral hemorrhage
Hypertension is asymptomatic in 85% of cases. It is Myocardial infarction
extremely vital to diagnose hypertension before any Left ventricular hypertrophy
systemic side effects are used. Aortic aneurysm
Peripheral vascular disease
RULE OF HALVES Retinopathy
For every 800 adults in the community, 400 are HT (either Chronic kidney failure
↑ SBP or ↑ DBP or both). Of them only 200 are diagnosed
HT. Of them only 100 are started on treatment. Of them Approach to hypertension:
Are all patients screened for hypertension?
only 50 are on correct drug. Of them in only 25 the goal
Are all hypertensives correctly identified?
BP is attained. Means 25 ÷ 400 = 6% only have goal BP.
Are they evaluated for comorbidities/TOD?
How many are really Diagnosed and Are they assessed for CHD risk factors?
Precriptioned (Fig. 1) Are the correct drug combinations prescribed?
Diseases attributable to hypertension: Is the goal BP achieved and maintained?
Coronary heart disease Are there any complications/side effects?
Heart failure —— Issues in measuring hypertension (Fig. 2)
Fig. 1: How many are really Dx. and Rx.ed?

Fig. 2: Measurement of blood pressure
—— Hypertension is a variable phenomenon Abstinence from alcohol—2–4 mm Hg

—— Normally, the blood pressure reading is taken —— Here we see the importance of lifestyle modi
after patient has sat down for 5–10 minutes fication.

—— However, this is reading in controlled settings —— In our busy clinical practice, we tend to just skim
—— This does not show daily variation/variation when over lifesyle modifications whereas more stress
the person is under physical stress/mental stress should be put on this.
—— Hence, before deciding complete treatment one —— Proper counseling needs to be given for lifestyle
should measure the blood pressure immediately modification.

when a patient comes and also after exertion/stress —— Also regular follow up needs to be done to ensure
—— This will show both the trough and crest in blood that lifestyle modifications are maintained.
pressure measurement and hence the physician
The many facets of HT therapy:
is more alert about maximum and minimum Centrally acting agonists
ranges, which makes it easy to prescribe an Diuretics
accurate drug (Fig. 2). Beta blockers
CCBs
Lifestyle Modification ACE inhibitors
Lifestyle modification is the sheet anchor in the ARBs
management hypertension.
This surely reduces the number of drugs used and Which Drug Should We Prescribe ?
their dosage in controlling HT. Choice must be tailored to individual patient
Any drug treatment has value only when coupled Should be rational and as per approved guidelines
with lifestyle modification. Only class1 evidence based medications to be used
Lifestyle modification: Suitable to patients’ purse
Weight reduction—5–20 mm/10 kg weight loss Can never be arbitrary
Adopt DASH eating plan—8–14 mm Hg
Dietary sodium reduction—2–8 mm Hg Physicians’ Bias in HT

Physical activity—4–9 mm Hg Isolated SHT is often dubbed as ‘aging factor’
CHAPTER 11: Grey Areas in Diagnosis and Management of Hypertension 69
To consider HT is only in the ‘ARM’ and not in the Calcium Channel Blockers
body Action: Blocks calcium access to muscle cells. Examples
No concept of ‘pulse pressure’—Not seeing the whole of calcium channel blockers: Verapamil, Nifedipine,
Worry about side effects—Need to watch, not to worry Diltiazem
OK, some control is achieved—Why attain goal BP? Side effects
Not insisting on compliance with drugs and assess BP
ments Bradycardia
Pressure from patients—BP How much? May precipitate AV block
Concentrating on the pill and not on the ill—TLC Headache
forgotten Abdominal discomfort

We discuss side effects of medicines, used for Peripheral edema
hypertension which by their side effects prevent Headache—can cause persistent discomfort and
proper control of hypertension.
hence increase in hypertension
Abdominal discomfort—this can cause hypertension
Diuretics
due to the distress it creates
Most widely prescribed: Thiazides
Also peripheral edema that is seen due to calcium
Mild to moderate HTN—primarily
channel blockers causes discomfort in the lifestyle of
Hydrodiuril—hydrochlorothiazide (HCTZ)
the patient, i.e prevent patient from active walking,
Hypokalemia
Potassium supplement—KCL
cause psychological stress and hence cause increase
in hypertension.
Potassium‐sparing: Prevent hypokalemia
Mild HTN
ACE inhibitors
Angiotensin converting enzymes ending pril
Used in combination with other diuretics
Captopril
No supplement taken
Enalapril
Watch for hyperkalemia
Benzapril
Side effects —— Action
Orthostatic hypotension
—— Peripheral vascular resistanse without
Dry mouth, irritation
cardiac output
Report cardiac rate
Electrolyte imbalance—hypokalemia (potassium cardiac contractility
<3.5)
Side effects
Disorientation
Headache
Dehydration
Orthostatic hypotension‐infrequent
Hypokalemia—Muscle pain and fatigue
Cough
Hyperuricemia—Inhibition of urate excretion
GI distress
Both cause pain, patient feels fatigued, not proper rest
and hence hypertension is not relieved adequately ACE inhibitors

This results in increase in dose of antihypertensives Headache can cause stress due to hypertension
and hence thiazide diuretics should be discontinued. Cough can cause a patient to stay awake in the night
Diuretics cause electrolyte imbalance which can can cause lack of sleep and hypertension.
cause disorientation which can cause missed doses of Hence, a patient receiving ACE inhibitors should be
antihypertensives which cause increase in hypertension. carefully monitored for these side effects.
Beta Adrenergic Blocking Agents

Known as Beta‐blockers
Axn: Inhibit cardiac response to sympathetic nerve
stimulation by blocking Beta receptors
Decreases heart rate increases CO
Decreases blood pressure
Examples – “olol” names
Beta 1: Atenolol
Beta 1 and 2: Propranolol
Side effects
Bradycardia
Bronchospasm, wheezing
Diabetic: Hypoglycemia
Heart failure: Edema, dyspnea, rhales
Bronchospasm, wheezing can cause a patient to stay
awake at night, and cause hypertension

Also these drugs should not be abruptly discontinued.
Fig. 3: Recommendations for follow-up

Alpha‐1 adrenergic blockers
Alternative if b‐blockers and diuretics do not work
Never suddenly DC = rebound HTN
Also used to treatment mild to mod. urinary
Clonidine—Catapres (available in TTS)
obstructive dx. (BPH) Methyldopa—Aldomet
Cardura (doxizosin)
More frequent side effects—drowsiness, dry mouth,
Minipress (prazosin)
dizziness
Hytrin (terazosin)
Dizziness can cause imbalance and falls and hence
Side effects cause hypertension due to the stress assosciated
Drowsiness
Headache
Direct Acting Vasodilators
Dizziness, tachycardia, fainting
Action: Direct arteriolar smooth muscle relaxation,
Weakness, lethargy
decreasing PVR
Uses: HTN, renal dx., toxemia of pregnancy
Interactions: Other antihypertensives (enhance
Ex: Apresoline, Minoxidel

effects)
SE: Tachycardia, orthostatic hypotension, dizziness,
Alpha‐1 adrenergic blockers palpitations, nausea, nasal congestion

Headache—patient can feel irritable and cause stress
Orthostatic hypotension, dizziness, which can cause
which causes hypertension hypertension due to the symptoms symptoms caused

Weakness, lethargy—can cause irritation and this can
by it
cause increase in hypertension Recommendations for follow-up for diagnosis of
Centrally acting alpha‐2 agonists hypertension is shown in Figure 3.
Stimulate Alpha‐2 receptors in brainstem
Decreases HR, SBP and DBP TYPES OF BLOOD PRESSURE

More frequent side effects—drowsiness, dry mouth, INSTRUMENTS
dizziness Devices: Aneroid, Mercury, Electronic
CHAPTER 11: Grey Areas in Diagnosis and Management of Hypertension 71
Features —— Averages the remainder

Ease of use: Electronic > Aneroid > Mercury —— Interval between readings from 1 to 5 minutes
Cost: Electronic > Mercury > Aneroid apart
—— User can auscultate using the digital readout
Accuracy: Mercury > Aneroid > Electronic
Memory: Electronic only. when desired
Time of Measurement Blood Pressure Monitoring?

Use multiple readings at different times during the For Dx mild to mod HTN
waking hours of the patient. For elderly women with ISH
For patient taking antihypertensive medications For apparent Rx resistance
monitoring of blood pressure should be done before For anxiety prone patients
taking the scheduled dose. When marked fluctuations in office BP present
For symptoms suggestive of hypotension present on
Benefits of Automated Rx
BpTRU™ BP Devices White coat HTN unlikely
—— If DM coexists
Standardizes BP readings from one operator to the
—— If TOD present
next
Removes many of the errors associated with manual
readings Pressure and Target Organ Damage
Accurate, reliable and reproducible readings 24‐h blood pressure correlates most closely with
Multiple readings with averaging target organ damage (TOD) (compared to clinic or
“Opportunistic screening” casual BP)
Accurate, independently validated device Higher incidence of cardiovascular events when blood
Automatically zeroes with each inflation pressure remains elevated at night (nondippers)
Performs full system check every time on powering‐ Blood pressure variability is an independent
up determinant of TOD
—— Performs six readings Highest incidence of cardiovascular events occurs in
—— Discards the first reading AM
SECTION
2
Cardiology
Atherosclerosis: Can We Tame it? Rheumatic Valvular Heart Disease
Harendra Kumar RR Singh
Cardiac Cachexia Advances in Management of Pulmonary Arterial
AKP Singh Hypertension
Is Intervention Still Relevant in Stable CAD?
Santanu Guha, Bappaditya Kumar Infective Endocarditis: An Update
Newer Oral Anticoagulants in Clinical Practice
Anshul Kumar Jain Pregnancy and Heart Disease
Dual Antiplatelet Therapy: How Long?
Sameer Kumar, Girish MP, Mohit D Gupta A Review of Cardiorenal Syndrome
Newer Biomarkers in Heart Failure
Saumitra Ray Heart Failure with Reduced Ejection Fraction:
Treatment Strategy
Coronary Microvascular Dysfunction: An Update
Amal Kumar Banerjee
SM Mustafa Zaman
Pulmonary Embolism: Focus on New Drugs
How did Fractional Flow Reserve Change My
Clinical Decisions? Case-based Discussions
Nagendra Boopathy Senguttuvan Echocardiographic Navigation of AF from Irregular
Pulse to Slurring of the Speech: Relevant at All
Mega Trials in Cardiology
Stages in India and the Real World
Sundeep Mishra
HK Chopra, Ravi R Kasliwal,
Manish Bansal, Shraddha Ranjan
CHAPTER
12
Atherosclerosis: Can We Tame it?
Harendra Kumar
INTRODUCTION progress with inflammation and subsequent activation

Cardiovascular diseases are major causes of mortality and of cellular and other elements. In due course, there is
morbidity worldwide including low income countries.1 formation of atheroma. This occurs at various sites of
The mortality has declined in high income countries, vessels. Inflammation is a major contributory factor of
whereas it is on the rise in low income developing atherosclerosis.
countries.2 The underlying pathology is atherosclerosis
in the arteries, but affection of coronary and cerebral Assessment of Atherosclerosis
arteries are major causes of death. Risk factors are shown Majority of coronary thrombosis are due to plaque
in Table 1. rupture or erosion and usually occurs in arteries with
Approximately 80% of observed risk factors were 50–60% obstructive lesion. So, assessment by ECG, stress
due to diabetes (DM), hypertension (HTN), smoking, ECG, ECHO, stress thallium may not be diagnostic. In
lipids and obesity in the INTERHEART trial.3 Initially many cases, coronary angiography may show noncritical
there is endothelial dysfunction with deranged vascular lesions. But there can be myocardial infarction (MI) and
environment. Then there is deposition of LDL in the 30% person may have sudden cardiac death (SCD). It is
intima, i.e. fatty streak formation. This may disappear or important to pick up subclinical atherosclerosis.
TABLE 1: Common risk factors for atherosclerosis METHODS ARE CAROTID

Hypertension Physical inactivity
INTIMA-MEDIA THICKNESS (CIMT)
Diabetes mellitus (DM) Family history of CVD It is a noninvasive and cheap method to assess carotid
Smoking and tobacco Lipid abnormalities atherosclerosis by ultrasound which is acceptable and
Obesity ↑ Homocysteine level relates with coronary artery lesions. So, one can guess
↑ Dietary fat CKD severity of coronary lesions.
Increasing age
Lipid abnormalities Cardiac CT and Calcium Scoring
↑ LDL ↑ TG Higher the calcium score, more extensive is the disease
↑ Cholesterol ↑ LP (a) usually. It is a noninvasive and so many go for it. It is
↑ Non-HDL cholesterol ↑ APO-B available at many cardiac centers but there is exposure
↓ HDL to radiation.
76 SECTION 2: Cardiology
CT Coronary Angiography Drug Therapy

It is a noninvasive angiography and plaque is also (1) Statins (2) Fenofibrate (3) Ezetimibe (4) PCSK-9
visualized. But radiation exposure is hazard. Secondly, Inhibitors (5) ACEI/ARB (6) Anti-inflammatory drugs.
catheter angiography will be needed before PTCA for
CABG. Statins
Statins are cornerstone in the treatment of atherosclerosis.
Method for Assessment of Plaque They can arrest progression, can slow down, regress
Morphology atherosclerosis and stabilize atherosclerotic plaque.
Intravascular Ultrasound (IVUS) and OCT Large number of trials have shown enormous benefit by
statins. Earlier studies/Trials for primary prevention of
These are invasive and catheters are costlier than simple
CAD like, AFCAPS/TexCAPS4, WOSCOPS5, Ascot-LLA6,
catheters. But these give good view of atheroma. Optical
JUPITER7, etc. have shown impressive results in reducing
coherence tomography (OCT) gives magnified and detail
AMI or death. Secondary trials of earlier days with normal
visualization of plaque and its morphology.
or near normal cholesterol level, LIPID8, MIRACL9 have
By PET-imaging, one can also visualize status of
shown significant reduction in morbidity and mortality.
plaque morphology and composition. But, not only
Several meta-analysis have shown efficacy of statins
there is exposure to radiation, it is costly also and it is
in primary prevention of CAD.10-12 A Meta-analysis of
available in tertiary centres. As of now, it is mainly used
2010 including 26 RCT’s on statins which included large
for research.
number of patients showed benefits. After 5 years of
follow up, there was 38% reduction in LDL, 29% decrease
Cardiac MRI (CMRI)
in major CV events, 19% reduction in revascularization
It can be used to visualize plaque and we get information
and 16% decrease in CVA events.13 Reduction in plaque
about morphology. Although devoid of radiation, it is not
volume is not significant as shown in Table 2.
common, costly and also not cost effective in India.
It is already evident from several trials that there is
significant reduction in lipids and clinical events. This is
Management of Atherosclerosis
due to change in plaque morphology. Statins act beyond
Prevention and Taking Care of Risk Factors lipid lowering, the so called pleotropic actions. They
First and foremost thing is to take care of risk factors reduce inflammation which is an important factor in
mentioned in Table 1. Majority of risk factors are atherosclerosis. There was reduction of hsCRP, a marker
preventable or can be controlled. It someone has already of inflammation by 34–38% in PROVE IT TIMI-22 18
some disease, life style modification will go a long way and MIRACL9 study. They also reduce IL-6, and other
in delaying or slowing atherosclerosis. Progression of interleukins, ICAM-1 other markers of inflammation.
atherosclerosis due to aging can also be halted or slowed
down with several measures. Care of lipid abnormalities TABLE 2: Reduction in plaque on statin treatment
will also be of great help. Those with HTN should take
Study Drug Reduction in size of plaque
proper treatment. Majority of diabetic patients die of CV 14
MAAS Simvastatin 0.1–0.2 mm regression in size of
diseases. Combination of DM and HTN is also dangerous atheroma
and proper selection of drugs for these have great impact
MARS15 Lovastatin 4.1%
on morbidity and mortality in this situation. So, control 16
ASTEROID Rosuvastatin 6.1% Plaque vol.
of risk factors has far-reaching consequences. Most of
COSMOS17 Rosuvastatin 5.1%
risk factors are common to CAD and CVA.
CHAPTER 12: Atherosclerosis: Can We Tame it? 77
High Dose Statin Trials: IDEAL, 19 TNT, 20 PROVE IT with abnormal deposition of collagen, 26,27 leading to
TIMI-22,18 MIRCL9 have given good results. The benefit ventricular dysfunction after AMI. Ang-II stimulates
of statins starts early, in PROVE IT TIMI-22, Clinical fibroblasts to produce collagen and enhances chanses
benefits appeared in four weeks and MIRACL study after of fibrosis. So, there is evidences that Ang-II enhances
four months. High dose use of statin has been found atherosclerotic process. ACE inhibitors are beneficial for
to significantly reduce MI, unstable angina, CVA and CV health due to anti-inflammatory, plaque stabilizing,
chances of revascularization.21 anti-atherothrombotic and antiproliferative properties.
A recent meta-analysis involving 8 trials has shown a ACE inhibitors also reduce MMPs, hsCRP and platelet
statistically significant reduction of CV events when LDL aggregation.28 Meta-analysis of several trials have shown
level between 75 and 100 mg/dL was brought to less than reduced CV events on use of ACE inhibitors.29 The benefit
50 mg/dL.22 of HOPE and LIFE trials are well known. In PROGRESS
trial, risk reduction was 26% in CVD and 28% in stroke.30
CHOLESTEROL ABSORPTION INHIBITOR
Addition of Ezetimibe, when required, may be helpful in Anti-inflammatory Agents
further lipid lowering. Keeping in mind the immense role of inflammation
in causation of atherosclerosis, role of other anti-
Fibrates inflammatory agents such as methotrexate, colchicin,
Hypertriglyceridemia (↑ TG) appears to increase risk hydroxychloroquin, etanercep, toclizumab, cana
of CVD. There is some evidence that post prandial kinumab are being studied. Anti-inflammatory agent
increased level of TG may be a potent risk factor for canakinumab which is IL-1 beta inhibitor, has been
CVD and it may be an independent risk factor.23 A more recently evaluated in the CANTOS trial, 31 results of
recent and large meta-analysis involving 61 studies (N which came out in August 2017 only. This large trial
= 330566) has reported 22% increase in risk of CVD for included cases of previous MI with elevated hsCRP
every 88 mg/dL increase in TG.24 and were already on standard treatment including high
dose statin. Patients were given 150 mg canakinumab
PCSK-9 Inhibitors: Alirocumab, injection subcutaneous once in three month. Follow-up
Evolocumab period was four years. There was reduction in hs-CRP
Evolocumab subcutaneous monthly injection may be level by 37% and reduction in risk of major CV events by
used in extreme risk and still elevated LDL level despite 15% independent of lipid lowering. There was reduction
statins. It can be combined with statins. In the FOURIER in the incidence of lung cancer also. These findings are
trial25 on 27500 patients with baseline LDL level of 75 revolutionary.
mg/dL and already on statin treatment were given
evolocumab for 2.2 years. They showed 20% decrease CONCLUSION
in risk compared to placebo group. But this is expensive So,we have many weapons in our hand to check
and not cost effective. atherosclerosis. Life-style measures, control of risk
factors, lipid lowering drugs like statin (which have actions
ACE Inhibitors and ARB beyond lipid lowering including anti-inflammatory
Harmful effects of angiotensin-II (Ang-II) are well known. actions), PCSK-9 inhibitors which are more potent (but
It causes vasoconstriction, vascular inflammation, availability and cost are concerns) are well known. ACE
cardiac hypertrophy, activation of sympathetic inhibitors and ARB have already established their role
nervous system. Ang II has toxic effects on myocytes; in atherosclerosis. Anti-inflammatory agents such as
stimulates fibroblasts and causes muscle hypertrophy canakinumab has shown great promise. All methods are
rewarding, but important factor is how intelligently, and The MIRACL study, a randomized controlled trial. JAMA.
optimally we utilize them. 2001;285 (13):1711-8.
10. Brugts JJ, Yetgin T, Hocks SE, et al. The benefits of statins in
Taming of atherosclerosis has become possible and
people without established cardiovascular disease but with
is bound to increase longevity of mankind; efforts must cardiovascular risk factors: Meta-analysis of randomized
go on. controlled trials. BMJ. 2009;338:b2376.
11. Taylor F, Ward K, Moore TH, et al. Statins for the primary
REFERENCES prevention of cardiovascular disease. Cochrane Database
1. Gersh B , Mayosi B. Sliva K, et al. The epidemic of Sys Rev. 2011;1:1
cardiovascular diseases in developing world global 12. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of
implication. Eur HJ. 2010; 31:642-8. cardiovascular outcomes trials comparing intensive versus
2. Yusuf S, Reddy S, Oun PPu S et al. Global burden of moderate statin therapy. JACC. 2006;48:438-45.
cerebrovascular diseases: Part-I General considerations, 13. Balgent C, Keech A, Kemney FM, et al. Efficacy and safety of
the epidemiologic transition, risk factors and impact of cholesterol-lowering treatment: Prospective meta-analysis
urbanization circulation. 2001;104:2746-53. of data from 90056 participants in 14 randomised trials on
3. Yusuf S, Hawken S, ounpau S, et al. Effect of potentially statins. Lancet. 2010;376:1670-81.
identifiable risk factors associated with myocardial 14. Effect of simvastatin on coronary atheroma: the multi
infarction in 52 countries (The INTERHEART Study): case centre atheroma study (MAAS). Lancet. 1994;344:633-8.
control study. Lancet. 2004;364:937-52. 15. Blankenorn DH, Azen SP, Kramsch DM, et al. MARS
4. Downs JR, Clearfild M, Weis S, et al. Primary prevention of research group, coronary angiographic changes with statin
acute coronary events with lovastatin in men and women therapy. The monitored atherosclerosis regression study
with average cholesterol level: Results of AFCAPS/TexCAPS, (MARS). Ann Intern Med. 1993;119:969-76.
air force/Texas coronary atherosclerosis prevention study. 16. Nissen SE, Nicholls SJ, Sipahi T, et al. Effect of very
JAMA. 1998;279:1615-22. high intensity statin therapy on regression of coronary
5. Shepherd J, Cobbe SM, Ford J, et al. For the west of atherosclerosis in the ASTEROID trial. JAMA. 2006;295:
Scotland coronary prevention study group. Prevention 1556-65.
of coronary heart disease with pravastatin in men with 17. Takayama T, Hiro T, Yamagishi M. For the COSMOS
Hypercholesterolemia. N Engl J Med. 1995;333:1301-7. study. Effect of rosuvastatin on coronary atheroma on
6. Sever PS, Dahloe F, Poulter NR, et al. Prevention of coronary stable coronary artery disease: Multicentre coronary
and stroke events with atrovastatin in hypertensive patients atherosclerosis study measuring effects of rosuvastatin
who have average or lower than average cholesterol using IVUS in Japanese subjects (COSMOS). CIR J.
concentration, in the anglo-scandinavian cardiac outcome 2009;73(11):2110-17.
trial-lipid lowering arm (ASCOT-LLA): A multicentre 18. Murphy SA, Cannon CP, Wiviott SD, et al. Reduction in
randomized trial. The Lancet. 2003;361:1149-58. recurrent cardiovascular events with intensive lipid lowering
7. Ridker PM, Fonseca FA, Genest J, et al. Baseline statin therapy compared with moderate lipid lowering statin
characteristics of participants in the JUPITER trial: A therapy after acute coronary syndromes from the PROVE
randomized placebo controlled primary prevention trial of IT TIMI 22 (Pravastatin or Atorvastatin evaluation and
statin therapy among individuals with low LDL-cholesterol infection therapy + thrombolysis in myocardial infarction
and elevated high sensitivity C-reactive protein. AM J 22) trial JACC. 2009;54(25):2358-62.
Cardiol. 2007;100:1659-64. 19. Pedersen TR, Paergeman O, Kastelein JJ, et al. High dose
8. LIPID Study Group. Prevention of cardiovascular events atorvastatin vs usual dose simvastatin for secondary
and death with pravastatin in patients with coronary heart prevention after myocardial infarction. The IDIAL study: A
disease and a broad range of initial cholesterol level. The randomized controlled trial. JAMA. 2006;294(19):2437-45.
long term intervention with pravastatin in ischaemic heart 20. Larosa JC, Deedwania PC, Shepherd, et al. TNT investigators,
disease (LIPID) study group. N Engl J Med. 1998;339:1349- comparison of 80 versus 10 mg of atorvastatin on
57. occurrence of cardiovascular events after the first event
9. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Myocardial (from the treating to new targets [TNT] trial). Am J Cardiol
ischaemia reduction with aggressive cholesterol lowering 2010;105(3):283-7.
(MIRACL) study investigators. Effect of atrovastatin on early 21. Ridker PM, Danielson E, Fonseca FA, et al. Reduction of
recurrent ischaemic events in acute coronary syndrome: C-reactive protein and LDL cholesterol and cardiovascular
CHAPTER 12: Atherosclerosis: Can We Tame it? 79
event rates after initiation of rosuvastatin: A prospective 27. Weber KT, Brilla CG. Pathological hypertrophy and cardiac
study of JUPITER trial. Lancet. 2009;373:1175-82. interstitium, fibrosis and rennin-angiotensin-aldosterone
22. Boekholdt SM, Houingh GK, Mora S, et al. Very low levels system. Circulation. 1991;83:1849-65.
of atherogenic lipoproteins and the risk of cardiovascular 28. Scheiffer B, Bunte C, Witte J, et al. Comparative effects
events: A meta-analysis of statin trials. JACC. 2014;64:485- of AT-1 antagonism and angiotensin converting enzyme
94. inhibition upon markers of inflammation and platelet
23. Bansal S, Buring JE, Rifai N, et al. Fasting compared with aggregation in patients with coronary artery disease. JACC.
non fasting triglyceride and the risk of cardiovascular events 2004;44:362-8.
in women. JAMA. 2007;298:309-16. 29. Al-Mallah MH, Tleyjeh IM, AbdeL-Latif AA, et al. Angiotensin
24. Liu J, Zeng FF, Liu ZM, et al. Effects of blood triglycerides on converting enzyme inhibitors in coronary artery disease and
cardiovascular and all cause mortality: A systematic review preserved left ventricular systolic function: A systematic
and meta-analysis of 61 prospective studies. Lipid Health review and meta-analysis of randomized controlled trials.
Dis 2013;12:159. JACC. 2006; 47:1575-83.
25. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab 30. PROGRESS collaborative group. Randomised trial of
and clinical outcomes in patients with cardiovascular a perindropril based blood pressure lowering regimen
disease N Engl J Med. 2017. among 6105 individuals with previous stroke or transient
26. Lonn EM, Yusuf S, Jha P, et al. Emerging role of angiotensin- ischaemic attack. Lancet. 2001;358:1033-41.
converting enzyme inhibitors in cardiac and vascular 31. Ridker PM, et al. Anti-inflammatory therapy with canakinumab
protection. Ciruculation. 1994; 90:2056-69. for atherosclerotic disease. N Engl J Med. 2017.
CHAPTER
13
Cardiac Cachexia
AKP Singh
INTRODUCTION
Heart failure is currently appreciated as a systemic
and other multiorgan syndrome. The myocardium,
peripheral tissues and organs are affected by metabolic
failure, resulting in a global imbalance between catabolic
and anabolic signals, leading to tissue wasting and
ultimately to cachexia.
Cachexia is recognized today as severe complication
of CHF that worsens clinical symptoms and carries a
particulary Grave prognosis. Mortality in HF patients
with cachexia was as high as 50% at 18 months of follow-
up, compared with 17% in noncachectic patients.
PATHOPHYSIOLOGY Fig. 1: Summarized pathophysiology of heart failure

The neuroendocrine activation—it is the cornerstone
of metabolic regulation and is increasingly recognized
as contributing both to major symption (muscle CATABOLIC ACTIVATION
weakness, fatigue, exercise limititation and dyspnea)
Catabolic activation is particularly apparent in adipose
and to disease progression.
tissue, as several independent pathway exert lipolytic
Inflammatory activation
signals on hormone-sensitive lipase.
Metabolic impairment (Fig. 1).
ANABOLIC FAILURE INSULIN RESISTANCE

The normal anabolic response to insulin and amino acid The normal anabolic response to insulin and amino
stimulation was reduced in HF patients by more than acid stimulation was reduced in HF patient by more
50% because of both a blunted protein anabolic response than 50% because of both a blunted protein anabolic
and increased proteolysis. response and increased proteolysis. Even in nondiabetic
CHAPTER 13: Cardiac Cachexia 81
patients, insulin resistance in HF progresses in parallel to CONCLUSION

HF severity and predicts impaired functionl capacity of The complex interactions between metabolic, immuno
cardiovascular and particulary of muscle function. logic, and neuroendocrime signals in HF are still
incompietely understood. Evidence is mounting that the
SKELETAL MUSCLE abnormal and imbalanced metabolism represents an
Skeletal muscle is the main effector organ for physical intrinsic aspect of HF pathophysiology, with fundamental
activity and the body’s largest amino acid storage pool. symptomatic and prognostic implication.
CHAPTER
14
Is Intervention Still Relevant in Stable CAD?
Santanu Guha, Bappaditya Kumar
INTRODUCTION ivabridine in optimum and rational combinations.

In patients with stable stable coronary artery disease Even among patients undergoing revascularization,
(CAD) the goals of therapy are to alleviate symptoms, progression of CAD is an important determinant of
delay or prevent the progression of CAD, and decrease clinical outcome with time.1 Patients with stable CAD
the risk of adverse outcomes such as myocardial should undergo risk stratification with stress testing
infarction, heart failure or death. To meet the goals all and an echocardiographic assessment of left ventricular
patients should receive optimal medical therapy (OMT). function. These tests should be performed soon after the
Revascularization by means of percutaneous coronary onset of symptoms and when there is a significant change
intervention (PCI) or coronary artery bypass grafting in symptom status. Coronary angiography should be
(CABG) is reserved for patients having unacceptable performed when noninvasive testing has not adequately
angina or has a high likelihood of survival benefit answered the question regarding the severity of the
from revascularization based upon the anatomic disease or when clinical and noninvasive assessment is
characteristics of the lesion, the number of diseased suggestive of high-risk features such as large amount of
vessels, presence of left ventricular dysfunction and viable myocardium at risk of ischemia (as determined by
associated risk factors such as diabetes mellitus. noninvasive imaging or suggested by a strongly positive
treadmill test) or significant underlying left ventricular
MANAGEMENT OF STABLE CORONARY dysfunction.
ARTERY DISEASE In patients who remain symptomatic even on optimal
A l l p a t i e n t s w i t h e s t a b l i s h e d a t h e ro s c l e ro t i c medical therapy or when there is anatomic and/or
cardiovascular disease (CVD) should receive aspirin physiologic evidence that revascularization will improve
and statin as well as management of risk factors such as survival coronary artery revascularization with either
hypertension, smoking, diabetes, hypercholesterolemia, PCI or CABG should be performed; such as patients
and physical inactivity. Patients with stable CAD having with left main CAD; three vessel CAD, particularly with
angina should receive antianginal medications such a decreased left ventricular ejection fraction (usually
as Beta blocker, Calcium channel blocker, long acting <40%); or two vessel CAD with more than 75% stenosis
nitrates or newer drugs like ranolazine, nikorandil and in the proximal part of left anterior descending artery.2-4
CHAPTER 14: Is Intervention Still Relevant in Stable CAD? 83
INDICATIONS FOR PCI by comparing different stent types. Early generation

PCI is recommended for two groups of patients who are stents included paclitaxel, sirolimus, and zotarolimus
receiving OMT: (Endeavor) eluting stents and new generation stents
1. Those patients of stable CAD in whom CABG offers a included everolimus and zotarolimus eluting (Resolute)
survival advantage but who cannot receive this form stents. Compared with initial medical management new
of revascularization generation DES were associated with reduced mortality.
2. Those who are symptomatic despite OMT or having The estimated rate-ratios for balloon angioplasty, bare
intolerable medication side effects. metal stents, paclitaxel eluting stents, and sirolimus
eluting stents were less than one but were not significant
IMPROVEMENT IN SURVIVAL WITH PCI (0.92, 0.92, 0.91, and 0.88 respectively). This meta-
There has been no definite evidence that PCI when analysis raises the possibility that new generation
compared to optimal medical therapy in patients with DES may be associated with improved survival when
stable ischemic heart disease who do not have a clear compared to medical therapy. However, this meta-
indication for CABG improves survival.5 analysis had multiple limitations such us paucity of trials
The COURAGE trial had a major impact on the directly comparing a new generation DES to medical
management of stable CAD. In this randomized trial, therapy, trials comparing different types of DES with
2287 patients were taken who had objective evidence another and lack of individual patient data. Presently
of myocardial ischemia and significant CAD at 50 US there is no enough data to alter the recommendations to
and Canadian centers. Among these, 1149 patients were recommend PCI with stent in patients with stable CAD.
assigned to undergo PCI with bare metal stent with OMT Other meta-analyses comparing OMT to PCI have
(PCI group) and 1138 to receive OMT alone (medical- come to somewhat different conclusions regarding a
therapy group). The primary outcome was nonfatal possible mortality benefit with PCI. 9,10 A 2013 meta-
myocardial infarction and death from any cause during a analysis involving 12 randomized controlled trials
follow-up of 2.5–7.0 years. with over 37,000 patient-years of follow-up showed a
Number of primary events in the PCI group was non-significant 12% reduction of all-cause mortality
211 as compared to 202 events in the medical-therapy comparing PCI to OMT (incident RR 0.88–95% CI
group. The 4.6-year cumulative primary-event rates in 0.75–1.03).10 Another meta-analysis of three randomized
the PCI group were 19.0% and in the medical-therapy controlled trials included 1557 patients with documented
group were 18.5% (hazard ratio for the PCI group 1.05; myocardial ischemia: FAME 2 trial, the nuclear substudy
95% confidence interval [CI], 0.87–1.27; P=0.62). No of COURAGE trial, and SWISS 2 trial. During a mean
significant differences were present between the PCI follow-up period of 3.0 years PCI was associated with
group and the medical-therapy group in the composite of lower all-cause mortality (hazard ratio 0.52, 95% CI
myocardial infarction, stroke and death; hospitalization 0.30–0.92). 11,12 It is possible that in a subset of stable
for acute coronary syndrome or myocardial infarction. CAD patients particularly those with moderate to
As an initial management strategy in patients with stable severe ischemia might derive survival benefit from
CAD, PCI did not reduce the risk of myocardial infarction PCI compared to OMT. Further studies are required to
or other major cardiovascular events or death when confirm this findings.
added to OMT.6,7
A 2014 network meta-analysis evaluated all-cause RELIEF OF ANGINA
mortality in 95 trials involving 93,553 patients that For patients with inadequate control of anginal symptoms
compared one type of coronary revascularization (CABG with OMT, the addition of PCI improved symptom status.
or PCI with stent) to another or placebo.8 For patients Though it is recommended to control symptoms with
receiving a drug-eluting stent the analysis was done medical therapy before recommending PCI, there is
evidence that PCI improves anginal status. The MASS angiographically significant with fractional flow reserve
II trial randomly assigned 611 patients with multivessel (FFR) measurement.12
disease, preserved left ventricular systolic function, and Patients who had at least one stenosis in a major
stable angina to CABG, PCI or optimal medical therapy.13 coronary artery having an FFR of 0.80 or less were
At one year, 88% of the patients in the CABG group, 79% randomly assigned to undergo FFR-guided PCI (stenoses
in the PCI group, and 46% in the medical therapy group with FFR ≤0.80 were to be treated with a drug-eluting
were angina free (p<0.0001). Furthermore, 10-year rates stent) along with best medical therapy or best medical
of freedom from angina were 64% with CABG, 59% with therapy alone. It was found that FFR guided PCI along
PCI, and 43% with medical therapy (P<0.001). with the best available medical therapy, as compared
with the best available medical therapy alone in patients
PATIENTS WITHOUT CLEAR with stable CAD and functionally significant stenoses
INDICATIONS FOR INTERVENTION decreased the need for urgent revascularization.
However in patients without ischemia, the best available
In some patients with stable CAD, the choice between
medical therapy appeared to have a favorable outcome.
revascularization and optimal medical therapy is not
Important limitations of FAME 2 include the absence
clear. The following factors need to be considered in this
of noninvasive documentation of ischemia prior to
patients.
diagnostic coronary angiography and the fact that it
was stopped early. Despite these limitations, FAME
Patient Preference
2 supports the use of PCI with stent in patients with
Patient preference becomes important for those
documented ischemia involving at least a moderate
who are not found to have anatomy that mandates
myocardial territory.
revascularization based upon a survival benefit. A
thorough discussion of the potential benefits and risks Reduced Left Ventricular Systolic Function
of revascularization should be explained to the patient.
Most of the patients enrolled in the randomized trials of
The discussion should emphasize both the benefits of
stable CAD had normal or near normal left ventricular
PCI (less angina and a lower likelihood of requiring an systolic function. Revascularization was found to
intervention in the first few years) and the drawbacks of improve symptoms as well as provide survival advantage
PCI, including the inherent risks of the procedure and in those subset of patients having a depressed left
the potential problems of long-term dual antiplatelet ventricular systolic function.
therapy. This discussion should take place before
diagnostic coronary angiography, since PCI is often REFERENCES
performed immediately after. The concept of the “heart 1. Alderman EL, Kip KE, Whitlow PL, et al. Native coronary
team” to fully discuss the risks and benefits of both PCI disease progression exceeds failed revascularization as
and CABG as well as OMT is encouraged.14,15 cause of angina after five years in the Bypass Angioplasty
Revascularization Investigation (BARI). J Am Coll Cardiol.
2004;44:766.
Severity of Coronary Artery Disease 2. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery
There is some evidence that in patients with more severe bypass graft surgery on survival: overview of 10-year results
CAD, but who do not meet criteria for CABG, outcomes from randomised trials by the Coronary Artery Bypass Graft
are better with PCI than optimal medical therapy. Surgery Trialists Collaboration. Lancet. 1994;344:563.
3. Myers WO, Schaff HV, Gersh BJ, et al. Improved survival
In the FAME 2 randomized trial, patients with stable
of surgically treated patients with triple vessel coronary
CAD who were being considered for PCI underwent artery disease and severe angina pectoris. A report from
diagnostic coronary angiography with subsequent the Coronary Artery Surgery Study (CASS) registry. J Thorac
evaluation of all stenoses that were thought to be Cardiovasc Surg. 1989;97:487.
CHAPTER 14: Is Intervention Still Relevant in Stable CAD? 85
4. Passamani E, Davis KB, Gillespie MJ, Killip T. A randomized 12. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow
trial of coronary artery bypass surgery. Survival of patients reserve-guided PCI versus medical therapy in stable
with a low ejection fraction. N Engl J Med. 1985;312:1665. coronary disease. N Engl J Med. 2012;367:991.
5. Katritsis DG, Ioannidis JP. Percutaneous coronar y 13. Hueb W, Soares PR, Gersh BJ, et al. The medicine,
intervention versus conservative therapy in nonacute angioplasty, or surgery study (MASS-II): a randomized,
coronary artery disease: a meta-analysis. Circulation. controlled clinical trial of three therapeutic strategies for
2005;111:2906-12. multivessel coronary artery disease: one-year results. J Am
6. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical Coll Cardiol. 2004;43:1743.
therapy with or without PCI for stable coronary disease. N 14. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/
Engl J Med. 2007;356:1503. ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and
7. Sedlis SP. Effect of PCI. N Engl J Med. 2015; 1937. management of patients with stable ischemic heart disease:
8. W i n d e c ke r S , S to r te c k y S , S te f a n i n i G G , e t a l . executive summary: a report of the American College of
Revascularisation versus medical treatment in patients Cardiology Foundation/American Heart Association task
with stable coronary artery disease: network meta-analysis. force on practice guidelines, and the American College
BMJ. 2014;348:g3859. of Physicians, American Association for Thoracic Surgery,
9. Stergiopoulos K, Brown DL. Initial coronary stent implantation Preventive Cardiovascular Nurses Association, Society for
with medical therapy vs medical therapy alone for stable Cardiovascular Angiography and Interventions, and Society
coronary artery disease: meta-analysis of randomized of Thoracic Surgeons. Circulation. 2012;126:3097.
controlled trials. Arch Intern Med. 2012;172:312. 15. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/
10. Bangalore S, Pursnani S, Kumar S, Bagos PG. Percutaneous ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis
coronary intervention versus optimal medical therapy and management of patients with stable ischemic heart
for prevention of spontaneous myocardial infarction in disease: a report of the American College of Cardiology
subjects with stable ischemic heart disease. Circulation. Foundation/American Hear t Association task force
2013;127:769. on practice guidelines, and the American College of
11. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical Physicians, American Association for Thoracic Surgery,
therapy with or without percutaneous coronary intervention Preventive Cardiovascular Nurses Association, Society for
to reduce ischemic burden: results from the Clinical Cardiovascular Angiography and Interventions, and Society
Outcomes Utilizing Revascularization and Aggressive Drug of Thoracic Surgeons. Circulation. 2012;126:e354.
Evaluation (COURAGE) trial nuclear substudy. Circulation.
2008;117:1283.
CHAPTER
15
Newer Oral Anticoagulants
in Clinical Practice
Anshul Kumar Jain
The term ‘newer oral anticoagulants’ (NOACs) refers to above VKAs in being safe, easy to use, not requiring any
a class of direct inhibitors of factor Xa or thrombin that blood tests and assured anticoagulant efficacy. Of course,
have been introduced recently in clinical practice. The the cost remains a major deterrent for wide scale use
major indications of use of the oral anticoagulants are of these drugs in India. One needs to exercise caution
in treatment and prevention of deep vein thrombosis for potential drug interactions and presence of renal
(DVT) and pulmonary embolism dysfunction while using them.
and stroke prevention for nonvalvular atrial The SAMe-TT2R2 scale identifies the patients that are
fibrillation (based on CHAD2DS2-VASc score) unlikely to respond well to VKAs (time in therapeutic
The term ‘nonvalvular’ excludes the patents with range less than 65%) and hence predicts preference for
atrial fibrillation who have either moderate to severe use of NOACs. This scale includes in Table 1.
mitral stenosis or a prosthetic valve. All cases with aortic The NOACs available for clinical use are summarized
stenosis, mitral regurgitation, postmitral repair, or in Table 2 with their basic pharmacology and dosing for
bioprosthetic valve (except first three months of surgery) various indications of oral anticoagulation.
are considered ‘non-valvular’.
Well-designed large trials have confirmed the efficacy TABLE 1: The SAMe-TT2R2
of using the NOACs in the above indications as compared zz Sex (female) 1
to the traditionally used Vitamin K antagonists (VKAs). zz Age<60 1 Total points 0–2 predicts
good response to VKA.
zz Medical history (at least 2 of 1
COMPARISON OF NOACs WITH VKA the following: hypertension,
diabetes, congestive heart
The VKAs are very effective oral anticoagulants which
failure, previous stroke,
have been used for the past several decades. They require pulmonary, hepatic or renal
the INR to be maintained within a predefined therapeutic disease)
range for which repeated blood tests are needed. Dietary zz Treatment-interacting drugs 1 2 or more favors use of
restrictions and drug interactions further complicate especially like amiodarone NOACs
zz Tobacco intake within 2 years 2
the use of these drugs. The most dreaded adverse effect
zz Race (non-caucasian) 2
includes intracranial bleeding, to which the Asian
Maximum score 8
population is very susceptible. The NOACs score well
CHAPTER 15: Newer Oral Anticoagulants in Clinical Practice 87
TABLE 2: Newer oral anticoagulants (NOACs)

Dabigatran Apixaban Rivaroxaban Edoxaban
(Pradaxa) (Eliquis) (Xarelto) (Not available in India)
Action Direct thrombin Activated factor Xa Activated factor Xa inhibitor Activated factor Xa
inhibitor inhibitor inhibitor
Bioavailability 3–7% 50% 66% without food 62%
Almost 100% with food
Clearance nonrenal/renal of 20–80% 73%/27% 65%/35% 50%/50%
absorbed dose
Liver metabolism: CYP3A4 No Yes Yes Minimal
(elimination, moderate (elimination, moderate (<4% of elimination)
contribution) contribution)
Intake with food No No Mandatory No
Recommended?
G1 tolerability Dyspepsia No problem No problem No problem
Elimination half-life 12–17 h 12 h 5–9 h (Young) 10–14 h
11–13 h (Elderly)
Phase III clinical trial RE-LY Aristotle Averroes Rocket -AF Engage-AF
Dosing for atrial fibrillation (Based on GFR)
50 mL/min 150 mg BID 5 mg BID 20 mg OD *60 mg OD
30–50 mL/min 110 mg BID 2.5 mg BID** 15 mg OD 30 mg OD
75 mg BID
(in USA only)
15–30 mL/min Not recommended
<15 mL/min Not recommended
Abbreviations: BID: twice daily, OD: once daily, *Not to be used when creatinine clearance is more than 95 mL/min, **age >80 and weight <60 kg
Note:
zz Treatment of VTE and prevention of recurrent VTE
—— Dabigatran 150 mg twice a day (110 mg for GFR 30-50 mL/min) as per need. This therapy must be started after initial therapy with
parenteral anticoagulation.
—— Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg daily as per need.
—— Apixaban 10 mg twice a day for 7 days followed by 5 mg twice daily as per need. The dose for prevention of recurrent events is 2.5 mg
twice daily.
zz DVT prophylaxis after hip or knee replacement (dose to be started 24 hours after low risk surgery or 48–72 hours after high-risk surgery):
—— Dabigatran 220 mg (150 mg if GFR 30–50 mL/min) once daily for 2 weeks after TKR and 35 days after THR
—— Rivaroxaban 10 mg once daily for 2 weeks after TKR and 35 days after THR
—— Apixaban 2.5 mg once daily for 2 weeks after TKR and 35 days after THR.
The following points need to be stressed while using monitored at one month and then six monthly. In
the NOACs: case of pre-existing renal dysfunction, more frequent
tests may be ordered.
Patient Education Female patients must be warned about potential
Follow-up: The patients must be counselled about increase in menstrual flow with these drugs. Available
the need to use this class of drugs carefully. Routine data suggests a minimally increased menstrual
monitoring for any bleeding, renal impairment must bleeding with rivaroxaban specially. In case of
be done. Blood counts and renal function must be unusual bleed, the dose may be reduced, or the
drug may be discontinued for a few days or changed elderly who may better tolerate/or not tolerate the
to apixaban, which is supposed to have a lesser anticoagulation.
incidence. (Female sex is an independent risk factor
for thrombotic episodes in the CHAD 2DS 2-VASc Extreme Weight
score but is not associated with overall higher rates of Obese patients have a higher risk of developing atrial
bleeding in response to NOAC administration). fibrillation (AF) (4% increase per unit increase in BMI).
Drug interactions: In our country, where a large There is no need to increase the dose of NOACs in obese
number of drugs are easily available without patients but there are some suggestions that these drugs
prescription, one must warn the patients about the should not be used in patients with BMI more than 40 kg/
use of NSAIDs, antibiotics, and antiplatelet agents. m2 or weight more than 120 kg because of limited data
Special note must be made of concomitant use of on drug usage in this subgroup and fear of suboptimal
macrolide group, antifungals and rifampicin used anticoagulation attained.
commonly in India that may inhibit or induce the The low weight on the other hand is a risk factor
drug metabolism. Similarly, antiarrhythmic drugs for excessive bleeding and the dosage of Apixaban and
like cordarone, verapamil, and diltiazem and anti- Edoxaban needs to be modified as per guidelines (Table 1).
epileptic drugs like carbamazepine also need careful
attention, if coadministered. Renal Failure
Missed dose: In case of missed dose of a drug with Table 2 summarizes the dosage of NOACs in patents with
twice a day dose, next dose may be taken upto 6 hours renal dysfunction.
before the next dose, else it has to be omitted. For
once a day dosing, the dose may be taken upto 12 Bleeding Complications/Antidote
hours after the scheduled time, else omitted. Though rare, bleeding by far is the most important
Double dose: In this case, omit the next dose after 12 adverse effect of these drugs. The effect of the drugs
hours and resume the routine next day. For once a vains off in 12–24 hours (may be delayed in presence of
day drugs, resume the schedule the next day. renal dysfunction). Other measures to contain bleeding
include:
Age/Fraility Maintenance of local hemostasis
3
The elderly patients more than 75 years of age are highly Replenish blood, and platelets (<60,000 cells/mm ),
prone to atrial fibrillation. One must assess the bleeding if needed

risk in these patients (HAS-BLED/HEMORR2HAGES Maintain volume-colloids, fresh frozen plasma (only
score) and then start the drug. Utmost attention must be as a plasma expander, not as a reversal agent)
paid to “fraility index”: D e s m o p re s s i n ( i n ca s e o f c o a g u l o p at hy o r
Involuntary weight loss, thrombopathy)

Slow walking, Tranexamic acid (as adjuvant)
Low endurance, Prothrombin complex concentrate (PCC-dose 50
Weakness, fatigue, units/kg) or

Reduced physical activity. Activated PCC (aPCC–50 U/kg upto 200 U/kg/day)
‘Pre-fragile’ state is defined as the presence of 1–2 of may be used in cases of severe bleeding or conditions
above criterion and more than 3 is classified as ‘fragile’ mandating immediate reversal of anticoagulant
state. This scale helps in better characterization of those effect.
CHAPTER 15: Newer Oral Anticoagulants in Clinical Practice 89
Activated factor VII (rVIIA) in doses of 90 U/kg may BIBLIOGRAPHY

be used. 1. Clinical Excellence Commission, 2016, Non-vitamin K
Idarucizumab is the specific antidote for dabigatran Antagonist Oral Anticoagulant (NOAC) Guidelines (http://
approved for use recently. www.cec.health.nsw.gov.au/)
2. Heidbuchel H, et al. Updated European Heart Rhythm
Cost and availability are major constraints for the use
Association Practical Guide on the use of non-vitamin K
of these agents.
antagonist anticoagulants in patients with non-valvular
artrial fibrillation. Europace. 2015;17:1467-507.
Emergency Surgery 3. Pan Kuo-Li, et al. Effects of Non-Vitamin K Antagonist
All efforts must be made to delay the operation for 12–24 Oral Anticoagulants Versus Warfarin in Patients with Atrial
hours, the time in which the drug gets washed off the Fibrillation and Valvular Heart Disease: A Systemic Review
and Meta-Analysis. J Am Heart Assoc. 2017;6:e005835.
body. In dire emergencies, same steps must be followed
as described in the section on control of bleeding.
Change from VKAs to NOACs

INR <2 Start NOAC immediately
INR 2–2.5 Start NOAC next day
INR >2.5 Start NOAC after reassessing INR
CHAPTER
16
Dual Antiplatelet Therapy: How Long?
Sameer Kumar, Girish MP, Mohit D Gupta
INTRODUCTION ischemic events and bleeding events. Currently, various

Dual antiplatelet therapy (DAPT) forms the cornerstone debates are held to address the appropriate duration of
of management after coronary stenting. There are a DAPT. However, the research and discussion should be
variety of other indications for dual antiplatelet therapy on selecting appropriate clinical substrate for DAPT. The
including post CABG, peripheral artery stenting, acute therapy and its duration hence should be weighed in
cerebrovascular accidents, etc. The present review proper clinical substrate (Fig. 1).
mostly limits its focus to dual antiplatelet therapy after
PCI, duration, switching of antiplatelet agents and RISK STRATIFICATION
special circumstances. DAPT should be individualized in all patients after
carefully weighing its benefits and risks. The risk of
WHAT IS THE DEBATE? bleeding in patients on DAPT increases with the duration
It is well known that addition, prolongation and of DAPT. There are various scoring system s to ascertain
intensification of DAPT is a delicate tradeoff between the bleeding risk in patients on DAPT including HAS-
Fig. 1: Factors influencing thrombotic and bleeding events

CHAPTER 16: Dual Antiplatelet Therapy: How Long? 91
TABLE 1: Variables used to calculate DAPT score when newer antiplatelets like prasugrel and ticagrelor
Variables Points were introduced.
Age >75 years –2 DAPT in ACS: The use of DAPT in patients with ACS was
Age 65–75 years –1 incorporated for the first time when CURE trial showed
Age <65 years 0 that addition of clopidogrel to aspirin versus placebo,
Current cigarette smoker 1 reduced MI, stroke and CV death by 20%. But there was
Diabetes mellitus 1 an increase in major bleeding observed. Further, PLATO
MI at presentation 1 and TRITON TIMI 38 trials showed that ticagrelor and
Stent diameter <3 mm 1 prasugrel were superior to clopidogrel respectively to
Prior PCI or prior MI 1 reduce ischemic events, in patients with ACS. Hence, all
Paclitaxel eluting stent 1 the present guidelines prefer prasugrel or ticagrelor over
CHF or LVEF <30% 2 clopidogrel for DAPT in patients with ACS.
Saphenous vein graft PCI 2
DAPT in stable CAD: The CREDO trial studied 2116
patients undergoing BMS PCI receiving 12 months
BLED, PARIS registry, and PRECISE-DAPT and DAPT
versus 28 days of DAPT. The incidence of ischemic
score. These scores have a moderate but not high level of
events was significantly lower at the ned of 1 year with
discrimination. The simplest and appropriate of them all
12 months of DAPT. With widespread use of DES, there
is the DAPT score (Table 1).
was an increase in the incidence of late stent thrombosis.
Results from the DAPT trial found that patients with
So after USFDA advisory in 2006, 12 months DAPT was
DAPT score >2, there was an 8.2 times greater reduction
recommended with all the generations of DES PCI by
in thrombotic events compared to increase in bleeding
AHA/ ACC.
in patients on prolonged DAPT. Likewise, there was
also increase in bleeding events, 2.4 times the absolute Shorter duration DAPT: Many trials examined safety and
reduction in thrombotic events. Patients on DAPT with efficacy of 6 months vs 12 months DAPT in stable CAD
DAPT score >2 should be treated with prolonged DAPT. after PCI with 2nd generation DES.
Higher the DAPT score (>2), higher is the benefit with
prolonged DAPT. DURATION OF DUAL ANTIPLATELET
THERAPY IN CASES OF STABLE
SHORT-TERM VERSUS LONG TERM CORONARY ARTERY DISEASE (CAD)
DAPT: THE EVIDENCE SO FAR AFTER PCI
In the debate of short term versus long term DAPT, it After PCI with bare metal stents (BMS): BMS is presently
is prudent to understand how the standard duration of limited to patients with bleeding tendency, high
DAPT of 12 months has evolved. Before 2000, clopidogrel likelihood of poor compliance to DAPT or planned
and ticlopidine were the only P2Y12 inhibitors available. elective surgical procedure. Atleast 1 month of DAPT
Ticlopidine use was phased out due to hematologic is recommended to prevent stent thrombosis (Class I)
complications. Till mid 2000, 28 days of DAPT was After PCI with first generation drug eluting stents (DES):
recommended as BMS was in use. Once DES were Earlier, it was thought that patients with first generation
introduced, concerns of late stent thrombosis and DES are at higher risk of acute stent thrombosis. So,
delayed endothelization needed to be addressed. So an 12 months of DAPT was recommended. However,
‘arbitrary cut off’ of 12 months duration of DAPT was 5 RCTs showed that incidence of stent thrombosis
recommended. The spectrum of DAPT became larger were comparable between shorter duration (3–6
TABLE 2: Randomized controlled trials that examined <12 months vs >12 months DAPT
Trials DAPT duration ACS (%) 2nd gen DES Composite primary end point Rates of primary
(%) end point
ISAR-SAFE 6 vs 12 m 40 72 Death, MI, stroke, ST or TIMI major bleeding at 9 m 1.5% vs 1.6%
Italic 6 vs 24 m 24 100 Death, MI, TVR, stroke or TIMI major bleeding at 12 m 1.6% vs 1.5%
Optimise 3 vs 12 m 32 100 Death, MI, stroke or major bleeding at 12 m 6.0% vs 5.8%
Security 6 vs 12 m 38 100 Cardiac death, MI, stroke, ST, BARC 3 or 5 bleeding at 12 m 4.5% vs 3.7%
Prodigy 6 vs 24 m 75 50 Death, MI or stroke at 24 m 10% vs 10.1%
Reset 3 vs 12 m 55 82 Cardiac death, MI, ST, ischemia-driven TVR or bleeding at 12 m 4.7% vs 4.7%
Excellent 6 vs 12 m 51 75 Cardiac death, MI or ischemia-driven TVR at 12 m 4.8% vs 4.3%
(Source: Eisen A, Bhatt DL. Heart. 2016:1–14)
months) DAPT and extended duration DAPT (12 DURATION OF DUAL ANTIPLATELET
months) (Table 2). So atleast 6 months of DAPT is THERAPY IN PATIENTS PRESENTING
recommended (Class I) WITH ACUTE CORONARY
After PCI with newer drug eluting stents (everolimus/
SYNDROME (ACS)
zotarolimus): Atleast 6 months of DAPT is recommended
(Class I) Patients of ACS Treated with
In all of the above three groups, DAPT can be extended Medical Therapy Alone
beyond the recommended duration if the patient has low Aspirin is recommended at a daily dose of 81 mg
bleeding risk (Class IIb).
(75–100 mg).
Among patients with stable CAD, clopidogrel is the P2Y12 inhibitor (clopidogrel or ticagrelor) should be
only P2Y12 inhibitor used.
continued for 12 months.
If the patient does not have overt bleeding or high risk
After DES PCI (any generation): of bleeding, DAPT can be continued over 12 months.
6 months
Ticagrelor is preferred over clopidogrel in cases
Duration of • If high bleeding risk after DES:
DAPT in SIHD 3 months presenting with NSTEACS.
• If old MI 1–3 years back: Continue
In SIHD, only DAPT, if low bleeding risk Patients of ACS Treated with Fibrinolysis
clopidogrel is After BMS PCI: 1 month
approved with aspirin If low bleeding risk: continue DAPT
Aspirin is recommended at a daily dose of 81 mg (75–100
>1 year after PCI mg). Clopidogrel is the P2Y12 inhibitor recommended
After CABG: Complete DAPT of and is given for atleast 14 days and ideally continued for
12 months
duration of 12 months.
DAPT can be continued beyond 12 months, if
High bleeding risk includes patients having overt patients tolerate well with no bleeding episodes and are
bleeding, or when they are at high risk of bleeding (e.g., at low bleeding risk.
oral anticoagulant therapy use, major intracranial or
vascular surgery) Patients of ACS Treated with PCI
Low bleeding risk denotes those patients who have After BMS or DES implantation, P2Y12 inhibitor should
not developed bleeding and DAPT score <2. be continued for a minimum duration of 12 months.
Ticagrelor and prasugrel are preferred over clopidogrel clopidogrel. Likewise, in the PLATO trial, use of ticagrelor
for maintenance therapy. Prasugrel should be used only reduced cardiovascular mortality at 1 year compared to
in patients < 75 years, weighing > 60 kg and without clopidogrel.
history of stroke/TIA or bleeding tendency. CABG after PCI: Continue DAPT for duration of 12
In patients who are not at increased risk of bleeding, months (or as per recommended duration) after PCI
P2Y12 inhibitor can be continued beyond 12 months. If (Class I).
patients are at high risk of bleeding (oral anticoagulant CABG after ACS: Continue DAPT to complete the
use, intracranial surger y) or develop bleeding

duration of 12 months after ACS (Class I).
complication, P2Y12 inhibitor should be stopped after
CABG for SIHD: Continue DAPT for 12 months after
6 months.
CABG (Class IIb).
Patients of ACS Treated with CABG For all patients after CABG, daily dose of 81 mg (75–
After ACS, in patients undergoing CABG, aspirin should 100) mg aspirin is recommended.
be continued during the perioperative phase. P2Y12
inhibitor should be resumed after CABG and continued ELECTIVE NONCARDIAC SURGERY
to complete 12 months of DAPT after ACS. IN PATIENTS TREATED WITH
DAPT AND PCI
• Medical therapy: 12 months About one-fifth of patients on DAPT worldwide would
Duration of Ticagrelor > clopidogrel
DAPT in ACS
need to undergo noncardiac surgery within two years of
• After fibrinolysis: Atleast 14 days;
Ideally 1 year PCI. The 90% of these are subjected to elective surgeries.
If low bleeding risk, Clopidogrel preferred So, its pertinent to understand and explain to the patient
continue DAPT for • After PCI (BMS/DES): 12 months
>12 months
Ticagrelor/Prasugrelor >
regarding the risks and benefits of continuing DAPT peri-
If high bleeding risk, limit Clopidogrel and post-procedure and also have a clear communication
DAPT to atleast PCI:
• After CABG: Complete 12 months with the operating surgeon. The decision to reduce the
6 months; Fibrinolysis:
DAPT
14 days dose or continue DAPT depends on various factors such
as:
Elective versus emergency surgery
DURATION OF DAPT IN PATIENTS Time interval of surgery from DES implantation
UNDERGOING CABG Major versus minor surgery
Aspirin improves vein graft patency and reduces
Vascular and neurosurgery or others
mortality up to one year after CABG. Most studies
Bridging with heparin in the perioperative period
including CURE trial have demonstrated that the
Type of stent implanted (BMS or DES), etc.
addition of clopidogrel improves vein graft patency
Elective noncardiac surgery should be delayed 30
and mortality till 1 month. However, clopidogrel did
not improve arterial graft patency. A meta-analysis has days after BMS and 6 months after DES implantation.
revealed that DAPT lowered the venous graft occlusion In cases where surgery is mandatory, aspirin should be
without significant improvement in arterial graft patency continued in the perioperative period. P2Y12 inhibitor
at one year when compared to aspirin alone. Major should be restarted as soon as possible. Elective surgery
bleeding after surgery was more frequent with DAPT. For can be considered after DES implantation after 3 months
the newer antiplatelets, TRITON TIMI 38 study showed of P2Y12 therapy, if risk of delaying the surgery outweighs
reduced 30 day mortality with prasugrel compared to the benefits of DAPT.
Based on ACC/AHA focused update on DAPT, these —— Chronic phase: No need for clopidogrel loading.
practice guidelines would be useful in management of Start with 75 mg OD
these patients: —— To start 24 hours after last dose of prasugrel
Delay any elective non cardiac surgery to atleast 1 Ticagrelor to clopidogrel:

month and 6 months after BMS and DES respectively. —— Acute phase: 600 mg LD (24 hours after last dose
If noncardiac surgery was already planned at the of ticagrelor)

time of PCI and patient has to undergo elective PCI, —— Chronic phase: 600 mg LD (24 hours after last
persuade the patient to undergo noncardiac surgery dose of ticagrelor)

first. Prasugrel to ticagrelor:
If surgery is unavoidable, atleast aspirin should be —— Acute phase: 180 mg LD (24 hours after last dose
continued during perioperative period. of prasugrel)

Risks of stent thrombosis and other atheroembolic —— Chronic phase: 180 mg LD (24 hours after last
complications should be communicated to the dose of prasugrel)

patient and be documented. Ticagrelor to prasugrel:
The second antiplatelet (P2Y12 inhibitor) should be —— Acute phase: 60 mg LD (24 hours after last dose
restarted as soon as possible after surgery. of ticagrelor)

—— Chronic phase: 60 mg LD (24 hours after last dose
SWITCH OVER BETWEEN of ticagrelor)

ANTIPLATELETS * LD = Loading dose
The switch over from one antiplatelet to another
requires a clear idea of the clinical presentation of the SPECIAL CIRCUMSTANCES
patient, duration of therapy, contraindications, drug Aspirin Resistance
used for loading dose (in acute settings) and financial Aspirin (acetylsalicylic acid) is one of the most commonly
considerations. A clear and well-written prescription and used drugs worldwide. Since its discovery in 1897,
proper patient education are very important to ensure aspirin has been used for a variety of indications. Its
patient compliance. Here is a brief overview of how to antiplatelet effect is due to irreversible acetylation
change over from one antiplatelet to another: of cyclooxygenase-1 (COX-1) leading to reduced
Clopidogrel to prasugrel: thromboxane A2 production by platelets. The COX-1
—— Acute phase: 60 mg LD (irrespective of timing of inhibition by aspirin is dose dependent, rapid and
last dose of clopidogrel) permanent as platelets lack DNA to replenish it.
—— Chronic phase: No need for prasugrel loading. About 5–45% of the general population is resistant to
Start with 10 mg OD aspirin. Aspirin resistance can be classified as laboratory
—— To start 24 hours after last clopidogrel dose resistance and clinical resistance. Laboratory aspirin
Clopidogrel to ticagrelor: resistance is the failure of aspirin to inhibit platelet
—— Acute phase: 180 mg LD (irrespective of timing of thromboxane A2 production or inhibit platelet function
last dose of clopidogrel) tests that are dependent on platelet thromboxane
—— Chronic phase: No need for ticagrelor loading. production (Table 3). Clinical aspirin resistance is
Start with 90 mg BD defined as the failure of aspirin to prevent clinical
—— To start 24 hours after last clopidogrel dose thromboembolic ischemic events in patients on aspirin
Prasugrel to clopidogrel: therapy (Table 4). There are three types of aspirin
—— Acute phase: 600 mg LD (24 hours after last dose resistance, which have been detailed based on their
of prasugrel) mechanism. They are as follows:
TABLE 3: Laboratory tests for aspirin resistance TABLE 4: Aspirin challenge protocol for patients with aspirin
exacerbated respiratory disease (AERD)
Thromboxane production Thromboxane dependent
platelet function Time 0 Time 3 hours Time 6 hours
Serum thromboxane B2 PFA 100 (Most commonly used) Day 1 Placebo Placebo Placebo
Urine 11 deoxytromboxane B2 Optical aggregation (Gold Day 2 ASA 30 mg ASA 60 mg ASA 120 mg
standard) Day 3 ASA 150 mg ASA 325 mg ASA 650 mg
Impedence aggregation
Ultegra RPFA
TABLE 5: Wong et al. protocol
Type I resistance: Also called as pharmacokinetic Time (min) ASA (Dose in mg)
resistance. It is because of insufficient bioavailability 0 0.1
which can be due to missing compliance, inadequate 15 0.3
dosing, or protection of COX-1 against acetylation by 30 10
NSAIDs. 45 30
Type II resistance: Also known as pharmacodynamic 60 40
or true resistance. It is due to genetic changes in the 85 81
COX-1 protein, disabling acetylation by aspirin, or 110 162
acquired, transient overexpression of less aspirin- 135 325
sensitive COX isoforms.
Type III resistance: Least common mechanism. It
Types I, II, III are due to COX-1 inhibition. Type IV
occurs due to heightened stimulation of platelets by and Type V are immune mediated. Patients who have
aspirin sensitive mechanisms. Type II allergy cannot be desensitized. Since there is no
No treatment has been described for aspirin resistance fixed standard protocol for aspirin desensitization, there
till date. Higher dose of aspirin is not useful and has to be are no standard guidelines for the same.
avoided, as it increases the incidence of major bleeds.
Aspirin challenge protocol for patients with aspirin
induced cutaneous disease.
Aspirin Allergy
Studies have shown that low dose aspirin (75-100
The two common side effects of aspirin include aspirin
mg) to be beneficial in terms of lower bleeding and
exacerbated respiratory disease (10%) and aspirin
comparable ischemic protection compared to higher
induced urticaria (0.1%). Majority of the allergic
dose of aspirin (Table 5). Hence in patients on dual
reactions of aspirin are due to preferential activation
of leucotrienes and reduction of PGE2. Most cases of antiplatelet therapy, 81 mg aspirin (75–100 mg) is
aspirin allergy are able to safely undergo desensitization recommended and should be continued indefinitely.
except in cases of chronic idiopathic urticaria. Aspirin
should be indefinitely continued in all patients after
Clopidogrel Resistance
desensitization to prevent resensitization. Various types The 10–15% of patients exhibit resistance to clopidogrel.
are described below: Most common mechanisms include variations in
Type I: Rhinitis and Asthma due to NSAIDs concentrations of nitric oxide, ADP, etc. and genetic
Type II: Urticaria/Angioedema due to multiple polymorphisms in CYP3A4. Diagnosis is confirmed
NSAIDs in chronic idiopathic urticaria (CIU) by optical aggregation for ADP receptors. Treatment
Type III: Urticaria/Angioedema due to multiple options include increasing the maintenance dose of
NSAIDs clopidogrel to 300 mg OD, and replacing clopidogrel
Type IV: Urticaria/Angioedema due to single NSAID with prasugrel or ticagrelor. Routine genetic testing for
Type V: Anaphylaxis due to NSAIDs. clopidogrel resistance screening is not recommended.
TABLE 6: Triple antiplatelet therapy: Practical guidelines weeks versus 6 months of DAPT. More than 600 patients
zz Individualize triple therapy by carefully assessing ischemic and who were on anticoagulation for atrial fibrillation, and
bleeding risks. now undergoing DES inplantation were randomized
zz Triple therapy duration should be appropriate: Too much or too to either 6 weeks or 6 months of triple therapy with
short duration should be avoided. aspirin, clopidogrel and warfarin, followed by dual
zz In selected patients, dual therapy (clopidogrel plus oral therapy with aspirin and warfarin thereafter. At 9 months,
anticoagulant) may be considered.
the incidences of definite stent thrombosis, bleeding
zz If warfarin is used, INR target to be lowered to 2.0–2.5. Low dose
aspirin (max. upto 100 mg) is preferred.
episodes, cerebrovascular accidents and mortality were
zz When either antiplatelet has to be chosen, clopidogrel is the
comparable between the two groups.
antiplatelet of choice. However, a large trial published recently, evaluated
zz In patients with previous GI bleed or for those at higher risk, PPIs more than 10,000 patients of atrial fibrillation undergoing
should be used. PCI and its long term results (6 year follow up) showed
zz BMS is preferred over DES so that minimum duration of DAPT that triple therapy did not decrease ischemic events.
can be restricted to 14 days in case of major bleeding. However, it increased the incidence of major bleeds and
hemorrhagic stroke.
Triple Therapy
Triple therapy refers to addition of an oral anticoagulant CONCLUSION
(VKA or NOAC) to DAPT in patients of AF undergoing Each patient needs an individualized approach based on
PCI. This therapy also seems to be a double edged sword, his risk factors for bleeding. Application of DAPT score in
as it could lead to life threatening bleeding (Table 6). routine outpatient department practice gives reasonable
Various modification have been tried, including VKA guidance on the duration of DAPT. Switch over of
plus P2Y12 inhibitor, continuing DAPT only or VKA plus antiplatelets and their dose adjustments during non
aspirin to reduce the bleeding risks. However, all these cardiac surgery should be meticulously planned. Newer
strategies resulted in increased ischemic events. guidelines regarding aspirin and clopidogrel resistance,
The ISAR-TRIPLE trial compared the incidence of and particularly aspirin desensitization are required. Its
thrombotic and bleeding events in patients receiving 6 apt to conclude with: Treat the patient, not the stent.
CHAPTER
17
Newer Biomarkers in Heart Failure
Saumitra Ray
INTRODUCTION or diastolic dysfunction. The same criteria are applied to

Heart failure (HF) is defined as a clinical syndrome of diagnose HFmrEF but with LVEF 40–49%.
characteristic symptoms such as breathlessness, fatigue
and dependent swelling which may be accompanied by Role of Natriuretic Peptides in
signs such as raised jugular venous pressure, pulmonary Diagnosis of HF
crepitations and pitting ankle edema, caused by a The natriuretic peptides are the most accepted
structural and/or functional abnormality of the heart, biomarkers in both HFpEF and HFrEF. Commonly used
which results in reduced cardiac output and/or raised peptides are atrial natriuretic peptide and BNP. The
intracardiac pressures at rest and exercise. natriuretic peptides are formed and released due to
Some authorities such as the American College of stretching of myocardium. Besides BNP, NT-proBNP is
Cardiology categorize preclinical HF as stage A HF and also validated as an important marker. Pro BNP is split
stage B HF and overt HF as stage C and terminal HF as into NT-pro BNP and BNP in equal proportions.
stage D. NT-proBNP is exgreted by the kidneys and BNP is
HF is broadly classified as heart failure with reduced excreted by both kidney and liver.
ejection fraction, HFrEF, HF with mid-range ejection As elaborated in the last section, BNP and NT-proBNP
fraction, HFmrEF, and heart failure with preserved play a vital role in the diagnosis of HF. In an appropriate
ejection fraction, HFpEF, depending on whether the clinical set up with symptoms and signs, a normal
LVEF below 40%, 40–49% and 50% or above respectively. natriuretic peptide, NP may rule out the diagnosis of
HF. Elevated NP, on the other hand, is not necessary to
DIAGNOSIS diagnose HFrEF, but is useful in the other two types. An
As already mentioned HFrEF is diagnosed with echocardiogram may be done as a first step in clinically
appropriate symptoms with or without signs in presence suspected HF or may be preserved to be done once NPs
of LVEF<40%. For diagnosing HFpEF a similar clinical are elevated.
picture with LVEF >=50% and elevated level of NPs In many cardiac and noncardiac conditions apart
(B-type natriuretic peptide, BNP, >35 pg/ml or N-terminal from HF, NPs are elevated. Among cardiac causes
pro-B type natriuretic peptide, NT-proBNP, >125 pg/mL) important are acute coronary syndromes, atrial
along with either structural heart disease (left ventricular fibrillation, myocarditis, pericarditis, cardiac surgery and
hypertrophy, LVH and/or left atrial enlargement, LAE) cardioversion. Important non cardiac causes include
advanced age, bacterial sepsis, renal failure, pneumonia, sensitive assays almost 2/3 rd cases are positive. In both
pulmonary hypertension, anemia and burn. Obesity at-risk normal populations and those with structural
may cause lower levels of NPs. Only BNP and not the heart disease, higher troponin levels are independently
NT pro-BNP is a substrate of neprilysin. So the new drug associated with known HF risk. The elevated troponin
for HF, angiotensin receptor neprilysisn inhibitor, ARNI, levels reflect chronic processes rather than acute
increases only the BNP level and not that of NT pro BNP. ischemia.
NP levels are used both in setting of chronic HF and
in acute set up of patients presenting with dyspnea. A OTHER BIOMARKERS
normal or mildly elevated NP in an acute setting keeps Many other biomarkers, are being studied to diagnose,
the HF diagnosis at the bottom of the list. prognosticate or guide therapies for HF. But none of these
In STOP-HF study, patients of stage A HF were has still been approved to be used outside experimental
subjected to BNP testing versus no BNP testing. settings.
Intervention group patients who had BNP more than These biomarkers may be classified as: (a) markers
50 pg/mL had echocardiography and were seen by of inflammation, e.g. CRP, TNF-alpha, IL-1,6,10,18,
cardiovascular specialist. This group had less er number lipoprotein associated phopholipase A2, adiponectin;
of composite end points. In another RCT, rapid up- (b) markers of oxidative stress, e.g. oxidized LDL,
titration of renin-angiotensin-aldosterone blocking myeloperoxidase; (c) markers of extracellular matrix
and beta adrenergic blocking showed reduction in remodeling, e.g. MMP, IL-6, galectin-3, myostatin; (d)
cardiovascular endpoints in diabetic patients with high neurohormones, e.g. noradrenalin, rennin, angiotensin
NT pro-BNP but without clinical heart disease. However, II, aldosterone, endothelin-1; (e) markers of myocyte
to develop a protocol for stage A HF patients is difficult. injury and apoptosis, e.g. troponi T and I, CPK-MB,
myosin light chain kinase-1; (f ) markers of myocyte
Prognostic Value of NP stress, e.g. NPs, sST2 and (g) markers of extracardiac
The ACC/AHA/HFSA 2017 update on HF guideline gives involvement, e.g. cystatin-C, NGAL, B2 microglobulin,
a class IA recommendation for measurement of BNP and tri-iodothyronine.
NT pro-BNP for assessing disease severity and outcome NGAL, neutrophil gelatinase-associated lipocalin
in chronic HF and for prognostication of hospitalised is produced by neutrophils and some epithelial cells
patients with acute HF. High initial value of NT pro BNP and increases in renal injury. Chronic HF patients have
indicates higher mortality and morbidity. higher levels in blood and urine. NGAL levels can predict
Predischarge NP levels can predict chance of early renal outcomes in HF patients.
re-hospitalization. But evidences are so far not strong Some other biomarkers such as soluble ST2 receptor
and ACC guideline recommends a class IIa indication and andgalectin-3 may be useful, particularly over and
for the predischarge NP level to establish a postdischarge above BNP levels. More trials are required in this field.
prognosis. Several biomarkers are awaiting validation with well-
defined outcome studies. At present, ACC gives a class
Cardiac Troponin IIb recommendation for such additional tests.
Cardiac troponin levels may increase in both chronic and
acute HF set ups indicating muscle injury. Troponins T
BIOMARKERS OF HFpEF
and I increase similarly in acute HF as in ACS. Raised Role of Natriuretic Peptides in HFpEF
values of either troponin T or I levels in acute HF indicate NPs may increase a little in symptomatic phases of
a poorer prognosis. HFpEF and normalize Natriuretic paptides (NPs) during
Troponins are found in blood in asymptomatic symptom-free periods. As myocardial stretch is not a
people of stage A and B of HF in 1 to 5 % cases. With high major feature of HFpEF, rise of NP is not significant.
CHAPTER 17: Newer Biomarkers in Heart Failure 99
Under specific circumstances, such as supraventricular The ALDO-HF trial with HFpEF, Galectin 3 predicted
tachycardia or fluid overload, levels of natriuretic peptides mortality and rehospitalization rates.
may become very high (as in HFrEF), but this is uncommon. In the RELAX trial of 216 stable outpatients with
Natriuretic peptides are measured as a screening test HFpEF (LVEF ≥ 50 %), Galectin 3 was associated with
in clinics for patients presenting with dyspnea. There renal dysfunction but not with congestion.
negative predictive value is very high.
HFpEF in Acute Setting ST2

In acute HF, both with and without preserved EF, NP rise In a trial of Afro-American people with HFpEF, ST2
sharply due to myocardial stretch and the usual value was found to be better predictor of outcome than
of BNP is 600-1000 pg/mL. Compensated patients may BNP. But echocardiographic correlation could not be
have values of 100-600 pg/mL. found.
Friões et al. showed that ST2 was more useful in
Prognostic Value of Plasma Biomarkers HFrEF than in HFpEF. But, again, data of 447 patients
in HFpEF with HFpEF with acute heart failure showed similar
The i-PRESERVE and the PEP-CHF studies showed good results for HFrEF and HFpEF.
predictive values of baseline and changing measures of
NT pro BNP for mortality and morbidity in hospitalize
patients with HFpEF.
CONCLUSION
Serum biomarkers have assumed an important role in
Galectin 3 and ST 2
all phases of HF, from diagnosis to prognostication to
These emerging biomarkers may add predictive values to
therapy decision. Recent guidelines on HF from America
NP levels. For asymptomatic HFpEF patients, they may
and Europe have upgraded the class of recommendation
be of special value.
of biomarker assay, particularly in the area of diagnosing
Galectin 3 and classifying HF. Newer biomarkers are evolving
The COACH trial examined patients at discharge after fast and in near futures combined assessment of
acute HF admission. About 20% were HFpEF. Galectin 3 multiple biomarkers may be recommended for HF
was of special value to this set of patients. management.
CHAPTER
18
Coronary Microvascular
Dysfunction: An Update
SM Mustafa Zaman
INTRODUCTION simultaneously, depending on the clinical condition.

Chest pain without obstructive epicardial CAD is a The aim of this article was to provide an update on CMD
common entity, occurring in upto 30% of patients based onthe more recent literature published on this
undergoing invasive coronary angiography for chest subject.
pain.1 Studies trying to explain this phenomena have
shown that structural and functional abnormalities
RISK FACTORS AND
inherent to the microcirculation can impair myocardial PATHOPHYSIOLOGY (FIG. 1)
perfusion and cause ischemia.2 This disease process Coronary microvascular dysfunction is associated with
is called coronary microvascular dysfunction and hypertension, dyslipidemia, smoking, insulin resistance
and diabetes and accelerated by early menopause
the resulting ischemia is known as microvascular
and obesity. Study shows CFR is also impaired with
ischemia. 3 When addressing angina pectoris, the
aging. These risk factors are also associated with visible
majority of attention and research has focused on
atherosclerotic changes in the epicardial coronary
pathology of the epicardial coronary arteries. Although
arteries. A higher proportion of female patients had
the importance of the coronary microcirculation in
somesort of coronary microvascular abnormality
maintaining appropriate myocardial perfusion has been
compare with male patients (66% vs. 60%).11
recognized for several decades, the substantial morbidity
Despite similar microvascular function in women
of coronary microvascular dysfunction (CMD) has not and men by Index of microcirculatory resistance (IMR),
been appreciated until recently. Several studies have CFR is lower in women. This discrepancy appears to be
shown that CMD among patients with and without due to differences in resting coronary flow between the
obstructive CAD denotes a poor prognosis with higher sexes. 11
rates of MACE.4-10 In 2007, Camici and Crea reviewed Significant reductions in endothelial dependent and
this subject and classified CMD on the basis of the four endothelial independent coronary vasodilatation are
clinical setting in which it occurs: (i) CMD in the absence found in chronic hyperglycemia, insulin resistance and
of myocardial diseases and obstructive CAD, (ii) CMD hyperinsulinemia12,13 in patients with diabetes. Studies
in myocardial diseases, (iii) CMD in obstructive CAD, have shown that improving insulin sensitivity improve
and (iv) iatrogenic CMD. There are multiple underlying endothelial function, reduce myocardial ischemia in
mechanisms of CMD and some of them can occur patients with no obstructive epicardial CAD.14
CHAPTER 18: Coronary Microvascular Dysfunction: An Update 101
Fig. 1: In addition to the ‘classic mechanisms’ (i.e. atherosclerotic disease and vasospastic disease) that lead to myocardial ischemia, coronary
microvascular dysfunction (CMD) has recently emerged as a ‘third’ potential mechanism of myocardial ischemia. As in the case of the other
two mechanisms, coronary microvascular dysfunction (alone or in combination with the other two) can lead to transient myocardial ischemia
as inpatients with coronary artery disease (CAD) or cardiomyopathy (CMP) or to severe acute ischemia as observed in Takotsubo syndrome.
Abbreviations: CFR, coronary flow reserve
Source: Adapted from Filippo Crea, et al. European Heart Journal. 2014;35:1101-11
High levels of C-reactive protein foundin patients CFR is reduced in aortic stenosis by multiple
with microvascular angina, having a role of inflammation mechanisms that include reduced diastolic filling time,
in the modulation of coronary microvascular responses. increased diastolic filling pressure and intramyocardial
CMD was prevalent in patients with systemic lupus pressure, leading to reduced subendocardial perfusion,
erythematosus and rheumatoid arthritis. Marked increased intramyocardial systolic pressure, and delayed
structural abnormalities ofthe small intramural myocardial relaxation after systole.17-19
coronary arteries, including medial hypertrophy, MVD presents in infiltrative cardiac diseases such
intimal hyperplasia, and decreased luminal size, are
as amyloidosis. The mechanism of MVD in these
considered themost relevant substrate producing CMD
diseases can be attributed to secondary changes,
and myocardial ischemiain HCM.15
including myocyte hypertrophy and fibrosis. Endothelial
Observations suggest that Takutsobu syndrome
dysfunction due to endothelial deposits and perivascular
is caused by intense microvascular constriction with
fibrosis leads to increased microvascular resistance.20, 21
subclinical CMD persisting over time, perhaps facilitated
by endothelial dysfunction.16 CMD may present with obstructive atherosclerotic
In myocarditis even there is no atherosclerosis, chest coronary arteries. Stable IHD patient may share common
pain may be caused by intense coronary vasoconstriction risk factors for microvascular dysfunction and these
due to myocarditis induced endothelial dysfunction may lead to presence of both micro and macrovascular
of the coronary microvasculature, together with direct disease. In ACS patient MVO is caused by the variable
infection of endothelial and/or vascular smooth muscle combination of four pathogenetic mechanisms: (i) distal
cells. atherothrombotic embolization; (ii) ischemic injury;
Fig. 2: Pathophysiology of microvascular angina

Source: Adapted from SR Mittal. Indian Heart Journal. 2015;67:552-60.
(iii) reperfusion injury; and (iv) individual susceptibility CLINICAL PROFILE

of coronary microcirculation to injury. It is not possible to clearly differentiate isolated
The main mechanisms underlying iatrogenic CMD microvascular angina from angina due to isolated
after PCI are coronary vasoconstriction and embolization epicardial coronary artery disease by clinical features
of coronary microcirculation. A similar phenomenon has only. 26,27 Persistence of symptoms after successful
also been observed after coronary artery bypass grafting intervention/surgery, symptoms disproportionate to
(CABG).22-25 angiographic findings, absence of quick and/or sufficient
relief with nitroglycerine or after cessation of effort have
DIAGNOSIS (FIG. 2) been suggested as clues to suspect CMD. Patients with
Definite clinical diagnosis of microvascular angina microvascular coronary spasm have been shown to have
i s n o t p o s s i b l e w i t h t h e e x i s t i n g k n o w l e d g e. symptoms more frequently at rest, more often at night
Resting electrocardiogram may be normal, and and in early morning.28
exercise electrocardiogram may be unremarkable. Cardiac syndrome Y also presents as rest angina.
Echocardiography usually does not show regional wall Hemodynamically, it is characterized by an abnormally
motion abnormalities. Radioisotope imaging can detect high microvascular resistance at rest but a normal
only severe localized disease. So noninvasive techniques vasodilatory response to direct vasodilators and pacing.
need high index of suspicion to detect CMD. At present, Angiographically, it presents as coronary slow flow.29 It
definite diagnosis is based on documentation of normal may be transient and ECG stress test response is usually
epicardial coronaries, coronary flow reserve less than 2.5 normal.
on adenosine-induced hyperemia, and absence of spasm Patients with ‘‘angina equivalent’’ symptoms have
of epicardial coronaries on acetylcholine provocation. not been evaluated in any study. On the other hand,
actual role of microvascular dysfunction in ST elevation Invasive Methods

myocardial infarction is not clear.30 Chronic, diffuse, While diagnosing primary microvascular angina, it
persistent, and progressive coronary microvascular is necessary to document that epicardial coronary
dysfunction can produce global diastolic and/or systolic arteries are normal not only in structure but also in
dysfunction with normal coronary angiogram in DCM function. Acetylcholine and adenosine respectively
patients. cause endothelium dependent and endothelium
independent vasodilatation of epicardial coronaries.
Noninvasive Method Epicardial coronaries cannot be considered functionally
Resting electrocardiogram may not show ST segment normal only on the ground of normal response to
depression even during chest pain. 31 In patients with pharmacological stress. Microvascular dysfunction
microvascular coronary spasm were likely to have frequently coexists with epicardial coronary artery
minor borderline ischemic electrocardiogram findings disease. At present, fractional flow reserve (FFR) is used
at rest.28 Though it has been suggested that chest pain to assess functional significance of a coronary lesion.
and ischemia like electrocardiographic changes without Corrected thrombolysis in myocardial infarction (TIMI)
any wall motion abnormality on echocardiography can frame count is also used for quantitative assessment of
suggest microvascular angina.26 Tissue Doppler imaging coronary blood flow.35 Slow coronary flow is likely to be
may detect early long axis diastolic dysfunction in present only when there is microvascular dysfunction
patients with diffuse disease. Adenosine may induce such involving major portion of a coronary artery and may be
an abnormality not present on baseline examination.32 positive only in advanced stage of disease.36 It can also
Strain rate imaging with speckle tracking may identify occur due to diffuse spasm or increased basal coronary
vascular tone. Slow flow confined to one coronary
focal diastolic and/or systolic dysfunction. Exercise
artery can also be due to transient thrombosis followed
ECG is usually unremarkable. 26 Negative treadmill
by thrombolysis and micro embolization. Myocardial
stress test dose not exclude possibility of intermittent
opacification during coronary angiography allows
coronary microvasculardysfunction. Patients with
an approximate visualization of microcirculation. 37
coronary microvascular spasm and ‘cardiac syndrome
However, it is subjective and has low sensitivity. In
Y’ usually have normal treadmill stress test. It has
patients with history suggestive of vasospastic angina,
been suggested that slow recovery or unsatisfactory
coronary vasospasm is precipitated by intracoronary
response to sublingual nitrates may suggest component
injection of acetylcholine. Appearance of angina and
of microvascular dysfunction. 33 Flow in left anterior
ECG changes without spasm of epicardial coronary
descending coronary artery can be evaluated by artery suggests coronary microvascular spasm. However,
transthoracic Doppler echocardiography. Coronary coronary microvascular spasm frequently coexists with
flow velocity is measured at baseline and again after spasm of epicardial coronaries.38 Right coronary artery is
adenosine induced maximal hyperemia. Difference most susceptible to vasospasm. Therefore, assessment
is taken as representative of coronary flow reserve of coronary microvascular function only in left anterior
(CFR). In absence of epicardial coronary artery disease, descending coronary may be insufficient. Index of
increased flow is taken as an indirect marker of dilatation microcirculatory resistance (IMR) is calculated as distal
of coronary microvasculature in response to adenosine. coronary pressure multiplied by the hyperemic mean
Other noninvasive investigations includes Contrast transit time. There are some limitations in transpolating
stress echocardiography, 99 Tc-sestamibi imaging , these conclusions to humans (Fig. 3).
cardiovascular magnetic resonance (CMR) Nuclear However, each component of diagnostic criteria
magnetic resonance spectroscopy.34 has some limitations and one should also be careful to
Fig. 3: Diagnostic algorithm

Abbreviations: ACH, acetylcholine; ACS, acute coronary syndrome; CAD, coronary artery disease; CAG, coronary angiography; IMR, index of
microcirculatory resistance; FFR, fractional flow reserve; TMT, treadmill stress test.
avoid over diagnosis. There is need to develop a cheap, do not improve CFR and show inconsistent effects
effective, safe, and widely available noninvasive test for on symptoms, 42 while beta-blockers are effective for
detection of coronary microvascular dysfunction. improving chest pain symptoms.43 Ranolazine improves
both angina status and exercise stress test results in
TREATMENT OF CORONARY patients with MVA. In patients with abnormal cardiac
MICROVASCULAR DYSFUNCTION pain perception and normal coronary angiograms
In patients with MVA, a first important line of treatment imipramine improves symptoms; possibly through a
is represented by life style modification such as smoking visceral analgesic effect (Fig. 4). Finally, more demanding
cessation and weight-loss, which are known to improve forms of treatment are spinal cord stimulation 44 and
endothelial dysfunction and CMD. Perindopril and enhanced external counter pulsation.45 Cognitive behavioral
indapamide for 6 months can be prescribed in the therapy may be considered. Large-scale, practical, outcome
absence of myocardial diseases andobstructive coronary trials testing the efficacy of currently available traditional
artery disease. 39 Statins and angiotensin converting anti-atherothrombotic and anti-ischemic therapy, as
enzyme (ACE) inhibitors should bepresent as first line of well as novel therapies in this population, are warranted.
treatment in patients with MVA.40,41 Calcium antagonists Menopausal hormone therapy may improve emotional
Fig. 4: Treatment algorithm for patients with microvascular angina

Abbreviations: SCS,spinal cord stimulation; EEC, enhanced external counterpulsation.
wellbeing in postmenopausal women with angina and also on symptoms in patients with refractory angina,
‘normal’ angiograms; yet, there is no symptom benefit for i.e. those who are judged not to be candidates for
this patients.46 revascularization procedures. Gene therapy initially
In HCM, alcohol septal ablation seems to improve appeared as the most valid approach to stimulate and
CFR and septalendocardial-to-epicardial MBF. 47,48 enhance microcirculation and collateral growth in
While verapamil, disopyramide, and ACE inhibitors refractory angina, but controlled randomized studies
fail to improve myocardial perfusion.49-52 In patients have on the whole been disappointing. Recently,
with dilated cardiomyopathy, beta-blockers,53,54 but not attempts to promote collateral have been based on the
calcium antagonists or ACE inhibitors55 seem to have intramyocardial administration of progenitor vascular
beneficial effects on CMD, likely as a result of improved cells but that need to be addressed in larger studies.
hemodynamics. Of note, favorable effects on CMD have In the setting of ACS two small randomized studies57,58
recently been reported by treatment with allopurinol.56 found a beneficial effect of manual thrombus aspiration
While CMD can be present and play an important vs. the standard procedure on surrogate endpoints of
role in the clinical presentation of acute myocarditis, myocardial reperfusion. Regarding pharmacological
no study has hitherto assessed the effects of any form therapy, intracoronary adenosine administration appears
of intervention on CMD in these patients. Drugs that to be the most promising approach. An attractive form of
increase diastolic time, like beta-blockers, might help treatment is ischemic conditioning, in particular, ischemic
in delaying the ominous onset. As an alternative to postconditioning59,60 and remote pre-conditioning61 have
beta-blockers, ivabradine, known to selectively reduce been found to improve MVO (Fig. 5).
heart rate but not blood pressure, might be of help in
this setting. Clinical outcome are lacking and should CONCLUSION
therefore be investigated in prospective randomized Patients with angina but no significant obstructive
trials. Therapeutic interventions able to promote epicardial coronary disease on standard coronary angio
collateral growth may have an impact on outcome and graphy are at increased risk of adverse cardiovascular
Fig. 5: Diagnosis, prognostic value, and treatment of coronary microvascular dysfunction in different clinical settings
Abbreviations: ACH, acetylcholine test; AFD, Anderson-Fabry’s disease; AS, aortic stenosis; BG, blush grade; CABG, coronary aortic bypass
graft; CMD, coronary microvascular dysfunction; CMR, cardiac magnetic resonance; COCM, congestive cardiomyopathy; HCM, hypertrophic
cardiomyopathy; MVA, microvascular angina; MVO, microvascular obstruction; PET, positron emission tomography; pPCI, primary percutaneous
coronary intervention; PVB, Parvovirus B9; RF, risk factors; STR, ST segment resolution; Tn, troponin; TTDE, transthoracic Doppler
echocardiography. It is unknown the incremental prognostic value of coronary microvascular dysfunction in addition to that conveyed by risk
factors.
Source: Filippo Crea, et al. European Heart Journal. 2014;35:1101-11.
events compared with people without angina. CMD 3. Camici PG, Crea F. Coronary microvascular dysfunction.
is highly prevalent and clinicians need to be aware of N Engl J Med. 2007;356(8):830-40.
their clinical implication. Patients with CMD with and 4. Murthy VL, Naya M, Foster CR, et al. Improved cardiac
risk assessment with noninvasive measures of coronary
without epicardial CAD have been shown to have a poor
flow reserve. Circulation. 2011;124:2215-24. [PubMed:
prognosis including an increase in cardiac death, nonfatal 22007073]
MI, and hospitalizations. So, future effort is necessary 5. Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary
to refine noninvasive methods for easy evaluation of microvascular reactivity to adenosine predicts adverse
microvascular and endothelial function. Now-a-days outcome in women evaluated for suspected ischemia:
PET, MRI or CT-perfusion, and contrast-enhanced Results from the national heart, lung and blood institute.
Doppler echocardiography offer significant promise to WISE (women’s ischemia syndrome evaluation) study. J Am
Coll Cardiol. 2010;55:2825-32. [PubMed: 20579539]
diagnose CMD. Identifying the mechanism underlying
6. Serruys PW, di Mario C, Piek J, et al. Prognostic value
the patient’s symptoms in important to provide a rational
of intracoronary flow velocity and diameter stenosis
treatment that aims at both improving the quality of life in assessing the short- and long-term outcomes of
and long term prognosis when feasible. Taken together, coronary balloon angioplasty: The DEBATE study (doppler
evidence gathered in recent years has shown that CMD is endpoints balloon angioplasty trial europe). Circulation.
a true clinical entity rather than a mystery or an academic 1997;96:3369-77. [PubMed: 9396429]
curiosity. 7. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes
DR, Lerman A. Long-term follow-up of patients with mild
REFERENCES coronary artery disease and endothelial dysfunction.
1. Löffler AI, Bourque J. Coronary microvascular dysfunction, Circulation. 2000;101:948-54. [PubMed: 10704159]
microvascular angina, and management. Curr Cardiol Rep. 8. Fukushima K, Javadi MS, Higuchi T, et al. Prediction of short-
2016;18(1):1. term cardiovascular events using quantification of global
2. de Silva R, Camici PG. Role of positron emission tomography myocardial flow reserve in patients referred for clinical
in the investigation of human coronary circulatory function. 82Rb PET perfusion imaging. Journal of Nuclear Medicine.
Cardiovasc Res. 1994;28(11):1595-612. 2011;52:726-32. [PubMed: 21498538]
9. Taqueti VR, Hachamovitch R, Murthy VL, et al. Global coronary 20. Elliott PM, et al. Coronary microvascular dysfunction
flow reserve is associated with adverse cardiovascular in male patients with Anderson-Fabry disease and the
events independently of luminal angiographic severity and effect of treatment with alpha galactosidase A. Heart.
modifies the effect of early revascularization. Circulation. 2006;92(3):357-60.
2015;131:19-27. This paper was recently published and of 21. Eng CM, et al. Safety and efficacy of recombinant human
great importance as it showed that low CFR independent of alpha-galactosidase A--replacement therapy in Fabry’s
angiographic score predicts poor outcome. It also showed disease. N Engl J Med. 2001;345(1):9-16.
that those with lowest CFR received greatest benefit from 22. Uren NG, et al. Delayed recovery of coronary resistive vessel
revascularization. [PubMed: 25400060] function after coronary angioplasty. J Am Coll Cardiol.
10. Murthy VL, Naya M, Foster CR, et al. Association between 1993;21(3):612-21.
coronary vascular dysfunction and cardiac mortality in 23. Gregorini L, et al. Postischemic left ventricular dysfunction
patients with and without diabetes mellitus. Circulation. is abolished by alpha-adrenergic blocking agents. J Am Coll
2012;126:1858-68. This paper is of an importance as Cardiol. 1998;31(5):992-1001.
it illustrated the importance of determining CFR among 24. el-Tamimi H, et al. Inappropriate constriction of small
diabetics. They found that diabetic patients without known coronary vessels as a possible cause of a positive exercise
CAD who have an impaired CFR have a risk of cardiac test early after successful coronary angioplasty. Circulation.
death comparable to and possibly higher than nondiabetic 1991;84(6):2307-12.
patients with known CAD. [PubMed: 22919001] 25. Spyrou N, et al. Persistent but reversible coronary
11. Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, microvascular dysfunction after bypass grafting. Am J Physiol
Lerman A. Prevalence of coronary microvascular dysfunction Heart Circ Physiol. 2000;279(6):H2634-40.
among patients with chest pain and nonobstructive coronary 26. Lanza GA, Crea F. Primar y coronar y microvascular
artery disease. JACC Cardiovasc Interv. 2015;8(11):1445- dysfunction: clinical presentation, pathophysiology and
53. management. Circulation. 2010;121:2317-25.
12. Di Carli MF, et al. Role of chronic hyperglycemia in the 27. Kothawade K, Merz NB. Microvascular coronary dysfunction
pathogenesis of coronary microvascular dysfunction in in women: pathophysiology, diagnosis management. Curr
diabetes. J Am Coll Cardiol. 2003;41(8):1387-93. Probl Cardiol. 2011;36:291-318.
13. Reaven GM. Role of insulin resistance in human disease 28. Ohba K, Sugiyama S, Sumida H, et al. Microvascular
(syndrome X): an expanded definition. Annu Rev Med. coronary artery spasm presents distinctive clinical features
1993;44:121-31. with endothelial dysfunction as nonobstructive coronary
14. Jadhav S, et al. Effects of metformin on microvascular disease. J Am Heart Assoc. 2012;1:E0002485.
function and exercise tolerance in women with angina 29. Fragasso G, Chierchia SL, Arioli F, et al. Coronary slow flow
and normal coronary arteries: a randomized, double-blind, causing transient myocardial hypoperfusion in patients
placebo-controlled study. J Am Coll Cardiol. 2006;48(5):956- with cardiac syndrome X: long term clinical. Int J Cardiol.
63. 2009;137(2):137-44.
15. Camici PG, Crea F. Coronary microvascular dysfunction. 30. Lerman A, Holmes DR, Herrmann J, et al. Microcirculatory
N Engl J Med. 2007;356:830-40. dysfunction in ST elevation myocardial infarction: cause,
16. Crea F, Camici PG, BaireyMerz CN. Coronary microvascular consequence or both? Eur Heart J. 2007;28:788-97.
dysfunction: an update. Eur Heart J. 2014;35(17):1101-11. 31. Hurst T, Olson T, Olson L, et al. Cardiac syndrome X and
17. Marcus ML, et al. Decreased coronar y reser ve: a endothelial dysfunction: new concepts in prognosis and
mechanism for angina pectoris in patients with aortic treatment. Am J Med. 2006;119:56066.
stenosis and normal coronary arteries. N Engl J Med. 1982; 32. Vinereanu D, Fraser AG, Robinson M, Lee A, Tweddel A.
307(22):1362-6. Adenosine provokes diastolic dysfunction in microvascular
18. Dunn RB, Griggs DM Jr. Ventricular filling pressure as a angina. Postgrad Med J. 2002;78:40-2.
determinant of coronary blood flow during ischemia. Am J 33. Lanza GA, Manzoli A, Bia E, et al. Acute effects of nitrates
Physiol. 1983;244(3):H429-36. on exercise testing in patients with syndrome X. Circulation.
19. Breisch EA, et al. Myocardial blood flow and capillary 1994;90:2695-700.
density in chronic pressure overload of the feline left 34. Buchthal SD, den Hollander JA, Bairey-Merz CN, et al.
ventricle. Cardiovasc Res. 1980;14(8):469-75. Abnormal myocardial phosphorus – 31 nuclear magnet
resonance spectroscopy in women with chest pain but normal flow reserve after alcohol septal ablation in patients
coronary angiograms. N Eng J Med. 2000;342:829-35. with hypertrophic obstructive cardiomyopathy. Heart.
35. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: 2009;95:564-9.
a quantitative method of assessing coronary artery flow. 48. Soliman OI, Geleijnse ML, Michels M, Dijkmans PA,
Circulation. 1996;93:879-88. Nemes A, van Dalen BM, et al. Effect of successful alcohol
36. Bettrame JF, Limaye SB, Wuttke RD, et al. Coronary septal ablation on microvascular function in patients with
hemodynamic and metabolic studies of the coronary slow obstructive hypertrophic cardiomyopathy. Am J Cardiol.
flow phenomenon. Am Heart J. 2003;146:84-90. 2008;101:1321-7.
37. Vant Hof AW, Liem A, Suryapranata H, et al. Angiographic 49. Choudhury L, Elliott P, Rimoldi O, Ryan M, Lammertsma AA,
assessment of myocardial reperfusion in patients treated Boyd H, et al. Transmural myocardial blood flow distribution
with primary angioplasty for acute myocardial infarction: in hypertrophic cardiomyopathy and effect of treatment.
myocardial blush grade. Jwolle Myocardial Infarction study Basic Res Cardiol. 1999;94:49-59.
group. Circulation. 1998;97:2302-6. 50. Gistri R, Cecchi F, Choudhury L, Montereggi A, Sorace
38. Teragawa H, Mitsuba N, Ishibashi K, et al. Evaluation of O, Salvadori PA, et al. Effect of verapamil on absolute
coronary microvascular function in patients with vasospastic myocardial blood flow in hypertrophic cardiomyopathy. Am J
angina. World J Cardiol. 2013;5:1-7. Cardiol. 1994;74:363-8.
39. Neglia D, Fommei E, Varela-Carver A, Mancini M,Ghione 51. Hongo M, Nakatsuka T, Takenaka H, Tanaka M, Watanabe N,
S, Lombardi M, et al. Treatment of hypertension with Yazaki Y, Sekiguchi M. Effects of intravenous disopyramide
perindopril plus indapamide leads to reverse coronary on coronary hemodynamics and vasodilator reserve in
microvascularremodelling and improved blood flow. J hypertrophic obstructive cardiomyopathy. Cardiology.
Hypertens. 2011;29:364-72. 1996;87:6-11.
40. Kayikcioglu M, Payzin S, Yavuzgil O, Kultursay H, Can 52. Kyriakidis M, Triposkiadis F, Dernellis J, Androulakis AE,
LH, Soydan I. Benefits of statin treatment in cardiac Mellas P, Kelepeshis GA, et al. Effects of cardiac versus
syndrome-X. Eur Heart J. 2003;24:1999-2005. circulatory angiotensin-converting enzyme inhibition on
41. Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long-term left ventricular diastolic function and coronary blood flow
angiotensin-converting enzyme inhibition reduces plasma in hypertrophic obstructive cardiomyopathy. Circulation.
asymmetric dimethylarginine and improves endothelial 1998;97:1342-7.
nitric oxide bioavailability and coronary microvascular 53. Erdogan D, Gullu H, Caliskan M, Ciftci O, Baycan S, Yildirir
function in patients with syndrome X. Am J Cardiol. A, et al. Nebivolol improves coronary flow reserve in
2002;90:974-82. patients with idiopathic dilated cardiomyopathy. Heart.
42. Sutsch G, Oechslin E, Mayer I, Hess OM. Effect of diltiazem 2007;93:319-24.
on coronary flow reserve in patients with microvascular 54. Fan Y, Lin JH, Dong G, Zhu J, Yin F, Yang SS. The effect of
angina. Int J Cardiol. 1995;52:135-43. carvediloloncoronary flow reserve in patients with dilated
43. Lanza GA, Colonna G, Pasceri V, Maseri A. Atenolol versus cardiomyopathy. Zhonghua Nei Ke ZaZhi. 2010;49:217-9.
amlodipine versus isosorbide-5-mononitrate on anginal 55. Neglia D, Sambuceti G, Giorgetti A, Bartoli M, Salvadori
symptoms in syndrome X. Am J Cardiol. 1999;84:854-56. P, Sorace O, et al. Effects of long-term treatment with
44. Sgueglia GA, Sestito A, Spinelli A,Cioni B, Infusino F, verapamil on left ventricular function and myocardial blood
Papacci F, et al. Long-term follow-up of patients with cardiac flow in patients with dilated cardiomyopathy without overt
syndrome X treated by spinal cord stimulation. Heart. heart failure. J Cardiovasc Pharmacol. 2000;36:744-50.
2007;93:591-7. 56. Erdogan D, Tayyar S, Uysal BA, Icli A, Karabacak M, Ozaydin
45. K r o n h a u s K D , L a w s o n W E . E n h a n c e d e x t e r n a l M, et al. Effects of allopurinol on coronary microvascular
counterpulsation is an effective treatment for Syndrome X. and left ventricular function in patients with idiopathic
Int J Cardiol. 2009;135:256-7. dilated cardiomyopathy. Can J Cardiol. 2012;28:721-7.
46. Adamson DL, Webb CM, Collins P. Esterified estrogens 57. Burzotta F, Trani C, Romagnoli E, Mazzari MA, Rebuzzi AG,
combined with methyltestosterone improve emotional De Vita M, et al. Manual thrombus-aspiration improves
well-being in postmenopausal women with chest pain and myocardial reperfusion: the randomized evaluation of the
normal coronary angiograms. Menopause. 2001;8:233-8. effect of mechanical reduction of distal embolization by
47. Jaber WA, Yang EH, Nishimura RA, Sorajja P, Rihal CS, thrombus-aspiration in primary and rescue angioplasty
Elesber A, et al. Immediate improvement in coronary (REMEDIA) trial. J Am Coll Cardiol. 2005;46:371-6.
58. Silva-Orrego P, Colombo P, Bigi R, Gregori D, Delgado 60. Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol
A, Salvade P, et al. Thrombus aspiration before primary G, et al. Long term benefit of postconditioning. Circulation.
angioplasty improves myocardial reperfusion in acute 2008;117:1037-44.
myocardial infarction: the DEAR-MI (Dethrombosis to 61. Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M,
Enhance Acute Reperfusion in Myocardial Infarction) study. Kaltoft AK, Terkelsen CJ, Munk K, et al. Remote ischaemic
J Am Coll Cardiol. 2006;48:1552-9. conditioning before hospital admission, as a complement
59. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’HuillierI, to angioplasty, and effect on myocardial salvage in patients
et al. Post conditioning the human heart. Circulation. with acute myocardial infarction: a randomised trial. Lancet.
2005;112:2143-8. 2010;375:727-34.
CHAPTER
19
How did Fractional Flow Reserve Change My
Clinical Decisions? Case-based Discussions
INTRODUCTION be defined as the ratio of distal pressure to the proximal

Angiography has been the gold standard investigation pressure across a stenosis at maximal hyperemia.
of choice before any form of coronary interventions. FFR = Pd – Pv/Pa – Pv
But, it has its own limitations. It is a two dimensional Where, Pd, distal pressure; Pp, proximal pressure
(aortic pressure); Pv, coronary venous pressure.
investigational modality. Hence, it may miss eccentric
As coronary venous pressure is low, it could be
lesions especially in ostial location, highly tortuous
removed from the equation and making FFR as Pd/Pa. A
anatomy. It might be overcome by imaging modalities
value of <0.75 is definitely significant; while a value of 0.81
like intravascular ultrasound (IVUS) and optical
and above are insignificant. Value between 0.75-0.8 fall
coherence topography (OCT). Another major limitation
under grey zone. But it is recommended to revascularize
of angiography is anatomy based assessment of a lesion.
the territory. Hyperemia is achieved by intracoronary
It is overcome by fractional flow reserve (FFR) which
NTG along with intracoronary or intravenous adenosine.
assesses the physiology of a particular lesion. In FAME-1
study, it was observed that 20% of lesion which had been CHARACTERISTICS OF FFR
classified as significant by angiogram (70–90%) were
It is easy to do and interpret with less intra- and inter-
found be physiologically insignificant. It was also found observer variations. It accounts for collateral flow. It
that the chance to have a major adverse coronary event is independent of heart rate, blood pressure and LV
due to FFR insignificant lesion is 0.02% over a year which function. It is considered as the gold standard test for
is very minimal. assessing a lesion’s significance at present.
FRACTIONAL FLOW RESERVE How did FFR Change My Clinical

When resistance is constant, pressure is directionally Decisions?
proportional to flow. FFR measures the flow across a I will be discussing more about change in therapeutic
lesion by quantifying the pressure across the lesion when strategies attributed to FFR in clinical practice in the
resistance is constant or at its lowest level. Coronary following paragraphs.
arterioles play the primary role in increasing the coronary
circulation resistance. By doing vasodilation of arterioles Selecting Revascularization Strategy
(hyperemia), pressure measured across a lesion helps A 51-year-old diabetic with history of recent ACS
as to know the flow across the lesion. Hence FFR can have stress test which was strongly positive. He
CHAPTER 19: How did Fractional Flow Reserve Change My Clinical Decisions? Case-based Discussions 111
Fig. 1: Left coronary angiogram showimg borderline
underwent angiogram which showed critical long

segment right coronary artery disease (RCA) with
significant bifurcation disease in obtuse marginal artery
(OM). He also had a borderline 50–60% disease in LAD
(Fig. 1). After doing an FFR to LAD, it was found to be
0.78 (significant). According to FREEDOM trial coronary-
artery bypass grafting (CABG, any diabetic with triple
vessel disease irrespective of their SYNTAX score, an
option of CABG should be provided to them as preferred
revascularization strategy. He agreed for the same and
underwent CABG. Without FFR, he might have received Fig. 2: LAD and diagonal lesions before and after intervention
two long stents in RCA and two or one stents in OM. Story
does not end here. A month later, he was admitted for adenosine, Pd/Pa was significant (0.73). He underwent
severe abdominal pain and was diagnosed with acute PCI to LAD and diagonal using V stentiong strategy and is
necrotizing, gangrenous cholecystitis with impending doing fine. But for FFR, he might have had PCI to diagonal
rupture. He underwent the surgery and is doing well. alone leaving him on persisting unstable angina. FFR is
There was no hesistation in stopping anti-platelet drugs useful in patients with NSTEMI too (Fig. 2).
at the later scenario, as he had CABG done. Hence an
appropriate decision taken for a right patient saves us FUNCTIONAL PCI
from future collateral damages too. When FFR is used to do a PCI, it is called functional PCI.
A 69-year-old diabetic female with recent NSTEMI and
Identifying Culprit Vessel and Doing good LV function had an angiogram done elsewhere and
Appropriate Revascularization was found to have calcified critical triple vessel disease.
A 75-year-old elderly man presented with NSTEMI. She was advised CABG but was not willing for the same.
Coronary angiogram done elsewhere was reported to Hence a function PCI was done (Figs 3A to D). FFR to
have a critical diagonal disease with borderline LAD RCA was done and was found to be 0.91 (not significant
disease and was advised to have a PCI to diagonal and and hence was deferred revascularization. Considering
was put on maximal medical medical treatment. But, the critical nature of LAD and LCx, PCI to LAD and LCx
he was having recurrent unstable angina. Hence, he was done. As LAD was severely calcified, a rotablation
was taken up for FFR guided PCI to LAD. Even without (a diamond burr based technology to modify the plaque
A B C
D
Figs 3A to D: Angiographically significant RCA (A), long segment, bifurcating lesion in LCx-OM (B) and calcified long
segment LAD (C) disease. The lower panel shows a FFR which is not significant (D)
to enable better stent deliverability and expansion) was All that is Seen by Dye is not True
done with 1.25 burr. Later circumflex-OM was stented A 50-year-old female who is a known insulin dependent
with good end results (Figs 4A to E). After one and half diabetes presented with NSTEMI acute heart failure with
year follow-up, she is doing fine without any coronary moderate LV dysfunction which globally reduced. She
events. Here FFR avoided an additional stent in RCA. also had LBBB which is old. After initial stabilization,
she underwent angiogram which showed critical RCA
DEFERRED PCI and LCx disease with borderline LM and LAD diseases.
A 45-year-old female a known diabetic presented Hence, she underwent FFR to LM and LAD. FFR to LM-
with exertional angina and dyspnea class 2. She was LAD was done which was 0.71. As she is IDDM patient
started on antianginals and became asymptomatic. She with TVD (Figs 6A and B), she was advised to have CABG.
underwent angiogram elsewhere. She was found to have She underwent the procedure and her LVEF was normal
eccentric proximal 70% LAD disease and was advised to after a month post-CABG. This case emphasizes the use
have PCI to proximal LAD. She approached us later. A of FFR when angiographic findings are ambiguous.
FFR guided PCI was suggested. FFR was found to be 0.81
(Not significant even after repeating the test for multiple ASSESSMENT OF SERIAL LESIONS
times) (Figs 5A and B). Hence PCI to FFR was deferred. FFR is very useful in patients who have serial lesions.
One and half years now, she is asymptomatic and is able After crossing the serial lesions, the wire was kept in the
to walk for 3 miles a day. But for FFR, she might have distal vessel and slowly pulled back with intravenous
received a stent which is not warranted. adenosine producing maximal hyperemia. Lesions with
CHAPTER 19: How did Fractional Flow Reserve Change My Clinical Decisions? Case-based Discussions 113
A B C
Figs 4A to E: The pre PCI lesion in LAD

along with rotablation burr that was
used to modify the calcified plaque for
better stent expansion and post PCI
picture of LAD. Lower panel shows the
pre and post PCI picture of LCx
D E
A B
Figs 5A and B: Eccentric proximal LAD disease (arrow)
A B
Figs 6A and B: Bordeline LM (Bold arrow in Figure A)
Proximal Distal
Lesion A Lesion B
Proximal FFR FFR between Distal FFR
lesion A and B
FFR value 1 0.9 0.6
Mean pressure 85 76 52
Mean pressure drop 9 24
Fig. 7: Picture showing the presence of two tandem lesions. Here FFR pull back showed
significant pressure drop across the distal lesion. Hence it should be intervened first
and a repeat FFR should be done again to assess proximal lesion
A B
Figs 8A and B: Final FFR >0.8
maximal pressure drop will be identified and intervened of 0.78 with maximum drop in proximal lesions. Later
first and FFR should be repeated again SAS distal or proximal lesions were also stented with a final FFR >0.8
proximal lesion can affect the severity of the second (not suggestive of ischemia) (Figs 8A and B). In the
lesion (Fig. 7). A 59-year-old patient who is a known absence of FFR, an unwarranted intervention might have
diabetic, hypertensive with CAD underwent PCI to been done in diagonal while warranted interventions in
LAD/diagonal and OM in 2013. He presented to us in LAD might have been missed.
2016 with exertional angina and dyspnea. A TMT was
done which was showing evidence of stress induced
ischemia. Angiogram done revealed a tight ostial
CONCLUSION
diagonal disease and serial lesions in LAD (Fig. 7). FFR FFR is a useful tool in contemporary cardiology practice.
was done to diagonal which was 0.92 only and hence PCI It changes the management of clinical decision in both
to diagonal was deferred. A FFR to LAD was found to be stable CAD patients and patients with acute coronary
0.75 (suggestive of inducible ischemia) A slow pull back syndrome of a at least one-third of patients. In spite of
of FFR showed maximum pressure drop at the leval of such robust data, the use of FFR is less. Increasing the
lesion C and D. Hence PCI to mid and diatal LAD was utility of FFR based revascularization will definitely
done. Later FFR was repeated which again showed FFR improve the clinical outcomes of patients.
CHAPTER
20
Mega Trials in Cardiology
Sundeep Mishra
INTRODUCTION HYPERTENSION TRIALS

As we move through the modern times the medical HOT Trial was a pivotal multicenter, RCT in the field of
practice has become more and more differentiated hypertension. Enrolling nearly 19,000 patients (patients)
depending more and ever more on overwhelming from 26 different countries, it enquired “What is the
evidence provided by impressive and ever growing optimal target to treat hypertension? 1 Inclusion criteria
number of large randomized controlled trails (RCTs) also- were standard but rather severe diastolic hypertension;
called “mega-trials.” In this evidence-based medicine, a diastolic blood pressure (DBP) of 100–115 mm Hg. The
clinical trials are custom designed to investigate the tested treat to target DBP level were; ≤90 mm Hg, ≤85 mm
effects of therapies or pharmaceutical agents on hard end Hg, or ≤80 mm Hg with standard measures but treatment
points, something which cannot be done by individual with either aspirin (ASA) 75 mg daily or placebo. The
doctors in their busy day-to-day clinical practice. The titration was done using standard antihypertensives;
growing role of this epidemiologic approach to medicine, Felodipine, angiotensin-converting-enzyme inhibitor
which is based mostly on the assessment of the average (ACE-I), beta-blockers and diuretics in a graded fashion.
response or behavior of large populations rather than 1. Step 1 – Initially, felodipine 5 mg daily (a long acting
of idiosyncratic individuals, is systematically replacing calcium was the starting dose with additional therapy
the former experience based practice of the physician, given to reach the target blood pressure.
which has now become an aid rather than substitute for 2. Step 2 – If still uncontrolled, ACE-I or beta-blocker
evidence based discourse. Thus, besides and beyond was added next.
the mere personal clinical experience and professional 3. Step 3 – If targets still not achieved, felodipine up-
skills or just a knowledge of mechanistic concepts and titrated to 10 mg daily
pharmacologic/pharmaco-dynamic drug properties, 4. Step 4 – If still unable to achieve the targets, the dose
today it is the responsibility of each and every physician to of either ACE inhibitor or beta-blocker was doubled.
be aware of the results of many trials and to employ them 5. Step 5 – If still resistant, a diuretic was added.
in individual clinical practice. On a more practical note, MACE defined as all myocardial infarctions (MI) and
the guidelines are generally a summary of important and strokes (fatal and nonfatal), and all other cardiovascular
landmark clinical mega-trials and therefore mastery of (CV) deaths and was the primary outcome of the trial
this area may be a short-cut to knowing all the trials. and patients were followed for an average of 3.8 years.
The trial was able to achieve the prerequired outcomes heart failure (CHF). The statin used was pravastatin
in nearly all patients in all the groups. Interestingly, 40 mg daily versus placebo. The trialists investigated
despite different thresholds for DBP control there was cardiovascular outcomes, the primary endpoint being a
no differences between the three groups with regards to composite of:
MACE (p = 0.50). Even secondary end-points; all stroke 1. CV mortality
(p = 0.74), all MI (p = 0.05), CV mortality (p = 0.49), and 2. Nonfatal MI. At the end of 5.0 years, patients on
total mortality (p = 0.32) were also not different. The pravastatin fared much better; lower rate of the
only group were there seemed to be benefit with tight primary endpoint (RR 24%). For secondary end-
control of DBP (≤80 mm Hg group) were diabetic patients points there was a lower nonfatal MI (RR 23%) but
where MACE rates seemed to be lower, RR 2.06, 95% CI there was no significant difference in CV mortality.
1.24–3.44, p = 0.005 as well as lower CV mortality, RR 3.0, Risk of revascularization (CABG/PCI ), another
p = 0.016 vis-à-vis those with a loose control (≤90 mm CVS event was also significantly lower in patients
Hg) group. Interestingly, it was notable that patients par taking pravastatin (RR 27%). There were a couple of
taking ASA fared better; fewer MACE - RR 0.85, p = 0.03 interesting points in the study:
and MI - HR 0.64, p = 0.002, however, the risk of bleeding Women experienced significantly larger magnitude of
in this group was higher; nonfatal major bleeding (RR reductions in the risk of coronary events as compared
1.8, p<0.001). Regarding other side effects, they were few; with men (p=0.05).
dizziness, headache, leg edema, flushing, and coughing Patients with higher baseline values of LDL (LDL
but overall all antihypertensives, in all the groups were >150 mg/dL) witnessed a larger benefit in terms of
well tolerated. risk reduction vis-a-vis to those with near normal
LDL between 125 mg/dL and 150 mg/dL at baseline
Take Home Message (35% vs. 26%, p=0.03).
Tight control of blood pressure is not required in
majority of patients. Take Home Message
Threshold of blood pressure control should be lower Statins are useful for secondary prevention of CAD
for diabetics. even in those without manifest dyslipidemia.
Overall, aspirin use in hypertensives is not required The benefit seems to depend on baseline LDL values,
(it does decrease cardiac events but this benefit is the higher starting values, the greater benefit.
over-ruled by increased bleeding risk. Women seem to benefit more with statin therapy.
SECONDARY PREVENTION OF CAD HOPE TRIAL

The CARE trial is landmark trail of statin use for This is another Practice Changing Trial in cardiology.
secondary prevention of coronary artery disease (CAD). While ACE-Is has always been known to improve
It was again a RCT involving >4000 patients all over outcomes, including long-term outcomes in patients
North America (80 centers).2 It included already known with CHF, those with reduced ejection fraction (LVEF),
CAD patients (secondary prevention trial) but with near hypertensives (also effective in controlling blood pressure
normal lipid levels (total cholesterol <240 mg/dL, LDL besides reducing events), diabetics (particularly in the
cholesterol between 115–174 mg/dL, fasting triglyceride presence of microalbuminuria) but they were not known
<350 mg/dL); acute MI 3 mg/dL 20 months (prior to to benefit CAD in absence of these comorbidities. HOPE
randomization), age between 21 years and 75 years, trial changed all that; it was RCT, enrolling nearly 10,000
fasting glucose levels <220 mg/dL, normal left ventricular patients from all over the world (281 centers) evaluating
functions (left ventricular ejection fractions of ≥25%), the effect of ramipril in high-risk CAD patients, >55
and no clinical evidence of heart failure, i.e. congestive years age, with normal LVEF. The primary end-point
CHAPTER 20: Mega Trials in Cardiology 117
was MACE and the patients were followed up for 5 from any cause (primary endpoint). The third arm
years.3 Patients with reduced left ventricular function was of placebo. Interestingly, there was no difference
(EF<40%) or with a history of CHF or those already in outcomes between amiodarone and placebo group
on a ACE-I therapy were excluded from HOPE study. (Mortality: placebo group - 29% versus miodarone
Patients received either ramipril (titrated to upto 10 mg group - 28%), but the outcomes were better in the
daily) or placebo. Investigators looked for a composite ICD group (Mortality: 22% versus 29% for placebo; p =
of MI, stroke, or CV death, as primary end-point. The 0.007), a risk reduction of 23%. Furthermore, the drug
ramipril arm demonstrated significantly reduced MACE amiodarone discontinuation rates were high (32% vs.
(compared to the placebo). Interestingly, the findings 22% of the placebo group), both mild; higher rates of
remained consistent in all sub-groups irrespective of sex, tremor (4%, p = 0.02) and serious; hypothyroidism
age, cardiac risk factors, presence of diabetes, evidence (6%, p < 0.001). Comparatively, only 5% of patients
of CV, baseline BP, or evidence of microalbuminuria. receiving ICDs experienced a significant complication,
However, the most common adverse effect of ramipril at least at the time of implantation (surgical correction,
was cough. hospitalization, new/unanticipated drug therapy),
although on follow-up 9% of patients developed such
Take Home Message complication. Thus, overall, while ICD implantation led
ACE-I are beneficial for secondary prevention of to a significant reduction in mortality, there was no such
CAD. advantage with amiodarone. Consequently, ICDs have
The benefit occurs irrespective of symptoms, now become the new gold-standard in patients with
hypertension, diabetes mellitus, presence of heart stable CHF and reduced LVEF.
failure or ejection fraction.
Take Home Message
ARRHYTHMIA In patients with stable CHF and reduced ejection
In the subspecialty of pacing and arrhythmia’s The fraction there is no benefit of amiodarone.
Sudden Cardiac Death in Heart Failure Trial (SCD- Amiodarone therapy is associated with both short
HeFT) remains a pathbreaking trial. Initially effective and long-term complications.
antiarrhythmics including drugs were considered ICD therapy is the gold-standard for preventing SCD
“gold standard.” Defibrillators were considered far too in these patients.
expensive reserved for really resistant cases. The SCD-
HeFT took a revolutionary approach for the time. They HEART FAILURE
evaluated effect of amiodarone vis-a-vis intracardiac Progression of heart failure is thought to be multifactorial
defibrillators (ICDs) while treating patients with mild- involving various pathophysiological systems, but perhaps
to-moderate heart failure.4 They included adults (age most important are neuroendocrine compensation of the
≥18 years) with significant symptoms (NYHA class II or body to decreased effective circulating volume leading to
III) with evidence of left ventricular dysfunction (LVEF the activation of the sympathetic and renin-angiotensin-
≤35%). Overall > 2500 patients were randomized and aldosterone system (RAAS). All this leads to myocardial
followed up for nearly 4 years (median of 45.5 months) remodeling and slow but progressive reduction in
and outcomes evaluated in all surviving patients One cardiac output. Most therapeutic agents target one or
arm composed of amiodarone loaded as per standard the other pathophysiological mechanisms. Aldosterone
protocol and then weight-adjusted maintenance dose blockade is relatively new therapeutic target and RALES
(a median dose of 300 mg daily). For the second arm, was the landmark RCT evaluating the role of aldosterone
a Medtronic single-chamber ICD was chosen and kept blockade in treating CHF.5 While RAAS and beta-blokade
on shock-only mode. The outcome measured was death remained cornerstone of mortality reduction while
diuretics were useful for symptom reduction particularly Diabetes Study (UKPDS) undertook a number of trials
in volume overloaded states, aldosterone-inhibitors, like to enquire into exactly that: morbidity and mortality
spironolactone were considered minor players, more associated with DM. UKPDS series 33 and 34, was carried
like an add on to diuretic, on the background of ACE-I out in 23 participating centers and included patients
therapy. The hypothesis that aldosterone blockade with newly diagnosed T2DM, with broad range spectrum
would have additional role beyond the near optimal (aged 25–65 years). These patients were allocated in a
block RAAS with ACE-I/ARB seemed implausible. randomized controlled manner to different treatment
Furthermore, there was an additional risk of inducing groups versus conventional management (which involved
hyperkalemia with the use of aldosterone inhibitors. only lifestyle modifications) and were followed up for 10
However, there was some evidence that there could be years.6, 7 The UKPDS 33 demonstrated that while median
a escape from RAAS pathway even on optimal ACE- HbA1c levels were significantly lower in the treatment
inhibition or in other words ACE-I alone may not be groups: patients receiving sulfonylureas or insulin (7.0%
that effective in suppression of this pathway. With this compared to 7.9% for the control group, P<0.0001) and
in mind RALES trial sought to investigate whether the risk of microvascular complications (defined as
spironolactone would reduce mortality in patients with retinopathy, vitreous hemorrhage, neuropathy, and
advanced CHF, who were already on standard medical renal failure) was significantly reduced as well (a 25% risk
therapy. It was a multicentric (195 centers), multicountry reduction, 95% CI 0.60–0.93) but there was no significant
(15 countries) RCT enrolling 1,663 relatively sicker differences between pharmacologic therapy versus
patients, NYHA functional class III-IV, with markedly lifestyle modifications alone for the development of
reduced left ventricular function (LVEF <35%) on optimal macrovascular complications; CAD, peripheral vascular
medical therapy (as per that time); ACE-I, loop diuretic ± disease and cerebrovascular disease. Furthermore,
digoxin. On the top of that patients received either 25-50 in the treatment group, than was significantly higher
mg spironolactone once daily or the placebo. They had rates of hypoglycemic episodes than the control group
planned to follow-up the patients for 3 years but it had (P<0.0001). The other study, UKPDS 34, evaluated the
to be terminated at around 1 year because the benefits of impact of treating patients with T2DM with metformin.
spironolactone were so obvious. The study demonstrated They found that when compared to conventional therapy
not only a significant reduction in all-cause mortality (i.e. lifestyle changes alone), treatment with metformin
but death due to CHF, SCD and hospitalizations due was found to reduce diabetes-related death by 42% (95%
to CHF were also significantly reduced. Surprisingly, CI 0.37–0.91) and all-cause mortality by 36% (95% CI
the incidence of serious hyperkalemia was rare in both 0.45–0.91). Furthermore, metformin therapy was linked
groups. with fewer hypoglycemic episodes than treatment with
sulfonylureas or insulin. The UKPDS 38 took a different
Take Home Message route, they undertook to evaluate the effects of blood
Addition of aldosterone antagonists on the background pressure control in patients with newly diagnosed
of optimal medical therapy leads to improved oputcomes T2DM. It was a multicentric study (23 participating
in symptomatic patient. hospitals) of relatively long duration (10 years), with
very good follow-up program (Blood pressure was
DIABETES MELLITUS measured at clinic visits every 3–4 months). This trial
Diabetes mellitus (DM) is another important area for sought to compare outcomes of tight blood pressure
cardiologists. Many consider DM as CAD equivalent. control (<150/85 mm Hg) versus less tight control
Conventional wisdom would suggest that treating blood (<180/105 mm Hg). Patients received mandated blood
sugar effectively would decrease morbidity and mortality pressure agents; ACE-Is, beta-blockers to achieve these
associated with DM. The United Kingdom Prospective targets. The investigators found that unlike glycemic
CHAPTER 20: Mega Trials in Cardiology 119
control, a tight control of blood pressure (<150/85 mm aim was to prevent the development ESRD (need for
Hg) was associated with not only significantly fewer dialysis or renal transplantation), doubling of serum
microvascular complications but also macrovascular creatinine level, and death, taken as a composite primary
complications and even diabetes-related deaths when end-point. Other outcomes evaluated were morbidity
compared to control subjects with less tight blood and mortality from CV causes, progression of renal
pressure control (<180/105 mm Hg).8 The study revealed disease, and changes in the degree of proteinuria–all
that a tight control of BP led to a 32% reduction in the risk secondary end-points. Most patients received 100 mg of
of diabetes-related mortality compared to the less tight losartan (71%), while the rest received 50 mg of losartan
group (P=0.019). Diabetes-related mortality was defined in active group. It was found that treatment with losartan
as deaths resulting from myocardial infarction, sudden lead to 16% risk reduction in the composite primary
death, stroke, peripheral vascular disease, renal disease, endpoint (43.5% vs. 47.1%, p=0.02). Furthermore, the
hyperglycemia, or hypoglycemia. Furthermore, the risk risk of doubling serum creatinine was reduced by 25%
of macrovascular complications were 34% lower in the (21.6% vs. 26.0%, p=0.006) and end-stage renal disease by
tight control group (P=0.019). 28% (19.6% vs. 25.5%, p=0.002), all secondary end-points.
However, there was no significant difference in mortality
Take Home Message between the two groups (21.0% vs. 20.3%, p=0.88) as
In patients with diabetes mellitus a tight control also the secondary endpoint of morbidity and mortality
of blood sugar results in lower microvascular from CV causes. Patients in the losartan arm, however,
complications but has no effect on macrovascular did experience significant reductions in the amount of
complications or overall mortality. proteinuria (p<0.001).
There is a risk of episodes of hypoglycemia when In patients with T2DM, treatment wityh losartan
a tight control in blood sugars is achieved with leads to improvement in renal outcomes.
sulphonylureas or insulin.
Metformin therapy in T2DM was associated with CONCLUSION
reduction in total and diabetes related mortality. The HOT trial demonstrated that tight control of blood
Tight control of blood pressure was associated with pressure hypertensive patients but with no other
not only reduced macrovascular complications but comorbidities led to no benefit either in terms of MACE
also diabetes related mortality. or CV mortality—a DBP ≤90 mm Hg as good as that of
The RENAAL Trial aimed to investigate aspects of ≤85 mm Hg or ≤80 mm Hg. On the other hand, if patients
renal disease in diabetes mellitus. It was a prospective, had associated diabetes mellitus, targeting a DBP of
RCT enrolling >1,500 T2DM patients with usual age ≤80 mm Hg led to significant improvement in the risk
(31–70 years), and evidence of nephropathy (defined as of MACE and CV mortality (vis-à-vis a higher target
urinary protein ≥0.5 g/24 hours and serum creatinine of ≤90 mm Hg). Another important finding from this
between 115–254 μmol/L). type 1 diabetes, nondiabetic study was that along with antihypertensive treatment,
renal disease, or a history of CHF, recent MI, PCI, if a concurrent low-dose ASA was added, while it led
CABG or CVA were excluded from this study. The to significantly lower rates of MACE and MI but higher
study was carried out at 250 centers in 28 countries, rates of bleeding. Finally, antihypertensive therapy was
followed up for a mean period of 3.4 years.9 All patients generally well tolerated, with only some patients afflicted
received standard therapy, including conventional with dizziness, headache, leg edema, and coughing.
antihypertensive therapy (calcium-channel blockers, The UKPDS group of studies demonstrated that the
diuretics, alpha-blockers, and beta-blockers, but not use of pharmacologic agents like sulfonylureas, insulin,
ACE-I or ARBs) as mandated. In addition they were metformin and antihypertensives in patients with T2
randomized to receive either losartan or placebo. The DM. They found that while antidiabetic drugs such as
insulin and sulfonylueas significantly reduced their risk ramipril, on cardiovascular events in high-risk patients. N
for developing microvascular complications, it was only Engl J Med. 2000;342(2000):145-53.
metformin that also reduced diabetes-related mortality, 4. Bardy, Gust H, et al. Amiodarone or an implantable
cardioverter–defibrillator for congestive heart failure. New
all-cause mortality, and had a lower risk of hypoglycemia.
England Journal of Medicine. 2005;352(3):225-37.
This study led to the establishment of metformin as the
5. Pitt, Bertram, et al. The effect of spironolactone on morbidity
first-line pharmacotherapy in managing T2DM. On the
and mortality in patients with severe heart failure. New
other hand, while antidiabetic pharmacotherapy was England Journal of Medicine. 1999;341(10):709-17.
ineffective in reducing macrovascular complications. 6. Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, et
It was tight control of blood pressure control which led al. Intensive blood-glucose control with sulphonylureas or
to significant reductions in both microvascular and insulin compared with conventional treatment and risk
macrovascular complications, as well as diabetes-related of complications in patients with type 2 diabetes (UKPDS
mortality. These groups of studies have received most 33). Lancet. 1998;352(9131):837-53.
citations compared to any other cardiovascular mega trials. 7. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes
(UKPDS 34). Lancet. 1998;352(9131):854-65.
REFERENCES
8. UK Prospective Diabetes Study Group. Tight blood pressure
1. Kjeldsen, Sverre E, et al. Hypertension Optimal Treatment
control and risk of macrovascular and microvascular
(HOT) Study. Hypertension. 1998;31(4):1014-20.
2. Sacks, Frank M, et al. The effect of pravastatin on coronary complications in type 2 diabetes: UKPDS 38. British
events after myocardial infarction in patients with average Medical Journal. 1998;317(7160):703.
cholesterol levels. New England Journal of Medicine. 9. Brenner, Barry M, et al. Effects of losartan on renal and
1996;335(14):1001-9. cardiovascular outcomes in patients with type 2 diabetes
3. Heart Outcomes Prevention Evaluation Study Investigators. and nephropathy. New England Journal of Medicine.
Effects of an angiotensin-converting–enzyme inhibitor, 2001;345(12):861-9.
CHAPTER
21
Rheumatic Valvular Heart Disease
RR Singh
Rheumatic heart disease, which is one of complication ASO titer, and CRP to check for the presence of strep
of rheumatic fever damages heart valves. Rheumatic antibodies and ECG. However, it is common, that signs
fever is a kind of inflammatory disease beginning of the streptococcal infection may be gone by the time
with Streptococcus haemolyticus of lance field group C patient is brought to the physician or cardiologist. In that
causing sore throat. It affects connective tissue of body case, the consultant will need to ask or remember whether
throughout, with special affection to the heart muscle the child or patient recently had a sore throat, joint pains
and valves, joints, skin and brain. As we know that or other symptoms of a streptococcal infection.
rheumatic fever affects human being irrespective of age. The clinician should do a physical examination and
Rheumatic fever is very common in children between check for signs of rheumatic fever, including flittering or
4 to 15 years age group. One has to treat streptococcal migrating joint pains and inflammation. The consultant
infection with antibiotics and that is best way to prevent should look for loud S1 and for abnormal rhythms
rheumatic fever and sore throat. or murmurs that may signify that the heart has been
strained.
SIGNS AND SYMPTOMS In addition to this, there are a few common tests,
Since the symptoms of rheumatic heart disease vary that may be used to check the heart and assess damage
till they cause damage to the heart muscle often is not including CBC, ESR, ASO titer, CRP, ECG, chest X-ray,
readily noticeable. When symptoms do appear, they may echocardiography and cardiac catheterization.
depend on the extent and location of the heart damage
patients may have migrating joint pain. TABLE 1: Jones criteria fo rheumatic fever
Infact, symptoms of rheumatic fever appear about
Major criteria Minor criteria
two weeks after the onset of an untreated strep throat
Pancarditis (pericarditis, endocarditis, Fever
infection. Apart from the sore throat caused by the strep myocarditis)
infection, children have a fever like symptoms joint
Polyarthritis Arthralgia
pains. Occasionally, the patient may be having shortness
Sydenham chorea Prolonged PR interval
of breath or dyspnea on exertion (Table 1).
Subcutaneous nodules Increased ESR or CRP*
The first step initially in diagnosing rheumatic heart
Erythema marginatum Leukocytosis
disease is establishing that child recently had a history of
*Erhtrocyte sedimentation rator or C-reactive protein
streptococcal infection. The consulting physician should **Two major or 1 major and 2 minor must be present to diagnoses
advice a throat culture, a blood test including CBC, ESR, rheumatic fever
MITRAL STENOSIS heart disease. However, it is the most common valvular

Mitral stenosis is a valvular heart disease, which is heart disease observed/diagnose during pregnancy.
characterized by the narrowing of the orifice of the mitral Other causes include infective endocarditis in which
valve in between left atrium and left ventricle of the heart. vegetations increase the risk of stenosis. Other rare causes
include mitral annular calcification, endomyocardial
MITRAL STENOSIS WITH CLOSE-UP fibroelastosis, malignant carcinoid syndrome, systemic
lupus erythematosus (SLE), whipple disease, Fabry’s
ON MITRAL VALVE (FIG. 1)
disease, and rheumatoid arthritis, Hurler’ disease,
Signs and Symptoms Hunter’s disease and amyloidosis.
Heart failure symptoms, such as dyspnoea on exertion
(DOE), orthopnea and paroxysmal nocturnal dyspnea Pathophysiology
(PND) The normal area of the mitral valve orifice is about 4–6
Palpitation cm2. In normal cardiac physiology, the mitral valve opens
Chest pain during left ventricular-diastole, to allow blood to flow
Hemoptysis from the left atrium to the left ventricle.
Thromboembolism in later stages when the left atrial When the value of mitral valve area goes below 2.0
2
volume is increased (i.e. dilation). It leads to increase cm , the valve causes an impediment to the flow of blood
risk of atrial fibrillation (AF), which increases the risk into the left ventricle, creating a pressure gradient across
of blood stasis and increases the risk of coagulation. the valve leading to pulmonary congestion.
Ascites, edema and hepatomegaly (if right-sided
In case, the mitral valve area is less than 1.0 cm2, there
heart failure develops) will be an increase in the left atrial pressures (required
Fatigue and weakness increase with exercise and
to push blood through the stenotic valve), which causes
pulmonary arterial hypertension leading to congestive
pregnancy.
heart failure and pulmonary edema).
It has been found that most of the patients of mitral
The constant pressure overload of the left atrium
stenosis have disease due to disease in the heart muscles
will cause the left atrium to increase in size that leads to
secondary to rheumatic fever. Uncommon causes
development of atrial fibrillation (AF).
include calcified mitral valve as a form of congenital
When AF persists the chances of systemic embo
lization becomes high.
Mitral stenosis typically progresses slowly (over
decades) from the initial symptoms to development of
signs till the diagnosis is made.
Physical Examination
An opening snap that is a high-pitch additional sound
may be heard after the A 2 (aortic) component of the
second heart sound (S2), which correlates to the forceful
opening of the mitral valve. The mitral valve opens when
the pressure in the left atrium is greater than the pressure
in the left ventricle. This happens in ventricular diastole
(after closure of the aortic valve), when the pressure in
the ventricle precipitously drops. In individuals with
Fig. 2: Rheumatic heart disease at autopsy had characteristic
findings, i.e. thickened mitral valve, thickened chordae tendinae, mitral stenosis, the pressure in the left atrium correlates
hypertrophied left ventricular myocardium with the severity of the mitral stenosis. As the severity
CHAPTER 21: Rheumatic Valvular Heart Disease 123
of the mitral stenosis increases, the pressure in the left Echocardiography (Fig. 2)
atrium increases, and the mitral valve opens earlier in Diagnosis of mitral stenosis is most easily made by
ventricular diastole. echocardiography, which shows left atrial enlargement,
A mid-diastolic rumbling murmur with presystolic thick and calcified mitral valve with narrow and “fish-
accentuation will be heard after the opening snap. The mouth”-opening orifice and signs of right ventricular
murmur is best heard at the apical region and is not failure in advanced disease. It can also show decreased
radiated. Since it is a low-pitch sound, it is heard best opening of the mitral valve leaflets, and increased blood
with the bell of the stethoscope. Its duration increases flow velocity during diastole. Doppler echocardiography
with worsening disease. Rolling the patient toward left is the gold standard in the evaluation of the severity of
as well as isometric exercise will accentuate the murmur. mitral stenosis (Table 2).
A thrill might be present when palpating at the apical
region of the precordium. Cardiac Chamber Catheterization
Advanced disease may present with signs of right- Another method of measuring the severity of mitral
sided heart failure such as parasternal heave, raised stenosis is the simultaneous left and right heart
jugular venous pressure, congested liver, ascites and/or chamber catheterization. The right heart catheterization
loud P2. (commonly known as Swan-Ganz catheterization) that
Almost all signs increase with exercise and pregnancy. gives cardiologist the clue of mean pulmonary capillary
Other peripheral signs include: wedge pressure, which is a reflection of the left atrial
Malar flush—due to back pressure and buildup of pressure.
carbon dioxide which is a natural vasodilator.
Atrial fibrillation—irregular pulse and loss of a-wave TABLE 2: Severity of mitral stenosis
in jugular venous pressure Degree of mitral stenosis Mean gradient Mitral valve area
Left parasternal heave—suggestive of right ventricular Progressive mitral stenosis <5 mm Hg >1.5 cm2
hypertrophy due to pulmonary hypertension Severe mitral stenosis 5–10 mm Hg 1.0–1.5 cm2
Tapping apex beat. Very severe mitral stenosis >10 mm Hg < 1.0 cm2
Fig. 2: Severe mitral stenosis

Other Routine Techniques

Chest X-ray may also show straightening ot left cardiac
silhouette suggestive of left atrial enlargement.
Electrocardiography may show P mitrale, that is,
broad, notched P-waves best seen in lead S2.
MEDICAL TREATMENT
Treatment of acute rheumatic fever includes antibiotics
to treat the streptococcal infection and supportive
treatment of symptoms. Usually, aspirin is given in large
doses until the joint inflammation subsides. Some times,
steroids are required. Once the acute disease phase
passes, patients need to take penicillin, or an equivalent
Fig. 3: Mitral valvuloplasty
antibiotic, till the age of 21 years to prevent recurrences.
This is a very important treatment because the risk of
Calcified valve and/or associated mitral regurgitation are
heart valve damage increases, if rheumatic fever recurs.
contraindications.
Any angina is treated with short-acting nitrovaso
Other serious complications with PBMV usually
dilators, beta-blockers and/or calcium-channel blockers.
relate to the technique of trans-septal puncture (TSP).
Any hypertension is treated aggressively, but caution Immediate results of PBMV are often quite gratifying.
must be taken in administering beta-blockers.
Heart failure is treated with digoxin, diuretics, nitro- BIBLIOGRAPHY
vasodilators and, if not contraindicated. One should be 1. Carapetis JR. Rheumatic heart disease in Asia. Circulation.
cautious inpatient administration of ACE inhibitors. 2008;118:2748-53.
2. Kaplan MH, Bolande R, Rakita L, Blair J. Presence of bound
SURGICAL TREATMENT immunoglobulins and complement in the myocardium in
acute rheumatic fever: association with cardiac failure. N
The indication for invasive treatment with either a mitral Engl J Med. 1964;271:637-45.
valve replacement or valvuloplasty is NYHA functional 3. Sanyal SK, Thapar MK, Ahmed SH, Hooja V, Tewari P. The
class III or IV symptoms. initial attack of acute rheumatic fever during childhood
in: North India; a prospective study of the clinical profile.
Mitral Valvuloplasty (Fig. 3) Circulation. 1974;49:7-12.
4. WHO Technical Report Series 923. Rheumatic fever
Mitral valvuloplasty which is a minimally invasive and rheumatic heart disease. Report of a WHO expert
common procedure to correct an uncomplicated mitral consultation, Geneva, Oct 29–Nov 1, 2001. World Health
stenosis by dilatation of the valve using a balloon. Organization, Geneva; 2004.
CHAPTER
22
Advances in Management of
Pulmonary Arterial Hypertension
INTRODUCTION India and China, PAH associated with CHD (congenital

Pulmonary arterial hypertension (PAH) is defined as heart disease) is the predominant cause. Recent
‘mean pulmonary arterial pressure (PAP) measured by registries like REVEAL have noted significant changes
right heart catheterization of 25 mm Hg or higher at rest in the epidemiology of PAH including change in the
with a pulmonary capillary wedge pressure (PCWP) <15 mean age of patients with IPAH (45–65 years). With the
mm Hg and pulmonary vascular resistance (PVR) ≥3 development ofvasodilator drugs patient outcomes have
wood units’. also improved as documented by the REVEAL registry
According to the latest updated ESC guidelines, PAH is in which the 5-year survival of newly diagnosed patient
classified into 5 groups: improved to 61%.
1. Group 1: Patient with idiopathic PAH, PAH due to
congenital heart disease, PAH due to secondary MANAGEMENT OF PAH
causes like connective tissue diseases, pulmonary Mediators involved in vasodilation of pulmonary artery
veno-occlusive disease and primary pulmonary are the current targets of therapies in PAH. These include
hypertension of newborn. key pathways and targeted therapy:
2. Group 2: PAH due to left heart disease like LV Prostac ycline (P GI ) pathway: Prostac ycline
2
dysfunction or valvular heart disease. PGI 2 is predominately a vasodilator. It also has

3. Group 3: PAH due to lung disease or hypoxia like antiproliferative and anti-inflammatory effects
COPD. on vessel wall. Various prostacycline analogues
4. Group 4: PAH due to chronic thromboembolism. currently in use are Epoprostenol (iv), Iloprost
5. Group 5: PAH due to unclear/multifactorial (Inhaled), and Treprostinil (iv, sc, inhaled). The first
mechanisms like hematological disorders. specific therapy to have shown survival benefits
and improved outcome in IPAH was intravenous
CURRENT EPIDEMIOLOGY epoprostenol. Inhaled treprostinil is also effective,
Incidence of PAH from western data is 2.5–7.1 cases but has to be administered at least 6 times/day, due to
per million and the estimated prevalence ranges from 5 shorter half life. Hence, patients can be transitioned
to 52 cases per million adults. In major PAH registries, from iv epoprostenol to sc treprostinil to increase
approximately half of all patients had Idiopathic or compliance. These drugs are currently not available
heritable PAH. However, in developing country such as in India.
Endothelin (ET-1) pathway: One of the potent vaso US-FDA approved for group 1 PAH in October 2013, it is
constrictors, ET-1, acts on 2 receptor subtypes (ETA not yet available in India.
and ETB). ETA and ETB receptors mediate smooth Riociguat should not be combined with PDE5
muscle constriction and proliferation, whereas ETB inhibitors. In 2015, riociguat was studied as a combination
also induces vasodilation mediated by the release therapy with sildenafil (PDE5 inhibitor) in PATENT PLUS
of NO and PGI2. Bosentan and ambrisentan are two study. 18 patients received sildenafil 20 mg thrice daily
widely available pulmonary vasodilators. In various with or without riociguat for 12 weeks. The study did not
BREATHE trials bosentan has shown efficacy in PAH demonstrate any significant clinical benefit and higher
patients, but transaminitis is a common side effect. rates of hypotension with combination therapy lead to
Ambrisentan is equally effective but is associated discontinuation over a period of 305 days.
with less liver injury. Routine liver function testing
is not needed with ambrisentan as compared to Macitentan
bosentan therapy. Most common side effect is Macitentan is a newer oral agent that has nonselective
peripheral edema. antagonist action on endothelin A/B (ETA/ETB)
Nitric oxide (NO) pathway: Endothelial dysfunction receptors. Macitentan is an endothelin antagonist
may be caused or aggravated by reduced NO that has high binding affinity to ETA and greater tissue
production and bioavailability. The nitric oxide penetration. Macitentan was evaluated in the SERAPHIN
pathway may be manipulated either by administration trial. Unlike most of the previous trials of PAH that had
of NO, phosphodiesterase-5 (PDE5) inhibitors or 6MWD as the primary end point, in this trial the primary
by the stimulation of soluble guanylate cyclase. end point was a composite of time to clinical worsening
Sildenafil and tadalafil are the commonly available (TTCW). ‘TTCW event defined as worsening PAH,
PDE-5 inhibitors. Sildenafil showed improvement in initiation of parenteral prostanoids, lung transplantation,
6 minute walk distance (6MWD) in the SUPER-1 trial. atrial septostomy, or death’. The trial included WHO FC
Later, Tadalafil, with a longer half-life, is shown to be II and III patients of group 1 PAH and 64% of patients
similarly efficacious in PHIRST-1 trial. were already on background therapy. Macitentan at 3
mg and 10 mg doses reduced time to clinical worsening
NEWLY APPROVED as compared to placebo. The trial was not powered to
MEDICATIONS FOR PAH show a difference in mortality, but there was significant
Riociguat improvement in functional class, exercise capacity
Another novel compound, riociguat, stimulates soluble and hemodynamics at 6 months. Macitentan was well
guanylate cyclase (sGC) and thereby modulates the nitric tolerated and did not result in more transaminitis or
oxide pathway. However, unlike PDE5 inhibitors riociguat edema. Headache, nasopharyngitis and anemia were the
does not alter the amount of NO. Riociguat increases the common side effects. Macitentan 10 mg was approved by
cGMP production by sensitizing sGC to endogenous NO US-FDA in 2013.
and directly stimulating sGC independently of NO.
PATENT 1 and 2 trials evaluated the safety and efficacy Oral Treprostinil
of riociguat in patients with group 1 PAH. Riociguat Treprostinil is a prostacycline analogue that can be
was found to be well tolerated; however syncope was given by subcutaneous or intravenous and inhaled
the most frequent side effect. There was significant formulations. Treprostinil diolamine is an oral form of
improvement in 6MWD, NT-pro BNP, functional class prostacycline analogue Treprostinil. Oral Treprostinil
and time to clinical worsening. These improvements has been studied in a series of FREEDOM studies. In
were maintained for up to 1 year. Although riociguat is the FREEDOM-M trial, Treprostinil showed significant
CHAPTER 22: Advances in Management of Pulmonary Arterial Hypertension 127
improvements in 6MWD at 12 weeks. However, there

was no improvement in TTCW or FC. Combination PAH confirmed
of Treprostinil and either ET receptor antagonist or Alternative diagnosis General measures and
PDE5 inhibitor was tested in the FREEDOM-C and C-2 excluded supportive therapy
studies. Combination of oral treprostinil did not result in

improvement in 6MWD. Only some selected secondary
Acute vasoreactivity Calcium-channel blockers, if
end points improved. It was approved as monotherapy in testing vasodilatory response present
2013 by US-FDA.
No vasoreactivity
Selexipag
Selexipag is potent pulmonary vasodilator acting as Class II: Start with Bosentan/Ambrisentan or Sildenafil/Tadalafil
a non-prostanoid prostacyclin receptor (IP receptor) (combination, if response is inadequate)
Class III/IV: Start with initial combination
agonist. It is known to significantly increase the cardiac
index and reduce PVR in a short term follow up phase
II study. In the GRIPHON study, selexipag was studied In inadequate response*, consider–
class III and IV PAH patients. Patients on pre-existing Balloon atrial septostomy/Pott’s shunt
therapy were also included, but patients already on
prostanoid therapy were excluded. The primary endpoint
Lung transplantation
of the study was a composite of all-cause mortality
and any PAH complication. The primary end point *Nonavailability of prostanoids and other newer agents in India is a major
handicap in the management of PAH patients with advanced disease.
occurred significantly less with selexipag. The effect was
irrespective of background therapy suggesting potential Fig. 1: Algorithm for the treatment of pulmonary hypertension in India
for combination therapy.
response). At a follow-up of 517 days, primary end point
COMBINATION THERAPY occurred in 18% and 31% respectively among patients
on combination therapy and on pooled monotherapy.
Initiating with Combination Therapy: Combination therapy resulted in greater improvements
AMBITION Trial in 6MWD (+49 minutes) as compared to monotherapy
PAH drugs were commonly used in sequence; that is start with ambrisentan (+27 minutes) or tadalafil (+22
with one group of agents, increase the dose and if nor minutes). However, combination therapy resulted in
response at a reasonable dose add another class. Since the more frequency of adverse effects in the form of edema
various pulmonary vasodilators have different modes of (45% versus 30%), headache (42% versus 34%), and
action, it is always thought that a simultaneous initiation anemia (15% versus 9%). Based on these results, recent
of different classes of agents may be more beneficial in guidelines do recommend upfront combination therapy
PAH. This question was addressed in the AMBITION trial. of tadalafil and ambrisentan as first line therapy in PAH
In this trial, eligible 500 treatment-naïve WHO class II patients (Group 1) presenting in FC II or III (Fig. 1). In
and III PAH patients were randomly assigned in a double India, considering the cost and side effects, we prefer to
blind randomized manner either to a monotherapy with still use sequential addition of agents in class II patients,
tadalafil/ambrisentan or a combination therapy with while a initial combination may be preferable in class III
tadalafil and ambrisentan. The primary end-point of state.
the trial was time to clinical failure (defined as all-cause Patients with PAH should be managed in a step-wise
mortality, hospitalization for worsening PAH, >15% therapy based on WHO FC and response to treatment
decline in 6WMD from baseline or unsatisfactory clinical (Fig. 1).
NONPHARMACOLOGICAL OPTIONS STEM CELL THERAPY

Atrial Septostomy Studies have shown qualitative and quantitative
alterations in the circulating endothelial progenitor cells
Creation of a small hole in the atrial septum leads to a
right to left shunt that decompresses RV, but at the cost of (EPCs) in patients with PAH. In a small study of IPAH,
systemic desaturation. It is usually done percutaneously infusion of EPCs is shown to result in improvement
by puncturing the interatrial septum followed by graded of 6MWD. Further studies are needed to ascertain the
balloon dilation. Balloon atrial septostomy is invaluable patient population likely to benefit, type of stem cells,
in patients presenting with syncope and with persistent and dose of stem cells to be used.
symptoms despite optimal medical therapy.
LUNG TRANSPLANTATION
Pott’s Shunt Lung transplantation is the only destination therapy for
RV decompression may also be done be creating patients with PAH who failed targeted therapies. Heart-
an anastomosis between left pulmonary artery and lung transplantation may be needed for patients with
descending thoracic aorta, which is known as Pott’s severe RV dysfunction with refractory right heart failure
shunt. Usually done under surgery, it may also been and Eisenmenger syndrome.
done using percutaneous methods. It has theoretical
advantage over BAS in that only low lower body gets CONCLUSION
desaturated blood. Initial results of Pott’s shunt are Treatment advances for PAH have been dependent on
promising in patients with advanced IPAH, who are various pathways of vasomotion and current focus is on
refractory to all available therapies. upfront combination therapy. Many novel agents are
being tested in various ongoing clinical trials which may
Pulmonary Artery Denervation change the future management and prognosis of patients
Based on the initial promising results of RDN (renal artery with PAH.
denervation) for resistant hypertension, pulmonary
artery denervation is suggested for IPAH. Pulmonary BIBLIOGRAPHY
artery sympathectomy done using radiofrequency 1. 2015 ESC/ERS guidelines for the treatment and diagnosis
of pulmonary artery hypertension. European Heart Journal.
energy may abolish/reduce the sympathetic nerve
2016;37:67-119.
supply of pulmonary circulation. In a first in man trial, RF
2. Oudiz RJ. Pulmonary hypertension cardiology clinics.
catheter ablation of PA is shown to result in reduced PAP 2016;34(3):359-500.
and 6MWD improvement. Further studies are needed to 3. Treatment of pulmonary hypertension in adults. Uptodate
recommend this therapy as a routine. chapter.
CHAPTER
23
Infective Endocarditis: An Update
Infective endocarditis (IE) is a rare infectious disease but Echocardiography

with high morbidity and mortality. Multiple diagnostic, The corner stone of diagnosis and management
prognostic and therapeutic innovations have been in IE is early echocardiography (Table 1). Several
validated by recent guidelines. The novel challenges echocardiographic features also identity impending
include curbing healthcare associated endocarditis, complications or need for surgery, including large
early surgery and restrictive prophylaxis. vegetations (>10 mm diameter), severe new onset
valvular insufficiency, abscess and pseudoaneurysms,
CHANGING EPIDEMIOLOGICAL valvular dehiscence and decompensated congestive
PROFILE heart failure. Echocardiography also has a major
Recent data has confirmed that Staphylococcus aureus role intraoperative and post treatmentfor follow up.
is most common causative organism in developed 3D Echocardiography though improves accuracy but can
countries. Nasocomial infections due to aging, implants over estimate size of vegetation. CT, MRI and PET are
and devices may be responsible. Rheumatic heart evolving and their role in neurological and extra-cardiac
disease continues to be a major predisposing condition compications is vital.
and streptococci are most common pathogen in India.
ANTIMICROBIAL THERAPY
DIAGNOSTIC ISSUES The vegetation being infected pose unique challenges
Leaving aside a minority of patients, ‘classical’ clinical due to dense bacterial aggregation (inoculum effect).
profile can be missing, hence comprehensive diagnostic They grow slowly and the microbia exhibit low
evaluation is needed. The classically described Duke’s grade activity usually. Unique pharmacodynamics
criteria have been modified over the years (Table 1). and pharmacokinetics of antibiotics can be there
These are at best a guide and not an alternative to clinical contributing to the challenges of therapeutics including
judgments. the need for prolonged therapy. Certain group of
antibiotics, e.g. B-lactams, glycopeptides, etc. are less
Pathological Criteria and Blood Culture active against high density bacterial populations leading
They continue to the define IE and still most affirmative to resistance. Fluroquinolones and aminoglycosides
for diagnosis. In addition to culture the role of specific because of different mechanisms may be less effective
serology is emerging where culture is difficult. individually. In patients allergic to penicillin, cefazolin
TABLE 1: Adapted from modified Duke’s criteria for diagnosis of Cloxacillin/cefazolin administration may be associated
infective endocarditis with lower mortality rates as compared to other beta-
DEFINITE IE lactams. Antifungal agents include amphoterecin,
Pathological criteria echinocandin and voriconazole.
Culture or confirmatory histological evidence. Empirical therapy should be started promptly
Clinical criteria
after drawing three sets of blood cultures. For NVE
2 major criteria, 1 major criterion and 3 minor criteria, or 5 minor
criteria
(community acquired) ampicillin with cloaxacillin and
POSSIBLE IE gentamicin are recommended. For prosthetic valve
1 major criterion and 1 minor criterion, or 3 minor criteria cases, vancomicin, gentamicin and rifampicin may be
REJECTED started at appropriate dosage intravenously.
Confirmed alternative diagnosis It is reasonable suspect saureus, coagulase-negative
Early resolution of IE syndrome (≤ 4 days of antibiotics)
staphydococci, entrococci, fungi, gram negative bacill
Lack of pathological criteria at surgery criteria for IE not met
in intravenous drug users (IDUs). S. aureus may be the
MAJOR CLINICAL CRITERIA culprit with indwelling cardiac devices and catheters.
Blood culture and serology
Early (≤1 years prosthetic valve placement may be
Requires typical growth: at least 2 positive blood cultures samples
drawn > 12 hour apart or all 3 or a majority of ≥4 separate cultures
caused by coagulase negative staphytococcal or S. aureus
of blood (with first and last sample drawn at least 1 hour apart) infections. Fungi can also be the culprit along with
Single positive blood culture for Coxiella burnetii or antiphase 1 IgG other rare microbials in PVE. S. aureus in diabetes and
antibody titer ≥1:800 viridians group of streptococci postdental procedures are
Echocardiography commonly detected.
Evidence of oscillating intracardiac masses or vegetation, new
The duration of therapy varies from 2–6 weeks
valve regurgitation, annular abscess and prosthetic valve partial
dehiscence are major echocardiographic criteria. Transthoracic
depending on microorganism, native or prosthetic valve,
echocardiography (TTE) is initial choice for native valve drug combination used and location the vegetation.
endocarditis (NVE). Transesophageal echocardiography (TEE) is Treatment period is counted from the day blood culture
preferred, if IE if high suspicion TTE being negative, prosthetic valve becomes negative. An entire course of treatment is
patients with recent complications recommended if operative material is culture positive. It
MINOR CLINICAL CRITERIA imperative that on treatment, two sets of blood cultures
zz Heart condition predisposition, intravenous drug user be obtained every 24–48 hours till culture is negative.
zz Fever ≥38°C
Outpatient paraenteral antibiotic treatment after first
zz Vascular phenomena: Major arterial emboli, septic pulmonary
critical phase of 2 weeks is feasible.
infarcts, mycotic aneurysm, intracranial hemorrhage,
Suggested regimes based on common causative
conjunctival hemorrhages, and Janeway lesions
zz Immunological phenomena: Glomerulo nephritis, Osler nodes,
microorganisms are summarized in Table 2.
Roth spots, and rheumatoid factor
zz Culture positive but not as defined in major criteria. COMPLICATIONS
Heart Failure
and daptamycin are reasonable options. Bactericidal It is frequent and among the common indications for
drugs given together can act synergistically, e.g. certain surgery and usually due to severe or worsening aortic/
beta-lactams with aminoglycosides. mitral regurgitation.
Vanconycin as an alternative can be with poorer
outcomes. Rifampicin should be used only in PVE after Uncontrolled Infection
3–4 days of effective antibiotic therapy. Daptomycin It is among most dreaded complications leading to
and fusomycin are alternative agents for staphylococci surgery with high mortality rates. Persistent infection
and netilmicin for penicillin sensitive strepotococci. is defined as positive blood cultures after 7–10 days of
CHAPTER 23: Infective Endocarditis: An Update 131
TABLE 2: Common pathogens and antimicrobial therapy in infective endocarditis

Organism Antimicrobial agents Dose and route Duration
I. Streprotococci Penicillin or Ceftriaxone 12–18 million units/24 hr 4 weeks (6 weeks, if PVE)
Penicillin allergic +Gentamicin 2 gm/24 hr/IV 2 weeks
Vancomycin 3 mg/kg/24 hr IV or IM 4 weeks
30 mg/kg/24 hr, IV
II. Staphylococcal species
Oxacillin susceptible Nefcillin Or oxacilln 12 gm/24 hr, IV
Oxacillin resistant Vancomycin 30 mg/kg/24 hr in 2 doses, IV
Daptomycin 6–8 mg/kg/day
Penicillin allergic Cefazolin 6 gm/24 hr/in 3 doses, IV 4–6 weeks
III. Enterococci Ampicillin or 200 mg/kg/day, 4/6 doses, IV 4–6 weeks
Aq. Penicillin 18–30 million units/24 hours, IV
+ Gentamicin 3 mg/kg/24 hr IV or IM 2 weeks
or
Ampicillin+ Ceftriaxone 200 mg/kg/day, 4/6 doses, IV 4–6 weeks
2 g m/12 hr, IV
IV. HACEK Ceftriaxone 2 gm/12 hr, IV 4–6 weeks
Or
Ampicillin 2 gm/4 hr, IV
Or
Ciprofloxin 1000 mg/24 hr
Abbreviations: PVE (Prosthetic valve endocarditis) HACEK, Haemophilus, Aggregatibacter, Cardibacterium, Eikenella and Kingella sp.
treatment. Perivalvula rextension, abscess and fistulae INDICATIONS FOR SURGERY

may be the reason especially in PVE. Early surgery in IE is recommended under following
circumstances:
Embolic Events
Valve dysfunction leading to heart failure
The most potent independent predictor is vegetation >10
Fungal or resistant microorganisms
mm and is still higher with larger vegetations. Mobility,
mitral valve location, type of microorganism (S. aureus, Persistent infection
candida species, etc. and response to treatment may also Embolic events especially neurological and with
predict embolism and its outcome. vegetations >10 mm
Infectious aneur ysms (mycotic) are usually Severe valve regurgitation
located intracranially. An early detection can prevent PVE associated with valve dehiscence/severe dys
complications due to rupture. CT and MRI are reliable function or local complications
but conventional cereberal angiography is the gold In right-sided endocarditis since many patients are
standard. Splenic embolism and abscess can occur
IDUs and general approach is to treat them medically.
rarely, needing splenectomy.
Cardiac devices/implants need to be removed, if IE
Acute Renal Failure develops.
It is common and worsens prognosis. Immune complex
and vasulitic glomerulonephrtis, renal infarction, Follow-up after Antimicrobial Therapy
hemodynamic impairment, antibiotic toxicity, etc. may A concerted effort is needed to prevent future events.
be responsible. Echocardiography has a stellar role to play in all
stages of management. Early surgery when indicated this is in patients with implants and cardiac devices.
rehabilitation and prophylaxis must be considered. Urgent surgery is indicated in life-threatening situations
of hemodynamic compromise, uncontrolled infection
Endocarditis Team and embolic events. There is a need for creation of the
Multidisciplinary approach and referral centers are endocarditis team and referral IE centers.
desirable to tackle complicated and potentially lethal
endocarditis. BIBLIOGRAPHY
1. Ambrosioni J, Hernandez-Meneses M, Téllez A, Pericàs
PREVENTION J, Falces C, et al. The changing epidemiology of infective
endocarditis in the twenty-first century. Current Infect Dis
Universal prophylaxis is being discouraged due to global
Rep. 2017;19(21):1-10.
fear of antibiotic resistance. Recent studies have not 2. Baddour LM, Wilson WR, Bayer AS, Fowler Jr VG, Tleyjeh
shown negative impact of restrictive prophylaxis. IM, Rybak MJ, et al. Infective endocarditis in adults:
It is mandatory in prosthetic valve patients, implants, diagnosis, antimicrobial therapy, and management of
previous episodes of IE, congenital heart disease complications: a scientific statement for healthcare
cyanotic/repair with residual regurgitation/shunt. It professionals from the American Heart Association.
Circulation. 2015;132(15):1435-86.
is usually not recommended in native valve disease.
3. Bin Abdulhak AA, Baddour LM, Erwin PJ, Hoen B, Chu VH,
However, in rheumatic heart disease discretion is needed Mensah GA, et al. Global and regional burden of infective
for regurgitant lesions and aortic stenosis. endocarditis, 1990-2010: a systematic review of the
Low-grade bacteremia occurs during daily activities literature. Glob Heart. 2014;9(1):131-43.
like tooth brushing more frequently than with dental 4. Habib G, Lancellotti P, Antunes MJ, BongiorniMG, Casalta JP,
procedures which carry only a small risk. Judiciously Del ZF, et al. ESC guidelines for the management of infective
endocarditis: The task force for the management of infective
given 2 gm of amoxacillin (oral or IV) or Clindamycin
endocarditis of the European Society of Cardiology (ESC).
600 mg (if allergic to penicillin) 30–60 minutes before Endorsed by: European Association for Cardio-Thoracic
procedure is sufficient. In respiratory procedures Surgery (EACTS), the European Association of Nuclear
antistaphylococcal drugs and in major genitourinary/ Medicine (EANM). Eur Heart J. 2015;36(44):3075-128.
gastrointestinal procedures agents active against 5. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T,
enterococci should be included. Bashore T, Corey GR. Proposed modifications to the Duke
criteria for the diagnosis of infective endocarditis. Clin Infect
The consensus today is prevention by early diagnosis
Dis. 2000;30:633-8.
and treatment including surgery than prophylaxis. 6. National Institute for Health and Clinical Excellence (UK),
Centre for Clinical Practice at NICE (UK). Prophylaxis against
Infective Endocarditis Update: A Summary infective endocarditis. Antimicrobial Prophylaxis Against
Early diagnosis, early antibiotic therapy, and early Infective Endocarditis in Adults and Children Undergoing
surgery is crucial. No doubt, echocardiography is vital for Interventional Procedures. NICE Clinical Guidelines, No. 64.
In: 2008.
diagnosis, monitoring, treatment and follow up however
7. Pant S, Patel NJ, Deshmukh A, Golwala H, Patel N,
role of a multimodality imaging is emerging. Badheka A, et al. Trends in infective endocarditis incidence,
The indications for IE prophylaxis is shrinking and microbiology, and valve replacement in the United States
limited to high risk situations. Special concern regarding from 2000 to 2011. J Am Coll Cardiol. 2015;65(19):2070-6.
CHAPTER
24
Pregnancy and Heart Disease
INTRODUCTION the hemodynamic load is maximum. The problem here

Patients of heart disease that is acquired during is significant and needs close monitoring. Mitral stenosis
childhood will invariably come to physicians to ask or mixed mitral valve disease is the most common
whether they can go through pregnancy and child cardiac disease which poses problems during pregnancy.
Monthly penicillin (rheumatic fever) prophylaxis is to
birth. Primarily they fall into two categories: those
be continued throughout the pregnancy in these young
with Congenital Heart Disease (CHD) and young girls
women.
with Rheumatic Heart Disease (RHD). Corrected CHD
patients, i.e. those with postoperative ASD (Atrial Septal
PHYSIOLOGICAL CHANGES IN
Defect), VSD (Ventricular Septal Defect), PDA (Patent
PREGNANCY
Ductus Arteriosus) and total correction of Fallot’s
Pregnancy is associated with significant physiological
Tetralogy defect with good results can go through
changes of the cardiovascular system. The ventricular
pregnancy with nearly normal risk. Problems are mainly
wall mass, myocardial contractility and cardiac
with uncorrected defects that are hemodynamically
compliance increase. There is a 30–50% increase in the
significant.
maternal cardiac output (CO) from 4 L/min to 6 L/min
Young ladies with metallic valve replacement pose a
during pregnancy due to an increase in the heart rate
special problem since the anticoagulation protocol has
(HR) and stroke volume. During the third trimester, it is
to be altered in the first trimester and last trimester. For the increase in heart rate which is primarily responsible
this reason, some centers prefer bioprosthetic valves for the increase in the maternal CO.
for replacement in young women so that they can go The cardiac output plateaus between 28 weeks and 32
through pregnancy. Anticoagulation is not required weeks of pregnancy, and then remains the same almost
with bioprosthetic valves. However, bioprosthetic valves until delivery.
last for 10–12 years after which significant degeneration During labor and immediately postpartum, CO
occurs and they have to be reoperated which is sought increases as a result of increased blood volume (300–500
with risk. mL) with each uterine contraction, and then due to the
Sometimes physicians encounter patients who have “auto-transfusion” (the redirection of blood from the
a significant heart disease that gets detected for the first uteroplacental unit back to the maternal circulation)
time during pregnancy specially second trimester, when postdelivery.
Due to the vasodilatory effects of progesterone, nitric 3. Moderate-to-severe left ventricular outflow tract
oxide and prostaglandins the systemic vascular resistance obstruction (≥30 mm Hg).
and blood pressure decrease early in pregnancy, reaching 4. Left ventricular ejection fraction <0.30.
their lowest at 20–24 weeks causing hypotension which If a woman with one of these conditions falls pregnant,
is physiological at this gestation. Following this dip in early consultation with obstetrician and a cardiologist
blood pressure the systemic vascular resistance begins should take place in order to evaluate the patient’s risk
to rise and so does the blood pressure which reaches the and develop a care plan. Pregnancy with pulmonary
prepregnancy values by term. hypertension confers a very high risk for maternal
The maternal blood volume increases by 40–50% mortality. Termination is discussed in these conditions
above the nonpregnant level starting from 6 weeks to 8 for maternal concerns.
weeks of gestation and peaking at 32 weeks. Myocardial infarction, ischemic heart disease, and
Hence to summarize: There is an increase in plasma aortic dissection
volume by 50%, an increase in resting heart rate by Pregnancy itself increases the risk of acute myocardial
17% and an increase in cardiac output by 50% during infarction by three to four times, with the risk being
pregnancy. 30 times higher for women more than 40 years of age
compared to younger women (<20 years).
Normal Findings on Examination of the Other risk factors for ischemic heart disease include
Cardiovascular System in Pregnancy chronic hypertension, pre-eclampsia, diabetes, smoking,
These may include: obesity and hyperlipidemia.
Bounding/Collapsing pulse A high index of suspicion for myocardial infarction
Ejection systolic murmur in any pregnant woman presenting with chest pain is
Loud first heart sound essential for good management of these women. The
Third heart sound
differential diagnosis of aortic dissection should also be
Relative sinus tachycardia
kept in mind. All women with chest pain in pregnancy
Ectopic beats
should have an electrocardiogram analysed by a doctor
Peripheral edema
who is trained to pick up signs of cardiac ischaemia and
Normal ECG findings may include—Q–wave (small)
infarction. A thorough history taking and examination
and inverted T wave in lead III, ST segment depression including auscultation goes a long way in the correct
and T–wave inversion in inferior and lateral leads, left detection of the disease. In cases where the pain is
ward shift of the QRS axis. severe, patients should be referred for a CT scan or an
Cardiac disease is a leading cause of maternal death magnetic resonance imaging scan of the chest. A serum
in pregnancy in many developed and developing nations. troponin I measurement can also be useful.
One-third of these deaths are a result of myocardial Cardiac catheterization is permissible in pregnant
infarction/ischemic heart disease and a similar patients, with appropriate abdominal lead shielding for
number of late deaths are associated with peripartum the mother and fluoroscopy time should be kept minimal.
cardiomyopathy. Other significant contributors (5–10% Thrombolytic agents can be used, but the guidelines for
each) are rheumatic heart disease, congenital heart percutaneous coronary intervention should be followed.
disease and pulmonary hypertension.
Contraindications to Pregnancy Include 4 PERIPARTUM CARDIOMYOPATHY

Conditions It is defined as the development of heart failure at the end
1. Marfans syndrome with dilated aortic root (>4 cm). of pregnancy or in the months following delivery where
2. Pulmonary hypertension (pulmonary vascular no other cause for heart failure is found. The cause of
resistance, >6 Wood units). peripartum cardiomyopathy is idiopathic in most cases.
CHAPTER 24: Pregnancy and Heart Disease 135
It usually presents in late pregnancy or early postpartum Tachycardia is particularly a bad sign in patients with
period but can occur up to 6 months after delivery. MS. An echocardiogram is essential for the confirmation
Peripartum cardiomyopathy should be considered of the diagnosis and assessment of severity. Management
in any pregnant or postnatal woman who presents with: includes beta blockers, aggressive treatment of atrial
Increasing shortness of breath fibrillation, treatment and timely recognition of
Reduced exercise tolerance pulmonary edema. Balloon valvotomy and closed
Palpitations mitral valvotomy have very good results but are suited
Pulmonary and/or peripheral edema for noncalcified valves with minimal regurgitation. If
Symptoms relating to peripheral or cerebral emboli. women with severe MS attend prepregnancy they should
All such women should have an electrocardiogram, a be counselled regarding surgical options before planning
chest X-ray and an echocardiogram to evaluate the cause a pregnancy.
of the symptoms.
The management includes–delivery if antenatal. PROSTHETIC HEART VALVES
Thromboprophylaxis is essential. Anticoagulants are Anticoagulation for mechanical heart valves should be
necessary if there is severely impaired LV dysfunction, adjusted in pregnancy as warfarin must be discontinued
intra cardiac thrombus or arrhythmias. Conventional during the 1st trimester due to the risk of teratogenesis,
treatment of heart failure is given including diuretics, miscarriage, stillbirth and intracerebral bleeding.
vasodilators, cardio selective beta blockers (bisoprolol), Current guidelines support three approaches:
carvedilol, digoxin, ionotropes and ACE inhibitors 1. Low-molecular-weight (LMW) heparin administered
postdelivery. Approximately 50% patients make full subcutaneously twice daily throughout pregnancy
recovery. Mortality rate has reduced from 40% in the 2. Unfractionated heparin administered subcutaneously
older studies to 9–15% in more recent series. twice daily throughout pregnancy
3. Unfractionated or LMW heparin administered
RHEUMATIC HEART DISEASE subcutaneously twice daily until 13 weeks of
Mitral valve stenosis (MS) (the most common lesion and pregnancy followed by warfarin from weeks 13 to
the one that carries the highest risk) accounts for 90% of 35, followed by restarting unfractionated or LMW
rheumatic heart disease in pregnancy. If undiagnosed heparin subcutaneously twice daily until delivery.
MS can be dangerous in pregnancy. When LMWH is used, dose should be adjusted
according to anti factor Xa levels, maintaining 4-hour
Symptoms peak anti factor Xa levels at 0.8–1.2 U/mL. Low dose
May be asymptomatic aspirin (75 mg/day) should be added as adjuvant
Dyspnea, orthopnea, PND antithrombotic therapy.
Cough (pink frothy sputum or hemoptysis).
AORTIC DISSECTION
Signs Systolic hypertension is a key factor in most of the
Mitral facies deaths from aortic dissection. It is therefore essential
Tapping undisplaced apex beat to monitor blood pressure closely during pregnancy
Risk of atrial flutter/fibrillation and prompt antihypertensive therapy should be
Loud S1, loud pulmonary second sound (P2), opening given if the blood pressure becomes elevated. Aortic
snap. dissection (diagnosed by computed tomography scan,
Mid diastolic murmur, low pitched TOE or transthoracic echo, MRI scan) is the most
Sign of pulmonary edema common serious complication of Marfan syndrome. The
management is surgical and includes cardiac surgery to change in murmur or any lung changes associated with
replace the aortic root. pulmonary edema should also be undertaken regularly.
Women with cyanotic heart disease should have their
CONGENITAL HEART DISEASE oxygen saturations checked periodically (each trimester
Eisenmenger syndrome is an absolute contraindication or more often if any signs of worsening clinical status).
for pregnancy since there is high maternal mortality of A further multidisciplinary meeting should take place
upto 30–40%. Mothers with cyanotic heart disease and at 32–34 weeks to determine a plan of management for
low flow physiology (Fallot Tetralogy) those survive to delivery. Key features of the plan include deciding who
this age can go through pregnancy. However, fetal loss is should be involved in supervising the labor, whether a
frequent. Also, abortions are common. cesarean section is needed, whether bearing down is safe
Among the acyanotic heart disease those with in the second stage and appropriate prophylaxis against
regurgitant lesions tolerate pregnancy fairly well. postpartum hemorrhage (routinely used oxytocin
Patients of pulmonary stenosis also can have problems regimes may not be safe; a low-dose syntocinon infusion
and preferably balloon pulmonary valvotomy should is probably the best option and prophylactic uterine
be done before pregnancy is planned since it is a simple compression sutures during cesarean sections can
procedure. be considered instead of oxytocin). The plan should
Among the left to right shunt ASDs and VSDs tolerate also include postpartum management, including
pregnancy fairly well. Patients of PDA also tolerate thromboprophylaxis if recommended and the length of
pregnancy although there is some risk of rupture or postnatal stay in hospital.
aneurysm.
Several recent studies have addressed congenital INTRAPARTUM
heart disease (CHD) in pregnancy. In general, regurgitant A general principle of intrapartum management is to
lesions are well tolerated, whereas obstructive lesions are minimize any cardiovascular stress during labor. The use
poorly tolerated. of early epidural anesthesia and assisted vaginal delivery
to cut short the second stage of labor are recommended
GENERAL PRINCIPLES OF depending upon the cardiac condition. Cesarean section
MANAGEMENT is usually recommended for obstetric indications.
Routine antibiotic prophylaxis for delivery (vaginal
Preconception or cesarean section) is not recommended by the
Girls with congenital heart disease should be referred 2008 American Heart Association/American Dental
to a joint cardiac/obstetric clinic for advice about Association guidelines.
contraception (and preconception counselling) once
older around puberty (12–15 years). Preconception CONCLUSION
counselling should also be offered to older women with Thus, pregnant women with heart disease need special
a new diagnosis. care and a team approach between obstetrician and
cardiologist. Frequent communication is important
Antepartum between the two teams. Labor and delivery are specially
A risk assessment of every woman with a heart murmur stressful for these patients and institutional protocols
or a history of cardiac defect should be carried out early with cooperation of family anesthetic, obstetrician and
in pregnancy in a joint clinic by a consultant obstetrician, cardiologist should be preferred.
cardiologist and anesthetist. Drugs that can be harmful to the mother and
Women should have their heart rate and BP measured are teratogenic, like ACE inhibitors and ARBs are
regularly in pregnancy. Auscultation to assess any contraindicated and should not be used. Exposure to
CHAPTER 24: Pregnancy and Heart Disease 137
radiation (X-rays, CT scans) is to be avoided specially in BIBLIOGRAPHY

the first trimester. 1. Pacini L, Digne F, Boumendil A, Muti C, Detaint D, Boileau
Patients with obstructive lesions (mitral and aortic C, et al. Maternal complications of pregnancy in Marfans
stenosis) need special care. Regurgitant lesions (MR syndrome. Int J Cardiol. 2009;136(2):156-61.
2. RCOG. Good Practice No 13, June 2011. Cardiac Disease in
and PR) and shunts (ASD, VSD and PDA) are generally
pregnancy.
well tolerated. Those who have had peripartum
3. Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B,
cardiomyopathy are at very high risk of recurrence Buchmann E, et al. Current state of knowledge on aetiology,
and family should be informed about the risks. Fetal diagnosis, management, and therapy of peripartum
echocardiography is now available in many centers cardiomyopathy. Apposition statement from the Heart
in our country and can be used with ultrasound for Failure Association of the European Society of Cardiology
working group on peripartum cardiomyopathy. Eur J Heart
detecting birth defects specially in inherited disorders
Failure. 2010;12:767-78.
and previous sibling with congenital disorders.
4. Tsiaras S, Poppas A. Mitral valve disease in pregnancy:
Outcomes and management. Obstet Med. 2009;2(1):6-10.
CHAPTER
25
A Review of Cardiorenal Syndrome
INTRODUCTION dialysis quality initiative (ADQI) addressed these issues

Cardiac disease is commonly associated with deterioration in conjuncture with leaders in the field of nephrology,
of renal function and vice-versa. The coexisting cardiac cardiology and critical care and formulated a definition
and renal disease often lead to increased morbidity and for cardiorenal syndrome.4
mortality. Acute decompensated heart failure, cardiac CRS is defined as “disorders of the heart and kidneys
ischemia and arrhythmias often lead to decrease in whereby acute or chronic dysfunction in one organ may
cardiac output, which in turn lead to acute deterioration induce acute or chronic dysfunction of the other.” Five
of kidney function. Underlying mechanism may be subtypes of the syndrome have been identified.
decreased renal arterial perfusion secondary to low
cardiac output. In addition, various diagnostic and Type I CRS (Acute Cardiorenal Syndrome)
therapeutic procedures like coronary angiography, PCI This is a syndrome of acute deterioration of renal
in such patients also lead on to impairment of renal functions, which often complicates hospitalized/ICU
function. patients with acute decompensated heart failure, ACS,
Among one lakh patients registered in acute cardiogenic shock and patients undergoing cardiac
decompen-sated heart failure trial (ADHERE), more surgery. It is estimated that 30–40% of patients with acute
than 1/3rd of patients had history of renal disease. 1 heart failure develop AKI (as evident biochemically with
With worsening of NYHA class, the severity of renal increase in serum creatinine by atleast 0.3 mg/dL.5
impairment also worsened. The 31% patients of NYHA
class III and 39% patients of NYHA class IV had severe Type II CRS (Chronic Cardiorenal
impairment in renal function. The 44% of deaths in Syndrome)
patients with end stage renal disease are attributed to It is a state of chronic kidney disease, complicating
cardiovascular diseases. Acute rise in serum creatinine chronic heart disease. Hospitalized patients with
levels more than 0.3 mg/dL is associated with increased congestive heart failure are usually in stage III–V CKD,
mortality and prolonged hospital stay. which indicates EGFR < 60 mL/min/1.73 m2.6
Although many syndromes have described the
interplay between heart and kidney, but none of them Type III CRS (Acute Renocardiac Syndrome)
has clearly classified this interaction (Fig. 1).2,3 There is It is a state of abrupt deterioration of renal function,
limited literature about diagnostic criteria, treatment and leading on to decline in cardiac function. Clinical
prevention with context to cardiorenal syndrome. Acute condition associated with this includes, acute
CHAPTER 25: A Review of Cardiorenal Syndrome 139
Fig. 1: Cardiorenal syndrome: Kidney-heart bidirectionality10

Abbreviation: CRS, cardiorenal syndrome
kidney ischemia, acute glomerulonephritis, contrast PATHOPHYSIOLOGY (FIG. 2)

nephropathy and kidney allograft rejection.7
Neurohormonal Activation
Primary organ insult activates neurohormonal activity
Type IV CRS (Chronic Renocardiac
which is initially compensatory, but overtime contributes
Syndrome) to functional worsening and progression to CRS.
It is a state in which pre-existing chronic kidney disease Decrease in cardiac output in CHF leads to decreased
contributes to gradual decline in cardiac function. It renal perfusion and activation of RAAS.11 Overactivity of
is commonly associated with chronic glomerular and RAAS in either CHF or CKD activate sympathetic nervous
interstitial disease.8 system (SNS), leading to endothelial dysfunction. AT II
stimulates secretion of aldosterone, increasing sodium
Type V CRS (Secondary Cardiorenal and water reabsorption, exerting further damage to
Syndrome) kidneys and heart.
This subset of CRS occurs when both the organs are
concurrently affected by systemic illnesses (acute Oxidative Stress
or chronic). Common disorders include sepsis, SLE, Oxidative stress in CKD leads to imbalance in formation
diabetes mellitus or amyloidosis.9 of antioxidants and reactive oxygen species (ROS). ROS
TABLE 1: Biomarkers in cardiorenal syndrome

Cardiorenal Definition Biomarkers
syndrome
zz Acute CRS Acute worsening of Cardiac troponin,
heart, such as acute B-type natriuretic
coronary syndrome, peptide (BNP) and
acute decompensated HF, N-terminal pro-
cardiogenic shock and BNP (NT-proBNP),
cardiac surgery, leading to creatinine, cystatin
renal dysfunction C, NGAL
zz Chronic CRS Chronic heart failure BNP and NT-proBNP,
leading to renal failure creatinine, cystatin
C, albuminuria
zz Acute Acute kidney injury Creatinine, cystatin
renocardiac leading to cardiac C, NGAL, cardiac
Fig. 2: Pathophysiology of CRS syndrome dysfunction troponin, and BNP
and NT-proBNP
zz Chronic Chronic kidney diseases Creatinine, cystatin
stimulate inflammatory cytokines such as IL-1β, IL-6 and renocardiac leading to dysfunction of C, albuminuria, and
TNF-α, leading to ROS dependent other factors signal syndrome heart BNP and NT-proBNP
zz Secondary Systemic conditions C-reactive protein,
transduction in cardiac hypertrophy.
cardiorenal like diabetes mellitus creatinine,
syndrome sepsis, SLE, vasculitis and procalcitonin,
Other Factors amyloidosis causing both albuminuria, cystatin
Hypertension, anemia and uremic toxins may contribute impaired renal and cardiac C, NGAL, cardiac
function troponin, and BNP
to CRS. Anemia, CHF and CKD interact in a vicious circle
and NT-proBNP
to cause or worsen each other.12,13
Lack of oxygen supply to heart associated with
Natriuretic Peptides
anemia may be compensated by increasing heart rate
Acute HF is a key feature of types 1, 3, and 5 CRSs, and
and stroke volume and this may activate SNS and
chronic HF is a key feature of types 2 and 4 CRSs. The
RAAS.14 Hypertension itself causes severe renal disease
natriuretic peptides B-type natriuretic peptide (BNP) and
and hypertension also commonly develops in patients
N-terminal pro-BNP (NTproBNP) are widely recognized
with underlying renal disease. Several uremic toxins
to be the ‘‘gold standard’’ biomarker for the diagnosis of
like ADMA, homocysteine, advanced glycated end
heart failure.16
products are linked to endothelial dysfunction and
Besides the troponins and natriuretic peptides, other
atherosclerosis.15
biomarkers of myocardial fibrosis like, soluble ST2 and
galectin-3 have been evaluated as multimarker panels for
BIOMARKERS IN CARDIORENAL
cardiovascular risk profiling.
SYNDROME (TABLE 1)
Cardiac Biomarkers Renal Biomarkers
Cardiac Troponin Albuminuria
An acute cardiac ischemic event is often the primary Albumin is the predominant protein in urine in renal
event in type 1 CRS. ACS also features in types 3 and 5 damage, and measurement of the albumin-to-creatinine
CRSs, where an MI may be triggered by AKI in type 3 CRS ratio (ACR) in first morning or random spot urine is an
and by sepsis in type 5 CRS. The cardiac troponins (cTns) important biomarker in types 2 and 4 CRSs, and chronic
have a central role in the diagnosis of ACS. type 5 CRS secondary to diabetes mellitus.
Creatinine prognosis. In DOSE trial, it was found that use of high

CKD, a key feature of CRS types 2 and 4, is manifest as diuretic dose can worsen the renal functions at 72 hours
a GFR of <60 mL/min/1.73 m2. Both the Risk, Injury, but later on has better clinical outcome.
Failure, Loss, End-stage (RIFLE)17 and the Acute Kidney Symptomatic improvement in hemodynamically
Injury Network (AKIN)18 criteria use a decline in serum stable patients can be achieved with nitrates like
creatinine to define AKI, which is a key event in CRS nitroglycerine and nitroprusside. In hemodynamically
types 1, 3, and 5. unstable patients, transient inotropic support may be
required.
New Biomarkers of AKI Continous ultrafilteration is another modality to
Cystatin C, neutrophil gelatinase–associated lipocalin remove fluid from intravascular space with lesser
(NGAL), kidney injury molecule 1 (KIM-1), interleukin-18 neurohormonal activation because of contemporaneous
(IL-18), and liver-type fatty acid binding protein are shifting of fluid from interstitium into intravascular
newer biomarkers of AKI.19 Cystatin C is not influenced space.25
by changes in muscle mass, therefore is more accurate
for estimating GFR in patients with extremes of body Type II CRS (Chronic Cardiorenal
mass, including infants and elderly. 20 However, its Syndrome)
concentration is influenced by age, sex, smoking status, Blockage of Renin Angiotensin Aldosterone System
raised C-reactive protein, abnormal thyroid function, is primary target for Type II Cardiorenal syndrome.
certain cancers, and use of corticosteroids.21 Cystatin C Alongwith ACEI and ARBs, aldosterone antagonist–
has a half-life of 1.5 hours (compared with 4 hours for spironolactone should be used for complete blockage of
creatinine), so, after kidney injury its concentration rises RAAS. Erythropoietin stimulating agents can be used for
earlier than creatinine, enabling earlier identification of anaemia, associated with both CHF and CKD.26
AKI. Although NGAL has been compared, as a biomarker
of kidney injury as to cardiac troponins in the heart, it is Type III CRS (Acute Renocardiac Syndrome)
not specific for the kidney and is also produced by other Preventive modalities should be used in the form of
tissues.22 KIM-1 is upregulated in response to ischemic adequate hydration, diuretics, N-acetyl cysteine in
or nephrotoxic injury and expressed at high levels on the patients with underlying kidney disease (diabetic
apical membranes of proximal tubules in the kidney.23 nephropathy), elderly in those planned for angiographic
procedures. 27 Primar y renal diseases like acute
MANAGEMENT glomerulonephritis should be treated in time to reduce
Type I CRS (Acute Cardiorenal Syndrome) risk of type III Cardiorenal syndrome.
For acute heart failure, diuretics are mainstay of treatment
to reduce the extracellular fluid volume at a rate which Type IV CRS (Chronic Renocardiac
permits refilling of intravascular space from interstitium. Syndrome)
Loop diuretics in the form of infusion are better than Adequate treatment of chronic kidney disease with RAAS
intermittent dosing. 24 Although, in DOSE trial it was blocking agents alongwith specific therapies to control
found that both the bolus doses and continuous infusion blood pressure and serum glucose should be done.
of diuretics have similar clinical and renal outcomes. Anemia, dyslipidemia, proteinuria are other
Aggressive therapy with diuretics should be adopted complications of CKD should be given proper attention.28
in case of acute heart failure even if there is transient rise A multipronged approach is necessary to tackle
in creatinine. Rather than worsening of in-hospital renal complications and risk factors that are common to heart
function it is the baseline renal function which dictates failure and CKD.
Type V CRS (Secondary 7. Kellum JA, Levin N, Bouman C, Lameire N. Developing a

consensus classification system for acute renal failure. Curr
Cardiorenal Syndrome) Opin Crit Care. 2002;8:509-14.
Since it is caused by variety of systemic disorders such 8. Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease
as diabetes mellitus, SLE, sepsis and amyloidosis, and mortality risk: a systematic review. J Am Soc Nephrol.
it is complex and confounding to make a universal 2006;17:2034-47.
treatment protocol for this group. Interorgan interactions 9. Ronco C, Cruz DN, Ronco F. Cardiorenal syndromes. Curr
Opin Crit Care. 2009;15:384-91.
between heart and kidney are needed to be addressed
10. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N,
meticulously for type V Cardiorenal syndrome. Bagshaw SM, et al. Acute Dialysis Quality Initiative (ADQI)
consensus group. Cardio-renal syndromes: report from
CONCLUSION the consensus conference of the Acute Dialysis Quality
Early recognition of various subtypes of cardiorenal Initiative. Eur Heart J. 2010;31:703-11.
11. Brewster UC, Setaro JF, Perazella MA. The renin–
syndrome is critical to initiate adequate therapy, as
angiotensin–aldosterone system. Cardiorenal effects and
treatment directed at benefit of one organ may be
implications for renal and cardiovascular disease states.
detrimental for other. It is a herculean task to formulate Am J Med Sci. 2004;326:15-24.
a treatment strategy for Cardiorenal syndrome with 12. Silverberg D, Wexler D, Iaina A, Steinbruch S, Wollman Y,
highly interdependent pathophysiological mechanisms. Schwartz D. Anemia, chronic renal disease and congestive
Better understanding of interaction between two organs heart failure: The cardio renal anemia syndrome. The need
for cooperation between cardiologists and nephrologists. Int
is required for improvement in clinical outcome of this
Urol Nephrol. 2006;38:295-310.
syndrome.
13. Grune T, Sommerburg O, Siems W. Oxidative stress in
anemia. Clin Nephrol. 2000;53(Suppl. 1):18-22.
REFERENCES 14. Palazzuoli A, Gallotta M, Loving F, Nuti R, Siverberg D.
1. Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Anaemia in heart failure: A common interaction with renal
Costanzo MR, et al. Characteristics and outcomes of insufficiency called the cardio-renal anaemia syndrome. Int
patients hospitalised forheart failure in the United States: J Clin Pract. 2008;62:281-6.
rationale, design andpreliminary observations from the fi rst 15. Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P.
100,000 cases inthe Acute Decompensated Heart Failure Vascular incompetence in dialysis patients: Protein-bound
National Registry(ADHERE). Am Heart J. 2005;149:209-16. uremic toxins and endothelial dysfunction. Semin. Dial.
2. Ronco C, House AA, Haapio M. Cardiorenal syndrome: 2011;24:327-37.
refining the definition of a complex symbiosis gone wrong. 16. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC
Intensive Care Med. 2008;34:957-62. Guidelines for the diagnosis and treatment of acute
3. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam and chronic heart failure 2008: the Task Force for the
B. The severe Cardiorenal syndrome: ‘Guyton revisited’. Eur Diagnosis and Treatment of Acute and Chronic Heart Failure
Heart J. 2005;26:11-7. 2008 of the European Society of Cardiology. Eur Heart J.
4. Bongartz LG, et al. For the Acute Dialysis Quality Initiative 2008;29:2388-442.
(ADQI) consensus group (2009): Cardiorenal syndromes: 17. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P.
report from the consensus conference of the Acute Dialysis Acute Dialysis Quality Initiative workgroup. Acute renal
Quality Initiative. Eur Heart J. Epub ahead of print. failure—definition, outcome measures, animal models, fluid
5. Gottlieb SS, Abraham W, Butler J, et al. The prognostic therapy and information technology needs: the Second
importance of different definitions of worsening renal International Consensus Conference of the Acute Dialysis
function in congestive heart failure. J Card Fail. 2002;8:136- Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204-12.
41. 18. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury
6. Heywood JT, Fonarow GC, Costanzo MR, et al. High Network. Acute Kidney Injury Network: report of an initiative
prevalence of renal dysfunction and its impact on outcome to improve outcomes in acute kidney injury. Crit Care. 2007;
in 118,465 patients hospitalized with acute decompensated 11:R31.
heart failure: a report from the ADHERE database. J Card 19. Manley HJ. Disease progression and the application of
Fail. 2007;13:422-30. evidencebased treatment guidelines diagnose it early: a
case for screening and appropriate management. J Manag 24. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous
Care Pharm. 2007;13:S6-12. infusion versus bolus injection of loop diuretics in congestive
20. Shlipak MG, Mattes MD, Peralta CA. Update on cystatin heart failure. Cochrane Database Syst Rev. 2004;20:31-78.
25. Marenzi G, Lauri G, Grazi M, et al. Circulatory response
C: incorporation into clinical practice. Am J Kidney Dis.
to fluid overload removal by extracorporeal ultrafiltration
2013;62:595-603.
in refractory congestive heart failure. J Am Coll Cardio.
21. Knight EL, Verhave JC, Spiegelman D, et al. Factors 2001;38:963-8.
influencing serum cystatin C levels other than renal function 26. Fu P, Arcasoy MO. Erythropoietin protects cardiac myocytes
and the impact on renal function measurement. Kidney Int. against anthracycline-induced apoptosis. Biochem Biophys
2004;65:1416-21. Res Commun. 2007;354:372-8.
22. Devarajan P. Review: neutrophil gelatinase-associated 27. Jasuja D, Mor MK, Hartwig KC, Palevsky PM, Fine MJ, et al.
Provider knowledge of contrastinduced acute kidney injury.
lipocalin: a troponin-like biomarker for human acute kidney
Am J Med Sci. 2009;338:280-6.
injury. Nephrology (Carlton). 2010;15:419-28.
28. Manley HJ. Disease progression and the application of
23. Bonventre JV. Kidney injury molecule-1 (KIM-1): a urinary evidencebased treatment guidelines diagnose it early: a
biomarker and much more. Nephrol Dial Transplant. case for screening and appropriate management. J Manag
2009;24:3265-8. Care Pharm. 2007;13:S6-12.
CHAPTER
26
Heart Failure with Reduced
Ejection Fraction: Treatment Strategy
Amal Kumar Banerjee
INTRODUCTION determines the specific treatment used (e.g. valve

Heart failure (HF) is a growing epidemic and one of the repair or replacement for valvular disease, specific
leading causes of hospitalizations and death throughout pharmacological therapy for HF with reduced EF,
the world. HF is a clinical syndrome characterized by reduction of heart rate in tachycardiomyopathy, etc).
typical symptoms (e.g. breathlessness, ankle swelling The main goals of medical therapy in heat failure
and fatigue) that may be accompanied by signs (e.g. are to prevent hospital admissions, improve functional
elevated jugular venous pressure, pulmonary crackles capacity and to survival.
and peripheral edema) caused by a structural and/or
functional cardiac abnormality, resulting in a reduced CLASSIFICTION
cardiac output and/or elevated intracardiac pressures at The ACC/AHA guidelines have proposed a staging of
rest or during stress. severity of HF based on the structure and damage of
Before clinical symptoms become apparent, the heart muscle and symptoms.3 In this classification,
patients can present with asymptomatic structural or patients are classified as follows: Stage A—patients
functional cardiac abnormalities, systolic or diastolic left are at high risk for development of heart failure but do
ventricular (LV) dysfunction, which are precursors of HF. not present any structural or functional abnormality
Recognition of these precursors is important because or symptoms of HF; Stage B comprises patients
they are related to poor outcomes, and starting treatment with structural heart disease that is associated with
at the precursor stage may reduce mortality in patients development of HF but symptoms and sign of HF are
with asymptomatic systolic LV dysfunction.1,2 not present; Stage C includes patients with symptomatic
Patients without detectable LV myocardial disease HF associated with underlying heart disease; Stage
may have other cardiovascular causes for HF (e.g. D patients have advanced structural heart disease
pulmonary hypertension, valvular heart disease, etc.). and marked symptoms and signs of HF at rest despite
Patients with non-cardiovascular pathologies (e.g. maximal medical therapy. The recent European Society
anemia, pulmonary, renal or hepatic disease) may have of Cardiology guidelines 4 have provided diagnostic
symptoms similar or identical to those of HF and each criteria based on ejection fraction (EF) (Table 1).
may complicate or exacerbate the HF syndrome. Sometimes the term advanced HF is used to
Identification of the underlying cardiac problem is characterize patients with severe symptoms, recurrent
crucial for therapeutic reasons, as the precise pathology decompensation and severe cardiac dysfunction.
CHAPTER 26: Heart Failure with Reduced Ejection Fraction: Treatment Strategy 145
TABLE 1: Definition of heart failure

Type of HF HFrEF HFmrEF HFpEF
1 Symptoms ± Symptoms ± Signs Symptoms ± Signs
Criteria Signs
2 LVEF<40% LVEF 40–49% LVEF ≥ 50%
zz Elevated levels of natriuretic peptides zz Elevated levels of natriuretic peptides
3 zz At least one additional criterion: zz At least one additional criterion:
—— Relevant structural heart disease (LVH and/ —— Relevant structural heart disease (LVH and/
or LAE) or LAE)
—— Diastolic dysfunction —— Diastolic dysfunction
Abbreviations: HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction;
HFrEF, heart failure with reduced ejection fraction; LAE, left atrial enlargement; LVEF, left ventricular ejection fraction; LVH, left ventricular
hypertrophy
The Killip classification may be used to describe the features, particularly previous myocardial infarction,
severity of the patient’s condition in the acute setting greatly increase the likelihood of HF in a patient with
after myocardial infarction. appropriate symptoms and signs. Symptoms and
In clinical practice, a clear distinction between signs are important in monitoring a patient’s response
acquired and inherited cardiomyopathies remains to treatment and stability over time. Persistence of
challenging. In most patients with a definite clinical symptoms despite treatment usually indicates the need
diagnosis of HF, there is no confirmatory role for routine for additional therapy, and worsening of symptoms is
genetic testing, but genetic counselling is recommended a serious development (placing the patient at risk of
in patients with hypertrophic cardiomyopathy (HCM), urgent hospital admission and death) and merits prompt
idiopathic DCM or arrhythmogenic right ventricular medical attention.
cardiomyopathy (ARVC), since the outcomes of these
tests may have clinical implications. Investigations
The following diagnostic tests are recommended/should
DIAGNOSIS be considered for initial assessment of a patient with
newly diagnosed HF in order to evaluate the patient’s
Clinical suitability for particular therapies, to detect reversible/
Symptoms are often nonspecific and do not, therefore, treatable causes of HF and comorbidities interfering with
help discriminate between HF and other problem. HF.
Symptoms and signs of HF due to fluid retention may Hemoglobin and WBC, sodium, potassium, urea,
resolve quickly with diuretic therapy. Signs, such as creatinine (with estimated GFR), liver function tests
elevated jugular venous pressure and displacement of (bilirubin, AST, ALT, GGTP), glucose, HbA1c, TSH,
the apical impulse, may be more specific, but are harder ferritin, TSAT = TIBC should be done.
to detect and have poor reproducibility. Symptoms The plasma concentration of natriuretic peptides
and signs may be particularly difficult to identify and (NPs) can be used as an initial diagnostic test, especially
interpret in obese individuals, in the elderly and in in the nonacute setting when echocardiography is not
patients with chronic lung disease. Younger patients with immediately available. Elevated NPs help establish an
HF often have a different etiology, clinical presentation initial working diagnosis, identifying those who require
and outcome compared with older patients. A detailed further cardiac investigation; patients with values below
history should always be obtained. HF is unusual in the cutpoint for the exclusion of important cardiac
an individual with no relevant medical history (e.g. a dysfunction do not require echocardiography. Patients
potential cause of cardiac damage), whereas certain with normal plasma NP concentrations are unlikely
to have HF. The upper limit of normal in the nonacute (COPD), pulmonary function testing with spirometry is
setting for B-type natriuretic peptide (BNP) is 35 pg/mL needed. The chest X-ray may, however, show pulmonary
and for N-terminal pro-BNP (NT-proBNP) it is 125 pg/ venous congestion or oedema in a patient with HF,
mL; in the acute setting, higher values should be used and is more helpful in the acute setting than in the
[BNP, 100 pg/mL, NT-proBNP, 300 pg/mL and mid- nonacute setting. It is important to note that significant
regional pro A-type natriuretic peptide (MR-proANP) 120 LV dysfunction may be present without cardiomegaly on
pmol/L]. the use of NPs is recommended for ruling-out the chest X-ray.
HF, but not to establish the diagnosis. Cardiac magnetic resonance (CMR) is acknowledged
Although there is extensive research on biomarkers as the gold standard for the measurements of volumes,
in HF (e.g. ST2, galectin 3, copeptin, adrenomedullin), mass and EF of both the left and right ventricles. It
there is no definite evidence to recommend them for is the best alternative cardiac imaging modality for
clinical practice. patients with nondiagnostic echocardiographic studies
An abnormal electrocardiogram (ECG) increases the (particularly for imaging of the right heart) and is the
likelihood of the diagnosis of HF, but has low specificity. method of choice in patients with complex congenital
Some abnormalities on the ECG provide information heart diseases. CMR is the preferred imaging method
on etiology (e.g. myocardial infarction), and findings to assess myocardial fibrosis using late gadolinium
on the ECG might provide indications for therapy (e.g. enhancement (LGE) along with T1 mapping and can
anticoagulation for AF, pacing for bradycardia, CRT if be useful for establishing HF etiology. CMR allows the
broadened QRS complex). HF is unlikely in patients characterization of myocardial tissue of myocarditis,
presenting with a completely normal ECG (sensitivity amyloidosis, sarcoidosis, Chagas disease, Fabry disease
89%). Therefore, the routine use of an ECG is mainly noncompaction cardiomyopathy and hemochromatosis.
recommended to rule out HF. Single-photon emission CT (SPECT) may be useful in
Echocardiography is the most useful, widely available assessing ischemia and myocardial viability.
test in patients with suspected HF to establish the Positron emission tomography (PET) (alone or with
diagnosis. It provides immediate information on CT) may be used to assess ischemia and viability.
chamber volumes, ventricular systolic and diastolic Coronary angiography is recommended in patients
function, wall thickness, valve function and pulmonary with HF who suffer from angina pectoris recalcitrant
hypertension. This information is crucial in establishing to medical therapy, provided the patient is otherwise
the diagnosis and in determining appropriate treatment suitable for coronary revascularization. Coronary
The information provided by careful clinical angiography is also recommended in patients with
evaluation and the above mentioned tests will permit a history of symptomatic ventricular arrhythmia or
an initial working diagnosis and treatment plan in most aborted cardiac arrest. Coronary angiography should be
patients. Other tests are generally required only if the considered in patients with HF and intermediate to high
diagnosis remains uncertain (e.g. if echocardiographic pretest probability of CAD and the presence of ischemia
images are suboptimal or an unusual cause of HF is in noninvasive stress tests in order to establish the
suspected). ischemic etiology and CAD severity.
A chest X-ray is of limited use in the diagnostic The main use of cardiac CT in patients with HF is as
work-up of patients with suspected HF. It is probably a noninvasive means to visualize the coronary anatomy
most useful in identifying an alternative, pulmonary in patients with HF with low intermediate pretest
explanation for a patient’s symptoms and signs, i.e. probability of CAD or those with equivocal noninvasive
pulmonary malignancy and interstitial pulmonary stress tests in order to exclude the diagnosis of CAD,
disease, although computed tomography (CT) of the in the absence of relative contraindications. However,
chest is currently the standard of care. For the diagnosis the test is only required when its results might affect a
of asthma or chronic obstructive pulmonary disease therapeutic decision.
Molecular genetic analysis in patients with should be cautiously initiated in hospital, once the
cardiomyopathies is recommended when the prevalence patient is stabilized.
of detectable mutations is sufficiently high and consistent Mineralocorticoid (MRA) (spironolactone and
to justify routine targeted genetic screening. eplerenone) block receptors that bind aldosterone
and, with different degrees of affinity, other steroid
PHARMACOLOGIC TREATMENT hormone (e.g. corticosteroids, androgens) receptors.
The goals of treatment in patients with HF are to improve Spironolactone or eplerenone are recommended in
their clinical status, functional capacity and quality of all symptomatic patients (despite treatment with an
life, prevent hospital admission and reduce mortality. It ACEI and a beta-blocker) with HFrEF and LVEF ≤35%,
is now recognized that preventing HF hospitalization and to reduce mortality and HF hospitalization.12,13 Caution
improving functional capacity are important benefits to should be exercised when MRAs are used in patients
be considered if a mortality excess is ruled out.5-7 with impaired renal function and in those with serum
Neurohormonal antagonists (ACEIs, MRAs and beta- potassium levels ≥5.0 mmol/L. Regular checks of serum
blockers) have been shown to improve survival in patients potassium levels and renal function should be performed
with HFrEF and are recommended for the treatment of according to clinical status.
every patient with HFrEF, unless contraindicated or not Ivabradine reduces the elevated heart rate often seen
tolerated. A new compound (LCZ696) that combines the in HFrEF and has also been shown to improve outcomes,
moieties of an ARB (valsartan) and a neprilysin (NEP) and should be considered when appropriate.
inhibitor (sacubitril) has recently been shown to be A combination of hydralazine and isosorbide dinitrate
superior to an ACEI (enalapril) in reducing the risk of may be considered in symptomatic patients with HFrEF
death and of hospitalization for HF in a single trial with who can tolerate neither ACEI nor ARB (or they are
strict inclusion/exclusion criteria.8 Sacubitril/valsartan is contraindicated) to reduce mortality.
therefore recommended to replace ACEIs in ambulatory Digoxin may be considered in patients in sinus
HFrEF patients who remain symptomatic despite rhythm with symptomatic HFrEF to reduce the risk of
optimal therapy and who fit these trial criteria. ARBs hospitalization (both all-cause and HF hospitalizations).
have not been consistently proven to reduce mortality in In patients with symptomatic HF and AF, digoxin
patients with HFrEF and their use should be restricted to may be useful to slow a rapid ventricular rate, but it is
patients intolerant of an ACEI or those who take an ACEI only recommended for the treatment of patients with
but are unable to tolerate an MRA. HFrEF and AF with rapid ventricular rate when other
ARBs are recommended only as an alternative in therapeutic options cannot be pursued.
patients intolerant of an ACEI. These medications should be used in conjunction
Beta-blockers reduce mortality and morbidity in with diuretics in patients with symptoms and/or signs
symptomatic patients with HFrEF, despite treatment of congestion. The use of diuretics should be modulated
with an ACEI and, in most cases, a diuretic,9,10 but have according to the patient’s clinical status.
not been tested in congested or decompensated patients.
There is consensus that beta-blockers and ACEIs are NONSURGICAL DEVICE TREATMENT4
complementary, and can be started together as soon as
Implantable Cardioverter-defibrillator
the diagnosis of HFrEF is made. There is no evidence
favouring the initiation of treatment with a beta-blocker Primary prevention: An ICD is recommended to reduce
before an ACEI has been started.11 Betablockers should the risk of sudden death and all-cause mortality in
be initiated in clinically stable patients at a low dose and patients with symptomatic HF (NYHA Class II–III), and
gradually up-titrated to the maximum tolerated dose. In an LVEF ≤35% despite ≥3 months of OMT, provided they
patients admitted due to acute HF (AHF) beta-blockers are expected to survive substantially longer than one year
with good functional status, and they have: IHD (unless Patients with HFrEF who have received a conventional
they have had an MI in the prior 40 days), and DCM. pacemaker or an ICD and subsequently develop
worsening HF despite OMT and who have a high
Secondary prevention: An ICD is recommended to
proportion of RV pacing may be considered for
reduce the risk of sudden death and all-cause mortality
upgrade to CRT. This does not apply to patients with
in patients who have recovered from a ventricular
stable HF.
arrhythmia causing hemodynamic instability, and who
CRT is contraindicated in patients with a QRS
are expected to survive for >1 year with good functional
duration <130 msec.
status.
Cardiac Resynchronization Therapy Other Implantable Electrical Devices

For patients with HFrEF who remain symptomatic
CRT is recommended for symptomatic patients with
despite OMT and do not have an indication for CRT, new
HF in sinus rhythm with a QRS duration ≥150 msec
device therapies have been proposed and in some cases
and LBBB QRS morphology and with LVEF ≤35%
are approved for clinical use in several European Union
despite OMT in order to improve symptoms and
countries but remain under trial evaluation.
reduce morbidity and mortality.
Cardiac contractility modulation (CCM) is similar in
CRT should be considered for symptomatic patients
its mode of insertion to CRT, but it involves nonexcitatory
with HF in sinus rhythm with a QRS duration ≥150
electrical stimulation of the ventricle during the absolute
msec and nonLBBB QRS morphology and with LVEF
refractory period to enhance contractile performance
≤35% despite OMT in order to improve symptoms
without activating extra systolic contractions. CCM has
and reduce morbidity and mortality.
been evaluated in patients with HFrEF in NYHA Classes
CRT is recommended for symptomatic patients with
II–III with normal QRS duration (<120 ms). 14,15
HF in sinus rhythm with a QRS duration of 130–149
Most other devices under evaluation involve some
msec and LBBB QRS morphology and with LVEF
modification of the activity of the autonomic nervous
≤35% despite OMT in order to improve symptoms
system (ANS) by targeted electrical stimulation. These
and reduce morbidity and mortality.
include vagal nerve stimulation, spinal cord stimulation,
CRT may be considered for symptomatic patients
carotid body ablation and renal denervation, but so
with HF in sinus rhythm with a QRS duration of
far none of the devices has improved symptoms or
130–149 msec and nonLBBB QRS morphology and
outcomes in RCTs.
with LVEF ≤35% despite OMT in order to improve
symptoms and reduce morbidity and mortality.
MECHANICAL CIRCULATORY SUPPORT
CRT rather than RV pacing is recommended for
patients with HFrEF regardless of NYHA class who
AND HEART TRANSPLANTATION
have an indication for ventricular pacing and high Mechanical Circulatory Support
degree AV block in order to reduce morbidity. This For patients with either chronic or acute HF who
includes patients with AF. cannot be stabilized with medical therapy, mechanical
CRT should be considered for patients with LVEF circulatory support (MCS) systems can be used to
≤35% in NYHA Class III–IV despite OMT in order unload the failing ventricle and maintain sufficient end-
to improve symptoms and reduce morbidity and organ perfusion. Patients in acute cardiogenic shock
mortality, if they are in AF and have a QRS duration are initially treated with short-term assistance using
≥130 msec provided a strategy to ensure biventricular extracorporeal, nondurable life support systems so that
capture is in place or the patient is expected to return more definitive therapy may be planned. Patients with
to sinus rhythm. chronic, refractory HF despite medical therapy can be
treated with a permanent implantable left ventricular ARRHYTHMIAS AND CONDUCTANCE

assist device (LVAD). DISTURBANCES
To manage patients with AHF or cardiogenic shock
Ambulatory electrocardiographic monitoring can
(INTERMACS level 1), short-term mechanical support
be used to investigate symptoms that may be due to
systems, including percutaneous cardiac support devices,
arrhythmias, but evidence is lacking to support routine,
extracorporeal life support (ECLS) and extracorporeal
systematic monitoring for all patients with HF to identify
membrane oxygenation (ECMO) may be used to support
tachy- and bradyarrhythmias. There is no evidence
patients with left or biventricular failure until cardiac
that clinical decisions based on routine ambulatory
and other organ function have recovered. Typically the
electrocardiographic monitoring improve outcomes for
use of these devices is restricted to a few days to weeks.
patients with HF.
The Survival After Veno-arterial ECMO (SAVE) score can
Atr ial fibr illation, ventr icular ar rhythmias,
help to predict survival for patients receiving ECMO for
symptomatic bradycardia, pauses and atrioventricular
refractory cardiogenic shock.
block are managed according to relevant clinical
In addition, MCS systems, particularly ECLS and
guidelines.
ECMO, can be used as a ‘bridge to decision’ (BTD)
in patients with acute and rapidly deteriorating HF
MONITORING
or cardiogenic shock to stabilize hemodynamics,
High circulating NPs predict unfavorable outcomes in
recover end-organ function and allow for a full clinical
evaluation for the possibility of either heart transplant or patients with HF, and a decrease in NP levels during
a more durable MCS device. MCS devices, particularly recovery from circulatory decompensation is associated
continuous-flow LVADs, are increasingly seen as an with a better prognosis. Although it is plausible to
alternative to heart transplantation. monitor clinical status and tailor treatment based on
changes in circulating NPs in patients with HF, published
Heart Transplantation studies have provided differing results.16,17 So, presently,
Heart transplantation is an accepted treatment for end- a broad application of such an approach is not clinically
stage HF. Although controlled trials have never been feasible.
conducted, there is a consensus that transplantation—
provided that proper selection criteria are applied— CONCLUSION
significantly increases survival, exercise capacity, quality The increasing incidence and prevalence of chronic
of life and return to work compared with conventional HF and our improving ability to identify its main
treatment. pathophysiological mechanisms have been paralleled
by remarkable improvements in medical and device
HEART FAILURE AND COMORBIDITIES therapy. The developments of new pharmacological
Comorbidities are of great importance in HF and may and device therapies that have improved the prognosis
affect the use of treatments for HF (e.g. it may not be of patients require a constant update on the overall
possible to use renin–angiotensin system inhibitors is management strategies of patients with HF.
some patients with severe renal dysfunction). The drugs
used to treat comorbidities may cause worsening of HF REFERENCES
(e.g. NSAIDs given for arthritis, some anticancer drugs). 1. Wang TJ. Natural history of asymptomatic left ventricular
systolic dysfunction in the community. Circulation.
Management of comorbidities is a key component of the
2003;108:977-82.
holistic care of patients with HF. Many comorbidities
2. The SOLVD investigators. Effect of enalapril on mortality and
are actively managed by specialists in the field of the the development of heart failure in asymptomatic patients
comorbidity, and these physicians will follow their own with reduced left ventricular ejection fractions. N Engl J
specialist guidelines. Med. 1992;327:685-91.
3. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update 10. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi
incorporated into the ACC/AHA 2005 guidelines for the P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz
diagnosis and management of heart failure in adults : a MK, DeMets DL. Effect of carvedilol on survival in severe
report of the American College of Cardiology Foundation/ chronic heart failure. N Engl J Med. 2001;344:1651-8.
American Heart Association Task Force on Practice 11. Willenheimer R, van Veldhuisen DJ, Silke B, Erdmann E,
Guidelines developed in collaboration with the International Follath F, Krum H, Ponikowski P, Skene A, van de Ven L,
Society for Heart and Lung Transplantation. Circulation. Verkenne P, Lechat P, CIBIS III Investigators. Effect on
2009;119(14):e391-e479. survival and hospitalization of initiating treatment for
4. Ponikowski P, Voors AA. Anker SD, Bueno H, Cleland JG, chronic heart failure with bisoprolol followed by enalapril,
Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and as compared with the opposite sequence: results of the
treatment of acute and chronic heart failure. The Task randomized. Cardiac Insufficiency Bisoprolol Study (CIBIS)
Force for the diagnosis and treatment of acute and chronic III. Circulation. 2005;112:2426-35.
heart failure of the European Society of Cardiology (ESC). 12. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez
Developed with the special contribution of the Heart Failure A, Palensky J, Wittes J. The effect of spironolactone on
Association (HFA) of the ESC. European Heart Journal. morbidity and mortality in patients with severe heart failure.
doi:10.1093/eurheartj/ehw128. N Engl J Med. 1999;341:709-17.
5. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell 13. Zannad F, McMurray JJV, Krum H, Van Veldhuisen DJ,
S, McMurray JJJV. The current cost of heart failure to Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B. Eplerenone
the National Health Service in the UK. Eur J Heart Fail. in patients with systolic heart failure and mild symptoms. N
2002;4:361-71. Engl J Med. 2011;364:11–21.
6. Gheorghiade M, Shah AN, Vaduganathan M, Butler J, Bonow 14. Kadish A, Nademanee K, Volosin K, Krueger S, Neelagaru
RO, Rosano GMC, Taylor S, Kupfer S, Misselwitz F, Sharma S, Raval N, Obel O, Weiner S, Wish M, Carson P, Ellenbogen
A, Fonarow GC. Recognizing hospitalized heart failure as an K, Bourge R, Parides M, Chiacchierini RP, Goldsmith R,
entity and developing new therapies to improve outcomes: Goldstein S, Mika Y, Burkhoff D, Abraham WT. A randomized
academics’, clinicians’, industry’s, regulators’, and payers’ controlled trial evaluating the safety and efficacy of cardiac
perspectives. Heart Fail Clin. 2013;9:285-90, v–vi. contractility modulation in advanced heart failure. Am Heart
7. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, J. 2011;161:329-37.e2
Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN, 15. Borggrefe MM, Lawo T, Butter C, Schmidinger H, Lunati
Gheorghiade M. The global health and economic burden M, Pieske B, Misier AR, Curnis A, Bo¨cker D, Remppis A,
of hospitalizations for heart failure. J Am Coll Cardiol. Kautzner J, Stu¨hlinger M, Leclerq C, Ta´borsky´ M, Frigerio
2014;63:1123-33. M, Parides M, Burkhoff D, Hindricks G. Randomized,
8. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, double blind study of non-excitatory, cardiac contractility
Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg modulation electrical impulses for symptomatic heart
K, Zile MR. PARADIGM-HF Investigators and Committees. failure. Eur Heart J. 2008;29:1019-28.
Angiotensin-neprilysin inhibition versus enalapril in heart 16. Balion C, McKelvie R, Don-Wauchope AC, Santaguida PL,
failure. N Engl J Med. 2014;371:993-1004. Oremus M, Keshavarz H, Hill SA, Booth RA, Ali U, Brown
9. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, JA, Bustamam A, Sohel N, Raina P. B-type natriuretic
Waagstein F, Kjekshus J, Wikstrand J, ElAllaf D, Vı´tovec J, peptide-guided therapy: a systematic review. Heart Fail Rev.
Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Jańosi A, 2014;19:553-64.
Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz 17. Troughton RW, Frampton CM, Brunner-La Rocca H-P,
J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P. MERIT- Pfisterer M, Eurlings LWM, Erntell H, Persson H, O’Connor
HF Study Group. Effects of controlled-release metoprolol on CM, Moertl D, Karlstrom P, Dahlstrom U, Gaggin HK, Januzzi
total mortality, hospitalizations, and wellbeing in patients JL, Berger R, Richards AM, Pinto YM, Nicholls MG. Effect of
with heart failure: the Metoprolol CR/XL Randomized B-type natriuretic peptide-guided treatment of chronic heart
Intervention Trial in congestive Heart Failure (MERIT-HF). failure on total mortality and hospitalization: an individual
JAMA. 2000;283:1295-302. patient meta-analysis. Eur Heart J. 2014;35:1559-67.
CHAPTER
27
Pulmonary Embolism: Focus on New Drugs
INTRODUCTION PATHOPHYSIOLOGY
Venous thromboembolism (VTE) constitutes pulmonary Pathophysiologic cascade culminating in VTE includes
embolism (PE) and deep vein thrombosis (DVT). active inflammation, hypercoagulability and endothelial
It results in over one lac deaths annually in USA. insult. Venous thrombi form and flourish in an
While in-hospital mortality is 7% it rises to 30% if atmosphere of stasis, low oxygen pressure, oxidative
hemodynamic instability is associated. PE affects quality stress, enhanced expression of proinflammatory
of life and can cause major long-term complications markers and impaired endothelial cell mechanics.
which includes recurrent episode of VTE, chronic PE consequently, elicit a complex cardiopulmonary
thromboembolic pulmonary arterial hypertension response viz; heightened pulmonary vascular resistance,
(CTEPH) and chronic leg venous insufficiency. VTE neurohumoral activation, impaired gas exchange caused
although can affect any age, the incidence steadily by increased alveolar dead space and hypoxemia due
rises with age and recurrences despite anticoagulation to alveolar hypoventilation and right-to-left shunting
are common. VTE is usually outcome of interaction of blood. A sudden rise in pulmonary arterial pressure
between patients-related (permanent risk factors) and abruptly increases RV afterload with rise in RV wall
situation-related (temporary) risk factors. It’s considered tension resulting in RV dilatation (Fig. 1). Consequently,
“Provoked” if temporary or reversible risk factors viz; IVS shifts to left resulting in reduced LV filling causing
trauma, major surgery, immobilization, pregnancy, fall in systemic arterial pressure, impaired coronary
oral contraceptives or even hormone replenishment perfusion and myocardial ischemia. Elevated RV wall
therapy occur within preceding 6 weeks to 3 months. tension after massive VTE reduces right coronary
However, it is diagnosed “Unprovoked” in the absence flow, increases RV oxygen demand causing ischemia.
of such factors. Presence of risk factors influences the Perpetuation of this cycle results in RV infarction,
duration of anticoagulation. Advances in diagnostics, circulatory collapse, and death.
therapeutic modalities and preventive strategies added
with improved pathophysiologic understanding has CLINICAL PRESENTATIONS
resulted in improved outcome as there is now a focus on The symptoms and signs of PE are nonspecific. Dyspnea
newer modalities of treatment. is most prominent symptom and chest pain is unusual.
Fig. 1: Showing key factors and a vicious cycle of cardiogenic shock in PE

Abbreviations: BP, blood pressure; CO, cardiac output; LV, left ventricular; RV, right ventricular; TV, tricuspic valve
TABLE 1: Classic Well’s criteria to assess clinical likelihood of DIAGNOSIS

pulmonary embolism
PE masquerade number of clinical cardiopulmonary
Criteria Scoring**
conditions therefore, the diagnosis is often missed.
DVT symptoms and signs 3 Elevated D-dimer (end product of endogenous
An alternative diagnosis less likely 3 fibrinolysis) is sensitive but nonspecific for PE but has
Heart rate >100 bpm 1.5 a better negative predictive value in ER. ECG changes
Immobilization or surgery within 4 weeks 1.5 include sinus tachycardia, SL1, QL3 and T inversion in L3
Previous DVT or PE 1.5 (S1, QIII, TIII sign), ST-T changes in V1-3, RBBB. It may
Hemoptysis 1 also be normal despite massive PE. Chest skiagram may
Cancer treated within 6 months or metastasis 1 be normal despite severe breathlessness but may show
** >4 score=high probability, <4 score = nonhigh probability focal oligemia, a peripheral wedge shaped opacity above
the diaphragm (Hampton sign), a subtle PA enlargement.
Presentations of acute pulmonary embolism can In fact, chest X-ray more often rule other conditions
be—Massive PE (5–10%), submassive (20–25%) and mimicking PE.
small to moderate PE (70%). These categorization has
therapeutic implications. In massive PE thrombosis, Cardiac Biomarkers
there is wide spread thrombosis affecting at least ½ of Plasma levels of BNP and NT-proBNP reflect severity
pulmonary circulation, it is bilateral sometimes ‘saddle’ of RV dysfunction in acute PE. Similarly elevated
PE. It is susceptible to cardiogenic shock and multiorgan concentration of troponin and heart type fatty acid
failure viz; renal insufficiency, hepatic dysfunction and binding protein (H-FABP) are associated with poor
altered mentation. Pulmonary infarction (Table 1) is outcome.
characterized by pleuritic chest pain often accompanied
with hemoptysis and suggest peripheral arterial branch Chest Computed Tomography
obstruction. Well’s criteria for PE helps in deciding CT chest with pulmonar y angiography is intial
the probability of PE which influences the treatment modality to diagnose suspected PE allowing ready
initiation. Patients with high probability should undergo visualization of massive PE and confirmation of catheter
CT pulmonary angiography confirmation. or surgical accessibility to centrally localized thrombus.
CHAPTER 27: Pulmonary Embolism: Focus on New Drugs 153
Multidetector CT can identify upto 6 order branches of ovale and thrombus in RV or RA may be associated.
pulmonary artery and 3D images can be constructed. CT Other investigation like; lung scanning, venous
can also visualize 4-chambers of heart and pulmonary ultrasonography, MRI chest, pulmonary angiography are
artery and signs of RV dysfuction can be measured not routinely carried out in most patients of PE.
including
i. RV to LV diameter ratio (>0.9 suggest RV enlargement) MANAGEMENT OF ACUTE
ii. RV to LV volume ratio >1.2 abnormal PULMONARY EMBOLISM
iii. IVS bowing to left Risk stratification of acute PE is essential as it can have
iv. reflux of contrast into IVC. wide spectrum of presentations (Table 2). The patient
Echocardiography may be normal in upto 1/3rd of can be classified as high risk, intermediate (high or low )
patients. However, it is rapid, sensitive technique for RV and low risk PE based on clinical presentation and other
overload and dysfunction characterized by moderate to parameters as per risk score PESI as shown in pulmonary
severe RV hypokinesis with normal RV apex (McConell’s embolism severity index (PESI) identifies 11 clinical
sign), persistent PA hypertension, TR (>2.6 m/sec), parameters for risk stratification and 30 day mortality in
D-shaped LV and noncollapsing IVC, patent foramen class 5 is 10–24.5% (Table 3).
TABLE 2: Classification of patients with acute pulmonary embolism based on early mortality risk
Early mortality risk Risk parameters and scores
Shock or PESI Class III-V or Signs of RV dysfunction Cardiac laboratory

hypotension sPESI ≥1 on an imaging test biomarkers
High + (+) + (+)
Intermediate Intermediate-high – + Both positive
Intermediate-low – + Either one (or none) positive
Low – – Assessment optional; If assessed, both negative
TABLE 3: Original and simplified pulmonary embolism severity index (PESI)
Parameter Original version Simplified version
Age Age in years 1 point (if age > 80 years)
Male sex +10 points —
Cancer +30 points 1 point
Chronic heart failure +10 points

1 point
Chronic pulmonary disease +10 points
Pulse rate ≥ 110 bpm +20 points 1 point
Systolic blood pressure <100 mm Hg +30 points 1 point
Respiratory rate >30 breaths per minute +20 points —
Temperature <36°C +20 points —
Altered mental status +60 points —
Arterial oxyhemoglobin saturation <90% +20 points 1 point

RISK Strata (mortality %): Class I: <65 pointes (0–1.6%), Class II: 66–85 (1.7–3.5%), Class III: 86–105 (3.2–7.1%), Class IV: 106–125 (4–11.4%), Class
V: >125 (10–24.5%)
Treatment of Acute Phase 0.36; 95% CI: 0.15–0.84) hemorrhage. As a result, NOACs
are recommended in the 2014 ESC guidelines as an
Anticoagulation
alternative to the standard heparin/VKA treatment.
Conventional anticoagulants: Early anticoagulation
All four NOACs mentioned earlier are now licensed for
is recommended in acute PE with aim to prevent
treatment of VTE in the United States and the European
death and recurrence. This consists of parenteral
Union.
anticoagulation with Unfractionated Heaprin, LMWH
The dosages of NOAC are: Dabigatran 150 mg bid
or Fondaparinaux for 5–10 days overlapping with oral
from D5, Rivoroxaban 15 mg bid (D1) and 20 mg od from
anticoagulants-vitamin K antagonists (warfarin or
D5, Edoxaban 60 mg od D5 and Apixaban 10 mg bid from
Acenocoumarin). Anticoagulants are continued for 3
D1–5, 5 mg bid thereafter (conventional anticoagulation
months in unprovoked VTE (extended usage if provoked
from D1–5). For long term use after VTE, all NOAC
or second episode) with INR goal of 2–3. Dose of UFH
are better for both all-cause mortality and recurrent
should be IV bolus of 80 units/kg followed by continuous
VTE than with placebo. For reversal of anticoagulation
infusion of 18 units/kg/hr. The aPTT should be targeted
in NOAC-Idarucizumab, an antibody fragment for
between 1.5 seconds and 2.5 seconds. LMWH is given
Dabigatran and Andexanet alfa, a modified recombinant
per kg dose as per agent used. While UFH heparin acts
human factor Xa molecule, for Adixaban have been
by binding to antithrombin, LMWH has anti-Xa activity.
developed.
Newer oral anticoagulants (NOAC): Two classes of NOAC have not been tested in pregnancy and chronic
oral direct anticoagulant agents are now available kidney disease with CrCl <30 mL/min. Certain specific
for use in clinical practice to overcome the limits situations use of anticoagulants have been defined as
of conventional anticoagulation. These agents are shown in Table 4.
synthetic, selective, and reversible inhibitors of factor
Xa (rivaroxaban, apixaban, and edoxaban) or thrombin Aspirin
(dabigatran). These act rapidly and have predictable Aspirin (100 mg/d) is indicated over no aspirin to prevent
anticoagulant effect permitting use in fixed dose without recurrent VTE if anticoagulants are stopped. However,
lab control. The short half-life of NOAC allows quick asprin is not as effective as standard anticoagulants.
reversal of anticoagulation in situations viz; needed Asprin shows a 32% reduction in recurrences of VTE and
for invasive procedures and bleeding complications. 34% reduction in risk of major vascular events.
Rivaroxaban and edoxaban offer the possibility of once-
daily administration. Reperfusion Therapies
Phase 3 trials investigating the new, nonvitamin Thrombolysis: Systemic pharmacological thrombo
K dependent oral anticoagulant agents apixaban lysis is indicates in patients with massive and high risk
(AMPLIFLY), dabigatran (RE-COVER, RE-COVER-II), PE with hypotension. Streptokinase (2.5 lacs loading
edoxaban (HOKUSAI), and rivaroxaban (EINSTEIN, over 30 min followed by 1 lac IU/hr over 12–24 hrs),
EINSTEIN PE) in the treatment of VTE have been urokinase (4400 IU/kg loading in 30 min, followed
completed and published. A meta-analysis 15 showed by 4400 IU/kg over 12–24 hrs) and rTPA 100 mg over
that these agents are noninferior to the standard heparin/ 2 hrs or 0.6 mg/kg over 15 mins are the agents used.
VKA regimen, in terms of prevention of VTE recurrence Thrombolysis results in reduction in RV pressure,
(relative risk [RR]: 0.90; 95% confidence interval [CI]: prevention of release of serotonin which exacerbate
0.77–1.06), and that they are probably safer in terms of PAH and dissolution of thrombus in pelvic or leg
major bleeding (RR: 0.61; 95% CI: 0.45–0.83), particularly veins. However for intermediate high risk patients,
intracranial (RR: 0.37; 95% CI:0.21–0.68) and fatal (RR: thrombolysis is controversial.
CHAPTER 27: Pulmonary Embolism: Focus on New Drugs 155
TABLE 4: Treatment of VTE in specific clinical situations

Suggested anticoagulation regimen
Stage IV renal failure Prefer conventional treatment
Concomittant treatment with verapamil or dronidarone Prefer conventional treatment or Rivoroxaban
Treament with carbamazepine, phenobarbitone, phenytoin Prefer conventional treatment
Active cancer LMWH or conventional treatment or NOAC
Isolated distil DVT including upper arm Prefer LMWH or conventional treatment or NOAC
Unsuspected VTE If to be treated, treat as sympatomatic VTE
Splanchnic or cerebral CVT Prefer conventional treatment
APLA Prefer conventional treatment
Patient with vena cava filter Prefer conventional treatment
Catheter based reperfusion: 1% risk of intracranial months and platelet count <50000/uL. UFH, enoxaparin,
hemorrhage risk during thrombolysis has dampened asprin, warfarin, NOAC, fondaparinux (all in reduced
the enthusiasm of this therapy. Pharmacomechanical doses) and intermittent pneumatic compression of leg
catheter based directed reperfusion holds promise veins are all effective and can be given within 24 hours
with reduced dose of rtPA to 25 mg. Interventional of surgery.
techniques during this procedure includes mecha
nical fragmentation and aspiration of thrombus, BIBLIOGRAPHY
clot pulverization, rheolytic thrombectomy and 1. Agnelli G, Buller HR, Cohen A, et al. For the AMPLIFY
investigators. Oral apixaban for the treatment of acute
pigtail rotational catheter embolectomy. This may
venous thromboembolism. N Engl J Med. 2013;369:799-
be followed with balloon dilatation and stenting of 808.
pulmonary artery. 2. Becattini C, Agnelli G. Treatment of venous thromboembolism
Surgical embolectomy: Two indications are–Massive with new anticoagulant agents. J Am Coll Cardiol. 2016;67:
PE with hypotension, submassive PE with severe 1941-55.
3. EINSTEIN Investigators. Oral rivaroxaban for symptomatic
RV dysfunction having contraindications for
venous thromboembolism. N Engl J Med. 2010;363:2499-
thrombolysis or if thrombolysis failed. 510.
Inferior vena cava filters: AHA defines indication of 4. EINSTEIN–PE Investigators. Oral rivaroxaban for the
caval filters in treatment of symptomatic pulmonary embolism. N Engl J
i. contraindications to anticoagulation Med. 2012;366:1287-97.
ii. recurrent PE despite optimal anticoagulation 5. Goldhaber SZ. Pulmonary embolism, In braunwald’s heart
disease—A textbook of cardiovascular Medicine 10th
iii. very poor cardiopulmonary reserve.
edition Mann, Zipes, Libby, Bono weds volume-II, Elservier
Saunders. 2015. pp.1664-81.
In-hospital Prophylaxis 6. Hokusai-VTE Investigators. Edoxaban versus warfarin for
VTE once develops, is difficult to diagnose, potentially the treatment of symptomatic venous thromboembolism. N
lethal and expensive to treat and most preventable cause Engl J Med. 2013;369:1406-15.
7. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy
of death. Thus, VTE prophylaxis is essential and risk
for VTE disease: Antithrombotic therapy and prevention
assessment can be carried out utilizing Padua Prediction of thrombosis, 9th Edition: American College of Chest
Score. Three risk factors have been defined where risk of Physicians Evidence- Based Clinical Practice Guidelines.
bleeding is high viz; active GIT ulcer, bleeding in past 3 Chest. 2012;141:e419S-e94S.
8. Konstantinides SV, Barco S, Lankeit M, Meyer G. 11. Schulman S, Kakkar AK, Goldhaber SZ, et al. for the
Management of pulmonary embolism-Present and future– RE-COVER II trial investigators. Treatment of acute venous
an Update. J Am Coll Cardiol. 2016;67:976-90. thromboembolism with dabigatran or warfarin and pooled
9. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC analysis. Circulation. 2014;129:764-72.
guidelines on the diagnosis and management of acute 12. Schulman S, Kearon C, Kakkar AK, et al. For the RE-
pulmonary embolism. Eur Heart J. 2014;35:3033-69. COVER study group. Dabigatran versus warfarin in the
10. Righini M, Roy PM, Meyer G, et al. The simplified pulmonary treatment of acute venous thromboembolism. N Engl J Med.
embolism severity index (PESI): validation of a clinical 2009;361:2342-52.
prognostic model for pulmonary embolism. J Thromb
Haemost. 2011;9:2115-7.
CHAPTER
28
Echocardiographic Navigation of AF from
Irregular Pulse to Slurring of the Speech:
Relevant at All Stages in India and the Real World
HK Chopra, Ravi R Kasliwal, Manish Bansal, Shraddha Ranjan
INTRODUCTION definitive and potentially curative therapeutic approach.

The incidence and prevalence of atrial fibrillation (AF) Among the various diagnostic tools, echocardiography
is increasing steadily. The 2010 rates are higher than the has an important role in both the evaluation of cardiac
1990 rates with estimated numbers of men and women structure and function and risk stratification in AF
with AF 20.9 million and 12.6 million thus showing patients. It is a great and perhaps the most helpful
increase in both prevalence and incidence rates in both modality for the initial workup of all patients with AF, for
sexes. This increase in AF burden increases with age assessing left atrium (LA) and left ventricle (LV) size and
from 2% incidence in population less than 40 years of function along with presence of valvular, myocardial,
age to almost 10% in that with more than 80 years.1,2 This pericardial and congenital heart disease which may
potentially could be linked to better detection of silent predispose to AF.
AF alongside increasing longevity and risk factors such as Undoubtedly, the most dreaded complication of
hypertension, obesity and metabolic syndrome, etc. The AF is stroke and various risk factors are associated with
prevalence of AF in our population is not well studied the occurrence of stroke in AF patients. To be more
but a study done in UK found 6292 patients of different presumptive several risk scores have been developed
ethnicities with AF with age adjusted prevalence of to predict the risk of ischemic stroke and guide the
0.63% (1.2% white, 0.4% black African/Caribbean and decision to treat them with anticoagulants. The CHADS2
0.2% South Asian). South Asian patients though had risk score is the simplest score and assigns points to the
a lower prevalence but were at higher stroke risk than presence of congestive heart failure, hypertension, age
white patients.3 It is a well-known fact AF is associated >75, diabetes, and stroke. 5 To better identify patients
with higher morbidity and mortality, for example data that are truly at low risk, the CHA2DS2-VASc risk score
from the Framingham Heart Study suggested that the was developed that also included vascular disease, age
presence of AF is associated with a near doubling of between 65 and 74 years, and sex.6 The European Society
both overall and cardiovascular mortality leading to of Cardiology (ESC) and National Institute for Health
subsequent implications for public health policy and and Care Excellence (NICE) guidelines recommend that
healthcare costs.4 The main cause of mortality remains if the patient has a CHA2DS2-VASc score of 2 and above,
stroke as 50% of patients with AF related stroke die within oral anticoagulation therapy (OAC) is recommended.2
a year. It becomes imperative now to have a proper Recently a new clinically based risk score, the ATRIA
understanding of the disease in order to have a more (Anticoagulation and Risk Factors in Atrial Fibrillation)
study risk score, was developed and validated which uses In this article, we try to do the same by reviewing the role
factors incorporated in the CHADS2 risk score, along of echocardiography in the evaluation and management
with renal dysfunction.7 of patients with AF.
Role of transesophageal echocardiographic (TEE)
evaluation in ruling out left atrial thrombi to allow for ECHOCARDIOGRAPHIC NAVIGATION IN
early cardioversion in new onset AF is undebatable and AF MANAGEMENT
has become a dictum in everyday cardiology practice.
But apart from that it is discouraging to see that in all
Left Atrial/Left Atrial Appendage Clot
these risk scores there has been no consideration of The primary indication for performing assessment
echocardiographic parameters which can be of immense of the LAA is to rule out the presence of a thrombus.
value in management of AF patients. The study Stroke The risk of systemic emboli, probably arising in the
Prevention in Atrial Fibrillation (SPAF) confirmed the LA cavity or LAA as a result of circulatory stasis, is an
usefulness of TEE for predicting thromboembolism. important consideration in AF. TEE is highly accurate
It showed that the rate of stroke was increased over for this purpose with some studies reporting sensitivity
threefold when TEE evidence of dense spontaneous echo and specificity of TEE to be as high as 100% and 99%
contrast (SEC) was present, increased by threefold for respectively 9 (Figs 1 to 3). Cardioversion carries an
reduced (<20 cm/second) left atrial appendage (LAA) intrinsic risk of stroke in nonanticoagulated patients
peak ejection flow velocity and for LAA thrombus, and (upto 7% of patients) which is reduced substantially by
increased fourfold by complex aortic plaque.8 the administration of anticoagulation.10,11 Patients who
In our country, though true prevalence is still have been in AF for longer than 48 hours should start OAC
unknown, it is a fact that AF may be a bigger problem at least 3 weeks before cardioversion and continue it for
than in the West considering the extra burden of valvular at least 4 weeks afterwards.2 However, when acute onset
AF due to Rheumatic Heart Disease (RHD) along with AF is encountered and early cardioversion is desired, TEE
the nonvalvular AF. In most of the patients, there is no can exclude the majority of left atrial thrombi, allowing
way to determine the actual time of commencement of immediate cardioversion. The advantages of TEE-guided
AF, medical attention is sought later and records are not early cardioversion with short term anticoagulation
meticulously maintained, making it all the more essential over the conventional strategy include the following:
for developing echocardiography as a modality which (1) On TEE, if no thrombus is seen the total duration of
can give us most of the answers with limited resources. anticoagulation can be reduced by weeks, potentially
A B
Figs 1A and B: Large left atrial appendage clot. (A) Two-dimensional image; (B) Three-dimensional image
CHAPTER 28: Echocardiographic Navigation of AF from Irregular Pulse to Slurring of the Speech 159
A B
Figs 2A and B: Small clot in one of the lobes of the left atrial appendage.
The clot is visualized only in one plane (A) but not in the orthogonal plane (B)
development of left ventricular diastolic dysfunction, or

a mitral valve pathology there is progressive increase in
mean LA pressure. The increase in mean LA pressure
eventually leads to an increase in the LA size.12,13 There
ais now sufficient evidence to suggest that the left
atrial size is an independent predictor of recurrence
of atrial fibrillation, risk of stroke, heart-failure related
hospitalization and risk of overall mortality.14-26
LA size can be assessed by measuring it’s antero
posterior diameter, area or volume at the end of the
ventricular systole when the chamber size is at its
maximum. LA diameter and area are simple to measure,
the technique is less demanding and provides quick
Fig. 3: Large layered thrombus in the left atrium (arrow). Spontaneous
echo contrast is also seen filling the whole of the left atrium estimate of LA size. However, they may not be true
representative of the size in disease states as the LA often
reducing the risk of bleeding. (2) Early cardioversion enlarges nonuniformly.27,28 Therefore, measurement of
with a TEE-guided approach might prevent the atrial volume is considered to be the most accurate method for
remodelling due to AF and enable higher rates of sinus estimation of left atrial size and is recommended by the
conversion and maintenance. So, the assessment of LA American Society of Echocardiography (ASE).29
and LAA anatomy, function and presence or absence LA volume can be calculated either by the biplane
of clot carries immense significance and is discussed in area-length method based on ellipsoid model or by
detail in further sections of the article. the Simpson’s method. In past, the biplane area-length
method has been the preferred method (Figs 4A and
Left Atrial Size B) as most of the existing data is derived using this
LA is directly exposed to the hemodynamic agitations method only. However, the more recent guidelines
taking place within the LV during diastole as it is in have recommended the biplane Simpson’s method for
direct communication with the LV. As a result, with estimation of LA volume (Figs 5A and B).29
A B
Figs 4A and B: Measurement of left atrial volume by the biplane area-length method. Left atrial area and length are measured in both the
apical four and two-chamber views and used in the equation
A B
Figs 5A and B: Measurement of left atrial volume by the biplane Simpson’s method
Using the biplane area-length method, LA volume LAA are not included in the measurement. Irrespective
can be calculated as: of the method, the estimated LA volume should always
Left atrial volume= 8/3π (A1 × A2/L) be indexed to the body-surface area. The normal value of
indexed LA volume is ≤34 ml/m2.
A1 is the planimetric LA area in the four-chamber view The estimation of LA volume by the Simpson’s
A2 is the planimetric LA area in the two-chamber view method (Figs 5A and B) is based on the same principles
L is the length of the LA, measured as the perpendicular as for left ventricular volume estimation. LA endocardial
distance from the mid-point of mitral annular plane to border is trace in both the apical four-chamber and
the superior aspect of the left atrium (Figs 4A and B). the two-chamber views and the software inbuilt in the
The length is measured in both the four-chamber echocardiography machine automatically calculates the
and the two-chamber views and the shorter of the LA volume. While tracing the endocardial border, same
two is used in the equation. While doing planimetry precautions need to be exercised as described above for
foreshortening is avoided and pulmonary veins and the the area-length method.
Left Atrial Function Assessment

LA function, in addition to LA size, is also an important
determinant of adverse outcomes in various diseases
states that directly or indirectly affect the left atrium.
Furthermore, in some situations, LA function may even
have superior prognostic value than LA size alone.30
The recent advent of speckle tracking echocardiography
(STE) with its application for LA strain measurement A
has rendered assessment of LA function much easier,
providing a renewed impetus to evaluating its role in
clinical practice.
Strain is basically a measure of myocardial
deformation and is defined as the percent change in the
length of a myocardial segment during a given phase of
cardiac cycle. When the myocardial segment undergoes
shortening, strain assumes a negative value whereas B
lengthening would result in positive strain.
Figs 6A and B: Measurement of left atrial strain by speckle tracking
Unlike LV where myocardial deformation is echocardiography. (A) The colored curves depict segmental strain
multidirectional and strain is described along whereas the white dotted curve depicts the average of all the
segments; (B) Left atrial strain waveform using QRS as the reference
three principle directions-longitudinal, radial and point. There is an initial positive wave during ventricular systole which
circumferential, in case of LA most of the shortening is followed by reduction in strain during early rapid filling phase and
and lengthening occurs in longitudinal directional only subsequently during active atrial contraction.
Abbreviations: PACS, peak atrial contraction strain; PALS, peak atrial
and therefore only longitudinal strain is measured for all longitudinal strain
practical purposes.
There are primarily two methods for measurement which can be manually adjusted to conform to the
of myocardial strain—Doppler-based and the gray-scale contour of the LA wall. The software then divides LA
based or STE-based.31 Doppler-based strain is technically circumference in to 6 segments and tracks myocardial
more time consuming and less accurate. In comparison, motion for each segment frame-by-frame and generates
STE is simpler to use and, because of its relative angle strain curves for each myocardial segment (Figs 6A and
independence, can be used for strain measurement B). This process is repeated for both the 4-chamber
in any cardiac chamber and in any direction hence and the 2-chamber views, yielding 12 (6 for each view)
currently the preferred modality for measurement of LA segmental strain curves.
strain. The shape of the LA strain curve varies depending on
For LA strain measurement, gray-scale moving whether QRS onset or beginning of the P-wave is used
images are acquired in apical 4-chamber and 2-chamber as the reference point.31,32 QRS onset is used more often
views along its maximal dimensions, during breath-hold and hence only this method will be discussed here (Figs
with a stable ECG recording. These images are analyzed 6A and B). QRS onset marks the beginning of ventricular
using the same registered speckle-tracking software systole and the time when the left atrium is smallest in
which are used for LV strain analysis. The LA endocardial size. During progression of ventricular systole, the left
border is manually traced in the end-systolic (ventricular atrium increases in size resulting in positive strain that
systole) frame, excluding pulmonary vein ostia and LA reaches its peak just before the mitral valve opening.
appendage. The software then automatically generates Once mitral valve opens, the left atrium rapidly decreases
epicardial border tracing and creates a region of interest in size resulting in reduction in strain. This early rapid
emptying phase is followed by a phase of diastasis in developing AF. It’s role in clinical decision making is
which the strain curve plateaus. With the onset of atrial discussed below:
contraction, marked by P-wave on the ECG, the left
atrium shortens again, resulting in second phase of Prediction of Atrial Fibrillation
strain reduction. The strain curve eventually reaches
LA strain if reduced predicts occurrence of AF in
the baseline by the onset of QRS. Since QRS is generally
numerous clinical settings. Few studies which were done
used as the reference point, most of the nomenclature
on patients undergoing coronary artery bypass surgery
for LA strain is based on this method only.32 The peak
or valve surgery showed that LA strain and strain rate
atrial longitudinal strain (PALS), measured at the
were significantly impaired in patients who developed
end of the ventricular systole represents the reservoir
postoperative AF and were independent predictors of
function of the LA; the reduction in strain from this peak
the development of AF in the overall cohort.38-40 LA strain
to the plateau phase indicates the conduit function;
can be helpful in predicting the risk of AF in nonsurgical
and the final phase of LA strain reduction during atrial
contraction (termed peak atrial contraction strain or patients also specially in rheumatic mitral stenosis.41,42
PACS) represents the booster function. PALS averaged
for all 12 segments (or all analyzed segments) is used Prediction of Stroke Risk
as global LA strain. Global PACS can also be calculated Stroke is the most feared but possibly preventable
in a similar manner. In addition, LA contraction strain complication of AF. LA strain can also be a useful
index can also be calculated as global PACS X 100/global parameter along with the validated risk scores when
PALS and represents the contribution of the LA active prevention of stroke is the matter on hand. Hsu et al.
contraction to the total LV filling. followed up 190 patients with persistent AF and found
LA strain is briefly reduced in patients with short- that baseline LA strain was found to be a predictor of
duration AF but gradually recovers with time,33,34 unless stroke event in these patients and had incremental value
there have been chronic structural changes in LA over CHA2DS2-VASc score.43 In another study with 286
myocardium. If AF persists, there is structural and consecutive patients of paroxysmal or persistent AF with
functional remodeling of left atrium characterized by or without acute embolism global LA strain was found to
increased fibrosis of LA myocardium. In such patients, be lower not only in patients with acute embolism, it had
LA strain is persistently reduced and is a determinant
an incremental value over the CHA2DS2-VASc score.44
of adverse clinical outcomes. Several studies have
Several other studies have demonstrated association
demonstrated close correlation between LA fibrosis and
between LA strain and the CHA 2DS 2-VASc score. 45,46
LA strain.35 In a study patients with persistent AF were
previous history of stroke47 and the future occurrence
found to have greater degree of fibrosis than those with
of stroke. 48 Moreover, impairment of LA strain has
paroxysmal AF. 36 Apart from AF, LA remodeling also
also been demonstrated in patients with stroke of
occurs whenever the left atrium is chronically exposed
undetermined etiology where it may indicate the
to elevated LV filling pressures and LA strain has been
possibility of undiagnosed paroxysmal AF.49
shown to be impaired, before other echocardiographic
manifestations of LA structural remodeling appear in
patients with hypertension, diabetes and heart failure Outcomes after Cardioversion
with preserved LV ejection fraction.37 In patients undergoing electrical cardioversion for
AF, reduced LA strain before the cardioversion or a
Role of LA Function Assessment in dampened increase in LA strain immediately after
Clinical Decision Making cardioversion has been shown to predict failure of
Abnormalities of LA strain have several important conversion and associated with lower probability of
clinical implications in patients with or, at risk of maintenance of sinus rhythm respectively.50
Recurrence of Atrial Fibrillation after extending between the pulmonary artery above and the
Catheter Ablation LV. Internally LAA is trabeculated with the trabeculations,
Cather ablation of AF is an invasive procedure which known as pectinate muscles which run parallel to each
is associated with some risk of peri-procedural other, giving it a comb-like structure. In an autopsy study
complications and roughly 30–40% risk of AF recurrence of 500 normal human hearts, the LAA was bilobed in 54%
during follow-up.30,51 So, accurate selection of patients is and multilobed (>2 lobes) in 80% of hearts.62
crucial to optimize long-term clinical outcomes of this Although the LAA can be visualized on TTE also, in
procedure. Several studies have shown that LA strain most patients a detailed assessment is not possible due
can be a useful predictor of the recurrence of AF after to the posterior location of the LAA. Whereas, TEE, with
catheter ablation.30,52-54 Recently, a meta-analysis was the close proximity of the transducer to the LAA, allows
excellent imaging of the LAA and is therefore compulsory
performed of 8 studies evaluating role of LA strain for
for LAA assessment. On TEE, the LAA is best visualized in
prediction of AF recurrence after catheter ablation.55 A
the midesophageal two-chamber view (80–100°) and the
total of 686 patients were included in this analysis. LA
midesophageal aortic valve short-axis view (30–60°) and
strain was strongly associated with the recurrence of AF
are therefore the recommended views for this purpose.63
with a cut-off value of 22.8% (95% confidence interval
However, to exclude thrombus, it is essential to image
18.8–30%) yielding a sensitivity of 78% (95% confidence
the LAA from multiple imaging planes. This can be easily
interval 65–86%) and specificity of 75% (95% confidence
accomplished by first developing the midesophageal
interval 66–100%). LA strain have also been shown to
aortic valve short-axis view (30–60°) and then anteflexing
predict reverse LA remodeling after catheter ablation for
the transducer and rotating the multiplane angle from
AF.56
00 to 180°. This approach allows complete assessment
of LAA anatomy, its different lobes and the pectinate
Left Atrial Appendage Structure
muscles (Figs 7A and B). Sometimes it may be almost
and Function impossible to differentiate a thrombus from the pectinate
In conventional teaching, LAA was believed to be muscles or artefacts. The administration of ultrasound
a vestigial structure with no active role and hence contrast can be of great help in such situations.64-66 The
was not studied. However, with the advancements of recent availability of live-three dimensional TEE should
echocardiographic techniques, it has now become render imaging of the complex LAA anatomy much
apparent that the LAA is an actively contracting structure easier now.67
which plays an important role in cardiac hemodynamics. In addition to delineation of thrombus, TEE is also
More than that, dysfunction of LAA is the substrate helpful in detection of LAA SEC. SEC is a smoke-like
for thrombus formation which can lead to potentially swirling pattern seen on two-dimensional imaging
devastating embolic complications. 57-61 Therefore, a and is thought to reflect rouleaux formation resulting
comprehensive assessment of LAA structure and function from stasis of the blood. SEC has been shown to be
should be done to guide therapeutic decision-making the harbinger of thrombus formation and therefore, a
in a number of cardiac illnesses. Echocardiography, predictor of thromboembolic risk in many studies.68-70
particularly TEE, is currently the modality of choice for
evaluation of the LAA. It allows complete differentiation Assessment of LAA Function
of the LAA anatomy along with detailed assessment of its It has become obvious that an estimate of LAA function
function in most of the patients. can provide incremental information about the risk of
clot formation, embolic events, success of cardioversion,
Assessment of LAA Structure etc. Therefore, evaluation of the LAA function by doppler
The LAA is a small, pyramidal usually a multilobed measurement of LAA flow velocities is currently the
structure situated on the lateral aspect of the LA, preferred method of assessment of LAA function. 71
A B
Figs 7A and B: Multilobed anatomy of the left atrial appendage. (A) Only one lobe (arrow) is visualized in this plane; (B) The complete extent of
the left atrial appendage is visualized in an orthogonal plane (open arrows mark the boundary of the appendage). Pectinate muscles are also
clearly visualized (arrow)
It is now often undertaken as part of the standard Assessment of LAA Structure and Function in
echocardiographic examination of the appendage. The Clinical Practice
LAA flow velocities by pulsed-wave Doppler can be Assessment of LAA anatomy and function plays an
obtained from any of the standard imaging planes on impor tant role in the diagnostic w ork-up and
TEE by keeping the pulsed-wave sample-volume in the management of many clinical conditions. It may be
proximal one-third segment (towards LA) of the LAA.71,72 a mandatory investigation prior to performance of
In patients with sinus rhythm, a typical quadriphasic intervention procedures such as BMV, or can be routinely
flow pattern (Figs 8A to C) can be seen consisting of sought when the cause of ischemic stroke is not apparent
Early diastolic emptying velocity followed by the most and a cardiac source needs to be ruled out. In addition
important phase of Late diastolic emptying velocity or to these well-known indications research has revealed
LAA contraction flow which results from active LAA newer indications for which LAA function assessment
scontraction and is thus a marker of LAA contractile may be warranted. The most practical indications are
function. It correlates with LAA ejection fraction, discussed here:
LA size and pressure and is a significant predictor of
thromboembolic risk.73 This is followed by a negative Presence of Thrombus or SEC
wave of LAA filling velocity and multiple low velocity Cardioembolic strokes account for ≥15% of all ischemic
systolic reflection waves. strokes79 among which LAA is the source of embolus in
In contrast to LAA flow velocity, which is an indirect majority of the cases. Approximately, 90% of intracardiac
measure of LAA function, measurement of tissue velocity thrombi in nonrheumatic AF and 60% in patients with
provides direct estimate of the LAA contractility. On rheumatic mitral valve disease form within the LAA.80
tissue velocity imaging, a similar wave pattern is seen as In patients with recent embolic event and AF, LAA
in the corresponding flow velocity. It was found to have thrombus is found in roughly 14% patients with short
good feasibility and correlated with the presence of LAA duration AF (started <3 days before) and in roughly 27%
SEC or thrombus, history of thromboembolic events patients with longer duration of AF.9 Therefore, imaging
and quantification of LAA contractile dysfunction in of the LAA to rule out thrombus or SEC is an important
mitral stenosis, hypertension or HCM even in absence indication of performing TEE in patients suspected to be
of AF.61,74-78
100
cm/sec
Late diastolic emptying velocity
50 Systolic reflection Early diastolic

waves emptying
velocity
50
LAA filling
A B
Figs 8A to C: Left atrial appendage (LAA) flow pattern. (A) Schematic

diagram showing different flow waves during sinus rhythm; (B)
Pulsed-wave Doppler tracing of LAA flow in sinus rhythm; (C) Pulsed-
wave Doppler tracing of LAA flow in atrial fibrillation
Source: Modified from Bansal M, Kasliwal RR. Echocardiography
for left atrial appendage structure and function. Indian Heart J.
C 2012;64:469-75.
having cardioembolic stroke. The presence of SEC alone in patients with LAA dysfunction (75% versus 58%).
may be enough to label it a cardioembolic stroke in this Furthermore, the risk of ischemic stroke in patients
context.69,70 with lower velocities was 2.6 times greater than in those
As discussed above, exclusion of LA/LAA thrombi is with higher velocities. Many other studies concluded
obligatory when planning intervention procedures such similar findings as well.58,59,81 The thromboembolic risk
as BMV, radiofrequency ablation of atrial arrhythmias is greater with AF than with flutter for same degree of
and also prior to cardioversion for AF of >48 hours LAA dysfunction.82,83 LAA dysfunction is severely marked
duration in patients who have not been on adequate
in patients with rheumatic mitral stenosis in AF, who
anticoagulation.
typically have very low or even absent LAA velocities.84
LAA dysfunction is a predictor of stroke risk in
Prediction of Thromboembolism
sinus rhythm also. A study published by Reddy et al
LAA dysfunction has been shown to be a strong predictor
of thrombus formation and the risk of embolic events, even reports the effect of BMV on LAA function in patients
if no clot is found at the time of initial examination.57-59,81 with symptomatic mitral stenosis in sinus rhythm.
In the SPAF III (Stroke Prevention in Atrial Fibrillation Significant improvement was seen in LAA flow and tissue
III) TEE substudy that included patients with AF, 17% velocities on TEE performed on 3rd day after BMV. The
patients with LAA contraction velocities < 20 cm/s had improvement in LAA function was accompanied by
thrombi as compared to 5% of the patients with higher complete disappearance or reduction of SEC in all the
velocities.57 The prevalence of SEC was also much higher patients who had SEC prior to the procedure.85
Immediate and Short-term Outcome of 3. Mathur R, Pollara E, Hull S, Schofield P, Ashworth M, Robson
J. Ethnicity and stroke risk in patients with atrial fibrillation.
Cardioversion
Heart. 2013;99:1087-92.
As discussed with LA function, preserved LAA function 4. Va z i r i S M , L a r s o n M G , B e n j a m i n E J , L e v y D .
is associated with higher probability of conversion Echocardiographic predictors of nonrheumatic atrial
and subsequent maintenance in sinus rhythm. 86-90 A fibrillation. The Framingham Heart Study. Circulation.
multicenter study involving 408 patients undergoing 1994;89:724-30.
5. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused
cardioversion of AF showed that duration of AF <2
update of the ESC Guidelines for the management of
weeks, LA diameter <47 mm and mean LAA velocity >31 atrial fibrillation: an update of the 2010 ESC Guidelines
cm/s were the only independent predictors of success for the management of atrial fibrillation. Developed with
of cardioversion. 91 A temporary worsening of LAA the special contribution of the European Heart Rhythm
function, known as LAA stunning, can occur irrespective Association. European Heart Journal. 2012;33:2719-47.
6. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/
of the mode of cardioversion and is also seen after
HRS guideline for the management of patients with atrial
radiofrequency or surgical ablation of AF or flutter.92-96 fibrillation: a report of the American College of Cardiology/
Stunning is commonly associated with new or worsening American Heart Association Task Force on Practice
SEC and may thus predispose to thromboembolism.94,95,97 Guidelines and the Heart Rhythm Society. Journal of the
The time course of recovery of stunning varies but American College of Cardiology. 2014;64:e1-76.
7. Singer DE, Chang Y, Borowsky LH, et al. A new risk scheme
significant improvement in LAA function is known to
to predict ischemic stroke and other thromboembolism in
occur within 7–30 days after cardioversion.92,95,96
atrial fibrillation: the ATRIA study stroke risk score. Journal
of the American Heart Association. 2013;2:e000250.
CONCLUSION 8. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL,
AF is a leading cause of morbidity and mortality worldwide, Asinger RW, Hart RG. Transesophageal echocardiographic
with increasing incidence as age advances. Management correlates of clinical risk of thromboembolism in nonvalvular
atrial fibrillation. Stroke Prevention in Atrial Fibrillation III
of AF remains complex with numerous uncertainties
Investigators. Journal of the American College of Cardiology.
existing about its pathophysiology, clinical outcomes 1998;31:1622-6.
and the impact of various therapeutic approaches 9. Manning WJ, Silverman DI, Gordon SP, Krumholz HM,
employed for its management. Echocardiography, is Douglas PS. Cardioversion from atrial fibrillation without
the most practical modality for the evaluation of LA prolonged anticoagulation with use of transesophageal
echocardiography to exclude the presence of atrial thrombi.
structure and function and provides critical diagnostic
N Engl J Med. 1993;328:750-5.
and prognostic information and thus help in timely 10. Airaksinen KE, Gronberg T, Nuotio I, et al. Thromboembolic
appropriate intervention to reduce the cardiac inflicted complications after cardioversion of acute atrial fibrillation:
morbidity and mortality. Therefore, Echocardiographic the FinCV (Finnish CardioVersion) study. Journal of the
navigation of AF is the cornerstone and relevant in all the American College of Cardiology. 2013;62:1187-92.
11. Hansen ML, Jepsen RM, Olesen JB, et al. Thromboembolic
stages from irregular pulse to slurring of the speech.
risk in 16 274 atrial fibrillation patients undergoing direct
current cardioversion with and without oral anticoagulant
REFERENCES therapy. Europace : European pacing, arrhythmias, and
1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide cardiac electrophysiology : journal of the working groups
epidemiology of atrial fibrillation: a Global Burden of on cardiac pacing, arrhythmias, and cardiac cellular
Disease 2010 Study. Circulation 2014;129:837-47. electrophysiology of the European Society of Cardiology.
2. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC 2015;17:18-23.
Guidelines for the management of atrial fibrillation 12. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB.
developed in collaboration with EACTS. European Heart Left atrial volume as a morphophysiologic expression
Journal. 2016;37:2893-962. of left ventricular diastolic dysfunction and relation to
cardiovascular risk burden. The American Journal of 26. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Risks
Cardiology. 2002;90:1284-9. for atrial fibrillation and congestive heart failure in patients
13. Simek CL, Feldman MD, Haber HL, Wu CC, Jayaweera AR, >/=65 years of age with abnormal left ventricular diastolic
Kaul S. Relationship between left ventricular wall thickness relaxation. Am J Cardiol. 2004;93:54-8.
and left atrial size: comparison with other measures of 27. Lester SJ, Ryan EW, Schiller NB, Foster E. Best method in
diastolic function. J Am Soc Echocardiogr. 1995;8:37-47. clinical practice and in research studies to determine left
14. Abhayaratna WP, Seward JB, Appleton CP, et al. Left atrial atrial size. Am J Cardiol. 1999;84:829-32.
size: physiologic determinants and clinical applications. J 28. Loperfido F, Pennestri F, Digaetano A, et al. Assessment of
Am Coll Cardiol. 2006;47:2357-63. left atrial dimensions by cross sectional echocardiography
15. Benjamin EJ, D’Agostino RB, Belanger AJ, Wolf PA, Levy in patients with mitral valve disease. Br Heart J. 1983;50:
D. Left atrial size and the risk of stroke and death. The 570-8.
Framingham Heart Study. Circulation. 1995;92:835-41. 29. Lang RM, Bierig M, Devereux RB, et al. Recommendations
16. Bouzas-Mosquera A, Broullon FJ, Alvarez-Garcia N, et al. for chamber quantification: a report from the American
Left atrial size and risk for all-cause mortality and ischemic Society of Echocardiography’s Guidelines and Standards
stroke. CMAJ. 2011;183:E657-64. Committee and the Chamber Quantification Writing Group,
17. Di Tullio MR, Sacco RL, Sciacca RR, Homma S. Left atrial developed in conjunction with the European Association
size and the risk of ischemic stroke in an ethnically mixed of Echocardiography, a branch of the European Society of
population. Stroke. 1999;30:2019-24. Cardiology. J Am Soc Echocardiogr. 2005;18:1440-63.
18. Dini FL, Cortigiani L, Baldini U, et al. Prognostic value of 30. Yasuda R, Murata M, Roberts R, et al. Left atrial strain is
left atrial enlargement in patients with idiopathic dilated
a powerful predictor of atrial fibrillation recurrence after
cardiomyopathy and ischemic cardiomyopathy. Am J
catheter ablation: study of a heterogeneous population with
Cardiol. 2002;89:518-23.
sinus rhythm or atrial fibrillation. Eur Heart J Cardiovasc
19. Modena MG, Muia N, Sgura FA, Molinari R, Castella A,
Imaging. 2015;16:1008-14.
Rossi R. Left atrial size is the major predictor of cardiac
31. Mor-Avi V, Lang RM, Badano LP, et al. Current and
death and overall clinical outcome in patients with dilated
evolving echocardiographic techniques for the quantitative
cardiomyopathy: a long-term follow-up study. Clin Cardiol.
evaluation of cardiac mechanics: ASE/EAE consensus
1997;20:553-60.
statement on methodology and indications endorsed
20. Moller JE, Hillis GS, Oh JK, et al. Left atrial volume: a
by the Japanese Society of Echocardiography. J Am Soc
powerful predictor of survival after acute myocardial
Echocardiogr. 2011;24:277-313.
infarction. Circulation. 2003;107:2207-12.
32. Cameli M, Lisi M, Righini FM, Mondillo S. Novel
21. Nagarajarao HS, Penman AD, Taylor HA, et al. The predictive
echocardiographic techniques to assess left atrial size,
value of left atrial size for incident ischemic stroke and all-
cause mortality in African Americans: the Atherosclerosis anatomy and function. Cardiovasc Ultrasound. 2012;10:4.
Risk in Communities (ARIC) Study. Stroke. 2008;39:2701-6. 33. Donal E, Ollivier R, Veillard D, et al. Left atrial function
22. Ristow B, Ali S, Whooley MA, Schiller NB. Usefulness of left assessed by trans-thoracic echocardiography in patients
atrial volume index to predict heart failure hospitalization treated by ablation for a lone paroxysmal atrial fibrillation.
and mortality in ambulatory patients with coronary heart Eur J Echocardiogr. 2010;11:845-52.
disease and comparison to left ventricular ejection 34. Kaya EB, Tokgozoglu L, Aytemir K, et al. Atrial myocardial
fraction (from the Heart and Soul Study). Am J Cardiol. deformation properties are temporarily reduced after
2008;102:70-6. cardioversion for atrial fibrillation and correlate well with
23. Sabharwal N, Cemin R, Rajan K, Hickman M, Lahiri A, Senior left atrial appendage function. Eur J Echocardiogr. 2008;9:
R. Usefulness of left atrial volume as a predictor of mortality 472-7.
in patients with ischemic cardiomyopathy. Am J Cardiol. 35. Her AY, Choi EY, Shim CY, et al. Prediction of left atrial
2004;94:760-3. fibrosis with speckle tracking echocardiography in mitral
24. Takemoto Y, Barnes ME, Seward JB, et al. Usefulness of valve disease: a comparative study with histopathology.
left atrial volume in predicting first congestive heart failure Korean Circulation Journal. 2012;42:311-8.
in patients > or = 65 years of age with well-preserved left 36. Kuppahally SS, Akoum N, Burgon NS, et al. Left atrial strain
ventricular systolic function. Am J Cardiol. 2005;96:832-6. and strain rate in patients with paroxysmal and persistent
25. Tsang TS, Barnes ME, Bailey KR, et al. Left atrial volume: atrial fibrillation: relationship to left atrial structural
important risk marker of incident atrial fibrillation in 1655 remodeling detected by delayed-enhancement MRI. Circ
older men and women. Mayo Clin Proc. 2001;76:467-75. Cardiovasc Imaging. 2010;3:231-9.
37. Mondillo S, Cameli M, Caputo ML, et al. Early detection 50. Costa C, Gonzalez-Alujas T, Valente F, et al. Left atrial strain:
of left atrial strain abnormalities by speckle-tracking in a new predictor of thrombotic risk and successful electrical
hypertensive and diabetic patients with normal left atrial cardioversion. Echo Res Pract. 2016;3:45-52.
size. J Am Soc Echocardiogr. 2011;24:898-908. 51. Shaikh AY, Maan A, Khan UA, et al. Speckle echocardiographic
38. Gabrielli L, Corbalan R, Cordova S, et al. Left atrial left atrial strain and stiffness index as predictors of
dysfunction is a predictor of postcoronary artery bypass maintenance of sinus rhythm after cardioversion for atrial
atrial fibrillation: association of left atrial strain and strain fibrillation: a prospective study. Cardiovasc Ultrasound.
rate assessed by speckle tracking. Echocardiography. 2012;10:48.
2011;28:1104-8. 52. Motoki H, Negishi K, Kusunose K, et al. Global left atrial
39. Her AY, Kim JY, Kim YH, et al. Left atrial strain assessed strain in the prediction of sinus rhythm maintenance
by speckle tracking imaging is related to new-onset atrial after catheter ablation for atrial fibrillation. J Am Soc
fibrillation after coronary artery bypass grafting. Can J Echocardiogr. 2014;27:1184-92.
Cardiol. 2013;29:377-83. 53. Hwang HJ, Choi EY, Rhee SJ, et al. Left atrial strain as
40. Cameli M, Lisi M, Reccia R, et al. Pre-operative left atrial predictor of successful outcomes in catheter ablation for
strain predicts post-operative atrial fibrillation in patients atrial fibrillation: a two-dimensional myocardial imaging
undergoing aortic valve replacement for aortic stenosis. Int study. J Interv Card Electrophysiol. 2009;26:127-32.
J Cardiovasc Imaging. 2014;30:279-86. 54. Sar vari SI, Haugaa KH, Stokke TM, et al. Strain
41. Cameli M, Lisi M, Righini FM, Focardi M, Alfieri O, Mondillo echocardiographic assessment of left atrial function
S. Left atrial speckle tracking analysis in patients with mitral
predicts recurrence of atrial fibrillation. Eur Heart J
insufficiency and history of paroxysmal atrial fibrillation. Int
Cardiovasc Imaging. 2016;17:660-7.
J Cardiovasc Imaging. 2011.
55. Ma XX, Boldt LH, Zhang YL, et al. Clinical relevance of left
42. Pourafkari L, Ghaffari S, Bancroft GR, Tajlil A, Nader ND.
atrial strain to predict recurrence of atrial fibrillation after
Factors associated with atrial fibrillation in rheumatic mitral
catheter ablation: A Meta-Analysis. Echocardiography.
stenosis. Asian Cardiovasc Thorac Ann. 2015;23:17-23.
2016;33:724-33.
43. Hsu PC, Lee WH, Chu CY, et al. Prognostic role of left
56. Tops LF, Delgado V, Bertini M, et al. Left atrial strain
atrial strain and its combination index with transmitral
predicts reverse remodeling after catheter ablation for atrial
E-wave velocity in patients with atrial fibrillation. Sci Rep.
fibrillation. J Am Coll Cardiol. 2011;57:324-31.
2016;6:17318.
57. Transesophageal echocardiographic correlates of
44. Obokata M, Negishi K, Kurosawa K, et al. Left atrial
thromboembolism in high-risk patients with nonvalvular
strain provides incremental value for embolism risk
atrial fibrillation. The Stroke Prevention in Atrial Fibrillation
stratification over CHA(2)DS(2)-VASc score and indicates
Investigators Committee on Echocardiography. Ann Intern
prognostic impact in patients with atrial fibrillation. J Am
Soc Echocardiogr. 2014;27:709-716 e4. Med. 1998;128:639-47.
45. Shavarov A, Yusupov A, Kiyakbaev G, Moiseev V. 5a.06: 58. Mugge A, Kuhn H, Nikutta P, Grote J, Lopez JA, Daniel WG.
Correlation of thromboembolic risk with global left atrial Assessment of left atrial appendage function by biplane
strain in hypertensive patients with atrial fibrillation. J transesophageal echocardiography in patients with
Hypertens. 2015;33(Suppl 1):e65. nonrheumatic atrial fibrillation: identification of a subgroup
46. Saha SK, Anderson PL, Caracciolo G, et al. Global left atrial of patients at increased embolic risk. J Am Coll Cardiol.
strain correlates with CHADS2 risk score in patients with 1994;23:599-607.
atrial fibrillation. J Am Soc Echocardiogr. 2011;24:506-12. 59. Li YH, Lai LP, Shyu KG, Hwang JJ, Kuan P, Lien WP. Clinical
47. Shih JY, Tsai WC, Huang YY, et al. Association of decreased implications of left atrial appendage flow patterns in
left atrial strain and strain rate with stroke in chronic atrial nonrheumatic atrial fibrillation. Chest. 1994;105:748-52.
fibrillation. J Am Soc Echocardiogr. 2011;24:513-9. 60. Saygi S, Turk UO, Alioglu E, et al. Left atrial appendage
48. Cameli M, Lisi M, Focardi M, et al. Left atrial deformation function in mitral stenosis: is it determined by cardiac
analysis by speckle tracking echocardiography for prediction rhythm? J Heart Valve Dis. 2011;20:417-24.
of cardiovascular outcomes. Am J Cardiol. 2012;110:264-9. 61. Tenekecioglu E, Karabulut A, Yilmaz M. Comparison of
49. Sanchis L, Montserrat S, Obach V, et al. Left atrial function tissue Doppler dynamics with Doppler flow in evaluating
is impaired in some patients with stroke of undetermined left atrial appendage function by transesophageal
etiology: Potential Implications for Evaluation and Therapy. echocardiography in prehypertensive and hypertensive
Rev Esp Cardiol (Engl Ed). 2016;69:650-6. patients. Echocardiography. 2010;27:677-86.
62. Veinot JP, Harrity PJ, Gentile F, et al. Anatomy of the 73. Agmon Y, Khandheria BK, Meissner I, et al. Left atrial
normal left atrial appendage: a quantitative study of age- appendage flow velocities in subjects with normal left
related changes in 500 autopsy hearts: implications for ventricular function. Am J Cardiol. 2000;86:769-73.
echocardiographic examination. Circulation. 1997;96:3112- 74. Bauer F, Verdonck A, Schuster I, et al. Left atrial appendage
5. function analyzed by tissue Doppler imaging in mitral
63. Shanewise JS, Cheung AT, Aronson S, et al. ASE/SCA stenosis: effect of afterload reduction after mitral valve
guidelines for performing a comprehensive intraoperative commissurotomy. J Am Soc Echocardiogr. 2005;18:934-9.
multiplane transesophageal echocardiography 75. Cayli M, Acarturk E, Demir M, Kanadasi M. Systolic tissue
examination: recommendations of the American velocity is a useful echocardiographic parameter in
Society of Echocardiography Council for Intraoperative assessment of left atrial appendage function in patients
Echocardiography and the Society of Cardiovascular with mitral stenosis. Echocardiography. 2007;24:816-22.
Anesthesiologists Task Force for Cer tification in 76. Vijayvergiya R, Sharma R, Shetty R, Subramaniyan A, Karna
Perioperative Transesophageal Echocardiography. J Am Soc S, Chongtham D. Effect of percutaneous transvenous mitral
Echocardiogr. 1999;12:884-900. commissurotomy on left atrial appendage function: an
64. Ruiz-Arango A, Landolfo C. A novel approach to the immediate and 6-month follow-up transesophageal Doppler
diagnosis of left atrial appendage thrombus using contrast study. J Am Soc Echocardiogr. 2011;24:1260-7.
echocardiography and power Doppler imaging. Eur J 77. Yakar Tuluce S, Kayikcioglu M, Tuluce K, et al. Assessment
Echocardiogr. 2008;9:329-33. of left atrial appendage function during sinus rhythm in
patients with hypertrophic cardiomyopathy: transesophageal
65. von der Recke G, Schmidt H, Illien S, Luderitz B, Omran
echocardiography and tissue doppler study. J Am Soc
H. Use of transesophageal contrast echocardiography
for excluding left atrial appendage thrombi in patients
78. Uretsky S, Shah A, Bangalore S, et al. Assessment of left
with atrial fibrillation before cardioversion. J Am Soc
atrial appendage function with transthoracic tissue Doppler
echocardiography. Eur J Echocardiogr. 2009;10:363-71.
66. von der Recke G, Schmidt H, Illien S, et al. Transesophageal
79. Cardiogenic brain embolism. Cerebral Embolism Task
contrast echocardiography distinguishes a left atrial
Force. Arch Neurol. 1986;43:71-84.
appendage thrombus from spontaneous echo contrast.
80. Odell JA, Blackshear JL, Davies E, et al. Thoracoscopic
Echocardiography. 2002;19:343-4.
obliteration of the left atrial appendage: potential for stroke
67. Shah SJ, Bardo DM, Sugeng L, et al. Real-time three-
reduction? Ann Thorac Surg. 1996;61:565-9.
dimensional transesophageal echocardiography of the left
81. Li YH, Hwang JJ, Lin JL, Tseng YZ, Lien WP. Importance of
atrial appendage: initial experience in the clinical setting. J
left atrial appendage function as a risk factor for systemic
Am Soc Echocardiogr. 2008;21:1362-8.
thromboembolism in patients with rheumatic mitral valve
68. Jaber WA, Prior DL, Thamilarasan M, et al. Efficacy of disease. Am J Cardiol. 1996;78:844-7.
anticoagulation in resolving left atrial and left atrial appen 82. Santiago D, Warshofsky M, Li Mandri G, et al. Left atrial
dage thrombi: A transesophageal echocardiographic study. appendage function and thrombus formation in atrial
Am Heart J. 2000;140:150-6. fibrillation-flutter: a transesophageal echocardiographic
69. Black IW, Hopkins AP, Lee LC, Walsh WF. Left atrial study. J Am Coll Cardiol. 1994;24:159-64.
spontaneous echo contrast: a clinical and echocardiographic 83. Grimm RA, Stewart WJ, Arheart K, Thomas JD, Klein AL. Left
analysis. J Am Coll Cardiol. 1991;18:398-404. atrial appendage “stunning” after electrical cardioversion of
70. Kasliwal RR, Mittal S, Kanojia A, et al. A study of spontaneous atrial flutter: an attenuated response compared with atrial
echo contrast in patients with rheumatic mitral stenosis and fibrillation as the mechanism for lower susceptibility to
normal sinus rhythm: an Indian perspective. Br Heart J. thromboembolic events. J Am Coll Cardiol. 1997;29:582-9.
1995;74:296-9. 84. Hwang JJ, Li YH, Lin JM, et al. Left atrial appendage function
71. A gmon Y, Khandheria BK, Gentile F, Seward JB. determined by transesophageal echocardiography in
Echocardiographic assessment of the left atrial appendage. patients with rheumatic mitral valve disease. Cardiology.
J Am Coll Cardiol. 1999;34:1867-77. 1994;85:121-8.
72. Donal E, Yamada H, Leclercq C, Herpin D. The left atrial 85. Reddy VG, Rajasekhar D, Vanajakshamma V. Effect of
appendage, a small, blind-ended structure: a review of its percutaneous mitral balloon valvuloplasty on left atrial
echocardiographic evaluation and its clinical role. Chest. appendage function: transesophageal echo study. Indian
2005;128:1853-62. Heart J. 2012;64.
86. Mitusch R, Garbe M, Schmucker G, Schwabe K, Stierle U, velocity patterns after electrical cardioversion in patients
Sheikhzadeh A. Relation of left atrial appendage function with isolated atrial fibrillation. Am J Cardiol. 1997;79:615-
to the duration and reversibility of nonvalvular atrial 20.
fibrillation. Am J Cardiol. 1995;75:944-7. 93. Grimm RA, Leung DY, Black IW, Stewart WJ, Thomas
87. Tanabe K, Yoshitomi H, Asanuma T, Okada S, Shimada T, JD, Klein AL. Left atrial appendage “stunning” after
Morioka S. Prediction of outcome of electrical cardioversion spontaneous conversion of atrial fibrillation demonstrated
by left atrial appendage flow velocities in atrial fibrillation. by transesophageal Doppler echocardiography. Am Heart J.
Jpn Circ J. 1997;61:19-24. 1995;130:174-6.
88. Manabe K, Oki T, Tabata T, et al. Transesophageal 94. Falcone RA, Morady F, Armstrong WF. Transesophageal
echocardiographic prediction of initially successful electrical
echocardiographic evaluation of left atrial appendage
cardioversion of isolated atrial fibrillation. Effects of left
function and spontaneous contrast formation after chemical
atrial appendage function. Jpn Heart J. 1997;38:487-95.
or electrical cardioversion of atrial fibrillation. Am J Cardiol.
89. Perez Y, Duval AM, Carville C, et al. Is left atrial appendage
1996;78:435-9.
flow a predictor for outcome of cardioversion of nonvalvular
95. Omran H, Jung W, Rabahieh R, et al. Left atrial chamber
atrial fibrillation? A transthroacic and transesophageal
and appendage function after internal atrial defibrillation: a
echocardiographic study. Am Heart J. 1997;134:745-51.
prospective and serial transesophageal echocardiographic
90. Verhorst PM, Kamp O, Welling RC, Van Eenige MJ, Visser
CA. Transesophageal echocardiographic predictors for study. J Am Coll Cardiol. 1997;29:131-8.
maintenance of sinus rhythm after electrical cardioversion 96. Sparks PB, Jayaprakash S, Vohra JK, et al. Left atrial
of atrial fibrillation. Am J Cardiol. 1997;79:1355-9. “stunning” following radiofrequency catheter ablation of
91. Palinkas A, Antonielli E, Picano E, et al. Clinical value of left chronic atrial flutter. J Am Coll Cardiol. 1998;32:468-75.
atrial appendage flow velocity for predicting of cardioversion 97. Grimm RA, Stewart WJ, Maloney JD, et al. Impact of electrical
success in patients with non-valvular atrial fibrillation. Eur cardioversion for atrial fibrillation on left atrial appendage
Heart J. 2001;22:2201-8. function and spontaneous echo contrast: characterization
92. Tabata T, Oki T, Iuchi A, et al. Evaluation of left atrial by simultaneous transesophageal echocardiography. J Am
appendage function by measurement of changes in flow Coll Cardiol. 1993;22:1359-66.
SECTION
3
Diabetes
ADA Standards of Care: An Update GLP-1 Analogs: Benefits Beyond Glycemic Control
Abhishek Pandey Rajeev Chawla, Shalini Jaggi
Can Medical Care Change the Natural History of Gliptins versus Sulfonylureas: Which is Better?
T2DM: Turning Fiction into Reality? V Palaniappen
Rajesh Rajput
Metformin—the Molecule of the Decade:
Are all Gliptins the Same: How to Decide Old is Gold
and Choose? Sanjay Dash
A Decade of RCTs in Diabetes: Clinical Implications
Diabetes and Inflammation Suhas Erande
Insulin Pumps in India
Pollution and Diabetes: Is there a Link? Narendra Pal Jain, Rishu Bhanot
Brij Mohan
Newer Insulins and Art of Insulin Therapy
Musculoskeletal Manifestations Mangesh Tiwaskar
of Diabetes Mellitus
Individualization of Diabetes Care
How to Hold the HOLD?
Diabetes and Immunity
Dyslipidemia Management: Newer Avenues
Novel Therapeutic Approaches to Preserve Beta
Nirupam Prakash
Cell Function in Diabetes Mellitus
Metformin versus Insulin in Treatment of Vijay Negalur
Gestational Diabetes Mellitus
Management of Diabetes in Resource
Crunch Countries
Early Initiation of Insulin Therapy G Prakash
in Diabetes Mellitus
Exercise Prescription for Lifestyle Diseases:
A Cornerstone
Diabetic Complications in Indian Scenario: Anil Kumar Virmani
An Update
Nonhigh–Density Lipoprotein Cholesterol:
Primary Target for Lipid Lowering
SN Narasingan
CHAPTER
29
ADA Standards of Care: An Update
Abhishek Pandey
Diabetes is a chronic illness requiring continuous medical Level of Description

care with multifactorial risk-reduction strategies that evidence
go beyond glycemic control. Patient self-management Compelling nonexperimental evidence, i.e. “all or
education and support are critical in preventing both none” rule developed by the Center for Evidence Based
acute and long-term complications. The American Medicine at the University of Oxford
Supportive evidence from well-conducted randomized
Diabetes Association’s (ADA’s) “Standards of Medical
controlled trials that are adequately powered, including
Care in Diabetes,” referred to as the “Standards of Care”. zz Evidence from a well-conducted trial at one or more
It is intended to provide clinicians, patients, and other institutions

interested individuals with the components of diabetes zz Evidence from a meta analysis that incorporated
care, general treatment goals, and tools to evaluate the quality ratings in the analysis
quality of care. B Supportive evidence from well-conducted cohort
studies
SECTION CHANGES zz Evidence from a well-conducted prospective cohort
study or registry
Section 1: Promoting Health and zz Evidence from a well-conducted meta-analysis of
Reducing Disparities in Populations cohort studies

Supportive evidence from a well-conducted case
This section was renamed and now focuses on improving
control study
outcomes and reducing disparities in populations with
C Supportive evidence from poorly controlled or
diabetes. Recommendations were added to assess
uncontrolled studies
patients’ social context as well as refer to local community zz Evidence from randomized clinical trials with one or
resources and provide self-management support. more major or three or more minor methodological
flaws that could invalidate the results
Level of Description zz Evidence from observational studies with high
evidence
potential for bias (such as case series with
A Clear evidence from well-conducted, generalizable comparison with historical controls)
randomized controlled trials that are adequately zz Evidence from case series or case reports
powered, including
Conflicting evidence with the weight of evidence
zz Evidence from a well-conducted multicenter trial
zz Evidence from a meta-analysis that incorporated

supporting the recommendation
quality ratings in the analysis E Expert consensus or clinical experience
174 SECTION 3: Diabetes
Section 2: Classification and Diagnosis Section 3: Comprehensive Medical

of Diabetes Evaluation and Assessment of
The section was updated to include a new consensus Comorbidities
on the staging of type 1 diabetes and a discussion of This new section, including components of the 2016
a proposed unifying diabetes classification scheme section “Foundations of Care and Comprehensive
that focuses on b-cell dysfunction and disease stage as Medical Evaluation,” highlights the importance of
indicated by glucose status. assessing co-morbidities in the context of a patient-
Language was added to clarify screening and testing centered comprehensive medical evaluation.
for diabetes. Screening approaches were described, and A new discussion of the goals of provider-patient
was included to provide an example of a validated tool to communication is included. The Standards of Care
screen for prediabetes and previously undiagnosed type 2 now recommends the assessment of sleep pattern
diabetes. Due to recent data, delivering a baby weighing and duration as part of the comprehensive medical
9 lb or more is no longer listed as an independent risk evaluation based on emerging evidence suggesting
factor for the development of prediabetes and type 2 a relationship between sleep quality and glycemic
diabetes. A section was added that discusses recent control. An expanded list of diabetes co-morbidities now
evidence on screening for diabetes in dental practices. includes autoimmune diseases, HIV, anxiety disorders,
The recommendation to test women with gestational depression, disordered eating behavior, and serious
diabetes mellitus for persistent diabetes was changed mental illness.
from 6–12 weeks’ postpartum to 4–12 weeks’ postpartum
to allow the test to be scheduled just before the standard Section 4: Lifestyle Management
6-week postpartum obstetrical checkup so that the This section, previously entitled “Foundations of Care
results can be discussed with the patient at that time and Comprehensive Medical Evaluation,” was refocused
of the visit or to allow the test to be rescheduled at on lifestyle management. The recommendation for
the visit if the patient did not get the test. Additional nutrition therapy in people prescribed flexible insulin
detail was added to the section on monogenic diabetes therapy was updated to include fat and protein counting
syndromes describing the most common forms of in addition to carbohydrate counting for some patients
monogenic diabetes. A new section was added on post- to reflect evidence that these dietary factors influence
transplantation diabetes mellitus. insulin dosing and blood glucose levels. Based on new
evidence of glycemic benefits, the Standards of Care now
STAGING OF TYPE 1 DIABETES recommends that prolonged sitting be interrupted every
Stage 1 Stage 2 Stage 3 30 min with short bouts of physical activity.
Stage zz Autoimmunity zz Autoimmunity zz New-onset A recommendation was added to highlight the
zz Normoglycemia zz Dysglycemia hyperglycemia
zz Presymptomatic zz Presymptomatic zz Symptomatic importance of balance and flexibility training in older
Diagnostic zz Multiple zz Multiple zz Clinical adults. A new section and table provide information on
criteria autoantibodies autoantibodies symptoms situations that might warrant referral to a mental health
zz No IGT of IFG zz Dysglycemia: IFG zz Diabetes by
and/or IGT standard provider.

zz FPG 100–125 mg/dL criteria
(5.6–6.9 mmol/L)
zz 2-h PG 140–199 mg/ Section 5: Prevention or Delay of
dL (7.8–11.0 mmol/L)
zz A1C 5.7–6.4% (39–47 Type 2 Diabetes
mmol/mol) or ≥10% To help providers identify those patients who would
increase in A1C
benefit from prevention efforts, new text was added
CHAPTER 29: ADA Standards of Care: An Update 175
emphasizing the importance of screening for prediabetes needed. A section was added describing the role of newly
using an assessment tool or informal assessment of available biosimilar insulins in diabetes care.
risk factors and performing a diagnostic test when Based on the results of two large clinical trials, a
appropriate. To reflect new evidence showing an recommendation was added to consider empagliflozin
association between B12 deficiency and long-term or liraglutide in patients with established cardiovascular
metformin use, a recommendation was added to disease to reduce the risk of mortality. The algorithm for
consider periodic measurement of B12 levels and the use of combination injectable therapy in patients
supplementation as needed. with type 2 diabetes has been changed to reflect studies
demonstrating the noninferiority of basal insulin
Section 6: Glycemic Targets plus glucagon like peptide 1 receptor agonist versus
Based on recommendations from the International basal insulin plus rapid-acting insulin versus two
Hypoglycemia Study Group, serious, clinically significant daily injections of premixed insulin, as well as studies
hypoglycemia is now defined as glucose, 54 mg/dL (3.0 demonstrating the noninferiority of multiple dose
mmol/L), while the glucose alert value is defined as 70 premixed insulin regimens versus basal-bolus therapy.
mg/dL (3.9 mmol/L).
PHARMACOLOGIC THERAPY FOR
Section 7: Obesity Management for the DIABETES
Treatment of Type 2 Diabetes
To be consistent with other ADA position statements and
Recommendations
to reinforce the role of surgery in the treatment of type 2 Most people with type 1 diabetes should be treated
diabetes, bariatric surgery is now referred to as metabolic with multiple daily injections of prandial inslulin and
surgery. basal insulin or continuous subcutaneous insulin
To reflect the results of an international workgroup infusion (A).
re p o r t e n d o r s e d by t h e A D A a n d ma ny o t h e r Most individuals with type 1 diabetes should use
organizations, recommendations regarding metabolic rapid-activing insulin analogs to reduce hypoglycemia
surgery have been substantially changed, including risk (A).
those related to BMI thresholds for surgical candidacy, Consider educating individuals with type 1 diabetes
mental health assessment, and appropriate surgical on matching prandial insulin doses to carbohydrate
venues. intake, premeal blood glucose levels, and anticipated
physical activity (E).
Section 8: Pharmacologic Approaches to Individuals with type 1 diabetes who have been
Glycemic Treatment successfully using continuous subcutanesou insulin
The title of this section was changed from “Approaches infusion should have continued access to this
to Glycemic Treatment” to “Pharmacologic Approaches therrapy after they turn 65 years of age (E).
to Glycemic Treatment” to reinforce that the section Metformin, if not contraindicated and if tolerated,
focuses on pharmacologic therapy alone. Lifestyle is the preferred initial pharmacolic agent fot the
management and obesity management are discussed in treatment of type 2 diabetes (A).
separate chapters. Long-term use of metformin may be associated with
To reflect new evidence showing an association biochemical vitamin B12 deficiency, and periodic
between B12 deficiency and long-term metformin use, measurement of vitamin B12 levels should be
a recommendation was added to consider periodic considered in metformin-treated patients, especially
measureme of B12 levels and supplementation as in those with anemia or peripheral neuropathy (B).
Consider initiating insulin therapy (with or without can be achieved without undue treatment burden
additional agents) in patients with newly diagnosed (C).
type 2 diabetes who are symptomatic ad/or have A1C In pregnant patients with diabetes and chronic
≥10% (86 mmol/mol) and/or blood glucose levels hypertension, blood pressure targets of 120–160/80–
≥300 mg/dL (16.7 mmol/L) (E). 105 mm Hg are suggested in the interest of optimizing
If noninsulin monotherapy at maximum tolerated long-term maternal health and minimizing impaird
dose does not achieve or maintain the A1C target fetal growth (E).
after 3 months, add a second oral agent, a glucagon-
Treatment
like peptide 1 receptor agonist, or basal insulin (A).
Patients with confirmed office-based blood pressure
A patient-centered approach should be used to guide
>140/90 mm Hg should, in addition to lifestyle
the choice of pharmacologic agents. Consideration
therapy, have prompt initiation and timely titration
include efficacy, hypoglycemia risk, impact on
of pharmacologic therapy to achieve blood pressure
weight, potential side effects, cost, and patient
goals (A).
preferences (E).
Patients with confirmed office-based blood pressure
For patients with type 2 diabetes who are not
>160/100 mm Hg should in addition to lifestyle
achieving glycemic goals, insulin therapy should not
therapy, have prompt initiation and timely titration
be delayed (B).
of two drugs or a single pill combination of drugs
In patients with long-standing suboptimally
demonstrated to reduce cardiovascular events in
controlled type 2 diabetes and established athero
patients with diabetes (A).
sclerotic cardiovascular disease, empagliflozin
To better align with existing data, the hypertension
or liraglutide should be considered as they have
treatment recommendation for diabetes now suggests
been shown to reduce cardiovascular and all-cause
that, for patients without albuminuria, any of the four
mortality when added to standard care. Ongoing
classes of blood pressure medications (ACE inhibitors,
studies are investigating the cardiovascular benefits
angiotensin receptor blockers, thiazide-like diuretics,
of other agents in these drug classes (B).
or dihydropyridine calcium channel blockers) that have
Section 9: Cardiovascular Disease and shown beneficial cardiovascular outcomes may be used.
To optimize maternal health without risking fetal
Risk Management
harm, the recommendation for the treatment of pregnant
Recommendations patients with diabetes and chronic hypertension was
Screening and diagnosis changed to suggest a blood pressure target of 120–
Blood pressure should be measured at every routine
160/80–105 mm Hg. A section was added describing
visit. Patiens found to have elevated blood pressure the cardiovascular outcome trials that demonstrated
should have blood pressure confrmed on a separate benefits of empagliflozin and liraglutide in certain high-
day (B). risk patients with diabetes.
Goals
Most patients with diabetes and hypertension Section 10: Microvascular Complications
should be treated to a systolic blood pressure goal of and Foot Care
<140 mm Hg ana diastolic blood pressure goals of <90 A recommendation was added to highlight the
mm Hg. importance of provider communication regarding the
Lower systolic and diastolic blood pressure targets, increased risk of retinopathy in women with pre-existing
such as 130/80 mm Hg may be appropriate for type 1 or type 2 diabetes who are planning pregnancy
indivuals at high risk of cardiovascular disease, if they or who are pregnant. The section now includes specific
recommendations for the treatment of neuropathic blocker is reasonable to assess the response to
pain. A new recommendation highlights the benefits of treatment and progression of diabetic kidney
specialized therapeutic footwear for patients at high risk diseases (E).
for foot problems. An ACE inhibitor or an angiotension receptor blocker
is not recommended for the primary prevention of
Recommendations diabetic kidney disease in patients with diabetes
Screening who have normal blood pressure, normal urinary
At least once a year, assess urinary albumin (e.g. spot albumin-to-creatinine ratio (<30 mg/g creatinine),
urinary albumin-to-creatinine ratio) and estimated and normal estimated glomerular filtration rate. (B)
glomerular filtration rate in patients with type 1 diabetes When estimated glomerular filtration rate is <60
with duration of ≥5 years, in all patiens with type 2 mL/min/1.73 m 2, evaluate and manage potential
diabetes, and in all patients with comorbid hypertension complications of chronic kidney disease (E).
(B). Patients should be referred for evaluation for renal
replacement treatment if they have an estimated
Treatment
Optimize glucose control to reduce the risk of slow
glomerular filtration rate <30 mL/min/1.73 m2 (A).
Promptly refer to a physician experienced in the care
the progression of diabetic kidney disease (A).
Optimize blood pressure control to reduce the risk of
of kidney disease for uncertainty about the etiology
of kidney disease, difficult management issues, and
slow the progression of diabetic kidney disease (A).
For people with nondialysis-dependent diabetic
rapidly progressing kidney disease (B).
kidney disease, dietary protein intake should be
Lipid Recommendations
approximately 0.8 g/kg body weight per day (the
recommended daily allowance). For patients on Age Risk factors Statin intensity*
dialysis, higher levels of dietary protein intake should <40 years None None
be considered (B). ASCVD risk factor(s)** Moderate or high
ASCVD High
I n n o n p re g a n t p a t i e n t s w i t h d i a b e t e s a n d
40–75 years None Moderate
hypertension, either an ACE inhibitor or an ASCVD risk factors High
angiotensin receptor blocker is recommended for ASCVD High
those with modestly elevated urinary albumin-to- ACS and LDL cholesterol ≥50 Moderate plus
mg/dL ezetimibe
creatinine ratio (30–299 mg/g creatinine) (B) and
(1.3 mmol/L) or in patients with
is strongly recommended for those with urinary a history of ASCVD who cannot
alubumin-to-creatinine ratio ≥300 mg/g creatinine tolerate high-dose statins
and/or estimated glomerular filtration rate <60 mL/ >75 years None Moderate
min/1.73 m2 (A). ASCVD risk factors Moderate or high
Periodically monitor serum creatinine and potassium
ASCVD High
ACS and LDL cholesterol ≥ Moderate plus
levels for the development of increased creatinine 50 mg/dL (1.3 mmol/L) or ezetimibe
or changes in potassium when ACE inhibitors, in patients with a history of
angiotensin receptor blockers, or diuretics are used ASCVD who cannot tolerate
high-dose statins
(E).
Continued monitrong of urinary albumin-to-
*In addition to lifestyle therapy.
**ASCVD risk factors include LDL cholesterol ≥100 mg/dL) (2.6
creatinine ratio in patients with albuminuria treated mmol/L), high blood pressure, smoking, chronic kidney disease,
with an ACE inhibitor or an angiotensin receptor albuminuria, and family history of premature ASCVD
High-intensity statin therapy Moderate-intesity statin therapy atherosclerotic cardiovascular disease risk factors,
(lowers LDL cholesterol by ≥50%) (lowers LDL cholesterol by 30% clinical judgment is required (E).
– <50%)
Atorvastatin 40–80 mg Atorvastatin 10–20 mg Coronary Artery Disease
Rosuvastatin 20–80 mg Rosuvastatin 5–10 mg
Recommendations
Simvastatin 20–40 mg
Screening
Pravastatin 40–80 mg
In asymptomatic patients, routine screening for
Lovastatin 40 mg
coronary artery disease is not recommended as it
Fluvastatin XL 80 mg
does not improve outcomes as long as atherosclerotic
Pitavastatin 2–4 mg
cardiovascular disease risk factors are treated (A).
*Once-daily dosing, XL, extended release. Consider investigations for coronary artery disease
in the presence of any of the following: atypical

Antiplatelet Agents cardiac symptoms (e.g. unexplained dyspnea, chest
Recommendations discomfort); signs or symptoms of associated vascular
Use aspirin therapy (75–162 mg/day) as a secondary disease including carotid bruits, transient ischemic
prevention strategy in those with diabetes and a attack, stroke, claudication, or peripheral arterial
history of atherosclerotic cardiovascular disease (A). disease; or electrocardiogram abnormalities (e.g. Q
For patients with atherosclerotic cardiovascular waves) (E).
disease and documented aspirin allergy, clopidogrel Treatment
(75 mg/day) should be used (B). In patients with known atherosclerotic cardiovascular
Dual antiplatelet therapy is reasonable for up to a disease, use aspirin and statin therapy (if not
year after an acute coronary syndrome and may have contraindicated) (A) and consider ACE inhibitor
benefits beyond this period (B). therapy (C) to reduce the risk of cardiovascular
Consider aspirin therapy (75–162 mg/day) as a events.
primary prevention strategy in those with type 1 or In patients with prior myocardial infarction,
type 2 diabetes who are at increased cardiovascular b-blockers should be continued for at least 2 years
risk. This includes most men and women with after the event (B).
diabetes aged ≥50 years who have at least one In patients with symptomatic heart failure,
additional major risk factor (family history of thiazolidinedione treatment should not be used (A).
premature atherosclerotic cardiovascular disease, In patients with type 2 diabetes with stable congestive
hypertension, smoking, or albuminuria) and are not heart failure, metformin may be used if estimated
at increased risk of bleeding (C). glomerular filtration remains >30 mL/min but should
Aspirin should not be recommended for be avoided in unstable or hospitalized patients with
atherosclerotic cardiovascular disease prevention congestive heart failure (B).
for adults with diabetes at low atherosclerotic
cardiovascular disease risk, such as in men or women Section 12: Children and Adolescents
with diabetes aged <50 years with no other major Additional recommendations highlight the importance
atherosclerotic cardiovascular disease risk factors, of assessment and referral for psychosocial issues in
as the potential adverse effects from bleeding likely youth. Due to the risk of malformations associated
offset the potential benefits (C). with unplanned pregnancies and poor metabolic
When considering aspirin therapy in patients control, a new recommendation was added encouraging
with diabetes <50 years of age with multiple other preconception counseling starting at puberty for all
girls of childbearing potential. To address diagnostic Metformin and glyburide may be used, but both
challenges associated with the current obesity epidemic, cross the placenta to the fetus, with metformin likely
a discussion was added about distinguishing between crossing to a greater extent than glyburide. All oral
type 1 and type 2 diabetes in youth. agents lack long-term saftey data (A).
A section was added describing recent nonrando Metformin, when used to treat polycystic ovary
mized studies of metabolic surgery for the treatment of syndrome and induce ovulation, need not be
obese adolescents with type 2 diabetes. continued once pregnancy has been confirmed (A).
General principles for management of diabetes in
Section 13: Management of Diabetes in pregnancy
Pregnancy Potentially teratogenic medications (ACE inhibitors,
Recommendations statins, etc.) should be avoided in sexually active

Pre-existing diabetes women of childbearing age who are not using reliable
Starting at puberty, preconception counseling should contraception (B).
Fasting and postrandial self-monitoring of blood
be incorporated into routine diabetes care for all girls
of childbearing potential (A). glucose are recommended in both gestational
Family planning should be discussed and effetive diabetes mellitus and pre-existing diabtes in
contraception should be prescribed and used until pregnancy to achieve glycemic control. Some women
a woman is prepared and ready to become pregnant with pre-exising diabetes should also test blood
(A). glucose preprandially (B).
Due to increased red blood cell turnover, A1C is lower
Preconception counseling should address the
importance of glycemic control as close to normal as in normal pregnancy than in normal nonpregnant
is safely possible, ideally A1X <6.5% (48 mmol/mol), women. The A1C target in pregnancy is 6–6.5%
to reduce the risk of congenital anomalies (B). (42–48 mmol/mol); <6% (42 mmol/mol) may be
Women with preexisting type 1 or type 2 diabetes who
optimal if this can be achieved without significant
are planning pregnancy or who have become pregnant hypoglycemia, but the target may be relaxed to
<7% (53 mmol/mol) if necessary to prevent hypo-
should be counseled on the risk of development
glycemia (B).
and/or progression of diabetic retinopahty. Dilated
In pregnant patients with diabetes and chronic
eye examinations should occor before pregnancy
hypertension, blood pressure targets of 120–160/80–
or in the first trimester, and then patients should be
105 mm Hg are suggested in the interest of optimizing
monitored every trimester and for 1 year postpartum
long-term maternal health and minimizing impaired
as indicated by degree of retinopathy and as
fetal growth (E).
recommended by the eye care provider (B).
Insulin was emphasized as the treatment of choice in
Gestational diabetes mellitus pregnancy based on concerns about the concentration of
Lifestyle change is an essential component of metformin on the fetal side of the placenta and glyburide
management of gestational diabetes mellitus and levels in cord blood.
may suffice for the treatment for many women. Based on available data, preprandial self-monitoring
Medications should be added if needed to achieve of blood glucose was de-emphasized in the management
glycemic targets (A). of diabetes in pregnancy. In the interest of simplicity,
Insulin is the preferred medication for treating fasting and postprandial targets for pregnant women
hyperglycemia in gestational diabetes mellitus, as it with gestational diabetes mellitus and pre-existing
does not cross the placenta to a measurable extent. diabetes were unified.
Section 14: Diabetes Care in the Hospital Basal insulin or a basal plus bolus correction insulin
This section was reorganized for clarity. A treatment regimen is the preferred treatment for noncritically
recommendation was updated to clarify that either basal ill patients with poor oral intake or those who are
insulin or basal plus bolus correctional insulin may be taking nothing by mouth. An insulin regimen with
used in the treatment of non-critically ill patients with basal, nutritional, and corrretion components is the
diabetes in a hospital setting, but not sliding scale alone. preferred treatment for noncritically ill hospitalized
The recommendations for insulin dosing for enteral/ patients with good nutritional intake (A).
parenteral feedings were expanded to provide greater Sole use of sliding scale insulin the inpatient hospital
detail on insulin type, timing, dosage, correctional, and setting is strongly discouraged (A).
nutritional considerations. A hypoglycemia management protocl should be
adopted and implemented by each hospital. A plan
Recommendations for preventing and treating hypoglycemia should be
Perform an A1C for all patients with diabetes or establised for each patient. Episodes of hypoglycemia
hyperglycemia admitted to the hospital if not in the hospital should be documented in the medical
performed in the prior 3 months (B). record and tracked (E).
Insulin therapy should be initiated for treatment The treatment regimen should be reviewed and
of persistent hyperglycemia starting at a threshold changed as necessary to prevent further hypoglycemia
≥180 mg/dL (10.0 mmol/L). Once insulin therapy is when a blood glucose value is <70 mg/dL (3.9
started, a target glucose range of 140–180 mg/dL (7.8– mmol/L) (C).
10.0 mmol/L) is recommended for the majority of There should be a structured discharge plan tailored
critically ill patients (A) and noncritically ill patients to the individual patient with diabetes (B).
(C).
More stringent goals, such as <140 mg/dL (<7.8 ACKNOWLEDGMENT
mmol/L), may be appropriate for selected patients, The author would like to acknowledge contributors and
as long as this can be achieved without significant editorial team of Diabetes Care, January 2017, Volume
hypoglcemia (C). 40, Supplement 1.
Intravenous insulin infusions should be administered
using validated written or computerized protocols BIBLIOGRAPHY
that allow for predefined adjustments in the insulin 1. http://care.diabetesjournals.org/content/diacare/
suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_
infusion rate based on glycemic fluctuations and
final.pdf
insulin dose (E).
CHAPTER
30
Can Medical Care Change the Natural History
of T2DM: Turning Fiction into Reality?
Rajesh Rajput
BACKGROUND control, and abdominal obesity, are associated with the

The great Canadian physician Sir William Osler had development of dysglycemia. A national reflection on
once quoted, “When schemes are laid in advance, it is the epidemiology of dysglycemia is available from the
surprising how often the circumstances fit in with them.” ICMR-INDIAB study, which involved community-based
The scheme of early disease-modification has been evidence from over 57 thousand Indian adults, across
progressively recognized to benefit various chronic 15 states of our country.1 This study suggests that 1 in
diseases, including dysglycemia, cardiovascular disease, every 14 Indian adults, suffers from diabetes. An equally
chronic kidney disease, or arthritis. Proactive approaches alarming observation has been that 1 in every 10 Indian
to disease management, including primary prevention adults, suffers from prediabetes (as defined by the WHO).
of cardiovascular (CV) disease, or early disease- However, the ADA criteria qualify nearly 1 in every 4
modification in rheumatoid arthritis, or the legacy effect Indian adults, as a patient of prediabetes. In our own
of early multifactorial intervention in type-2 diabetes community-based study carried out in Rohtak, nearly
(T2D), have all impressed upon sustainable clinical 1 in every 5 adults were found to harbor prediabetes.2
benefits in the long-term. However, the acceptance and With such high prevalence, prediabetes assumes a
implementation of such proactive approaches has been common household-level problem in India. Prediabetes
far from satisfactory. Inertia in applying such promising increases the risk of development of diabetes by 5-fold.
evidence, to clinical practice, is partly explained by the Greater than half of the Indian adults with prediabetes,
‘prevention paradox’. Early interventions can translate progress to frank diabetes over a decade. Based on the
into promising benefits at the population-level; however, studies from India, an even higher rate of progression
at the individual level, the benefit may not be available of prediabetes, to overt diabetes, has been observed.3
for each patient. Hence, it is perceived that the clinical Thus, if these numbers are to be believed, India is
efforts and healthcare resources should be focused on likely to witness a steep rise in the number of patients
the patients with overt diseases. The jury is out on this with frank diabetes, as well as cardiovascular disease.
debate. Early intervention still remains an excellent Swaminathan et al observed a remarkable finding in
opportunity to modify the course of disease in long-term. their Nallampatti Noncommunicable Disease Study.4
This study was carried out in a farming village in Tamil
Prediabetes: The Indian Epidemiology Nadu. It demonstrated an astoundingly high prevalence
In Indian adults, the predisposing factors like age, of prediabetes, extending to 42% of the surveyed adult
positive family-history of diabetes, poor glycemic residents in this village. Also, nearly half of the surveyed
adult population demonstrated high CV risk, owing to contribute to the development of heart-failure. 5 A
uncontrolled risk-factors. This observation provokes a few recently presented update from the CARDIA study
noteworthy aspects, and prompts realization of the tasks demonstrated that prediabetes of a longer duration is
at hand. Firstly, it compels an introspection regarding our associated with subclinical atherosclerosis, as well as
national framework for public-health research, which cardiac dysfunction. For every 10-years of prediabetes,
has been conspicuous by its inadequacies. Secondly, the risk for coronary artery calcification increased by
regarding the CV risk prevailing in the healthy Indian 21%, suggestive of increased atherosclerosis. Longer
adult population, this finding surfaces the big bottom of duration of prediabetes also demonstrated a significant
the iceberg. Prediabetes and overt diabetes are different deterioration in the functioning of the heart.6 While the
stages of the same pathological continuum. If we believe pathological development of CVD is well recognized in
that diabetes has already achieved a pandemic status in prediabetes, the incidence of CV events is less adequately
India, it is high time to revisit our notion, on the extent studied. A study done in older adults remarkably
to which this pandemic will grow. Being a household- suggested a liner relationship between the HbA1c levels,
level disease, the translation of prediabetes to overt and the risk of CV events.7 This means that the CV events
diabetes can affect a considerable fraction of our Indian increase proportionately to the HbA1c levels. A meta-
households in the ensuing years, resulting in reduced analysis of 53 prospective cohort studies, suggested
productivity, increased morbidity, early mortality, and that prediabetes was associated with increased risk of
worsened quality of life. CV disease and all-cause mortality. 8 The analysis of
PARADIGM-HF trial involving patients with heart-failure
Is There Increased CV Risk in Prediabetes and reduced ejection fraction, confirmed an increased
and Early Diabetes? incidence of heart-failure related events (including CV
While diabetes is well-recognized as a high CV risk death and hospitalizations for heart-failure), in patients
condition, the significance of increased CV risk in with prediabetes.9
prediabetes cannot be understated (Fig. 1). In fact, the All these findings clearly reflect an increased risk of
clinical phenotype of prediabetes is similar to that of CV disease, events, and overall mortality in patients with
overt diabetes; the CV risk factors manifest similarly prediabetes. Early intervention in prediabetes may help
in the patients of diabetes as well as prediabetes. The in preventing the progression of CV disease, apart from
vascular pathological mechanisms of dysglycemia the conversion to overt diabetes.
facilitate early development of atherosclerosis,
as well as heart-failure. Prediabetes also prompts When should be Intervene: The Golden
certain changes in the myocardial metabolism, which Years
Insulin sensitivity is known to reduce more than a decade
before the onset of diabetes. A steeper decline is observed
over 5 years, before the diagnosis of diabetes is made.
Insulin secretion is elevated, with a marked increase a
few years prior to diagnosis, followed by a steep decrease
until diagnosis.10 Weight loss is the primary approach to
reduce insulin resistance in prediabetes. However, it is
not possible to preserve the declining beta-cell function
only through weight management. It is now realized that
timing an intervention at the prediabetes stage, may
Fig. 1: Schematic representation of CVD risk also significantly alter the course of CV disease over the
modification in prediabetes years.15
CHAPTER 30: Can Medical Care Change the Natural History of T2DM: Turning Fiction into Reality? 183
Screening for Prediabetes: A Shot in the drugs like DPP-IV inhibitors, GLP-1 receptor agonists,
Dark? alpha glucosidase inhibitors, pioglitazone and SGLT-2
inhibitors are preferred for IGT. For patients having both
The importance of early intervention in prediabetes, for
IFG and IGT one can choose drugs with complimentary
preventing the development of diabetes as well as CV
mechanism of action with focus on weight neutrality
disease, is well recognized. However, the moot aspect is
or loss and risk of hypoglycemia. Because of risk of
about optimizing our efforts, in view of the prevention
hypoglycemia sulfonylurea, short acting insulin and
paradox. It is consistently demonstrated that the primary
premix insulins are not preferred options in these class
prevention is the most cost-effective method to reduce
of patients. Almost all classes of antidiabetic medicines
the incidence of diabetes and its complications. The
have been assessed in prediabetes, although none
guidelines recommend screening for adults with risk-
is specifically approved for this indication. A review
factors for prediabetes, including other major CV risk-
of trials suggested that in patients with prediabetes,
factors, family history of CVD or diabetes, polycystic
lifestyle interventions, as well as the use of metformin,
ovary syndrome, acanthosis nigricans, nonalcoholic fatty
significantly reduce the progression to diabetes by
liver disease, history of gestational diabetes, or other
around 1/3 rd, and 1/4 th respectively. 12 In this regard,
iatrogenic causes. ‘Opportunistic screening’ may be a
metformin may have a supplementary role to lifestyle
feasible approach for early identification of prediabetes.
modification in prediabetes. In a small study, glimepiride
If possible, all adults over 30 years of age should be
therapy was found to effectively reduce the progression of
screened for prediabetes, regardless of any other risk-
prediabetes to overt diabetes, in nonobese patients with
factor.
prediabetes.13 An early glycemic control in prediabetes,
maintained over a few years, may have a legacy effect
Therapy of Prediabetes and Early in delayed progression to diabetes, even years after the
Diabetes: Role of Antidiabetic Medicines therapy is stopped. This was observed in the DREAM
Lifestyle modification holds the pivotal role in the study of rosiglitazone.14 Thus it is pertinent to ensure
management of prediabetes. A good metabolic control is good glycemia control in patients with prediabetes, for
essential to delay the progression of prediabetes to overt improved outcomes in the long-term. The ORIGIN trial
diabetes. In overweight or obese patients of prediabetes, has shown that basal insulin analogue glargine can be
studies have demonstrated effectiveness of weight loss used effectively and safely in patients of prediabetes and
interventions, in preventing the development of overt early diabetes. The treatment with glargine decreased the
diabetes by over 50%. Studies have also demonstrated risk of progression from prediabetes to diabetes by about
benefits of lifestyle interventions that do not target 30% while in combined early diabetes and prediabetes
weight loss, in nonobese patients with insulin resistance. group the amount of insulin needed to maintain the
Simple interventions like patient-reminders on lifestyle target over five years was increased by a small amount
modification through regular text messages, have i.e. from 0.31 units/kg to 0.40 units/kg. Although trial was
demonstrated reduction in the development of diabetes not designed primarily for this purpose but these indirect
by up to a third.11 inferences suggest that early intervention is useful and
Presently, the choice of pharmacotherapy for basal insulin can be used if needed for this purpose.15
management of prediabetes and early diabetes is not Newer medicines may offer metabolic benefits
clearly established. One way to choose drug therapy beyond glycemia control, in patients with prediabetes
is to decide whether patient has IFG, IGT or both IFG and early diabetes with additional positive effects on risk
and IGT. Although majority of drugs have some effect of weight gain and risk of hypoglycemia. However, the
on both fasting and postprandial glucose excursion, evidence is limited on these aspects. VERIFY trial (Study
metformin and basal insulin are preferred for IFG while to compare combination regimen with vildagliptin
and metformin versus metformin in treatment-naïve CONCLUSION

T2DM) is presently being carried out to test clinical Good health is the right for all and prediabetes and early
applicability of this hypothesis in real world. 16 The diabetes is certainly a signal to ensure course-correction
GLP1-RA liraglutide has also demonstrated improved through all possible means. We must always be mindful
gluco-metabolic outcomes, including glycemia control of the broader implications of this understated problem.
and weight loss, maintained over 3-years of therapy, in The understatement of the problem itself arises from
patients with prediabetes.17 clinical inertia, due to the underestimated benefit in
In patients with impaired fasting glucose, the managing every individual patient. Opportunities to
use of SGLT2-i agents have has also demonstrated overcome this inertia should be proactively capitalized
improvement in β-cell functioning, apart from glycemia on, to ensure changing the face of diabetes at-large.
control. SGLT2-i agents may have a particular relevance The CV phenotype of prediabetes and early diabetes
in overweight patients, owing to their supportive is similar to that of long standing poorly controlled
effect on weight-loss. 18 Further, the hemodynamic diabetes. While we recognize the ‘legacy effect’ of early
effects of these agents might also benefit vascular multifactorial intervention in diabetes, in sustainably
dysfunction, although there is no evidence to support improving the CV outcomes, effectively controlling the
this aspect. Apart from the known risks associated CV risk in prediabetes and early diabetes also translates
with the SGLT2-i agents, the urinary glucose excretion into a metabolic legacy in the long run and with recent
and resultant efficacy of these agents may also be advances in pharmacotherapy for diabetes it seems
slightly lower in prediabetes, as compared to overt possible now to convert this fiction into reality.
diabetes. There is also evidence to support improved
cardiovascular outcomes, by managing prediabetes REFERENCES
well. The IRIS trial of pioglitazone use in prediabetes, 1. Anjana RM, Deepa M, Pradeepa R, Mahanta J, Narain
demonstrated significant improvement in survival by K, et al. Prevalence of diabetes and prediabetes in 15
24% with pioglitazone therapy, as compared to placebo. states of India: results from the ICMR–INDIAB population-
A significant reduction in myocardial infarction and based cross-sectional study. Lancet Diabetes Endocrinol.
2017;5(8):585-96.
stroke events was observed with pioglitazone therapy,
2. Rajput R, Saini O, Rajput M, Shankar V. Comparison of
apart from a reduced progression to diabetes. However, HbA1c and FPG as a screening tool for diagnosis of pre-
the safety concerns of pioglitazone, including weight diabetes and diabetes in Indian population. Int J Diabetes
gain, fractures and fluid retention, were also evident in Dev Ctries. 2015;35(4):559-64.
prediabetes.19 The STOP-NIDDM trial of acarbose also 3. Ramachandran A, Snehalatha C, Yamuna A, Mary S, Ping
demonstrated significant reduction in CV events by Z. Cost-effectiveness of the interventions in the primary
prevention of diabetes among Asian Indians: within-trial
49%, apart from reduction in progression to diabetes, to
results of the Indian Diabetes Prevention Programme
hypertension, and also in regression to normal glucose (IDPP). Diabetes Care. 2007;30(10):2548-52.
tolerance.20,21 4. S w a m i n a t h a n K , G a n e s h Ve e r a s e k a r, N a l l a G .
Thus, weight-management and glycemia control Palaniswami. Noncommunicable disease in rural India:
have demonstrated effective outcomes in prediabetes, Are we seriously underestimating the risk? The Nallampatti
in reducing the conversion to diabetes, as well as CV noncommunicable disease study. Indian J Endocrinol
Metab. 2017;21(1):90-5.
disease. Further, holistic CV risk management is essential
5. DeFronzo RA, Abdul-Ghani M. Assessment and treatment
to improve the outcomes. Management of lipids and of cardiovascular risk in prediabetes: impaired glucose
blood pressure is equally important, for overall CV risk- tolerance and impaired fasting glucose. Am J Cardiol
reduction in patients with prediabetes. 2011;108[suppl]: 3B-24B.
CHAPTER 30: Can Medical Care Change the Natural History of T2DM: Turning Fiction into Reality? 185
6. Schöttker B, Rathmann W, Herder C, Thorand B, Wilsgaard 14. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et
T, et al. HbA1c levels in non-diabetic older adults – No al. Effect of rosiglitazone on the frequency of diabetes
J-shaped associations with primary cardiovascular events, in patients with impaired glucose tolerance or impaired
cardiovascular and all-cause mortality after adjustment for fasting glucose: a randomised controlled trial. Lancet.
confounders in a meta-analysis of individual participant 2006;368(9541):1096-105.
data from six cohort studies. BMC Medicine. 2016;14:26 15. Gerstein HC, Bosch J, Dagenais GR, et al. ORIGIN trial
DOI 10.1186/s12916-016-0570-1. investigators. Basal insulin and cardiovascular and other
7. Huang Y, Cai X, Mai W, Li M4, Hu Y. Association between outcomes in dysglycemia. N Engl J Med. 2012;367:319-28.
prediabetes and risk of cardiovascular disease and all 16. Novartis Pharmaceuticals. VERIFY: A study to compare
cause mortality: systematic review and meta-analysis. BMJ. combination regimen with vildagliptin and metformin versus
2016; 355:i5953. doi: 10.1136/bmj.i5953. metformin in treatment-naıve patients with type 2 diabetes
8. Kristensen SL, Preiss D, Jhund PS, Squire I, Cardoso JS, mellitus. In: ClinicalTrials.gov [Internet]. Available from
et al. Risk related to pre-diabetes mellitus and diabetes http://clinicaltrials.gov/show/NCT01528254.
mellitus in heart failure with reduced ejection fraction: 17. Abdul-Ghani M, DeFronzo RA. Is it time to change the type
Insights from prospective comparison of ARNI with ACEI to 2 diabetes treatment paradigm? Yes! GLP-1 RAs should
determine impact on global mortality and morbidity in heart replace metformin in the type 2 diabetes algorithm.
failure trial. Circ Heart Fail. 2016;9(1). pii: e002560. doi: Diabetes Care. 2017;40(8):1121-7.
10.1161/CIRCHEARTFAILURE.115.002560. 18. Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, et
9. Tabák AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimäki M, et al. Efficacy and safety of empagliflozin, a sodium glucose
al. Trajectories of glycaemia, insulin sensitivity, and insulin cotransporter 2 (SGLT2) inhibitor, as add-on to metformin
secretion before diagnosis of type 2 diabetes: an analysis in type 2 diabetes with mild hyperglycaemia. Diabetes Obes
from the Whitehall II study. Lancet. 2009;373(9682):2215- Metab. 2013;15(12):1154-60.
21. 19. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, et
10. Ferrannini E. Definition of intervention points in prediabetes. al. Pioglitazone after ischemic stroke or transient ischemic
Lancet Diabetes Endocrinol. 2014;2(8):667-75. attack. N Engl J Med. 2016;374(14):1321-31.
11. Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, et 20. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik
al. Effect of weight loss with lifestyle intervention on risk of A, et al. Acarbose for prevention of type 2 diabetes
diabetes. Diabetes Care. 2006;29(9):2102-7. mellitus: the STOP-NIDDM randomised trial. Lancet.
12. Hostalek U, Gwilt M, Hildemann S. Therapeutic use of 2002;359(9323):2072-7.
metformin in prediabetes and diabetes prevention. Drugs. 21. Chaisson JL. Acarbose for the prevention of diabetes,
2015;75(10):1071-94. hypertension, and cardiovascular disease in subjects with
13. Kabadi UM. Comparative efficacy between glimepiride and impaired glucose tolerance: the Study to Prevent Non-
metformin in preventing progression of prediabetes to type Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) Trial.
2 diabetes. Journal of Diabetes Mellitus. 2013;3(3):129-33. Endocr Pract. 2006;12(Suppl 1):25-30.
CHAPTER
31
Are all Gliptins the Same:
How to Decide and Choose?
INTRODUCTION involvement in the pathogenesis of type 2 DM has

Diabetes mellitus (DM) is a metabolic disease changed the scenario. Any agent that can augment the
characterized by high plasma glucose, which if not incretin system will promote beta cell health and thus
controlled effectively in time, will result in multiple control insulin release depending upon blood sugar
micro- and macrovascular complications. The level.
prevalence of diabetes is increasing world wild affecting Progressive decline in beta cell function was reported
382 million people in 2013 and is expected to rise to by UKPDS when SU and metformin were combined and
592 million by 2035. Diabetes is now recognized as this led to 50% decline in 3 years and additional agent will
the 8th leading cause of death and in 2012 and 2013, be required to maintain HbA1c levels. We need an agent
diabetes had resulted in 1.5–5.1 million deaths. Also, if which will control hyperglycemia without damaging Beta
not treated effectively in time, it is now recognized as cells, is weight neutral with minimal risk of hypoglycemia.
the leading cause of end-stage kidney disease (ESRD), Gliptins might take us closer to that dream.
nontraumatic lower-limb amputations, blindness, and a
major cause of cardio vascular disease and stroke in the PATHOGENESIS OF TYPE 2 DIABETES
individuals. With the availability of various oral drugs MELLITUS
and insulin, DM can be treated and its complications can Various factors responsible for pathogenesis of diabetes
be minimized through appropriate glycemic control. For are:
every 1% drop in HbA1C, there is a 40% reduction in the
Insulin resistance: At the level of liver as well as skeletal
risk of microvascular complication.
muscle resulting in more glucose formation by liver and
Before 1995, Sulfonylureas (SU) were the main agent
lesser glucose utilization by skeletal muscle.
for the treatment of diabetes mellitus. They increase
the insulin secretion irrespective of the blood sugar Progressive beta cell loss resulting decreased insulin
level and thus there is risk of hypoglycemia. Metformin producing capacity: Less than 10% insulin production
became popular after 1995 especially for obese type 2 is left after 10–15 years of disease and this has lead to
Diabetics. Metformin handles insulin resistance at the shift in search for agents which preserve beta cells and
level of Liver as well as peripheral tissues. It improves the their function. Sometime back thiazolidinediones were
Beta cell health and controls insulin release depending the only agent reported to conserve beta cell function
upon blood sugar levels. Discovery of incretin system along with improving insulin sensitivity at peripheral
CHAPTER 31: Are all Gliptins the Same: How to Decide and Choose? 187
tissues as well as liver. Incretin based treatment strategies in the hypothalamus. Increase in GLPI levels has an
have outsmarted all other antidiabetic options and any anorexigenic effect.
strategy which improves plasma incretin concentration
after carbohydrate meal also improves beta cell function. IDEAL ANTIHYPERGLYCEMIC DRUG
In 2009, in American Diabetic Association meet some The logic we draw from the above discussion is that any
new pathognomic factors have been proposed. agent that addresses the above factors e.g. improved beta
cell health (thiazolidine diones, GLP analogues, gliptins,
Lipotoxicity: Increasing resistance of the fat cells to the biguanides), suppression of glucagon production
antilipolytic effect of insulin results in higher levels of (incretin based drugs), decrease insulin resistance
free fatty acids (FFA). High fatty acid levels competitively (biguanides, TZD, incretin mimetics), decrease appetite
inhibit insulin mediated glucose metabolism, stimulate (GLPI analogues, biguanides), and suppress glucose
production of glucose in liver and reduces the insulin reabsorption in the kidneys (SGLT2 inhibitors) are
secretion rate resulting in impaired first and second useful in management of Type 2 DM. The most logical
phases of insulin release. combination out of these is incretin based agents with
metformin or thiazolidinediones.
Incretin: Incretins are hormones released from the gut in
response to oral carbohydrate meal and are responsible
DIPEPTIDYL PEPITIDASE-4 INHIBITORS
for efficient disposal of glucose. Two hormones identified
Since launch of first DPP4 inhibitor, Sitagliptin in 2006, a
are glucagon like peptide (GLPI) and gastric insulotropic
number of new agents have been approved (Vildagliptin,
peptide (GIP) and are responsible for 99% of incretin
Anagliptin, Linagliptin, Teneligliptin, Trelagliptin,
effect and amplification of this incretin effect is the basis etc). Now DPP4 inhibitors are an established class
of incretin based therapies. in management of Type 2 DM. They are reversible
Hyperglucagonemia: Alpha cells of pancreatic islets of competitive inhibitors of DPP4 and act at extracellular
Langerhans produce Glucagon which has an anti insulin level.
There are two groups of DPP4 inhibitors:
effect and increases blood sugar. GLPI in addition to
Peptidomimetics, that mimic the DPP4 molecule
increasing insulin secretion also suppresses glucagon
(vildagliptin, saxagliptin).
and hence reduces post prandial hyperglycemia.
Nonpeptidomimetics that do not mimic the DPP4
Kidneys: Glucose is filtered in the glomeruli of the kidneys. molecule (alogliptin, sitagliptin, linagliptin).
Out of this 90% is reabsorbed by the SGLT 2 (Sodium Nonpeptidomimetics interact with residues of DPP4
glucose like transporter type 2) transporter in the S1 substrate at the extra cellular site to form noncovalent
segment of proximal convulated tubule and remaining bond and results in immediate potent inhibition. In
10% is reabsorbed in S2 and S3 segment of proximal contrast peptidomimetics form a reversible covalent
tubule. Diabetic patients show increased glucose enzyme inhibitor complex. This complex binds to
reabsorption capacity resulting in hyperglycemia. the catalytic site of DPP4 substrate and dissociates
slowly resulting in DPP4 inhibition which is persistent
Brain: Brain has also been implicated in the pathogenesis and persists even after the inactivation of the drug.
of type 2 DM. These are wide spread receptors of This explains prolonged inhibition of DPP4 activity
GLPI throughout the brain and it is synthesized in the by Vidagliptin and Saxagliptin as compared to their
nucleus of the solitary tract. Potentiation of GLPI by short half lives. Various DPP4 inhibitors and their
any means will influence the satiety and feeding center pharmacological profile are mentioned in Table 1.
TABLE 1: Pharmacokinetics and pharmacodynamics of DPP4 inhibitors

Drug Chemistry Metabolism Elimination route Dose
Alogliptin Modified pyrimidinedione Minimal Predominantly renal 25 mg once daily
Anagliptin Cyanopyrrolidine Metabolite (hydrolysis) Metabolism + renal 100 mg twice daily, can be increased
to 200 mg
Gemigliptin Beta-amino acid based Active metabolite (hepatic) Metabolism + renal 50 mg once daily
Linaglitpin Methyl xanthine derivative Minimal Predominantly biliary 5 mg once daily
Saxagliptin Cyanopyrrolidine Active metabolite (hepatic) Metabolism + renal 5 mg once daily
Sitagliptin Beta-amino acid based Minimal Predominantly renal 100 mg once daily
Teneligliptin L-prolyl thiazolidine Active metabolite (hepatic) Metabolism + renal 20 mg once daily, can be increased
to 40 mg
Trelagliptin Pyrimidinedione based Minimal Predominantly renal 100 mg once weekly
Vildagliptin Cyanopyrrolidine Inactive metabolite Metabolism + renal 50 mg twice daily
EFFICACY Its absorption is not affected by food. Elimination is

DPP4 inhibitors have no direct action on the target primarily by the renal route and hence dose adjustment
tissues but is mediated by the increased levels of is required in kidney disease. Dose is reduced to 50 mg/
protected substrate i.e. GLPI which is responsible for day in moderate renal failure (creatinine clearance 30–50
its antihyperglycemic effects. If DPP4 inhibitors inhibit mL/min) and in severe renal failure with CC less than
DPP4 to same extent then efficacy of DPP4 inhibitors 30 mL/min. The dose is reduced to 25 mg/day or is not
should also be the same. Meta-analysis of short term used. No change in dose is required in patients with liver
trials with sitagliptin and vildagliptin has revealed no impairment. However, sitagliptin is not used in child
significant differences in improvement in glycemic grade C liver disease. As per Asian study sitagliptin has
control. higher HbA1c reduction (1.3%) in Indian population as
As monotherapy efficacy results observed with tried compared to placebo.
gliptin are:
Fasting blood sugar reduction of approximately 18
Vildagliptin
mg/dL (10–35 mg/dL)
Post prandial reduction of approximately 25 mg/dL
Although it is the second gliptin to be used but is still
(20–60 mg/dL) not approved by USFDA. It is used in daily dose of 50
HbA1c reduction of approximately 0.75% (0.4–1.2%).
mg two times a day. Its absorption is also not affected by
In comparison to metformin, SU and thiazoli food. It is metabolized by liver but no dose adjustment is
dinediones, gliptins are equally effective and noninferior. recommended for liver disease but dose is halved in case
In addition, in comparison to SU they have negligible of moderate and severe kidney disease.
hypoglycemia and are weight neutral. As per latest meta-
analysis greater number of cases achieved HbA1c goal of Saxagliptin
<7.0% with gliptins. Pharmacological characteristics of It is USFDA approved and was third gliptin approved for
commonly used DPP4 inhibitors are shown in Table 2. commercial use. 75% of drug is exerted by the kidneys
and 22% of saxagliptin is eliminated as metabolite in
Sitagliptin stools. Usual recommended dose is 5 mg once daily and
It was approved for use in T2DM by US FDA in October in moderate and severe kidney disease dose is reduced to
2006. Usual recommended dose is 100 mg once a day. 2.5 mg/day. No dose adjustment is done in liver disease.
CHAPTER 31: Are all Gliptins the Same: How to Decide and Choose? 189
TABLE 2: Pharmacological characteristics of DPP4 inhibitors

Drug Renal function Use in deranged renal function Liver function Use in deranged liver function
tests Mild Moderate Severe screening Mild/ moderate Severe
Alogliptin Yes Yes Yes, (12.5 mg once Yes, (6.25 mg once No Yes No
daily) daily)
Anagliptin Yes Yes Yes Yes, (100 mg once - Yes Yes
daily)
Gemigliptin Yes Yes Yes, with caution Yes, with caution - No No
Linagliptin No Yes Yes Yes No Yes Yes
Saxagliptin Yes Yes Yes, (2.5 mg once Yes, (2.5 mg once No Yes Yes
daily) daily)
Sitagliptin Yes Yes Yes, (50 mg once Yes, (25 mg once No Yes No data
daily) daily)
Teneligliptin No Yes Yes Yes - Yes Yes
Trelagliptin Yes Yes Yes, with dose No - Yes Yes
adjustment (50 mg
once weekly)
Vildagliptin Yes Yes Yes, with dose Yes, with dose Yes No No
adjustment (50 mg adjustment
once daily) (50 mg once daily)
Linagliptin is associated with increased risk of hypoglycemia

Linagliptin is a novel newer agent in the DPP-4 inhibitors. because of the inherent glucose lowering properties of
Usual dose is 5 mg once daily. Primarily, it has nonrenal SU’s and insulin. Reduction in dose of SU’s or insulin is
elimination and is primarily excreted via enterohepatic recommended when DPP4 inhibitors are added. There is
system, 85% of the drug is eliminated in the faeces and is no convincing evidence of increased risk of pancreatitis
thus safe in renal failure cases without dose adjustment. with insulin based regimens including DPP4 inhibitors.
Cardiovascular safety of DPP4 inhibitors has been
Teneligliptin extensively investigated. Trial concentrated on their
Teneligliptin is a novel DPP4 inhibitor being marketed cardiovascular safety rather than cardiovascular efficacy
since 2015 which does not require dose adjustment for and end points showed conclusively that DPP4 inhibitors
diabetic patients with end stage renal disease because are non inferior and cardiovascular events were not
it is actively metabolized (65.6%) and only 34.4% is higher in number when compared with comparator.
excreted. However, in severe liver disease it should be
used with caution. Daily dose is 20 mg once daily but can CONCLUSION
be increased up to 40 mg once daily. Gliptins are a newer group of drugs in the management
of diabetes and have provided a new hope for diabetes
SAFETY management. It has been shown to reduce HbA1c
Insulinotropic and Glucagonostatic effects of DPP4 from 0.5% to 2% without much side effects. Major
inhibitors depend upon blood sugar levels and thus diabetes management guidelines have incorporated
their use is associated with nonsignificant hypoglycemia. them for their safety, efficacy and minimal incidence
In general, they are well tolerated and side effects are of hypoglycemia and no weight gain. There are some
like placebo. Their concurrent use with SU’s or insulin controversies regarding increased risk of pancreatitis and
carcinoma but hope they will stand the test of time and 6. Japanese Pharmaceuticals and Medical Devices Agency.
emerge as the only class of drugs that improves beta cell Teneligliptin; Review report. Available from URL: http://
www.pmda.go.jp/ les/000153594.pdf.
health and controls hyperglycemia.
7. Meier JJ, Nauck MA. Risk of pancreatitis in patients treated
with incretin-based therapies. Diabetologia 2014;57:
BIBLIOGRAPHY
1320-4.  
1. American Diabetes Association. Standards of medical care
8. Mohan V, Yang W, Son HY, Xu L, Noble L, Langdon RB, et al.
in diabetes – 2014. Diabetes Care 2014;37(Suppl. 1):S14–
Efficacy and safety of sitagliptin in the treatment of patients
S80.
with type 2 diabetes in China, India, and Korea. Diabetes
2. Deacon CF, Lebovitz HE. Comparitive review of DPP4
Res Clin Pract. 2009;83:106-16.
inhibitors and sulphonylureas. Diabetes, Obes and Metab
9. UKPDS 28: A randomized trial of efficacy of early addition
2016;18:333-47.
of metformin in sulfonylurea-treated type 2 diabetes. U.K.
3. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the
Prospective Diabetes Diabetes Study Group. Diabetes Care.
treatment of type 2 diabetes: a comparative review.
1998;21:87-92.   
Diabetes Obes Metab 2011;13:7-18.
10. Wu D, Li L, Liu C. Efficacy and Safety of DPP4 inhibitors
4. Defronzo RA. Banting lecture. From the triumvirate to the
and Metformin as initial combination therapy and as
ominous octet: a new paradigm for the treatment of type 2
monotherapy in patients with type-2 diabetes mellitus: a
diabetes mellitus. Diabetes. 2009;58:773-95.  
metaanalysis. Diabetes Obes and Metab. 2014;16:30-7.
5. Gupta V, Kalra S. Choosing a Gliptin. Indian J Endocrinol
Metab. 2011;15:298-308.
CHAPTER
32
Diabetes and Inflammation
INTRODUCTION plasminogen activator inhibitor-1 (PAI-1) and tissue

It has been well established with abundance of evidence plasminogen activator (tPA) increase to a lesser extent.
that diabetes is associated with chronic low-grade Sialic acid, very low-density lipoproteins (VLDLs),
inflammation. Innate immunity activation, obesity, lipoprotein(a), a1-acid glycoprotein, von-Willebrand
endothelial dysfunction, reticular stress causing beta factor (vWF) and cortisol are also synthesized.
cell loss and inflammation lead to impairment of insulin
sensitivity and secretion and eventually diabetes.
Role of Toll-like Receptors
Toll-like Receptors (TLRs) are important factors in the
LINK BETWEEN DIABETES AND pathophysiology of chronic low-grade inflammation
caused by metabolic ‘endotoxinemia evidenced by
INFLAMMATION
increase in LPS secondary to increased fat absorption
Innate Immune System Activation from gut flora. 11 TLRs can sense pathological levels
The innate immune response is rapid, first-line defense of lipid and thus involve macrophage in production of
mechanism based on non-lymphoid tissue meant to cytokines like IL-6, TNF-a in response to saturated fatty
restore homoeostasis during and after external threats. acids. TLR4 mediates the activation of IKB kinase-f3
It works through germline-encoded receptors called (IKKf3) and nuclear factor-kappa B (NFKB) pathways in
‘pattern-recognition receptors’ (PRRs) like TLR4 which the presence of LPS leading to increased IKKf3 activity,
senses, the conserved components of microorganisms IL-6 and intercellular adhesion molecule (ICAM)
known as ‘pathogen-associated molecular patterns’ proteins in endothelial cells which are associated with
(PAMPs) like lipopolysaccharide (LPS) a component of insulin resistance and impaired insulin-stimulated
the Gram-negative bacterial wall. phosphorylation of endothelium-derived nitric oxide
The acute-phase response is part of the innate synthase (eNOS).
immune response carried by Sentinel cells such as
macrophages, endothelial cells and adipocytes who Role of Stress
detect environmental threats and release inflammatory Stress can lead to high blood pressure which through its
cytokines, which stimulate the production of acute- proinflammatory effect on endothelium can produce IL-
phase proteins (APP). C-reactive protein (CRP) and 6. It leads to excess corticoid secretion which promote
serum amyloid A (SAA) are the major APPs whereas visceral obesity: abdominal fat contains high levels
fibrinogen, tissue factor, complement components, of glucocorticoid receptors, and the glucocorticoid-
receptor complex binds to the lipoprotein lipase gene fraction that includes preadipocytes, fibroblasts,
promoter, which enhances fatty-acid uptake. In addition, endothelial cells, histiocytes and macrophages.
stress can cause contraction of the splanchnic vessels of Preadipocytes can differentiate into macrophages
the gastrointestinal tract, resulting in gut ischemia, which though majority of them are transformed from monocytes
promotes the entry of LPS into the portal system, leading or bone marrow derived precursors. AT macrophage
to inflammatory cytokine production by Kupffer cells accumulation ranges from <10% in lean humans to
and, possibly, by hepatocytes and hepatic endothelial nearly 40% in the obese favouring a direct proportion to
cells as well. the magnitude of adiposity and suggest the inflammatory
process associated with an expanded fat mass may be
Genetic Predisposition involved in the development of insulin resistance and
G e n e t i c p re d i s p o s i t i o n t o c h ro n i c l o w - g r a d e type 2 diabetes.
inflammation through gene polymorphisms in PRRs
has shown to affect the innate immune response. The Cytokine and Macrophage Phenotypes
polymorphism Asp299Gly of the TLR4 gene is known to Inflammatory molecules like TNF-a, CRP, PAI-1, SAA
inversely affect innate immune function and atheroma MIF iNOS CSF-1 MCP-1, IL-6, resistin are increased
by attenuating receptor signaling, and is also associated in adiposity because of activation of innate immunity.
with a decreased risk of atherosclerosis. In addition, the AT macrophages either possess anti-inflammatory
polymorphism is associated with reduced plasma CRP phenotype M2 which secretes cytokines IL-10 or pro-
levels, and a decrease in the prevalence of angiographic inflammatory phenotype M1 which secretes IL-1. IL-6
coronary artery disease and diabetes. and TNF-a. A shift from type M2 to M1 is seen in diet
induced obesity whereas reverse is seen in bypass
Type-2 Diabetes and Innate Immune System surgery induced weight loss. Visceral fat secretes more
The metabolic syndrome and type 2 diabetes share IL-6 than subcutaneous fat and majority of it comes
many metabolic abnormalities of lipid profiles and through stromavascular fraction It contributes to 25–30%
elevated APP, which are also present in malignancy of total IL-6 in circulation.
and infection. Role of innate immune system in the The low-grade inflammation observed in obesity is
pathogenesis of type 2 diabetes was implicated when a linked with altered levels of several circulating factors,
graded increase in CRP, IL-6 and SAA levels serum sialic including CRP, TNF-a, IL-6 and other inflammation
acid concentrations was observed, with the lowest levels markers. Adipocytes share some properties with
seen in healthy individuals and the highest levels in type macrophages: both can activate complement, and
2 diabetic patients. produce inflammatory cytokines, fatty-acid-binding
proteins (FABPs) and many other factors. Also, adipocytes
Role of Obesity in Low Grade- store lipids and regulate metabolic homoeostasis
whereas, in proatherosclerotic conditions, macrophages
Inflammation, Insulin Resistance and
can also accumulate lipids to become foam cells.
Type-2 Diabetes
Adipose Tissue Composition Macrophage Infiltration in White Adipose Tissue
Adipose tissue (AT) is an established endocrine organ The increase in macrophage infiltration is significantly
that secretes numerous adipokines, cytokines and correlated with body mass index (BMI) and adipocyte
chemokines. Out of two types of AT identified—brown cell size. Subcutaneous adipocytes contain fewer
AT and white AT only the latter significantly persists macrophages than visceral fat. Mature adipocytes
throughout life in humans. White AT is heterogeneous, secrete Adipokine like adiponectin, leptin which
composed of mature adipocytes, and a stromavascular stimulate the diapedesis of blood monocytes for their
CHAPTER 32: Diabetes and Inflammation 193
differentiation into macrophages through a complex kinase which involve NFKB pathway, IKKf3, activating
phenomenon. Adiponectin displays anti- inflammatory protein-1 (AP-1), c-JunNH2-terminal kinase (JNK)
activity by inhibiting the production of TNF-a and IL-6 and protein kinase C-theta (PKC0) are also implicated.
by macrophages, and by binding LPS. Adiponectin also These pathways could interact with insulin signaling via
decreases hepatic gluconeogenesis and increases lipid serine/threonine inhibitory phosphorylation of IRS. The
oxidation in skeletal muscle. Circulating adiponectin proinflammatory NFKB pathway is clearly implicated
levels are decreased in patients with abdominal in insulin resistance, as selective inhibition of the
obesity, type 2 diabetes and/or coronary heart disease. NFKB function in liver and AT protects against insulin
Adiponectin may even play a protective role against resistance in nutritional and genetic animal models of
atherosclerosis and insulin resistance. obesity.
Leptin in addition to its role in food intake and energy Macrophage itself can lead to insulin resistance
expenditure also regulates immune process by its control in obese patients. Phosphorylation of the insulin
on TNF-a production and macrophage activation. receptor-f3 subunit (p-INSR-f3) is significantly reduced
Hyperleptinemia seen in obesity is associated with an in mononuclear cells (MNC) from obese subjects
increased inflammatory response. compared with those from normal controls. Ghanim et
Conversely, leptin can improve insulin sensitivity al. found that MNC are also characterized by increased
through AMP-activated protein kinase (AMPK) activation of the inflammatory pathway, including
activation. protein kinase C-f32 (PKC- f32), and suppression of
Other adipokines related to AT include visfatin, an cytokine-signalling-3mRNA (SOCS-3), which may
inflammatory adipokine that is highly expressed in contribute to alteration of insulin signal transduction
carotid plaques and associated with unstable lesions in and, thus, induce a state of insulin resistance in MNC.
patients with coronary heart disease, as well as vaspin
and omentin, which are prominently expressed in Endothelial Dysfunction,
visceral fat. Inflammation and Diabetes
Studies have shown that AT in obesity is hypoxic. Hyperglycemia is associated with an increase in cytokine
Obesity is associated with increased expression of production mediated by oxidative mechanisms. Thus,
hypoxia-inducible factor-1a (HIF-1a). In human the excess production of reactive oxygen species (ROS),
subcutaneous fat, the HIF-1a gene is down-regulated together with the interaction of advanced glycation
after bypass surgery. end-products (AGEs) with their receptors (RAGEs) on
Prolonged overnutrition and increased saturated endothelium, lead to cytokine production by endothelial
fatty-acid intake can increase nutritional endotoxaemia cells. Cytokine overproduction is also associated
and stimulate the TLR4–NFKB pathway in adipocytes as with endothelial dysfunction which involves reduced
discussed earlier. This mechanism might also be a causal vasodilation and prothrombic properties.
factor in the macrophage infiltration of AT in obesity. TNF-a can accelerate experimental atherosclerosis
through induction of VCAM-1, ICAM-1, MCP-1 and
Inflammatory Pathways to Insulin Resistance E-selectin in endothelial and vascular smooth muscle
TNF-a directly decreases insulin sensitivity while cell.
increasing lipolysis in adipocytes and play a major role A positive correlation between the acute-phase
in the pathophysiology of insulin resistance through response, endothelial dysfunction and insulin resistance
phosphorylation of the insulin receptor substrate-1 has been suggested. Serine phosphorylation of IRS-
(IRS-1) protein on serine residues. IL-1 and IL-6 are also 1, induced by cytokines, is one of the implicated
implicated in insulin resistance in type 2 diabetes, as mechanisms. It contributes to impairment of the
are other cytokines, such as IL-8 and IL-18. Few other normal insulin response and NO synthesis, and leads to
reduced insulin-induced vasodilation. Increased plasma ATF6 on activation though its transit to Golgi
concentrations of soluble cell adhesion molecules have compartment leads to ERAD activation and chaperone
been reported in overweight and obese individuals, production.
suggesting that increased fat mass is associated with ER stress stimuli impair polypeptide folding, and try
early systemic endothelial activation. to preserve cell homoeostasis by adaptive increases in
chaperones and catalysts, within the ER lumen through
Role of Endoplasmic Reticulum unfolded protein response (UPR) sensor activation.
Stress in Type 2 Diabetes When this response cannot resolve ER stress, the cell
becomes subject to apoptosis using several pathways.
ER Stress and the Unfolded Protein Response
The endoplasmic reticutum (ER) is a membrane-bound ER Stress and UPR in Type-2 Diabetes
organelle that provides a unique environment for Presence of stressed ER in f3 cells and unfolded proteins
oxidative protein-folding in a correct manner to perform as proinsulin molecules suggest UPR activation as a key
specific functions and post-translational modification pathophysiological mechanism that might be involved in
of polypeptides such as disulphide bond formation. the initiation of diabetes. Proinsulin requires disulphide
Protein-folding in the ER needs molecular chaperones bond formation for its correct folding. Insulin resistance
such as binding immunoglobulin (Ig) protein (Bip) and is seen in XBP-1 deficiency whereas its overexpression
folding catalysts. in f3 cells show impair glucose-stimulated insulin
Three key factors act as sensors of unfolded protein secretion and increase f3-cell apoptosis. Deletion of the
accumulation in the ER: protein kinase (PKR)-like ER CHOP gene improves f3-cell function which makes it
kinase (PERK); inositol-requiring protein-1a (IRE-1a); responsible for protein-misfolding in the ER to oxidative
and activating transcription factor 6 (ATF6). These stress and apoptosis in f3 cells under conditions of
are collectively activated to maintain ER function by increased insulin demand.
degradation of misfolded proteins in case of heavy
translational load and preserve the cell against apoptosis. Fundamental Mechanism of β-Cell
The chaperone protein Bip is bound to the three ER Stress and Diabetes
sensory factors, which keeps them in an inactivated state. Various stimuli, including heat shock, energy deprivation,
However, when stress is present, Bip is released, leading hypoxia, metabolic dysfunction, drugs, increased levels
to activation of the three molecules PERK and IRE-1 and of circulating cytokines, FFA, nutrient excess cause ER
ATF6. stress and subsequent activation of the mammalian target
PERK when activated increases translation of ATF4 rapamycin (mTOR) pathway. Oxidative protein-folding in
mRNA through EIF-2a which is responsible for synthesis the ER can generate ROS which impede protein-folding
of ERAD machinery and enzymes that reduces oxidative through a complex mechanism and creates a vicious cycle
stress. ATF4 also induces transcription of the C/EBP of ER stress and oxidative stress. Periodic increases in
homologous protein (CHOP), which mediates apoptosis. proinsulin mRNA translation, induced by hyperglycaemia,
IRE-1 also activates genes encoding for ERAD can generate UPR activation in f3 cells.
machinery and chaperones through XBPI using a Obesity causes ER stress. which in turn, leads to
complex mechanism. It also has RNase activity, which suppression of insulin receptor signaling through
degrades mRNA to reduce the transcriptional load of hyperactivation of JNK and subsequent serine
newly synthesized proteins that require folding. IRE-1 phosphorylation of IRS-1.
can activate the NFKB pathway by interacting with JNK Thus, ER stress might be a common pathway that
and IKK which promotes apoptosis in response to ER induces both insulin resistance and f3-cell loss, thereby
stress. leading to type 2 diabetes.
CLINICAL IMPLICATIONS OF Anti-inflammatory Drugs

INFLAMMATION IN TYPE-2 DIABETES Based on inflammation theory anti-inflammatory drugs
Various inflammatory markers have been studied like Aspirin have shown to decrease CRP, Triglyceride
as a predictive risk for type-2 diabetes by measuring and total cholesterol but at a higher dose which carries a
their plasma concentrations which correlates with the major risk of gastric ulcer and bleeding.
chronic low-grade inflammation. The Atherosclerosis Salsalate a prodrug of salicylate with low GI bleed
Risk in Communities (ARIC) study used White cell risk also decreases CRP and increases Adiponectin and
counts, Sialic-acid concentrations, and orosomucoid improves insulin resistance and TINSAL-2D trial has
levels, Framingham offspring Study which used CRP shown a decrease in HbA1c up to 0.5%.
levels, Women’s Health Study (WHS) used IL-6 and Anakinra, a recombinant IL-1 receptor antagonist (IL-
CRP, MONICA-Augsburg project used CRP levels as IRA) used in rheumatic polyarthritis also lowers HbA1c
inflammatory markers to study the risk of diabetes in up to 0.46% but with no effect on insulin resistance.
nondiabetic population and found a strong association Polymorphisms of the ILIRN genes might be another
of risk of diabetes with increasing level of inflammatory predictive of a response of this treatment and need
markers. further trials.
In another meta-analysis, Higher level of adiponectin
were clearly associated with a lower risk of type-2 Thiazolidinedione
diabetes. PPAR agonist such as TZD can delay the development
Role of endothelial dysfunction with risk of diabetes of diabetes through its anti-inflammatory effect despite
has been studied and was significantly associated with weight gain. PRO-active trial has demonstrated an
E-selectin and ICAM values after adjusting all variables. improved cardiovascular outcome as these agents
Various circulatory biomarkers of inflammation improve factors which aggravate atherosclerosis.
pathways such as TNF-a, IL-6, CRP, VCAM-1 E-and P
selectin vWF, PAI, fibrinogen, adiponectin, etc. appears DRUGS RELATED TO THE
to be in close association with development of type-2
ENDOPLASMIC RETICULUM
diabetes.
STRESS THEORY
Chemical chaperones like 4-phenyl butyric acid (PBA)
CLINICAL BENEFITS BASED ON
and tauroursodeoxycholic acid (TUDCA) have shown
INFLAMMATORY THEORY
benefit by reversing ER stress. They restore insulin
Life Style Modifications and Metformin sensitivity, resolution of fatty liver and improves insulin
Based on this theory Life Style Modification and action in liver, skeletal muscle and AT. These molecules
Metformin has shown to reduce progression of diabetes which act as leptin sensitizers need further clinical
as evidenced by decline in CRP values in Diabetes studies.
Prevention Programme (DPP) and Diet and Exercise for
Elevated Risk (DEER) trial. BIBLIOGRAPHY
1. Allagnat F, Christulia F, Ortis F, Pirot P, Lortz S, Lenzen S, et
Insulin al. Sustained production of spliced X-box binding protein
Insulin has proven anti-inflammatory effects and is 1 (XBP1) induces pancreatic beta cell dysfunction and
apoptosis. Diabetologia. 2010;53:1120-30.
associated with inhibition of NFKB pathway, MCP-1
2. Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines:
andICAM-1. It lowers CRP, ROS and FFA release, has
the missing link between insulin resistance and obesity.
antithrombotic effects via PAI-1 inhibition and induces Diabetes Metab. 2008;34:2-11.
vasodilation via eNOS stimulation. Insulin has shown to 3. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H,
decrease TLR4mRNA expressions in monocytes. et al. Recent advances in the relationship between obesity,
inflammation, and insulin resistance. Eur Cytokine Netw. mononuclear cells of obese subjects. Diabetologia.
2006;17:4-12. 2007;50:278-85.
4. Black PH. The inflammatory response is an integral part 17. Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA,
of the stress response: implications for atherosclerosis, Shoelson SE. TINSAL-2D (Targeting inflammation using
insulin resistance, type II diabetes and metabolic syndrome salsalate in type 2 diabetes) study tem. Ann Intern Med.
X. Brain Behav Immun. 2003;17:350-64. 2010;152:346-57.
5. Camhi SM, Stefanick ML, Ridker PM, Young DR. Changes in 18. Heilbronn LK, Campbell LB. Adipose tissue macrophages,
C-reactive protein from low-fat diet and/or physical activity low grade inflammation and insulin resistance in human
in men and women with and without metabolic syndrome. obesity. Curr Pharm Des. 2008;14:1225-30.
Metabolism. 2010;59:54-61. 19. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S,
6. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica Segawa K, et al. Adipose tissue hypoxia in obesity and its
D, et al. Metabolic endotoxemia initiates obesity and insulin impact on adipocytokine dysregulation. Diabetes. 2007;56:
resistance. Diabetes. 2007;56:1761-72. 901-11.
7. Chase HP, Cooper S, Osberg I, Stene LC, Barriga K, Norris J, 20. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose
et al. Elevated C-reactive protein levels in the development expression of tumor necrosis factor-alpha: direct role in
of type 1 diabetes. Diabetes. 2004;53:2569-73. obesity-linked insulin resistance. Science. 1993;259:
8. Cunha DA, Hekerman P, Ladrière L, Bazarra-Castro1 A, Ortis 87-91.
F, Wakeham MC, et al. Initiation and execution of lipotoxic 21. Hundal RS, Petersen KF, Mayerson AB, Randhawa PS,
ER stress in pancreatic f3-cells. J Cell Sci. 2008;121:
Inzucchi S, Shoel-son SE, et al. Mechanism by which
2308-18.
high dose aspirin improves glucose metabolism in type 2
9. Dandona P, Chaudhuri A, Ghanim H, Mohanty P. Insulin as
diabetes. J Clin Invest. 2002;109:1321-6.
an anti-inflammatory and antiatherogenic modulator. J Am
22. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer
Coll Cardiol. 2009;53:S14-20.
F, Bonora E, et al. Toll-like receptor 4 polymorphisms and
10. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-
atherogenesis. N Engl J Med. 2002;347:185-92.
Benedetti M, Moules IK, et al. Secondary prevention of
23. Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler
macrovascular events in patients with type 2 diabetes in the
J, et al. Tolllike receptor-4 mediates vascular inflammation
PROactive Study (PROspective piogli- tAzone Clinical Trial
and insulin resistance in diet-induced obesity. Circ Res.
in Macrovascular Events): a randomised controlled trial.
2007;100:1589-96.
Lancet. 2005;366:1279-89.
24. Kvasnicka T, Kvasnicka J, Ceska R, Grauova B, Vrablik M.
11. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic
Increasing plasma levels of soluble cell adhesion molecules
reticulum stress in diabetes mellitus. Endocr Rev.
2008;29:42-61. (sE-Selectin, sP-Selectin and sICAM-1) in overweight adults
12. Esposito K, Nappo F, Marfella R, Giugliano G, Giuglialo F, with combined hyperlipidemia. Sb Lek. 2001;102:473-7.
Citoloa M, et al. Inflammatory cytokines concentrations are 25. Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath M,
acutely increased by hyperglycaemia in humans: role of Mandrup- Poulsen T. Sustained effects of Interleukin-1
oxidative stress. Circulation. 2002;106:2067-72. receptor antagonist treatment in type 2 diabetes. Diabetes
13. Fernandez-Real JM, Pickup JC. Innate immunity, insulin Care. 2009;32:1663-8.
resistance and type 2 diabetes. Trends Endocrinol Metab. 26. Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA,
2007;19:10-6. Seifert B, et al. Interleukin-1 receptor antagonist in type 2
14. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka diabetes mellitus. N Engl J Med. 2007;356:1517-26.
M, Kishimoto K, et al. Visfatin: a protein secreted by visceral 27. Meigs JB, Hu FB, Rifai N, Manson JAE. Biomarkers of
fat that mimics the effects of insulin. Science. 2005;307: endothelial dysfunction and risk of type 2 diabetes mellitus.
426-30. JAMA. 2004;291:1978-86.
15. Fève B, Bastard JP. The role of interleukins in insulin 28. Meigs JB, O’Donnell CJ, Tofler GH, Benjamin EJ, Fox CS,
resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. Lipin- ska I, et al. Hemostatic markers of endothelial
2009;5:305-11. dysfunction and risk of incident type 2 diabetes. The
16. Ghanim H, Aljada A, Daoud N, Deopurkar R, Chaudhuri Framingham Offspring Study. Diabetes. 2006;55:530-7.
A, Dandona P. Role of inflammatory mediators in the 29. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Ni D, et al.
suppression of insulin receptor phosphorylation in circulating Endoplasmic reticulum stress plays a central role in
development of leptin resistance. Cell Metab. 2009;9: 33. Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage
35-51. PJ, Offen-bacher S, et al. Markers of inflammation and
30. Pickup JC, Mattock MB, Chusney GB, Burt D. NIDDM as a prediction of diabetes mellitus in adults (Atherosclerosis
disease of the innate immune system: association of acute- Risk in Communities Study): a cohort study. Lancet. 1999;
phase reactants and interleukin-6 with metabolic syndrome 353:1649-52.
34. Thorand B, Löwel H, Schneider A, Kolb H, Meisinger C,
X. Diabetologia. 1997;40:1286-92.
Fröhlich M, et al. C-reactive protein as a predictor for
31. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM.
incident diabetes mellitus among middle-aged men. Results
C-reactive protein, interleukin-6, and risk of developing type
from the MONICA Augsburg Cohort Study, 1984–1998. Arch
2 diabetes mellitus. JAMA. 2001;286:327-34. Intern Med. 2003;163:93-9.
32. Scheuner D, Ron D, Pennathur S, Kaufman RJ. CHOP 35. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel
deletion reduces oxidative stress, improves f3 cell function, RL, Ferrante Jr AW. Obesity is associated with macrophage
and promotes cell survival in multiple mouse models of accumulation in adipose tissue. J Clin Invest. 2003;112:
diabetes. J Clin Invest. 2008;118:3378-89. 1796-808.
CHAPTER
33
Pollution and Diabetes: Is there a Link?
Brij Mohan
The prevalence of Type 2 diabetes has increased know currently regarding pesticides and human diabetes
alarmingly over the last two decades. There is extensive may be the tip of an iceberg, in future a lot more to be
ongoing research to explore multiple possible defects discovered. Available evidences suggesting that use of
in causing Type 2 diabetes, predominantly centered on pesticides has increased fifty fold during last 50 years, it
lifestyle, genetics and pathophysiological pathways. We would not be unreasonable to speculate that pesticides
know obesity is considered to be main driver of pandemic are a ‘cog in the wheel’, contributing in some way to
of T2DM, a possible contribution of environmental possibly huge explosion in incidence of diabetes.
contaminants and pollutants has been suggested. There are different types of pesticides available but
Potential pollutants implicated in causation of diabetes most widely used include organophosphates [OP],
are: organochlorines [OC] and carbamates. Newer pesticides
Persistent organic pollutants like nicotinoid pesticides and insect growth regulators
Air pollutants are also available. OPs and OCs are known to act at
multiple pathways that also effect glucose homeostasis
PERSISTENT ORGANIC POLLUTANTS apart from neurotoxicity and cardiotoxicity. These
Persistent organic pollutants (POPs) are organic and chemicals might collectively contribute to possible
lipophilic compounds that are totally resistant to hyperglycemia. These pesticides have direct effects
environmental degradation. Because of this resistance to on glycogenesis, glycolysis, gluconeogenesis, insulin
degradation they persist in environment, bio accumulate expression, stress-induced activation of hypothalamic-
in human beings, animal tissue and bio magnify in food pituitary adrenal axis, autonomic nervous system,
chains. oxidative stress, inhibition of blood paraoxonase activity,
There is growing interest in contribution of pancreatic inflammation, adrenal gland stimulation
environmental contaminants, especially pesticides, further leading to hypersecretion of adrenaline and
in causation of diabetes and metabolic syndrome. alterations in metabolism of liver tryptophans.
Nowadays, we see significant number of cases of diabetes Dioxins and POPs are commonly known as endocrine
in farmers who do not have major contributing risk disruptors, they also effect mitochondria. The United
factors for diabetes. There are increasing number of Nations Environment Programme Governing Council
animal and human studies that show an association (GC) originally created a list of 12 POPs–known as
between pesticide exposure and diabetes. Whatever we “dirty dozen”. These were aldrin, chlordane, dichlorodi-
CHAPTER 33: Pollution and Diabetes: Is there a Link? 199
phenyltrichloroethane (DDT), dieldrin, endrin, Flow chart 1: Possible mechanisms–POP and Diabetes
heptachlor, hexachlorobenzene, mirex, polychlorinated
biphenyls (PCBs), polychlorinated dibenzo-p-dioxins
(PCDD or dioxins), polychlorinated dibenzofurans
(PCDF or furans) and toxaphene.
Pesticides represent an increasingly widespread
environmental exposure today and some of them (e.g.
organo-chlorine [OC]) have potential to accumulate in
human tissues either through direct exposure or through
the food chain. Different types of pesticides including OC
compounds have been directly associated with increased
evidence that exposure of pesticides increase the risk
T2D risk in a dose-response way as well as with diabetes
of T2DM. Larger prospective studies may show more
risk factors including adiposity, insulin resistance and
conservative risk effects; however, these also show that
dyslipidemia.
pesticides are harmful.
Common Persistent Organic Pollutants are: Epidemiological evidence is supported by various
Pesticides mechanistic studies, which suggest potential mechanisms
A l d r i n , He x a c h l o ro b e n ze n e, C h l o rd a n e, D D T, through which these compounds may increase diabetes
Dieldrin, Endrin, Heptachlor, Mirex, Toxaphene, risk (Flow chart 1). Underlying pathogenic mechanisms
Chlordecone, Lindane pentachlorobenzene, Alpha under this association need to be further assessed
-hexachlorocyclohexane, Beta-hexachlorocyclohexane. experimentally. There should be guidelines on use of
pesticides and risk of diabetes should be considered in
Industrial Chemicals order to reflect current evidence.
Hexachlorobenzene, Polychlorinated biphenyls
(PCBs), Hexabromobiphenyl, Hexabromodiphenyl Some Evidences
ether and Pentachlorobenzene, Heptabromodiphenyl In a study on impact of pesticide exposure on about
Ether, Perfluorooctanesulfonic acid, Perfluorooctane 2000 outdoor staff working as a part of insecticide
sulfonyl fluoride, Tetrabromodiphenyl ether and program in Australia. This group was compared with a
Pentabromodiphenyl ether. similar number of workers not exposed to insecticides.
Diabetes was more commonly reported by subjects using
By-products herbicides. In addition, standardized mortality ratio in
Hexachlorobenzene; polychlorinated dibenzo-p-dioxins such subjects with diabetes was much higher compared
polychlorinated dibenzofurans (PCDD/PCDF), and PCBs, with Australian general population.
pentachlorobenzene, alpha hexachlorocyclohexane and Lee et al. evaluated prospective associations of Type
beta-hexachlorocyclohexane. 2 diabetes with some organic pollutants among elderly.
Data are there from different sources quantifying Three OC pesticides were found to have significant odds
risk for diabetes for a wide range of pesticides. All types ratio for Type 2 diabetes. Authors concluded selected
of pesticides have been examined for their relation to persistent organic pollutants substantially increased the
diabetes. Exhaustive research strategy revealed that risk of future Type 2 diabetes in an elderly population.
mostly OC pesticides have been studied. Evidence on National Health and Nutrition Examination survey
several other types of pesticides are still limited and (NHANES), in a cross-sectional study of 749 subjects
should be further considered in future studies. The without diabetes aged 20 years, OC pesticides were most
findings from various analysis, yielded supportive strongly associated with HOMA-IR. Association between
OC pesticides and HOMA-IR was further strengthened as association between air pollution exposure and diabetes
waist circumference increased. The authors concluded related traits and gestational diabetes cannot be presently
that OC pesticides and persistent organic pollutants drawn due to the limited data available. For short-term air
may interact with obesity, thereby increasing insulin pollution exposures, the results are more heterogeneous
resistance and further increased risk of Type 2 diabetes. and the evidence too weak to demonstrate a causal
Same authors also reported associations between relationship.
organochlorine pesticides and prevalence of metabolic Household indoor air pollution from solid fuels plays
syndrome. a major role in Asia, Latin America and Africa. Outdoor
air pollution from PM is of importance globally.
AIR POLLUTANTS SOURCES Recent studies have shown that there is some
Air pollution is a ubiquitous exposure effecting large evidence for an association between air pollution
proportion of global population. These compounds differ exposure and T2D. Several biological mechanisms have
in their dispersion, reactivity and toxicity. Air pollution in been proposed to explain such a link. PM exposure has
past has been linked to reduced life expectancy, mainly been associated with impaired endothelial function,
because of cardiovascular and respiratory diseases elevated systemic inflammation and oxidative stress,
such as coronary heart disease and lung cancer and endoplasmic reticulum stress, cardiac autonomic
obstructive lung disease. There is strong evidence that ner vous system dysfunction and mitochondrial
air pollution adversely influences many health indicators dysfunction. Further, epigenetic changes leading to
but links between air pollution and T2D development activation of key signaling pathways or changes in
have been only recently revealed. markers of coagulation, inflammation and endothelial
Air pollutants are emitted from many sources. These function, have been described following exposure to air
can be grouped as: pollutants.
Natural: a–volcanoes, b-wild/bush fires, human

Animal Experiment Showing Mechanism
resources – a-power plants, b-traffic, c-heavy industry,
d-household [Wood].
of Diabetes Association with Air Pollution
PM 2.5 as a mediator of endothelial dysfunction and
Gaseous pollutants: a- Nitric oxide [NO], Nitric dioxide IR: Air-pollution exposure alters endothelial function
[NO 2], b-Ground level ozone; c-Sulphur dioxide and in both animals and humans. These alterations in
sulphates d-Carbon monooxide [CO]. endothelial function often precede changes in IR and
Particulate material: a-PM10-diameter <10 micron, have been implicated in reduced peripheral glucose
b-PM 2.5 – diameter <2.5 micron, black carbon, c-UFP - uptake. In an experimental investigation directly linking
Ultrafine particle - diameter <100 nm inhalational exposure of PM2.5 with DM, exposure in
Possible mechanisms of air pollution leading to
T2DM and CVD in diabetics is systemic inflammation, Flow chart 2: Possible mechanisms - Air pollution and diabetes
oxidative stress, endothelial dysfunction, direct effect of
ultra-fine particles and changes in autonomic function
(Flow chart 2).
Evidences indicate association between long-term
exposure to air pollutants and the development of T2D
and diabetes related mortality in adults. Results from
studies that have investigated precursors of diabetes in
healthy individuals strengthen support for a potential
association. However, a firm conclusion regarding
CHAPTER 33: Pollution and Diabetes: Is there a Link? 201
conjunction with high-fat diet feeding, increased fasting, county level with PM2.5 (1% increase per 10 mg/m3);
postprandial glucose, insulin, and homeostasis model association persisted in counties with PM2.5 meeting
assessment-IR (HOMA-IR) measures. Changes in IR seen current annual standards (15 mg/m3).
with PM2.5 were incremental to that of high fat diet alone
Los Angeles: 3,992 women in the Black Women’s Health
over a period of 24 weeks. Mean concentration of PM2.5
Study: NO2 exposure by LUR and PM2.5 by local monitors;
was 60–65 mg/m3 (10-fold from ambient levels). Tumor
Results: NO2 exposure associated with 10-year incidence
necrosis factor (TNF)-a, interleukin-6 (IL-6), resistin,
of DM (adjusted HR 1.25; 95% CI 1.07–1.46); PM2.5 not
and leptin levels were all elevated following PM2.5
related
exposure in keeping with a proinflammatory insulin
An unanswered question exists regarding latent
resistant state. PM exposure also resulted in elevations
period of air pollution exposure. Does high air pollution
in prothrombotic adipokines such as plasminogen
exposure cause priming effects that manifest their
activator inhibitor 1 and increased circulating adhesion
risk even after a certain time of low exposure? Air
molecules such as intracellular adhesion molecule-1 and
pollution exposure sources are often located indoors.
E-selectin.
Household indoor air pollution concentrations often
In subsequent experiments, effect of PM2.5 exposure
exceed outdoor concentrations by a factor of two to
early in life with and without concomitant exposure to a
five and even occasionally up to a factor of 100. Air
high-fat diet was evaluated. C57BL/6 mice fed a normal
pollution concentrations in work environment are also
diet but exposed for 10 weeks exhibited metabolic
often higher than the mean concentration outdoors.
abnormalities including an increase in HOMA-IR and Air pollution concentrations indoors and in work
postprandial glucose that approached those seen environments have not yet been studied in relation to
with high-fat chow diet–fed mice exposed to filtered T2D. Another important gap is that role of potential
air. In another study, intratracheal exposure of PM2.5 environmental confounders, such as noise and reduced
potentiated IR at end of three weeks in high-fat fed male greenness, that are correlated with air pollution have not
rats. yet been extensively evaluated.
Taken together, these experiments do suggest Available evidences do support adverse effects
important interaction of PM2.5 exposure with high-fat of air pollution on diabetes. Its related high public
diet and they raise possibility that early life may represent health impact of an association justify need for further
a vulnerable period of enhanced susceptibility to PM2.5 investigations. More studies are needed to establish how
exposure effects. and to what extent air pollution control measures may
reduce global diabetes related burden of disease.
Human Studies
Ontario, Canada: 7,634 patients attending Individual BIBLIOGRAPHY
chronic exposure to two respiratory clinics NO2 (traffic- 1. Andersen ZJ, Raaschou-Nielsen O, Ketzel M, et al. Diabetes
related pollution) using LUR result : 1 ppb NO2 increased incidence and long-term exposure to air pollution: a cohort
the OR for DM prevalence (1.04; 95% CI 1.00–1.08) in study. Diabetes Care. 2012;35:92-8.
women; no significant association in men. 2. Beard J, Sladden T, Morgan G, Berry G, Brooks L, McMichael
A. Health impacts of pesticide exposure in a cohort of
Ruhr, Germany: 1776 nondiabetic women, PM10 (Mean: outdoor workers. Environ Health Perspect. 2003;111:724-
47; IQR 10 mg/m3) adjusted HR for developing DM over 30.
mean 16 years ranged from 1.15 to 1.42 per IQR increase 3. Brook RD, Jerrett M, Brook JR, Bard RL, Finkelstein MM. The
relationship  between diabetes mellitus and traffic-related
in PM10 or in relation to traffic exposures or NO2.
air pollution. J Occup Environ Med. 2008;50:32-8. 
United States, wide ecological study. Cross-sectional 4. Coogan PF, White LF, Jerrett M, et al. Air pollution and
data of. 2,700 counties, multiple models of long-term incidence of hypertension and diabetes mellitus in black
PM2.5 exposure adjusted DM prevalence associated at women living in Los Angeles. Circulation. 2012;125:767-72.
5. Lee DH, Lee IK, Jin SH, Steffes M, Jacobs DR Jr. Association National Health and Nutrition Examination Survey 1999–
between serum concentrations of persistent organic 2002. Diabetologia. 2007;50:1841-51.
pollutants and insulin resistance among nondiabetic adults: 7. Lee, et al. Diabetes Care. 2006.
results from the National Health and Nutrition Examination 8. Van Donkelaar A, et al. Use of satellite observations for long-
Survey 1999–2002 Diabetes Care. 2007;30:622-8. term exposure assessment of global concentrations of fine
6. Lee DH, Lee IK, Por ta M, Steffes M, Jacobs DR Jr. particulate matter. Environ Health Perspect. 2015;123:135-
Relationship between serum concentrations of persistent 43.
organic pollutants and the prevalence of metabolic 9. Wang, et al. Diabetes Care. 2008.
syndrome among non-diabetic adults: results from the
CHAPTER
34
Musculoskeletal Manifestations
of Diabetes Mellitus
INTRODUCTION TABLE 1: Musculoskeletal diseases commonly seen with diabetes

Diabetes mellitus leads to a number of musculoskeletal High association Moderate association with Dubious
abnormalities causing varying degrees HBA1c of morbidity. with diabetes diabetes association with
diabetes
Musculoskeletal complications, though less valued
zz Limited joint zz Adhesive capsulitis zz Carpal tunnel
compared to vascular ones, significantly compromise
mobility zz Neuropathic arthropathy syndrome
the quality of life of patients by causing morbidity,
syndrome zz Dupuytren’s contracture zz Osteoarthritis
pain and disability. The improved life expectancy has zz Muscular zz Flexor tenosynovitis zz Gout
increased the prevalence and clinical importance of the infarctions zz Diabetic amyotrophy
musculoskeletal changes. The causative factors for bone Diffuse
zz
zz Reflex sympathetic
and muscle diseases associated with diabetes include idiopathic dystrophy
low bone turn-over status, impaired Ca-metabolism, skeletal zz Osteoporosis
enhanced bone resorption (due to Ca and P release hyperostosis zz Septic arthritis
into urine), impaired parathyroid function, increased
oxidative stress, skeletal muscle contraction, ectopic fat
The changes begin in MCP and PIP joints of the
accumulation in muscles, etc., causing joint/muscle/
little finger and extend medially and may also involve
tendon abnormalities and enhanced fracture risk. It is
the distal interphalangeal joints. It may also involve
difficult to classify musculoskeletal conditions associated
with DM, because most of the pathophysiological larger joints such as the wrist, elbow, ankles, cervical
mechanisms remain obscure and the role of glycemic and thoracolumbar spine. The limitation is painless and
control is yet to be fully understood (Table 1). non-disabling. Involvement of the foot may contribute
Brief descriptions of some of the most common to abnormal foot pressures and damage. Limited Joint
musculoskeletal problems seen in diabetic population Mobility (LJM) can be elicited by the ‘Prayer sign’
are given here. (Fig. 1A) or the ‘Table-top sign’ (Fig. 1B).
Duration of diabetes is the most important variable
LIMITED JOINT MOBILITY/ in the onset of LJM/RS whereas the development of joint
ROSENBLOOM SYNDROME changes is determined by age rather than the duration of
The prevalence of Rosenbloom syndrome (RS), also diabetes. Limitation of joints can be mild, moderate or
known as diabetic hand syndrome, is 9–60% among severe. Mild limitation involves one or two PIP joints, one
T1DM patients and about 25–76% in T2DM. large joint or only the MCP joint bilaterally.
A B
Figs 1A and B: (A) Prayer sign in LJM; (B) Tabletop sign in LJM
Cervical joint involvement and obvious hand HYPEROSTOSIS

deformity at rest constitutes the severe form of LJM. Increased bone mineral density in Type 2 DM leads to
Incidence studies show that there is a strong relation diffuse idiopathic skeletal hyperostosis (DISH) which
between HbA 1c and LJM. For every 1% increase in may involve the spine, skull, pelvis or ligaments or as
average HbA1c from onset, there was approximately 46% large bony spurs at the heel or elbow. There may be mild
increase in the risk of LJM/RS. stiffness on rising in the morning, but the spinal mobility
is preserved and severe symptoms are usually absent.
ADHESIVE CAPSULITIS OF
Differential diagnosis of hyperostotic spondylosis is
THE SHOULDER ankylosis spondylosis. About 2–4% of general population
Adhesive capsulitis of the shoulder (ACS) is characterized may have hyperostotic changes, whereas it is about 25%
by pain in shoulder joint with restricted rotatory in the diabetic population. About 50% of all the patients
movement. The association between ACS and diabetes with hyperostosis are likely to have diabetes or IGT.
is well established with an incidence between 11–30%. Obesity and diabetes appear to operate independently in
Bilateral involvement is more common in diabetic
the determination of this condition. A line of calcification
subjects. Recent studies from India reported an incidence
in the right anterolateral position of spine, typically in
of around 18% of it in diabetes patients. The treatment
thoracic region with preservation of disc space is seen
options include non-steroidal anti-inflammatory drugs
radiologically (Fig. 2). Hyperinsulinemia for prolonged
(NSAIDs) and physiotherapy.
periods is may lead to new bone growth.
DUPUYTREN’S CONTRACTURE/DISEASE
Dupuytren’s contracture refers to subcutaneous fibrosis
CARPAL TUNNEL SYNDROME
of the palmar aponeurosis of the hands. Its incidence Carpal tunnel syndrome (CTS) is characterized by
among diabetic patients ranges 20–63% as compared to paresthesia over the thumb, index finger, middle
13% among the general population. It is characterized finger and a part of ring finger which is caused by
by focal flexion contracture associated with thickening the compression of median nerve while traversing
of palmar fascia with occasional tethering of skin. through the carpal tunnel. Diabetic neuropathy may
The treatment includes physiotherapy, NSAID, and worsen the symptoms. The overall prevalence of CTS is
intralesional glucocorticoid injections. Occasionally 11–16% with predominance in patients with diabetes.
surgical release of contracture is necessary. Analgesics, local splints and steroid injections constitute
CHAPTER 34: Musculoskeletal Manifestations of Diabetes Mellitus 205
Fig. 2: Radiograph of thoracolumbar spine showing hyperostosis Fig. 3: Trigger finger (Flexor tenosynovitis)
the treatment options. Surgery may be necessary, if there a development phase, a coalescence phase and a
is no improvement with conservative measures. remodeling phase. The off-loading of the affected joints
by total contact casts forms the mainstay of management
FLEXOR TENOSYNOVITIS of the disease.
Flexor tenosynovitis (FTS) or ‘Trigger Finger’ is due
to the proliferation of the fibrous tissue in the tendon DIABETIC AMYOTROPHY
sheath particularly over the pulleys (Fig. 3). The Diabetic amyotrophy is characterized by proximal lower
signs and symptoms include the locking in flexion or limb pain due to wasting and weakening of muscles.
extension with palpable or audible crepitus during Asymmetric loss of tendon jerks is typically observed. It
finger movements. The prevalence of FTS is around 11% occurs commonly in elderly males with type 2 diabetes
among and is linked to the duration of diabetes and not mellitus (T2DM) and weight loss. Management consists
age. Surgical decompression may be done in severely of stabilizing blood glucose levels and physiotherapy.
symptomatic cases.
OSTEOPOROSIS
NEUROARTHROPATHY A change in bone mineral density is seen in both T1DM
(CHARCOT’S JOINTS) and T2DM. In T1DM, the bone mineral density and bone
This condition results from impairment of joint sensa mass are reduced, though the mechanism is not clear
tions leading to progressive painless joint destruction and is detectable early in the disease. In T2DM, there
that can be established radiographically (Figs 4A and is increased incidence of fracture rates despite normal
B). Charcot’s joint are seen mostly in aged diabetics with bone mineral density due to increased bone porosity.
prolonged history of diabetic neuropathy. The weight
bearing joints are mostly affected, particularly, foot and DIABETIC MUSCLE INFARCTION
ankles. It occurs in chronic diabetics with uncontrolled blood
Patients remain unaware about the underlying sugar and microvascular complications. Patients present
changes in the foot structure due to poor sensation with acute pain and swelling of muscle which generally
and hence continue to mobilize. There are four stages subsides with conservative treatment. There is higher
of this condition: a prodromal inflammatory phase, risk of recurrence.
A B
Figs 4A and B: Radiographs showing Charcot’s joint
REFLEX SYMPATHETIC DYSTROPHY BIBLIOGRAPHY

Reflex sympathetic dystrophy (RSD) (algodystrophy/ 1. Baker JC, Demertzis FL, Rhodes NG, Wessel DE, Rubin DA.
sudeck’s atrophy) is a complex regional pain syndrome Diabetic musculoskeletal complications and their imaging
mimics. RadioGraphics 2012;32:1959-74.
affecting sympathetic nervous system characterized by
2. Deshmukh DP, Akarte AG. Musculoskeletal manifestations
localized or diffuse pain, usually with associated swelling, in type 2 diabetres mellitus. Int J Res Med Sci. 2017;5:398-
trophic changes and vasomotor disturbances. Treatment 402.
includes analgesics, physiotherapy, intravenous 3. Hordon L. Limited joint mobility and other musculoskeletal
bisphosphonates/calcium, blockade of sympathetic problems in diabetes. J Diab Nursing. 2016;20:166-70.
ganglion and occasional use of oral corticosteroids. 4. Husni ME, Kroop SF, Simon LS. Joint and bone manifestations
of diabetes mellitus. In: Khan CR, et al. (Eds). Joslin’s
Diabetes Mellitus. 14th edn. Philadelphia, Lippincott
CONCLUSION Williams and Wilkins, 2005;1061-8.
People with diabetes mellitus are at increased risk for 5. Inaba M (Ed). Musculoskeletal diseases associated with
bone and muscle diseases. Poor glycemic control for diabetes, 6th ed. 2016, Tokyo, Springer 296.
longer durations causes higher complication rates 6. Merashli M, Chowdhury TA, Jawad ASM. Musculoskeletal
manifestations of diabetes mellitus. Q J Med. 2015;108:853-7.
and worsening of several musculoskeletal/rheumatic
7. Sarkar R N, Banerjee S, Basu AK, Bandopadhyay D.
conditions. Early diagnosis, sensible pharmacotherapy,
Rheumatological manifestations of diabetes mellitus. J Ind
diet, and a regular monitored physiotherapy program aid Rheumatol Assoc. 2003;11:25-9.
in maintaining the glycemic control and minimizing the 8. Silva MBG, Skare TL. Musculoskeletal disorders in diabetes
musculoskeletal problems and related morbidities. mellitus. Rev Bras Reumatol. 2012;52:594-609.
9. Smith LL, Burnet SP, McNeil JD. Musculoskeletal
manifestations of diabetes. Br J Sports Med. 2003;37:30-5.
10. Umesh KS, Ranganatha YP, et al. Musculoskel and joint
manifestations in type II diabetes mellitus. Am J Adv Drug
Delivery 2015;3:59-63.
CHAPTER
35
How to Hold the HOLD?
HOLD refers to the ‘clustering’ of a number of metabolic prevalence increases with age. The increased prevalence
abnormalities namely Hypertension, Obesity, Lipid of metabolic syndrome in younger generation is very
abnormality and Diabetes. This is what has been viewed alarming. It implies to have a more prolonged exposure
as metabolic syndrome. Distinct clinical features and to atherosclerotic risk factors. HOLD prevalence is
metabolic predispositions are frequently noted in significantly more in among upper socioeconomic classes
people with abdominal adiposity, insulin resistance, compared to lower socioeconomic strata.
dyslipidemia, and hypertension. Current definitions
of metabolic syndrome differ and cardiovascular risk PECULIARITIES OF HOLD IN INDIA
appears to differ according to which component risk For any given BMI, Indians have more body fat in
factors present. comparison with whites and black Africans. It leads
There is greater cardiovascular risk with HOLD. It to higher levels of plasma non-esterified fatty acid
has been found that metabolic syndrome predisposes to and triglycerides and hyperinsulinemia. It has been
fivefold greater risk of developing diabetes in comparison found that 30–65% of adult urban Indians having either
with those without it. It also predisposes three times to
have a heart attack. Indians are highly Insulin resistant TABLE 1: Prevalence of metabolic syndrome in India
even with mild increase in (BMI) body mass index or
Author Percentage by NCEP- Year
abdominal adiposity. Interestingly compared with White ATP III
Caucasian neonates, Indians neonates have a higher Chow et al. 26.9% male, 2008
level of hyperinsulinemia as recorded at birth. [Atherosclerosis, 2007.] 18.4% female [Andhra
Pradesh rural areas]
PREVALENCE (TABLE 1) Deepa et al. 18.3% [Southern India] 2007
[Diabets Met Res Rev, 2007
The prevalence of HOLD is influenced by genetic
Swant et al. 19.52% [Mumbai] 2011
background, age, sex, unhealthy diet, levels of physical [Cholestero, 2011
activity, socioeconomic, environmental (obesogenic
Ramchandran et al. 41% [Urban Chennai] 2003
environment) and urbanization mainly. Different studies [Diabetes Res Clin Pract
from India show differences in prevalence of HOLD 2003;60:199–204]
components. Prevalence varies in different Indian studies Rajendra Pradeepa et al. 41.9% [South India]
in tune of urban (35%) and rural (19%). In both sexes, [JAPI, Vol.64(5) 2016]
overweight or obese have a direct correlation with the can hold the HOLD by tackling multiple risk factors like
increasing prevalence of HOLD. behavior modification, dietary modifications, physical
activity enhancement, and by modifying smoking and
MECHANISTIC CHARACTERISTICS alcohol habits. Individual-based approach has been
High qualities studies have shown that nutrient found beneficial but to have a wider impact population-
overload and lack of physical exercise are responsible based community intervention is needed.
for insulin resistance and metabolic derangements.
Once hyperinsulinemia occurs it can induce elevation BEHAVIORAL MODIFICATION
of blood pressure by activation of sympathetic nervous Individual behavior modification must be directed
system and renin angiotensin aldosterone system. Thus towards bad-eating habits. It should be rewarded, if
volume expansion, endothelial dysfunction and renal children and younger adults especially correct their
dysfunction are consequential. habits. For older individual, more efforts are needed. We
Recently, it has been proposed that unexpected rise must try for sustainable goal-based lifestyle interventions.
of HOLD cannot be explained only by traditional risk
factors and role of persistent organic pollutants (POPs) is Dietary Modifications (Fig. 1)
now deciding core component of epidemic of HOLD in The most important interventions should target
India. Recent plethora of research provide evidence that reduction in high salt intake, and reduction in intake
exposure to POPs commonly present in food chains leads of saturated fat and refined carbohydrate. Reduction
to insulin resistance and associated metabolic disorders. in high intake of sweetened beverages is in priority
considering that Indian adolescents prefer nowadays
How to hold the HOLD (Flow chart 1) too much. We must impress younger generation to
It is important to quantify factors contributing to HOLD. revert back to our traditional diets. These days due to
Increasing awareness of cluster of risk factors and how to nutritional transition Indians are tuned to take higher
prevent them comprehensively should be emphasized saturated and Tran’s fat containing food stuffs. They take
in population-wide prevention strategies in Indians. We too much salted snacks and processed food in between
Flow chart 1: How to hold the HOLD?

CHAPTER 35: How to Hold the HOLD? 209
meditation and relaxation responses have been quoted

in AHA statement in 2017.
GETTING RID OF PERSISTENT

ORGANIC POLLUTANTS
Persistent organic pollutants are these days being
considered as one of the key factors in causation of HOLD
as they behave as endocrine disruptors. Awareness
level is extremely low. Now regulatory authorities have
formulated a plan to curb use of POPs pesticides listed
Fig. 1: Evidence-based diet priorities to hold HOLD in Stockholm Convention. But, individual awareness on
how to pick-up organic food, proper washing of fruits
meals. Faulty nutrition during perinatal period and early
and vegetables, improving fish cleaning and cooking
childhood are known to influence insulin resistance and
methods need sustained efforts. At community level,
metabolic abnormalities. All-cause mortality is reduced
advocating elimination of POPs from industrial sources,
by taking more whole grains, fruits and vegetables, nuts
waste incineration and power generation are practical
and fish. This has been shown by recent meta-analysis.
solutions.
Thus population based approach to encourage these
items is urgently needed. Dietary modifications are one
Community-based Interventions (Table 2)
of the best ways to treat insulin resistance.
To curb obesogenic lifestyle, we need intervention at
schools. Children’s are amenable to change more easily.
PHYSICAL ACTIVITY
The school interventions should be considered as golden
To make insulin sensitive, physical activity is the magic
opportunity to halt the pathological process as this
Indians need to appreciate. It is key to increase energy
time reversibility is possible. In India, improvements
expenditure and achieve a sustainable weight loss. It
to nutritional quality of food supply available to
reduces blood pressure and boosts HDL. A walking
masses can be achieved through reformulations .It is a
programmer should be formulated for community. It
complementary strategy.
should be started gradually and graded. We must impart
It should also focused on sodium intake. Industry-
the scientific message in simplest manner. We can tell
wide food reformulations could benefit the entire
that how just as 150 min per week of moderate intensity
population irrespective of diet and health behaviors. It
physical activity is sufficient to modify all components of
will be a cost-effective approach.
HOLD. Not only aerobic activity but resistance exercises
and also needed to make insulin sensitive. It is high time
TABLE 2: Factors in the built environment which need to modify
to educate masses to break prolonged sedentary time.
Role of yoga to up-regulate beta cells of pancreas Urban planning that promotes car use, necessitates long commutes,
and restricts opportunities for walking
is quite clear in studies and community intervention
Limited and/or unsafe public space for recreational physical activity
is further needed to be make it accessible. Recently and for children to walk to school
American Heart Association (AHA) has endorsed The pervasive presence of food outlets and opportunities to eat
meditation as a beneficial intervention to reduce usually fast, energy-dense foods
cardiovascular risk. Insight meditation, mindful Increasing dependency on prepared foods, usually consumed away
meditation, Zen meditation, Raja Yoga, transcendental from home
There is a great need of quantification of environ BIBLIOGRAPHY

mental variables such as air pollution, traffic patterns, 1. Bhat RA, et al. Prevalence of the metabolic syndrome
and urban density in India. There are now incipient among North Indian adolescents using Adult Treatment
efforts to identify major factors in the built environment Panel II and pediatric International Diabetic Fedrerations.
Arch Med Health Sci. 2015;3:44-9.
associated with excess weight gain. We need a war to
2. Gressier M, Privet L, Kevin Mathias C, Vlassopoulos A,
correct these environment variables to curb HOLD. Vieux F, Masset G. Modeled dietary impact of industry-wide
food and beverage reformulations in the United States and
France. A m J Clin Nutr. 2017;106(1):225-32.
PHARMACOLOGICAL INTERVENTIONS
3. Paolo Magni, et al. Prospective: Improving Nutritional
There is no role of pharmacological interventions at Guidelines for Sustainable Health Policies: Current Status
present to hold the HOLD. and Perspective. Adv Nutr. 2017;8:532-45.
4. Prasad DS, Kabir Z, Dash AK. Prevalence and risk factors
for metabolic syndrome in Asian Indians: A community
Final Points study from urban Eastern India. J cardiovasc Dis Res.
How can we swing the pendulum back to a healthier BMI 2012;3(3):204-11.
5. Pundit K, Goswami S, Ghosh S Mukhopadhyay P, Chowdhary
level?
S. Metabolic syndrome in South Asian Indian. J Endocr
We can generate massive awareness on preventive Metab. 2012;16:44-55.
measure in schools and workplace. A sustainable, 6. Schwingshack L, Hoffman G. Diet quality as assessed by the
integrated and coherent prevention plan can change the Healthy eating Index, the Alternate Healthy Eating Index, the
unhealthy aspects of community living environment. Dietary Approaches to Stop Hypertension score, and health
We must remember that obesity is not a disorder of outcomes: a systemic review and meta-analysis of cohort
studies. J Aca Nutr Diet. 2015;115:780-800e5.
individual behavior. It is the socioeconomic environment
7. Schwingshackl L, Schwedhelm C, Hoffmann G, Lampousi
that brings components of HOLD to a large extent. A, Knüppel S, Iqbal K, et al. Food groups and risk of all-
Newer technology based social networks have a great cause mortality: a systematic review and meta-analysis of
role nowadays to modify lifestyle changes. All the prospective studies. Am J Clin Nutr. 2017;105(6):1462-73.
stakeholders need commitment to define a novel and 8. Sharma S, Aggarwal N, Joshi B, Suri V. Prevalence of
traditionally acceptable approach towards obstacles in metabolic syndrome in pre- and post–menopausal women:
A prospective study from apex institute of North India.
ways of healthy nutrition and physical exercise. These
Journal of Mid-life Health: 2016;7(4):169-74.
combined effects are responsible for improvement of 9. Tyrovolas S, Koyanagi A, Olaya B, et al. The role of muscle
systemic insulin sensitivity and metabolic homeostasis. mass and body fat on disability among older adults: a cross-
It paves ways to hold the HOLD. national analysis. Exp Gerontol. 2015;69:27-35.
CHAPTER
36
Dyslipidemia Management: Newer Avenues
Nirupam Prakash
INTRODUCTION failed to achieve LDL levels <2.5 mmol/L (95 mg/dL).

Dyslipidemia is a proven key factor in the accentuation Of these 27% were on combination therapy of high
of cardiovascular risk. The most commonly used drugs dose statins and ezetimibe.
High dose of statins may be intolerant or associated
to treat hypercholesterolemia are 3-hydroxy-3-methyl-
glutaryl (HMG) CoA reductase inhibitors, commonly with adverse effects. Although variably defined and
reported, incidence of statin intolerance ranges from
known as statins. Guidelines for the management of
5% to 20%.6
dyslipidemia have undergone an overall shift from LDL-
60–80% of residual risk remains even after control of
lowering targets to a focus on addressing risk reduction,
LDL levels which has been attributed to causation of
with statins being recommended as the most effective,
20% of CV events in individuals with coronary heart
safest and established way to achieve it. Statins in general
disease who achieved optimal LDL levels.
have been shown to reduce LDL-C by 30–60%, providing
Other agents like niacin and fibrates which reduce
an estimated 25–30% reduction in CVD. However, there
lipid fractions have not produced additional CV
are certain limitations of this approach and hence there
risk reduction over and above that of statins,
is a need to find newer therapeutic approaches:
excepting Ezetimibe in IMPROVE IT trial. Ezetimibe
Optimal LDL lowering may not be achieved in many
demonstrated a 24% greater LDL lowering which
patients despite administering highest dose of statins. contributed to modest 6% relative and a 2% absolute
Studies show that as many as 37% of subjects may not risk reduction in the primary CV endpoints.
achieve their LDL targets. Furthermore, nonachievers Statins use is not only associated with beneficial
may range from 40% to 80% in high-risk individuals increase in LDL receptors but also with an increase
and subjects with CVD. Also great interpersonal in PCSK9 (proprotein convertase subtilisin kinase
variability in reduction of lipid parameters viz. 9) levels a serine protease which degrades LDL
LDL-C, non-HDL-C, and apo B has been reported receptors and negate its beneficial effect.
with a fixed statin dose. Newer approaches in management of Lipid disorders
Genetic lipid disorders may be refractory/less which focus on alternate pathways viz CETP activity,
responsive to effect of statins. In an observational correction of low and dysfunctional ApoA1 molecules
study of statin treated subjects with heterozygous (HDL) and elevated triglyceride levels to reduce risk of
familial Hypercholesterolemia, approx 21% subjects atherosclerosis and CVD are being discussed as under:
Proprotein Convertase Subtilisin/Kexin In Patients with ASCVD (Atherosclerotic

Type 9 (PCSK9) Inhibitors Cardiovascular Disease)
PCSK9 is a serine protease which binds to the LDL In patients with stable (ASCVD) with additional
receptor on hepatocytes and prompts internalization risk factors, with LDL-C>70 mg/dL or non-HDL-C
of LDL receptors, lysosomal uptake and breakdown, >100 mg/dL on maximally-tolerated statin therapy ±
thereby making them unavailable for LDL uptake by ezetimibe. Strength A, Quality: High
the hepatocytes. Gain-of-function (GOF) mutations in In patients with progressive ASCVD with LDL-C >70
the PCSK9 gene decreases the number of LDL rceptors. mg/dL or non-HDL-C >100 mg/dL on maximally-
Loss of-function (LOF) mutations in the PCSK9 gene is tolerated statin therapy ± ezetimibe. Strength B,
associated with 28–40% lower levels of plasma LDL-C Quality: Moderate
and 88% reduction in risk for coronary heart disease In patients with LDL-C >190 mg/dL (including
(CHD). Therefore, interventions aimed at inhibition of polygenic hypercholesterolemia, heterozygous FH
PCSK-9 using monoclonal antibodies, small interfering and the homozygous FH phenotype)
RNAs, antisense oligonucleotide and mimetic peptides In patients ages 40–79 years with pretreatment
have been tried, to negate its binding to LDL receptors. LDL-C >190 mg/dL, no uncontrolled ASCVD risk
factors, or other key additional high-risk markers,
Approaches for PCSK9 Inhibition and on-treatment LDL-C >100 mg/dL or nonHDL-C
Currently monoclonal antibodies Evolocumab and >130 mg/dL on maximally-tolerated statin therapy
Alirocumab have shown great promise in clinical trials. ± ezetimibe, to further reduce LDL-C. Strength B,
The third molecule bococizimab is in Phase III clinical Quality: Moderate
trials. These agents have been found to lack effectiveness In patients aged 40–79 years with pre-treatment LDL-C
in LDLR deficient individuals. Both evolocumab and >190 mg/dL and presence of either uncontrolled
alirocumab when given subcutaneously have been ASCVD risk factors/key additional high-risk markers/
shown to reduce LDL levels by 60% when used as genetic confirmation of FH, and after treatment
monotherapy or as add on to maximum statin therapy. LDL-C >70 mg/dL or non-HDL-C >100 mg/dL on
The two agents have been approved for use in subjects maximally-tolerated statin ± ezetimibe. Strength: B,
with Heterozygous Familial Hypercholesterolemia Quality: Moderate
(HeFH), statin intolerant subjects and individuals In patients aged 18–39 years with pre-treatment LDL-C
not reaching goal LDL level with maximum statin >190 mg/dL and presence of either uncontrolled
therapy esp in high risk individuals with ASCVD with/ ASCVD risk factors/key additional high-risk markers/
without coexisting T2DM. Use of Evolocumab has been genetic confirmation of FH, and after treatment
shown to produce atherosclerotic plaque regression in
comparison to placebo in GLAGOV trial. Summary of TABLE 1: Summary of Clinical Trials establishing the role of
Clinical Trials establishing the role of PCSK9 inhibitors PCSK9 inhibitors in management of dyslipidemia
in management of dyslipidemia is provided in Table 1. Mode of inhibition Molecule characteristic Agents
Results from long-term studies like ODYSSEY outcomes, PCSK9 binding Human monoclonal Evolucumab,
ODYSSEY OLE and FH TAUSSIG would shed further light antibody Alirocumab
on their efficacy in reducing cardiovascular events. Humanized monoclonal Bococizumab
antibody
With recent series of positive trials for PCSK9
Modified binding protein Adnectin
inhibitors, the National Lipid Association 2017
Small molecule inhibitors SX-PCSK9
recommends their use in following situations to further
PCSK9 synthesis RNA interference ALN-PCSsc
reduce LDL-c levels.
CHAPTER 36: Dyslipidemia Management: Newer Avenues 213
TABLE 2: Clinical trials

Trial Study characterstics Result
Hereditary heterozygous hypercholesterolemia trials
ODYSSEY FH I N=486, Aliroc (75 mg/150 mg Q2W) vs Placebo on Max- −48.8 LDL reduction (Alirocu)
Phase 3 tolerated statin ± other LMT for 24 wk +9.1 (P)
Phase III Mendel 2 Evolocumab monotherapy >50% LDL reduction
Gauss 2 Evolocumab monotherapy >50% LDL reduction
Rutherford 2 N=331 subjects on Statin ± LMT for 12 wk Evolocumab 59% (2 wkly) and 61% (monthly) LDL reduction vs
140 mg 2 wkly and 420 mg 1 monthly vs placebo −2.0 (P Q2W) and +5.5 (p QM)
Homozygous familial hypercholesterolemia
TESLA Part B N=50; Diet + LMT, Evo (420 mg Q4W) vs Placebo 12 wk −23.1% reduction vs +7.9% (placebo)
Phase 3
Hypercholesterolemia and high cardiovascular risk
ODYSSEY COMBO II N=720, Max-tolerated statin, Aliroc (75 mg/150 mg Q2W) vs LDL reduction of 50.6% (Aliro) and 20.7 (EZE)
Phase III Placebo + EZE for 24 wk
Statin intolerance trials
ODYSSEY ALTERNATIVE, N=361; on lipid modifying therapy; aliroc vs EZE 24 wk 75 45.0% LDL reduction Aliroc vs
Phase 3 mg Q2W 14.6% (EZE)
GAUSS-2 N=307 low-dose statin ± LMT; Evo (140 mg Q2W, 420 mg −56.1% (P Q2W) vs −18.1(P)
Phase III QM) vs Placebo + EZE 12 wk −52.6% (P QM) vs −15.1 (P)
IVUS/Diabetic/CV risk reduction trials
GLAGOV (IVUS) N=968; On statins >4 wks with LDL >80 mg/dL or LDL –56.5 mg/dL LDL reduction (36.6 evo vs 93
60–80 with >1 major/3 minor CV RF, Epicardial stenosis placebo); percent atheroma vol ↓ 0.95% vs nil in
20–50%; Evo (420 mg QM) vs placebo; 78 wks placebo
ODYSSEY Diabetes N=413, T2DM with mixed dyslipidemia at high-risk of CVD; –32.5% Non-HDL-c vs Standard care.
Dyslipidemia Aliroc (75 mg/150 mg Q2W)vs standard therapy for 24 +
8 wks
FOURIER N=27564, ASCVD and LDL<70 mg/dL on maximal statin; –59% LDL(92 mg/dL–30 mg/dL); significant
Evo (140 mg Q2W, 420 mg QM) vs placebo; 48 wks reductionin primary end point (9.8% vs 11.3%)
FU median 2.2 yrs HR0.85; NNT 1 event of 67 treated for 2 yrs
LDL-C >100 mg/dL or non–HDL-C >130 mg/dL on Microsomal Triglyceride Transport

maximally-tolerated statin ± ezetimibe. Strength: E, Protein (MTP) Inhibitor
Quality: Low MTP expressed in the hepatocytes and enterocytes,
In patients with homozygous familial hypercholester- plays an essential role in transport of triglycerides,
olemia (unknown genotype/defective LDL receptor) cholesterol esters and phospholipids to Apo B molecules
on maximally-tolerated statin therapy ± ezetimibe and synthesis of VLDL and Chylomicrons. Hence, MTP
with LDL-C >70 mg/dL or non–HDL-C >100 mg/dL. inhibition provides a key therapeutic target to reduce
Strength B, Quality: Moderate synthesis and secretion of triglyceride rich VLDL in
Very-high-risk/statin intolerance: In selected very- liver and Chylomicrons in enterocytes. Clinical trials
high-risk patients with statin intolerance, requiring have demonstrated additional 38–50% reduction in
substantial additional atherogenic cholesterol LDLc over statin treatment with use of oral Lomitapide
lowering, despite the use of other lipid-lowering therapy on titration from 5 mg/day to 60 mg/day
therapies. Strength C, Quality: Low (Table 2). Inhibition of dietary fat absorption may
account for observed side effects of diarrhea, nausea and No reduction in markers of atherosclerosis viz
abdominal pain. Similarly, inhibition of VLDL synthesis plaque burden (ILLUSTRATE) and CIMT thickness
in liver produces trapping of triglycerides in the liver (RADIANCE 1 and 2) observed with torcetrapib.
and accounts for dose dependent increase in hepatic Increase in CRP levels reported with use of Dalcetrapib
steatosis and elevation in liver enzymes. Lomitapide is in the dal–OUTCOMES trial and Evacetrapib in the
currently approved for use in subjects with homozygous ACCENTUATE trial.
familial hypercholesterolemia. CETP inhibition with Dalcetrapib, produced minimal
reduction of LDL-c and Apo B levels in the dal-

Antisense Oligonucleotide Against OUTCOMES study. Polymorphism in ADCY9 gene
Apolipoprotein B (Apo B) being incriminated to account for pharmacogenomic
Inhibition of Apo B synthesis, a major structural variation observed in response to Dalcetrapib.
Low CETP levels in patients treated with statins has
protein of atherogenic LDL molecules, by antisense
oligonucleotide molecule mipomersen provides another been associated with increased mortality, suggesting
alternative approach to dyslipidemia management. that mere lowering of CETP levels in dyslipidemics
Mipomersen binds to Apo B mRNA as it shares a might not produce desired benefits.
It is also suggested that it’s just not the HDL number
complimentar y oligonucle otide s e quence and
inhibits translation and synthesis of Apolipoprotien but the HDL functional status determined by its
B molecule. This binding further makes the Apo B size, density, shape, surface and composition that
mRNA molecules susceptible to degradation by RNases. accounts for its antiatherogenic or proatherogenic
Mipomersen given in doses of 50–400 mg every 3 weeks activity. CETP inhibition possibly may increase the
subcutaneously, produced a dose dependent reduction dysfunctional HDL accounting for loss of efficacy and
in LDL-c and Apo B levels of up to 35–50%. Significant CV benefit.
LDL reduction with mipomersen therapy has been Newer molecules, anacetrapib and TA-8995 have
demonstrated in heterozygous and homozygous familial shown to increase HDL levels without adverse effects on
hypercholesterolemic subjects. Mipomersen therapy aldosterone levels, sodium, potassium levels and systolic
has been associated with injection site reactions, flulike or diastolic blood pressure. Results of the recently
symptoms, elevated liver transaminases and hepatic concluded, REVEAL trial with anacetrapib have shown
steatosis. CV benefit and holds promise for the future (Table 3).
CETP INHIBITORS
Although epidemiological studies provide definite TABLE 3: REVEAL trial with anacetrapib
association of low levels of HDL with increased CV risk,
Trial Study characteristics Result
the same has not been reproduced with interventions
aimed at increasing HDL levels. The studies with CETP Define N=Anacetrapib (100 mg/d) vs + 138.1% HDL;
control + other LMT for 76 wk in +44.1 Apo A1;
inhibitors (Torcetrapib, Dalcetrapib and Evacetrapib)
pts with CHD/at risk (>20%) of CHD −39.8% LDL;
have not shown any positive benefits. The possible −31.7% non-HDL
reasons are as under: (Anacetrapib) +9.1
Off target hyperaldosteronism causing increase in (P)
systolic blood pressure (by mean 5.4 mm Hg) and Na+ Reveal N=30000; Anacetrapib (100 mg/d) 9% reduction in risk
retention induced by Torcetrapib, as being a possible vs control + Atorva 20-80 mg/d of major CV events
> 50 yrs subjects with high r/o (10.8% vs 11.8%)
cause of increase in CV (25%) and all cause mortality
CVD(prev h/o CVD/CVA) 4 yrs
(58%) in the ILLUMINATE trial.
CHAPTER 36: Dyslipidemia Management: Newer Avenues 215
Therapies of the Future peptides maintain their efficacy when administered

orally and promote the formation and function of
Anti-PCSK9 Vaccination
endogenous lipoprotein molecules mainly HDL through
Animal studies to explore the feasibility of anti-PCSK9
the following mechanisms:
vaccination (AT04A vaccine) have been conducted in Associate with endogenous lipids
genetically modified APOE*3-Leiden, CETP mice, which Activate enzymes associated with HDL maturity and
were fed on fatty, western-style food in order to induce remodelling

high cholesterol and the development of atherosclerosis. Promote cholesterol efflux
The administration of AT04A vaccine reduced the total Bind to oxidized lipids
amount of cholesterol by 53%, atherosclerotic damage to Possess anti-inflammatory and antioxidant properties
blood vessels by 64%, and reduced by 21–28% biological Bind to lipid in the intestine and inhibit absorption
markers of blood vessel inflammation compared to The science of Apolipoprotein mimetics is still
unvaccinated mice. The induced antibodies were evolving with molecules like D4F, L4F and Apo A1 helix
functional over the whole study period with high 10 mimetics showing promising but mixed results of
concentrations maintained even at the end of the study. efficacy and yet not definite mode of action.
In contrast monoclonal antibodies (alirocumab and
evolocumab) show relatively short in vivo half-lives and Antisense Approach Against
therefore to produce long-term efficacy requires frequent Lipoprotein(a)
application and translate into high cost. IONIS APO(a) Rx and IONIS APO(a)LRx (ligand
conjugated) are two oligonucleotide molecule which
Apolipoprotein A1 (ApoA1) Mimetics inhibit Lp(a) synthesis. Oligonucleotide mediated
These class of drugs are designed to mimic the action inhibition of Lp(a) synthesis is shown to reduce their
of Apo A1 or HDL molecules to reverse the progression levels by 71–92%.
of atherosclerosis mainly through promoting reverse
cholesterol transport. The concept of use of ApoA1 arose, PCSK-9 Inhibition (Nonmonoclonal
when it was observed that individuals harbouring a Antibody)
variant of ApoA1 (Apo A1 Milano) had long lifespans and Small interfering RNA (siRNA) molecules have been
low atherosclerotic burden inspite of having low HDL targeted at mRNA of PCSK9 molecules, inducing RNA
levels. Since then trials with Apo A1 Milano have been induced silencing and degradation of PCSK9 mRNA
designed to study its role in prevention of CVD. Clinical and reducing its protein synthesis. Inclisiran a siRNA,
studies with infusion of Apo A1 Milano for 5 weeks administered as a single subcutaneous injection of
in patients with acute coronary syndrome has shown 300 mg in the phase 2 ORION trial produced 51%
regression in atheroma volumes by 4.2% as assessed on reduction in LDL levels over 6 months period.
intravascular ultrasound. In the AEGIS-1 trial, 4 weekly
infusions of CLS112 (a plasma derived Apolipoprotein Adenosine Triphosphate
A1 reconstituted and stabilised into disc shaped HDL) Citrate Lyase Inhibitor
when administered to subjects with acute MI showed Bempedoic acid is first in the class ATP citrate lyase
enhanced cholesterol efflux. inhibitor which inhibits cholesterol synthesis and
Following the success of apolipoprotein A1 infusion upregulates LDL-c receptors and LDL-c reuptake by
in regression of atherosclerosis, short synthetic hepatocytes. The ongoing Phase 3 CLEAR-Harmony
peptides with sequence homology to parts of natural and subsequent CLEAR outcomes trial will shed further
apolipoprotein have been designed retaining their in light on the efficacy and CV outcomes with the use of
vivo functional efficacy. These Apolipoprotein mimetic Bempedoic acid in subjects with increased CV risk.
PPAR Agonists future for individuals with high CV risk, statin intolerance
Saroglitazaar a dual acting PPAR α and γ acting has shown and genetic dyslipidemia definitely seems hopeful.
efficacy in patients with diabetic dyslipidemia. However,
results of trials to prove its efficacy in reducing CV BIBLIOGRAPHY
outcomes are yet awaited. MBX-8025, a selective PPAR δ 1. Ahn CH, Choi SH. New drugs for treating dyslipidemia:
Beyond statins. Diabetes Metab J. 2015;39(2):87-94.
receptor agonist plays important role in regulating lipid
2. Bergheanu SC, Bodde MC, Jukema JW. Pathophysiology
storage and transport. Trials are underway to prove its
and treatment of atherosclerosis: Current view and future
role in management of dyslipidemia. perspective on lipoprotein modification treatment. Neth
Heart J. 2017;25:231-42.
Angiopoietin like 3 (ANGPLT-3) 3. Ito MK, Santos RD. PCSK9 inhibition with monoclonal
ANGPLT-3 protein is the main regulator of lipid antibodies: Modern management of hypercholesterolemia.
metabolism which acts by inhibiting lipoprotein lipase The Journal of Clinical Pharmacology. 2017;57(1):7-32.
activity. Subject with low ANGPLT-3 levels have low 4. Kosmas CE, De Jesus E, Rosario D, Vittorio TJ. CETP
Inhibition: Past failures and future hopes. Clinical Medicine
cholesterol and triglyceride levels. Antisense inhibitors
Insights: Cardiology. 2016:10:37-42.
of ANGPLT-3 protein have been shown to reduce TG 5. Update on the use of PCSK9 inhibitors in adults:
levels by 66% and total cholesterol by 36%. Recommendations from an Expert Panel of the National
With promising results coming in from newer Lipid Association. Journal of Clinical Lipidology. 201;11(4):
therapeutic approaches to control dyslipidemia, the 880-90.
CHAPTER
37
Metformin versus Insulin in Treatment
of Gestational Diabetes Mellitus
American Diabetes Association (ADA) in the year 2017 hepatic glucose uptake, and decreased post-prandial
defines gestational diabetes mellitus (GDM) as diabetes insulin secretion. Women who have normal pancreatic
that is first diagnosed in the 2nd or 3rd trimester of function, have adequate insulin production for matching
pregnancy that is not clearly either pre-existing type 1 up with the insulin resistance during pregnancy and are
or type 2 diabetes. Females who have been diagnosed able to maintain glucose levels within normal levels,
with diabetes in the 1st trimester are said to have but women with GDM, cannot cope up with this stress
pre-existing pre-gestational diabetes (mainly type 2 and develop hyperglycemia which necessitates the
diabetes). Seshiah et al. reported in 2008 that GDM was treatment.
detected in 17.8% women in urban areas, 13.8% and 9.9%
in semiurban and rural areas in their study in which DIAGNOSIS OF GDM
prospective screening was done for GDM. The frequency There are two approaches to diagnose GDM and either of
of GDM is the highest in Indian women among all Asian two strategies can be used:
populations. 1. “One-step” 75-g OGTT.
2. “Two-step” approach with a 50-g screen followed by a
100-g OGTT.
MECHANISM OF DIABETES
IN PREGNANCY One-step Strategy
Increased insulin resistance lies at the core of GDM Screening for GDM is done in women who are not
pathogenesis. Insulin resistance increases during the diagnosed diabetic, at 24-28 weeks of pregnancy. Patient
2nd and initial part of 3rd trimesters and returns to the is advised fasting for minimum of 8 hours, after which 75
baseline level around the later part of the 3rd trimester. g OGTT (Oral Glucose Tolerance Test) is carried out and
There is a state of “facilitated insulin action” during 1st blood sugar is measured at 1 hour and 2 hour. Following
half of pregnancy and “diabetogenic stress” in the 2nd cut-off values have been set to diagnose GDM (Table 1):
half. This “Stress” is because of interplay of various factors Fasting plasma glucose: 92 mg/dL
such as high levels of counter-regulatory hormones (viz. 1 h plasma glucose: 180 mg/dL
progesterone, estriol and HCS) as well as decreased 2 h plasma glucose: 153 mg/dL
TABLE 1: Cut-off values set to diagnose GDM Increased RBC turnover during pregnancy results
TIME Carpenter/Coustan NDDG criteria in decreased HbA 1c levels. The target level of A 1c in
criteria pregnancy is 6–6.5%. Keeping it 6% is optimal, if not
Fasting 95 mg/dL 105 mg/dL associated with significant hypoglycemia, but the target
may be relaxed to 7%, if required to avoid hypoglycemia.
1 hour 180 mg/dL 190 mg/dL
2 hour 155 mg/dL 165 mg/dL TREATMENT MODALITIES OF GDM

3 hour 140 mg/dL 145 mg/dL
Life Style Modification, Medical Nutrition
NDDG, National Diabetes Data Group.
Therapy and Role of Exercise
*The ACOG recommends either 135 mg/dL or 140 mg/dL. A systema-
tic review determined that a cut-off of 130 mg/dL was more sensitive
After diagnosis, treatment is started with medical
but less specific than 140 mg/dL. nutrition therapy, weight management and physical
activity depending on pre-gestational weight. Low-
Two-step Strategy carbohydrate, low-fat (7% of total caloric intake),
Step 1: At 24–28 weeks of gestation, a 50-g glucose calorie-restricted may be effective in the short-term.
tolerance test (irrespective of fasting or nonfasting) is Low glycemic diet reduces the postprandial rise and
performed and plasma glucose is measured at 1 hour. If thus the need of insulin in GDM. At least 150 min per
measured plasma glucose levels, 1 h after the load is >130 week of moderate physical activity such as walking is
mg/dL, or >135 mg/dL, or >140 mg/dL* (different cut- recommended for women with GDM. Studies suggest
offs in different guidelines), a 100-g OGTT is performed. that about 70–85% of women with GDM can achieve
Step 2: Screened women are subjected to 100 g OGTT good glycemic control with lifestyle modification alone.
after 8 hour of fasting. Women are said to have GDM, if at
least 2 of the following 4 plasma glucose values are met Pharmacological Treatment
or exceeded: Early initiation of pharmacologic therapy is advocated in
The World Health Organisation (WHO) recommends
women who have higher degree of hyperglycemia at the
that “a standard OGTT should be performed after
time of presentation. Starting insulin and reducing HbA1c
overnight fasting (8–14 hours) by giving 75 g anhydrous
to <6.5% reduces the complications. Controlling the
glucose in 250–300 mL water. Plasma glucose is
postprandial sugar which is correlated to macrosomia is
measured as fasting, 1 hour and 2 hours after meal. Cut-
crucial. ADA, NICE and ACOG guidelines recommend
off values are:
Fasting: 92–125 mg/dL
the institution of insulin, if MNT fails to achieve glucose
1 hour: 180 mg/dlL
targets in women with GDM for 2 weeks (if FPG > 90 mg/
2 hours: 153–199 mg/dL
dL and 2-hour PG > 120 mg/dL). Insulin may also be
started early, if plasma glucose levels after fasting and at
GLYCEMIC TARGETS IN GDM 2-hour PP are >120 mg/dL and >200 mg/dL, respectively.
Postprandial (PP) monitoring has been found to be Types of insulin can be used during pregnancy are shown
associated with better glycemic control and reduced in Table 2.
risk of pre-eclampsia in females with GDM. Fifth Rapid-acting bolus insulin analogs may be preferred
International Workshop-Conference on GDM has given to regular insulin in view of better control of postprandial
following target values: glucose and lesser risk of hypoglycemia, although there
Fasting: <95 mg/dL and either is no benefit in perinatal outcomes. The disadvantages
1 hour PP: <140 mg/dL or of insulin for the mother include the need for injections,
2 hour PP: <120 mg/dL risk of hypoglycemia, increased appetite and weight
CHAPTER 37: Metformin versus Insulin in Treatment of Gestational Diabetes Mellitus 219
TABLE 2: Types of insulin used during pregnancy TABLE 3: The recommendations as per the latest evidence for the
use of metformin in GDM
Insulin Type Onset Peak Duration Dosing
name effect interval Institution Insulin OHAs
Aspart Rapid acting 15 min 60 min 2 hour At start of MOHFW 2014 RECOMMENDED NOT
each meal RECOMMENDED
Lispro Rapid acting 15 min 60 min 2 hour At start of DIPSI 2013 RECOMMENDED NOT
each meal RECOMMENDED
Regular Short acting 60 min 2–4 6 hour 60–90 CDA 2013 RECOMMENDED Metformin as
hour minutes alternative
before meal ACOG 2013 RECOMMENDED Equally effective as
first line therapy
NPH Intermediate 2 hour 4-6 8 hour Every 8 hour
acting hour ADA 2017 RECOMMENDED May be used
Insulin Long acting 2 hour - 12 hour Every 12 NICE 2015 RECOMMENDED Offer to those who
detemir hour deny insulin
gain. Insulin glargine, Glulusine and Degludec are not is mainly because of increased insulin resistance. The
recommended for use in GDM. recommendations as per the latest evidence for the use
of metformin in GDM is summarized in Table 3.
COMPARISON OF INSULIN VERSUS
METFORMIN IN GDM CONCLUSION
Insulin is the mainstay of pharmacologic therapy of Meta-analysis of various studies has now shown that
GDM. ADA, NICE and ACOG guidelines recommend metformin use and insulin therapy had comparable
to start insulin therapy, if MNT fails to achieve blood glycemic control profile. Metformin causes less neonatal
glucose targets in women with GDM. Amongst oral hypoglycemia, less weight gain in mothers as compared to
hypoglycemic agents only 2 drugs have been advocated in insulin and is more useful in PIH patients but associated
the management of GDM viz. Metformin and Glyburide with higher risk of prematurity. Glyburide causes more
(pregnancy category B drugs). There are some RCTs to macrosomia. ADA 2017 recommends that patients
support the efficacy and short-term safety of these drugs, who are being treated with OHAs should be counselled
but these are known to cross the placenta. There is lack of that metformin crosses the placenta. Although no fetal
data to support their long-term safety. Some studies have adverse effects have been demonstrated with metformin
shown that no significant difference is seen in controlling the long-term data regarding neurodevelopmental
high blood sugar in GDM with the use of metformin or outcomes are lacking. However, the guidelines from
insulin. MOHFW and Diabetes in Pregnancy Study Group in
Metformin also lowers the risk of pregnancy-induced India (DIPSI) does not recommends metformin use in
hypertension. When compared with insulin metformin GDM at present.
in a meta-analysis has shown to have lower average
2-hour postprandial glucose levels in the first week BIBLIOGRAPHY
after randomization as compared to insulin group, 1. Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I,
Corcoy R. Glibenclamide, metformin, and insulin for the
possibly because metformin reduces hyperglycaemia
treatment of gestational diabetes: a systematic review and
by suppression of glucose output from liver, increasing meta-analysis. BMJ. 2015;350:102.
insulin sensitivity and enhancing peripheral glucose 2. Diagnostic criteria and classification of hyperglycemia
uptake which is significant in GDM as this condition first detected in pregnancy: A World Health Organization
Guideline. Diabetes Research and Clinical Practice. 4. Seshiah V, Banarjee S, Balaji V. Consensus Evidence-
2014;103(3):341-63. based Guidelines for Management of Gestational Diabetes
3. Jiang YF, Chen XY, Ding T, Wang XF, Zhu ZN, SuSW. Mellitus in India. J Assoc Physicians India. 2014;62(Suppl
Comparative efficacy and safety of OADs in management 7):55-62.
of GDM: network meta-analysis of randomized controlled 5. Standards of Medical Care in Diabetes 2017, ADA guidelines.
trials. J Clin Endocrinol Metab. 2015;100:2071-80. (Standards of Medical Care in Diabetes—2017. http://care.
diabetesjournals.org.
CHAPTER
38
Early Initiation of Insulin
Therapy in Diabetes Mellitus
INTRODUCTION initiation. Furthermore, various trials showed delayed

Diabetes mellitus is one the most prevalent chronic insulin therapy after two or more oral antidiabetic
endocrine disorder. Its prevalence was booming in the drugs is associated with increased risk of recurrent
past few decades. International Diabetes Federation hypoglycemia, weight gain and higher complications.
(IDF) estimated one-fifth of adult diabetics reside Few trials demonstrate enhanced insulin sensitivity
in Southeast Asia. Current 2015 estimates indicate and secretion with early basal insulin. Thus, early
prevalence of diabetes in Indian subcontinent to be initiation of basal insulin provides favorable outcome for
8.8%, i.e. 153 million. The expected prevalence by maintenance of β-cell function.
2040 is approximately 9.0%, i.e. 215 million diabetics.
Similarly, the prevalence of impaired glucose tolerance CONCEPT AND EVOLUTION OF
is estimated to rise from 6.2% (106 million) to 7.2% BASAL INSULIN
(130 million). The pathological changes are secondary Insulin was originally derived from extracts of pork
to metabolic dysregulation in disease. These impose and beef pancreas. As methods of insulin purification
enormous morbidity on individual and financial burden and extraction improved leading to lesser antigenicity
on health care of a country. Achieving adequate control and fewer ill effects. Long acting insulin was developed
of hyperglycemia reduces disease related mortality in the late 1980s as neutral protamine Hagedorn
and morbidity. (NPH, isophane). NPH acted by a depot formation
American Diabetes Association (ADA) recommends postinjection. Thus, insulin slowly released with slower
treatment initiation with lifestyle modification and onset of action. But, it had various drawbacks like early
metformin. As observed by the daily practice of general morning hypoglycemia, hyperglycemia and variable
physician in India, we prescribe oral antidiabetic duration of action. With the evolution of recombinant
drugs as second and third line add on therapy. We DNA technology native human insulin was contrived.
delay insulin initiation, as far as possible due to lack These lead to more physiologically accepted insulin with
of awareness or poor patient compliance. Even in rapid absorption and predictable onset and duration of
the presence of unsatisfactory target HbA 1c and the action. In early twenty-first century basal insulin concept
presence of harmful complications we try to delay insulin evolved with the introduction of glargine.
Glargine is recombinant human insulin with acidic basal insulin with either GLP-1 Analog or short acting
solution leading to consistent depot formation with slow insulin for adequate control of HbA1c.
release. It showed predictable pharmacodynamics with a Multiple studies have shown injectable insulin with
smooth peak less 24 hours action. This resembles basal better achieved fasting and 2 hours postprandial glucose
insulin secretion of a healthy nondiabetic pancreas. compared oral agents in 2–3 months trials. Hanefeld et al.
Furthermore, it had no delirious effects like NPH. Various EARLY study showed significant reduction in HbA1c from
studies showed effective HbA 1c reduction and lower 8.7% to 7.4% after 24 weeks of insulin therapy. Patients
weight gain. also attained FBG levels and had better compliance
Detemir is modified analogue human insulin. compared to a maximum dose of oral agents. In a study
Addition of fatty acid leads to a longer duration of by S Jain showed baseline HbA1c reduction by 1.93% in
action. Detemir is pH neutral, thus enabling liquid form combined injectable therapy compared with 0.3% of
following injection, which differs from NPH and glargine. combined oral agents. Similarly Chen Hs in 2011 showed
In comparison to NPH, detemir is associated with fewer greater reduction of HbA1C from 11.3% baseline to 7.84%
complications like hypoglycemia and antigenicity. vs 11.9% baseline to 6.78% in oral agent vs basal insulin
Degludec is newest basal insulin introduced with respectively over 6 months. Moreover, early initiation
longest duration of action, i.e. more than 24 hours. of basal insulin showed better preservation of β-cell
Degludec is slowly and steadily absorbed, thus offers function and improved insulin sensitivity. Fonsea et al
simple titration with algorithm and shows more flexibility in 2008 observed similar benefits of early vs late use of
with the patient’s lifestyle. basal insulin. Similarly, hypoglycemia episodes were
lower with long acting basal insulin compared to oral
ROLE OF INSULIN IN TREATMENT OF hypoglycemic agent.
TYPE 2 DIABETES MELLITUS Weng J et al in 2008 showed that in vitro experimental
Insulin is the most potent glucose lower agent available hyperglycemia has toxic effects on pancreatic β-cell
at present. The initiation of insulin is feared by most function. With euglycemia these effects showed a
patients. Even physician delay its use, rather it should reversal in the form of improved β-cell function and
be a collaborated decision. The physician should insulin secretion. This concept was tested by Pennartz et
educate and motivate them. Various factors should be al in 2011 in new onset diabetes showed improved β-cell
taken into account like age, overall general health, cost, function with early initiation of glargine on a daily basis.
number of hypoglycemic episodes, macrovascular and Certain long-term studies have indicated the presence of
microvascular complications. metabolic memory in overt diabetes.
In ORIGIN (Outcome Reduction with an Initial
BENEFITS OF INSULIN THERAPY Glargine InterveNtion) results after a median follow-
IN DIABETES MELLITUS up of 6.2 years, concluded that all cause mortality or
Early Vs Late Use cardiovascular risk was similar in glargine group vs
ADA 2017 guidelines recommend that newly diagnosed standard care group. Hence, it disproved the belief of
diabetic with HbA1c less than 9% should initiate with increased cardiovascular risk with pre-diabetic or early
lifestyle modification and metformin monotherapy. type 2 diabetic with early insulin intervention.
Recommendations are made for HbA1c ≥ 9% to initiate
with dual therapy, i.e. metformin with either of BARRIERS TO BASAL INSULIN
sulfonylureas or DPP-4 inhibitors or SGLT-2 inhibitors IN TYPE 2 DIABETES MELLITUS
or GLP-1 analog or insulin. Whereas when HbA1c ≥ 10% Several surveys and studies were conducted to identify
or blood glucose ≥ 300 mg/dL or patient is symptomatic, barriers to diabetes care holistically, including insulin
recommended is combination injectable therapy with therapy, healthcare provider, doctor, patients and
CHAPTER 38: Early Initiation of Insulin Therapy in Diabetes Mellitus 223
their families. In second Diabetes Attitude, Wishes, or 10–20%. If target HbA 1c is not reached then either
and Needs (DAWN2) survey included over 15,000 the addition of a GLP-1 analog or rapid acting insulin
healthcare providers, patients and family members in should be added before largest meal. If still HbA1c is not
17 countries. The study concluded that nearly 2/3rd of controlled, then two or more boluses of rapid acting
the healthcare providing staffs need resources, training insulin with each meal or switch to pre-mixed insulin
and reimbursement to educate patients regarding self should be considered.
glucose monitoring and insulin therapy. Of 8596 patients
included in DAWN2 one-fourth reported suboptimal BIBLIOGRAPHY
self-monitoring. One-third reported worries about 1. Ghosal S, Batin M. The diabetes epidemic in India: where
hypoglycemia and one-fourth reported high disease we stand and future projections. Journal of the Indian
related stress. Family members reported high level of Medical Association. 2013;111(11):751-4.
frustration in not knowing how to help the individual 2. Gleason C, Gonzalez M, Harmon J, Robertson P. In
with diabetes; about one half were worried about various subjects determinants of glucose toxicity and its
reversibility in beta cell of the pancreatic islet, HIT-T15.
hypoglycemia and one half perceived as a financial
American Journal Physiology Endocrinology Metabolism
burden.
2000;279:E997-E1002.
In a 2013 study conducted by Sujeet Jha et al stated 3. Hanefeld M, Koehler C, Hoffmann C,Wilhelm K, Kamke
that most patients had psychological constraints to W: Effects of targeting fasting glucose level with long
insulin therapy, including fear of injection, social stigma, acting basal insulin glargine on glycaemic variability and
high gender based opposition by females, lack of home hypoglycemia risk with early diabetes: A randomized,
support and ineffective interpersonal interaction with controlled study. Diabetes Med. 2010;27:175-80.
healthcare providers. 4. Hu Y, Li L, Xu Y, Yu T, Tong G, Huang H, Bi Y, et al. Short-
term intensive therapy of insulin in newly diagnosed type 2
Similar results were published by Manjula GB in 2013
diabetes which partially restores both insulin sensitivity and
stating psychosocial and financial as major constrains
beta-cell function with long-term remission. Diabetes Care.
followed by fear of hypoglycemia and lack patient 2011;34(8):1848-53.
education. 5. International Diabetic Federation Atlas, 7th edition, South-
east regional data fact sheet, 2015.
HOW TO START INSULIN? 6. Larkin Mary E. Overcoming of psychological barriers to
Firstly, all patients should be well educated regarding insulin use in diabetes. US Endocrinology. 2008.pp.46-8.
their chronic condition, assessed for any complication 7. Lee P, Chang A, Blaum C, et al. Comparison of safety and
efficacy of long acting insulin glargine vs neutral protamine
and long term morbidity.
hagedorn insulin in older adult patients with type 2 diabetes
1. Newly diagnosed diabetes with HbA1c≥ 9% should be
mellitus: A pooled analysis. Journal American Geriatric
initiated on dual therapy, i.e. metformin with basal Society.2012;60(1):51-59.
insulin. 8. ORIGIN TRIAL investigators, Mellbin LG, Ryden L, Riddle MC,
2. In presence of cardiovascular complications basal et al. Does hypoglycemia increases the risk of cardiovascular
insulin should be preferred over oral agents. events? A definitive report from the ORIGIN trial. Eur Heart J.
3. Known diabetic patient on two or more oral agents 2013;34(40):3137-44.
with uncontrolled HbA1c. 9. Peyrot M, Burns KK, Davies M, Forbes A, Hermanns N,
Holt R, Kalra S, et al. Diabetes attitudes wishes and needs
Starting dose is usually 10U/day or 0.1–0.2 U/kg/day.
2(DAWN2): A multinational and multi-stakeholder study of
Titration of dose should be done twice weekly around
person centred care and psychosocial issues in diabetic
10–15% or 2–4 U to achieve target fasting blood glucose. patient. Diabetes Res Clinical Practical. 2013;99(2)174-84.
The patient should be advised to perform self blood 10. Plank J, Bodenlenz M, Sinner F,Magnes C, Gorzer E,
glucose monitoring. In case of hypoglycemia the cause Endahl LA, et al. Investigating the pharmacodynamics
should be addressed with a reduction of insulin by 4U and pharmacokinetic properties of the long-acting insulin
analog i.e.detemir. A double-blind and randomized study. 13. Wangnoo SK, Maji D, Das AK, Rao PV, Moses A, Sethi B,
Diabetes Care. 2005;28(5):1107-12. et al. Barriers and solutions to diabetes management:
11. Porcellati F, Rossetti P, Busciantella NR,Marzotti S, Lucidi An Indian perspective. Indian Journal Endocrinology
P, Luzio S, Owens DR, et al. Comparisons of the long-acting Metabolism. 2013;17(4):594-601.
insulin analogs glargine vs detemirin type 1 diabetes in 14. Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, Hu Y et. al.Effect
pharmacokinetic and dynamics: Double-blind randomized of intensive insulin therapy on beta-cell function in newly
study. Diabetes Care. 2007;30(10):2447-52. diagnosed type 2 diabetes and effect on glycaemic control:
12. Ray KK, Seshasai SR, Sivakumaran R, Nethercott S, et. al. Randomised, multicentre parallel-group trial.Lancet.
A meta–analysis of RCT. Effects of intensive glucose control 2008;24;371(9626):1753-60.
on cardiovascular system outcomes and death in patient
with diabetes mellitus. Lancet. 2009;73(9677):1765-72.
CHAPTER
39
Diabetic Complications in
Indian Scenario: An Update
INTRODUCTION late diagnosis of this disease in our part of the world

Diabetes mellitus (DM) is now a global pandemic. The seriously affects the youth in their most productive years.
global prevalence of diabetes is estimated to increase, Many of the diabetics at the time of diagnosis present
from 8.8% in 2015 to 10.4% by the year 2040. 1 India, with micro-and macrovascular complications. India
China and USA will be the countries with major diabetic with its large number of diabetics faces huge economic
population in the year 2040. 1 Rapid socioeconomic burden. Regarding the difference of Indian diabetics
development, demographic shift, rapid urbanization from the western world few attributes are very important.
and lifestyle changes have led to explosive increase in In Asia especially in India the prevalence of diabetes
the prevalence of diabetes mellitus (DM) over the past is increasing rapidly and the diabetes phenotype
four decades. Little is understood regarding the lower appears to be different from that in the United States
age of onset of DM in India, diabetes occurring at lower and Europe with an onset at a lower BMI and younger
BMI, complications differing from western population, age, greater visceral adiposity and reduced capacity of
more severity of complications in Asians specifically in insulin secretion. It is becoming increasingly apparent
Indians.2 Lack of awareness regarding the disease has led that DM in other ethnic groups (Asians, Africans and
to diabetes mellitus getting diagnosed later in the course Latin Americans) has a different, but yet undefined
of the disease, when one or two of the complications pathophysiology. In these groups, diabetes mellitus that
have already set in. The experience of Indian diabetics is ketosis prone (often obese) or ketosis resistant (often
and its management might be different from those in the lean) is commonly seen.” 2
western world. Regarding the complications, the two landmark
studies of UKPDS in Type 2 DM and DCCT in Type 1 DM
DIABETES IN INDIA have made it clear that tight control of hyperglycemia
According to the Diabetes Atlas published by the reduces the risk of complications in diabetes especially
International Diabetes Federation (IDF), there are an vascular complications to a great extent. In India a
estimated 69.2 million persons with diabetes in India in steep rise in the prevalence of DM and consequently
2015 and this number is predicted to rise to almost 123.5 its complications needs timely intervention in the
million people by 2040, by which time every fifth diabetic form of primary and secondary prevention which
patient in the world would be an Indian.1 As compared will unburden the health care facilities in India. The
to the Europeans, DM appears a decade earlier and diabetic complications can be acute or chronic. Acute
TABLE 1: Chronic complications in DM3

Microvascular complications Macrovascular complications Others
Eye disease: Coronary heart disease zz Gastrointestinal (Gastroparesis, diarrhea)
zz Retinopathy (Proliferative/Non Proliferative) zz Genitourinary (uropathy/sexual dysfunction)
zz Macular edema
Neuropathy: Peripheral arterial disease zz Dermatologic

zz Sensory and motor (mono and polyneuropathy) zz Infectious
zz Autonomic
Nephropathy Cerebrovascular disease zz Cataracts

zz Glaucoma
zz Periodontal disease
zz Hearing loss
Fig. 1: Long-term complications of type 2 diabetes
complications of hyperglycemia are diabetic ketoacidosis MACROVASCULAR COMPLICATIONS

and hyperglycemic hyperosmolar state (HHS). The
Coronary Artery Disease
chronic complications are represented in Table 1.3
Diabetes mellitus, type 2 in particular, is a progressive
macrovascular disease with universally established
COMPLICATIONS IN TYPE 2 DM excessive predilection for coronary arteries irrespective
The long-term complications of diabetes mellitus are of race, ethnicity, gender or geography. The presentation
illustrated in Figure 1. of coronary artery disease (CAD) in a diabetic is more
CHAPTER 39: Diabetic Complications in Indian Scenario: An Update 227
severe and with a higher complication rate than in with type 2 DM, particularly, those with the macrovascular
a nondiabetic. A diabetic subject may present as a disease was found in another recent study from New
case of myocardial infection (MI) or sudden cardiac Delhi. Persistent postprandial hypertriglyceridimia
death without any history of cardiac complaints. The may result in a proatherogenic environment leading to
CAD occurrence has a two to three decades earlier atherosclerosis (AS) and macrovascular disease (MVD)
presentation in diabetic patients as compared to their in T2 DM. 7
nondiabetic counterparts. Women diabetes patients are In the Chennai Urban Population Study (CPUS NO 5),
possibly more prone to develop CAD than men with the prevalence of CAD was 11% in the total population
diabetes.4 and the prevalence of CAD among diabetic subjects was
In Indians, the overall cardiovascular mortality is 21.4%, 14.9 % among impaired glucose tolerance (IGT)
predicted to have risen by 103% in men and 90% in and 9.1% among those with normal glucose tolerance
woman between 1985 and 2015. 1 A subject of great (NGT). The prevalence of CAD in Bikaner study was
concern is that 52% of the CAD death in India occurred in 25.8% and from North Delhi study was 7% in T2 DM
people aged below 70 years while the same was just 22% patients.8,9 A multicentric study conducted by Diabetes
in the developed countries.4 Another study from Eastern India (CINDI) had revealed that the prevalence of CAD
India in a tertiary care hospital revealed that the diabetics in newly diagnosed subjects with type 2 DM was 6%.10
with CAD had a higher prevalence of multivessel disease Incidence of cardiovascular disease among subjects with
along with more extensive involvement as compared to diabetes was 5–6 cases/1000 person years according to
nondiabetic cohort.5 an 11 year follow-up study from south India.11
The multifactorial pathogenesis of CAD in diabetes A North Delhi study regarding the prevalence of
is governed by various risk factors like traditional risk cardiovascular risk factor in the Type 2 DM without
factors viz. gender, increased total or LDL-c, decreased manifestation of overt CAD found that 28.9 % had silent
HDL-c, smoking and diabetes itself. Several novel CAD. This study observed, high LDL-c level and greater
risk factors proposed for CAD like apolipoproteins carotid intima–media thickness (CIMT) are particularly
A1 and B, microalbuminuria, plasminogen activator important parameters that can predict if a patient with
inhibitor–1 (PAI-1), prothrombin fragment 1 and 2, type 2 DM is at risk for silent ischemia.12
accelerated platelet activity and platelet aggregation, The prevalence of CAD amongst diabetics in India is
tissue plasminogen activator, fibrinogen, vascular and presented in Table 2.8-10
cellular adhesion molecules, lipoprotein (a) and insulin
resistance (IR). Cerebrovascular Disease
An urban South Indian study in patients of DM Diabetes is an independent risk factor for stroke. In
with CAD from India revealed a significant finding of patients with DM, there is recurrent stroke associated
increased platelet activation. Collagen induced GP IIb/ with higher mortality, with a female preponderance. The
IIIa binding was significantly higher among diabetic UKPDS study revealed 2.6% patients developed stroke on
subjects with CAD (p <0.05) and without CAD (P<0.05) a follow up of 7.9 years with the prevalence of recognized
and non diabetic subjects with CAD (P< 0.05) compared DM in patients with acute stroke approximating 8–20%
to nondiabetic subjects without CAD. Regression and unrecognized DM is estimated to the between 6 to
analysis showed collagen induced GP IIb/IIIa binding 42%.13 The prevalence of stroke is more than double in
to be significantly associated with CAD [odds ratio (OR) diabetic subjects compared to the general population.
: :1.029, P = 0.025] and diabetes (OR : 1.037, P = 0.007).6 The Indian studies conducted during 1970–80s revealed
A significant postprandial hypertriglyceridimia and incidence of stroke in diabetics varied from 0.5% to 9%.
significant delay in postprandial triglyceride clearance In 2011, our study from Cuttack showed the prevalence
following a standardized fat meal challenge in patients of DM was 38.75% among stroke patients. The same
TABLE 2: Prevalence of CAD amongst diabetics in India8-10,67 TABLE 3: Intima media thickness (IMT) of common carotid artery
(CCA) distribution in relation to comorbidity among patients and
Author Year Place Prevalence
controls14
67
ICMR* 1985-90 Multicentric 8.1% Male
4.7% Female IMT in mm Cases Control p-value
V. Mohan (CUPS-5) 16
2001 Chennai 21.4 Overall mean IMT 0.88 ± 0.19 0.60 ± 0.09 (N 0.000
(Population- (N =80) = 40)
based) IMT in diabetes 0.90 ± 0.16 0.64 ± 0.11(N 0.013
Gupta PB 67
2001 Surat 19% (N = 31) = 14)
67
Gupta S 2001 Nagpur 33.5%-Male IMT in HTN 0.88 ± 0.16 0.65 ± 0.10 (N 0.006
21.5%-Female (N = 53) = 14)
PODIS** 61 2001 Multicentric 4.5% IMT in smokers 0.93 ± 0.20 0.63 ± 0.06 (N 0.000
67
Ramachandran et al 2002 Chennai 11.5% (N = 49) = 17)
Phatak S 55 2002 Ahmedabad 20.2%-Male IMT is a dependable marker of atherosclerosis.
26.1%-Female
J Ahmad et al 66 2007 Aligarh 37.7%
TABLE 4: Pulsatility Index (CCA) distribution in relation to co-
R Chawla 9 2012 New Delhi 7%
morbidities among patients and controls14
A Sosale et al 10 2014 Multicentric 6% (Newly
detected DM) PI in mm Pts. with ischemic stroke Control p-value
RP Agarwal et al 8
2014 Bikaner 25.8% Overall mean PI 1.71 ± 0.18 mm 1.53 ± 0.11 0.000
(N = 80) (N = 40)
*ICMR – Indian Council of Medical Research
PI in diabetes 1.76 ± 0.20 mm 1.49 ± 0.09 0.000
**PODIS – Prevalence of Diabetes in India Study
(N = 31) (N = 18)
PI in HTN 1.69 ± 0.18 mm 1.49 ± 0.09 0.000
study depicted the relationship of carotid plaque, (N = 53) (N = 18)
Intima Media Thickness (IMT), Resistivity index (RI), PI in smokers 1.82 ± 0.22 1.49 ± 0.09 0.000
Pulsatility index (PI) in Asian-Indian patients with (N = 49) (N =18)
acute ischemic stroke with and without type-2 DM.
Resistivity Index distribution in relation to co-morbidities among
These findings are elaborated in Tables 3 and 4.14 The patients and controls
mean CIMT of diabetic subjects was significantly higher
RI in mm Pts. with ischemic Control p-value
than nondiabetic counterparts as showed in the CUPS stroke
study. The prevalence of carotid atherosclerosis was Overall mean RI 0.76 ± 0.05 0.61 ± 0.06 0.000
20% in diabetic subjects as compared to 1% among (N = 80) (N = 40)
nondiabetics.15 In the same population, arterial stiffness RI in diabetes 0.76 ± 0.04 0.59 ± 0.06 0.000
was also greater and endothelial dysfunction was also (N = 31) (N = 18)
severe among diabetic subjects than non diabetic RI in HTN 0.76 ± 0.04 0.59 ± 0.06 0.000
counterparts in the CUPS Study.16 Another study from (N = 53) (N = 18)
South India Endocrine Centre documented 1.12% of RI in smokers 0.77 ± 0.04 0.59 ± 0.06 0.000
(N = 49) (N = 18)
diabetics had a diagnosis of cerebrovascular disease at
the time of presentation.17 Further, studies from India had
revealed that DM is a more common a cause for cerebral Peripheral Vascular Disease
infarction (22.1%) than cerebral haemorrhage (6.35%).18 D i ab e t e s p re s e nt i ng w i t h p e r i p h e ra l va s c u l a r
The data on stroke and CVD in India is inadequate. disease (PVD) is a major risk factor for lower limb
Incidence of DM amongst patients with CVD is amputation and also invariably associated symptomatic
presented in Table 5.19 cardiovascular disease and cerebrovascular disease.
TABLE 5: Incidence of DM amongst patients with cerebro- in type 2 diabetics in a study conducted in Bikaner
vascular disease (prior to the last decade of the past century)19 (Rajasthan) was 28% and North Delhi was 7.4%.8,9 The
Place/Country % most recent study from South India showed prevalence
Study from 11 Countries 2–28 rate 7.6% (Female 11.8%, Male 5.1%) and crude incidence
North Carolina, USA 13.9 17/1000 patient years with progression of PVD seen in
Michigan, USA 18.3 16.5% cases.23
Africa 4-8
Hong Kong 33.5 TYPE 2 DM AND METABOLIC SYNDROME
Das S, Cuttack 8.0 There is sparse data on the prevalence of metabolic
Mumbai 14.2 syndrome (MS) amongst Indian diabetic patients. Basing
Puducherry 32 on the NCEP ATP III guidelines a study conducted
Toole, Janway, Choi 28
on urban Indian diabetic population reported that
the prevalence of MS in 77.2% of patients which was
Even in patients with TIA or VBI, the incidence of DM was as high as 28
significantly higher in females (87.71%) as compared to
and 20% respectively.
males (19.33%) (p<0.0001). This study clearly depicts
It is an underdiagnosed and undertreated entity in that in the urban Indian diabetics MS is highly prevalent.
several countries including India. A fourfold increase So it should be identified by regular screening to avert or
in prevalence is seen in people with DM than in non- delay the progression to type 2 diabetes and its related
diabetics. PVD in T2 DM typically involves the arteries morbidity and mortality.24
below the knee such as anterior tibial, posterior tibial
and peroneal arteries showing arterial stenosis and MICROVASCULAR COMPLICATIONS
occlusion due to atherosclerotic changes in diabetic IN TYPE 2 DM
subjects. The increased prevalence of PVD in patients The microvascular complications of DM include
with diabetes is attributed to added risk factors like retinopathy, nephropathy and neuropathy. The
smoking, hypertension and hyperlipidemia. microvascular disease also can contribute to diabetic
An estimated 20% of symptomatic PVD patients had cardiomyopathy, exacerbation of limb ischemia
diabetes as revealed by the Framingham Heart Study. in diabetic foot. Hyperglycemia, hypertension and
The prevalence rate of PVD in Indian subjects is lower possibly lipid abnormalities provide a solid medium
than that in other ethnic groups. There is a striking for microangiopathy. Multiple pathogenic sequences
difference in the prevalence of CAD and PVD in India, may be triggered, viz advanced glycation end products
despite both being macrovascular disease. CAD occurs (AGE) formation, protein kinase C (PKC) activation
at a much younger age and at high rates while PVD and increased flux through the polyol (sorbitol) and
appears to show opposite trend, i.e. lower prevalence hexosamine pathways, all of which culminate in
and occurrence at older age groups. The different trend oxidative stress resulting in pathological vascular
of these two complications may be attributable to the remodeling, altered vascular tone, changes in the
differences in risk factors. basement membrane and permeability. The subsequent
In Asians, the prevalence of PVD ranges from 3% to 6%. pathogenic changes are peculiar to the concerned
The first population based study in South India (CUPS) target tissues. The mesangium shows an abnormal
reported that the prevalence of PVD was 6.3% among extracellular matrix (ECM) accumulation in diabetic
diabetics compared to 2.7% among nondiabetics.20 The nephropathy. Ischemia due to acellular capillaries
prevalence of PVD was 3.9% and 4% in another South coupled with neovascularization triggered by vascular
Indian clinic based study which included 18 patients endothelial growth factor (VEGF) results in diabetic
with gangrene.21, 22 The reported prevalence rate of PVD retinopathy (DR).25
In New Delhi a recent study, done on the coagulation clinic-based studies to population-based studies. The
profile in diabetes and its possible association with population-based studies show that nearly 1 in every 5
diabetic microvascular complications revealed that diabetic individuals may have DR which is much lower
diabetic retinopathy was associated with decreased than that reported from west.
protein S and increas e d VWF levels. Diab etic The first population based study to document DR
nephropathy was associated with increased PAI-1 and in Indian population was the Chennai Urban Rural
VWF levels whereas diabetic neuropathy did not show Epidemiological Study (CURES), which revealed an
any significant relationship with any of the haemostatic overall prevalence 17.6% (among known diabetics 20.8%
variables. So, for the development of microvascular and 5.1% in newly detected diabetic subjects). Prevalence
complications of diabetes mellitus a hypercoagulable of DME in the total diabetic population was 5.0%. A 5
state as indicated by decreased fibrinolysis and increased year increase in duration of diabetes, increases the risk of
coagulability is responsible.26 DR by 1.89 times and for every 2% increase in HbA1c, the
It has been reported that some associations have also risk of DR increases by factor of 1.75 times was revealed
been noted between different diabetic microvascular by this study.27 A familial aggregation study documented
complications. The presence of diabetic retinopathy that familial clustering of DR was three times higher in
itself may reveal that the patients are at risk of diabetic siblings of type 2 diabetic subjects with DR compared
neuropathy and nephropathy. The CURE study identified to those without DR.29 A study carried out in rural Tamil
some common risk factors like age, glycosylated Nadu, The Chunampet Rural Diabetes Prevention Project
hemoglobin, duration of diabetes and serum triglycerides study (CRDPP Study) showed that the prevalence of DR
for these microvascular complications. The association also increases significantly with duration of diabetes. The
between retinopathy and nephropathy was stronger than prevalence of DR was seen in 6.6% even among diabetic
the association with neuropathy was also proved in the subjects with less than one year duration. According to a
CURE study.27 South India study conducted recently on prevalence and
risk factors for DR in Asian Indians with younger age of
DIABETIC RETINOPATHY onset revealed prevalence of DR in 52.7% in type 2 DM
A p o te nt ia l ly sight threaten i ng m i crova s cu la r patients. The age and gender adjusted prevalence of DR,
complication of diabetes is DR and is also an important DME, PDR in type 2 DM were 65.8%, 12.7% and 9.3%
preventable cause of blindness. DR is one of the respectively.28
hallmark of the disorder and considered as most specific The overall prevalence of DR in different parts of
complication of diabetes. Nonproliferative DR (NPDR) India as per different studies are presented in Tables 6
and proliferative DR (PDR) are the two major forms of and 7.8-10,30
opthalmological complications in T2 DM. The forms
which can lead to blindness are PDR and diabetic DIABETIC NEUROPATHY AND
macular edema (DME). The risk of DR is strongly DIABETIC FOOT
influenced by disease duration, glycemic status and Nearly 50% of all diabetic subjects are affected by diabetic
blood pressure control. The younger age of onset neuropathy (DN) and is considered to be the main cause
especially for type 2 DM may be an added risk for DR. A for morbidity. The severity and duration of hyperglycemia
patient with history of more than 15 years DM is affected governs the intensity and extent of diabetic neuropathy.
by DR in 60% and with a history of more than 25 years of Both type 1 and type 2 diabetes have an equal frequency
diabetes is affected to the tune of 90%.28 of affection. The prevalence of neuropathy varies from
In western population the prevalence of DR at 19% to 33% (clinic based studies) and 13–31% (population
diagnosis varies from 20% to 50% as compared to based studies).30 In an observational study at a tertiary care
5–7.3% in Indians. In India the prevalence varies from centre from Cuttack the clinical diabetic neuropathy were
TABLE 6: Prevalence of diabetic retinopathy in India (Clinic Based TABLE 8: Prevalence of Diabetic Neuropathy in India8-10,30
Studies)8-10,30
Author Year Type of City Prevalence
Author/Year Type of Study Place Prevalence (References) Study (%)
(References) (%) Ramachandran 1999 Clinic-based Chennai 27.5
Rema et al. 1996 63 Clinic-based Chennai 34.1 et al. 55
Ramachandran Clinic-based Chennai 23.7 Ashok et al. 56 2002 Clinic-based Chennai 19.1
et al. 1999 55 Chanda et al. 57 2006 Clinic-based Bengaluru 64.1
Pradeepa et al. Clinic-based South India 37.9 Pradeepa et al. 34
2011 Clinic-based Chennai 33.1
201134 9
Chawla et al. 2012 Clinic-based North Delhi 15.3
Chawla et al. 2012 9 Clinic-based North Delhi 21.2
Sosale et al. 10 2014 Clinic-based Multicentric 13.15 (Newly
Agarwal et al. 2014 62 Clinic-based Bikaner 32.5 detected DM)
Sosale et al. 2014 10 Clinic-based 14 centres 6.1 (Newly Agarwal RP 2014 Clinic-based Bikaner 26.8
detected DM) et al. 8
Pradeepa 2008 Population Chennai 13.1
TABLE 7: Prevalence of Diabetic Retinopathy in India (Population et al. 34 (CURES 55)
Based Studies)8-10,30 Vaz et al. 58 2011 Population Goa (Rural) 60
54
Author/Year Type of Place Prevalence Mohan et al. 2012 Population Chunampet 30.9
(References) Study (%) (CRDPP) (Tamil
Nadu)
Dandona et al. Population Hyderabad 22.4
199959
Though vasculopathy, infections and peripheral
Narendran et al. Population Palakkad 26.8
200260
neuropathy are traditionally blamed for diabetic foot
Rema et al. (CURES), Population Chennai 17.6
(DF), the common cause of diabetic foot problem in
200527 India is peripheral neuropathy. In India, 24% of hospital
Raman et al. 200964 Population Chennai 18 admission and 35% of total hospital days are due to
Vaz et al. 201158 Population Goa (Rural) 15.4 foot problems. Diabetic foot ulcers are common and
Mohan et al. 2012 Population Chunampet 18.2 estimated to affect 15% of all diabetic individuals during
(CRDPP)54 their lifetime. Diabetic foot ulcer precedes almost 85%
of amputations. According to a multicentric study from
in the following order of frequency: distal symmetrical India studying on pattern and cause of amputation
sensorimotor neuropathy, cranial mononeuropathy, in diabetic patients infection in 90% of cases results
mononeuropathy multiplex and autonomic neuropathy.31 in amputation in diabetic patients. The prevalence of
In the low body weight groups of type 2 DM the incidence neuropathy was 82% (high) and 35% had PVD in this
of peripheral neuropathy was common.32 study.35 The prevalence of neuropathy was 15% (n = 193)
A North-East Indian study on young diabetic patients and PVD was 3% (n = 64) in another multicentric study
documented peripheral neuropathy to be common in India. Infections were present in 7.6% (n = 100) of
(43.5%) in patients with fibrocalculous pancreatic patients. In the different centers of India, the infection
disease (FCPD).33 The CURES population based study rate varied from 6% to 11% in DF. Studies have revealed
reported the age-standardized prevalence of neuropathy that a minor or major amputation has to be performed in
to be 13.1% (Known diabetic (KD): 13.6% vs. 11.2% 3% of the patients.36
in Newly Detected DM (NDD), whereas the crude
prevalence rate was 26.1% (KD: 27.8%, NDD 19.5%).34 Diabetic Nephropathy
The prevalence rate of diabetic neuropathy in different The chronic kidney disease (CKD) which often goes
studies is presented in Table 8.8-10,30 unrecognized most of the times are closely related to
hypertension and DM. An epidemiological study by risk for development of ESRD which suggest a genetic
Indian CKD Registry established under the aegis of component apart from environmental and host factors.
Indian Society of Nephrology (ISN) had made certain In our own study from Cuttack there was a
pertinent observations. CKD Registry has documented greater degree of IR and beta-cell dysfunction and
DM as the cause of CKD in 31.2% of patients. CKD also atherosclerosis in diabetics than non-diabetic CKD
leads to CVD as disease progress: in 0.7% in Stage 1 patients. 38 Another study from our institute revealed that
CKD to 48.5% in stageV CKD.37 The SEEK (Screening and proteinuria is common and more related to glycemic
Early Evaluation of kidney disease) study reported a high status. Improvement in proteinuria can be achieved
prevalence of CKD 17.4% (Urban 25.5 versus Rural 9.4%). with strict glycemic control. Microalbuminuria in type-
The main causes of CKD were DM and hypertension.38 2 DM was found to be a marker of generalized vascular
Nephropathy developed in 20.4% of subjects with type 2 endothelial dysfunction.38
DM over years. According to a recent study from Jhansi,
incidence of nephropathy in newly diagnosed type 2 DM OTHER COMPLICATIONS IN TYPE-2 DM
was 17.34% (52/300) and the most important associated There are several other complications which also occur
factor contributing to development of nephropathy was in long-standing type 2 DM patients besides the micro-
hypertension.39 and macrovascular complications. The spectrum of
The prevalence of nephropathy according to different chronic complications of DM are illustrated in Figure 2.
studies are: CURE study (microalbuminuria 26.9%, overt
proteinuria 2.2%), CRDPP study in Tamil Nadu 24.3%, Noncoronary Cardiac Complications
30.2% in Bikaner study (Rajasthan), microalbuminuria Diabetic cardiomyopathy and heart failure (HF),
in 41% patients in North Delhi study. 8,9,40 Various cardiovascular autonomic neuropathy (CAN) and
population-based studies has also observed familial sudden cardiac death (SCD) can occur in addition
clustering of nephropathy. In individuals with a family to CAD. Cardiomyopathy is seen in one third of the
history of ESRD, there was three to nine fold greater diabetic patients. Diastolic dysfunction usually precedes
Fig. 2: Spectrum of chronic complications in DM

systolic dysfunction. Early degenerative changes in and mortality in DM. Diabetes is an independent risk
the conducting system give rise to heart blocks. DM factor for tuberculosis (TB) and there is a three-fold
is an independent risk factor for Congestive Cardiac higher risk of developing TB. Worldwide data suggests
Failure (CCF) in the elderly and every 1% increase in the that diabetes is found in 15% of all tuberculosis and 21%
HbA1c increases the risk of CCF by 15%. Prevalence of of smear positive TB. 46 The prevalence of TB among
DM in people with CCF is estimated to be around 20% diabetic populations in India according to different
compared to 4–6% in control population. Poor glycemic studies are 14% (Bhutia 1975), 4.5% (Bhalkar 1975), 12%
control and longer duration of diabetes increases the risk (Nanda & Tripathy, 1968), 14% (Deshmukh et al, 1966),
of HF in diabetic subjects. In 50–70% of long-standing 5.9% (Patel JC, 1989), etc. A study revealed that in urban
diabetic subjects, there is coexistence of CAN in Indian areas increased prevalence of DM is associated with
studies.41 15.2% greater Smear-positive TB incidence compared
to rural areas. The study predicted that in India 18.4%
Hypertension (12.5–29.9%) of people with pulmonary TB (both smear-
Globally in 40–60% of patients with type 2 DM, positive and smear-negative) have diabetes and that in
hypertension coexists. The prevalence of hypertension the smear-positive group diabetes prevalence is 23.5%
in newly detected type 2 DM was 39% in the HDS- (12–44%).47 Another study revealed that 36% of cases
1 (Hypertension in Diabetes Study) report. Indian suffer from multidrug resistant TB (MDR-TB) amongst
studies showed that about half of the diabetic patients diabetics compared to 10% in nondiabetics (p<0.01) and
have coexisting hypertension. Recently, the cross- out of these 36% of MDR TB patients 23% never received
sectional study, Screening Indians Twin Epidemic (SITE) antitubercular drugs. Death from active TB accounted
conducted in 10 Indian states reported that DM and for 14% in the diabetic group and 1% of nondiabetic
hypertension coexist in 20.6% of patients.42 group. The incidence of extrapulmonary TB was 20%
in diabetic compared to 5% in the nondiabetic group.48
Chronic Liver Disease In a south Indian study conducted recently on diabetes
The etiology of chronic liver disease with and without prevalence among a cohort of TB cases registered under
DM studied by Amarpurkar et al. (2002) from India RNTCP revealed DM prevalence was 25.3% (95% CI 22.6
compared and found higher evidence of nonalcoholic – 28.5) and that of prediabetes was 24.5% (95% CI 20.4-
steatohepatitis (NASH), NASH with cirrhosis of liver 27.6).49 The most common infection seen in diabetes is
and cryptogenic cirrhosis in diabetic subjects than non urinary tract infection (UTI) and is also a common cause
diabetic counterparts. 43 In our study constituting 42 of hospital admission. Symptomatic UTI was reported
patients of NASH, it was observed that the development of to be 14% in mostly menopausal diabetic women in an
NASH was a decade earlier than the western population Indian series.50 In another study, the prevalence of UTI
was likely due to the early onset of Type 2 DM in our was found to be 9%. In a study from north India, mortality
population. About 19 (45.2%) out of 42 patients had related to UTI in diabetic patients was 2.4%.51 Klebsiella
DM 45 , which was very high as compared to study was the most common organism isolated in another
conducted prior by Bacon et al. and Amarpurkar, where Indian study in 11.6% of diabetic patients presenting
the incidence of DM was 21% and 22% respectively.43,44 with pneumonia.50 Mortality due to bronchopneumonia
IR and dyslipidemia rather than the glycemic status were in diabetes was 17.4% in an Indian study. The detail
determinant factors that had positive correlation with infections caused in a diabetic are represented in
the higher histopathological grades of NASH.45 Table 9.52
Infections CONCLUSION
There is an increased susceptibility for various acute In the post-insulin era due to decline of acute
and chronic infections leading to increased morbidity complications and infections in diabetes, the chronic
TABLE 9: Infections in DM52 2. Powers AC. Harrison’s Principles of Internal Medicine, 19th
edn, 2015. pp. 2400-04.
Infections Risk (Proven association)
3. Powers AC. Harrison’s Principles of Internal Medicine, 19th
Tuberculosis 3–6 fold
edn, 2015. pp. 2418-2422.
Bacteriuria in females 4 fold 4. Bahl VK, Prabhakaran D, Karthikeyan G. Coronary artery
Malignant otitis externa 100 % disease in Indians. Indian Heart Journal. 2001;53:707-13.
Emphysematous cystitis 80 % 5. Mishra TK, Das S, Patnaik UK, Routray SN, Behera M.
Necrotising cellulitis 75 % Relationship of metabolic syndrome with quantum of
Emphysematous pyelonephritis 72 % coronary artery disease in Indian patients with chronic
stable angina. Metabolic Syndrome Related Disorders.
Acute papillary necrosis 57 %
2004;2:187-91.
Mucormycosis 42 %
6. Deepa R, Mohan V, Premanand C, Rajan VS, Karkuzhali K,
Emphysematous cholecystitis 38 % Velmurugan K, Agarwal S, Gross MD, Markovitz J. Acclerated
Perinephric Abscess 36 % platelet activation in Asian Indians with diabetes and
coronary artery disease. The Chennai Urban Population
complications more so macrovascular diseases such as Study (CUPS 13). Journal of Associations of Physicians of
India. 2006;54:704-8.
CAD, CVD and PVD have come to the forefront. Though
7. Kumar V, Madhu SV, Singh G, Gambhir JK. Post prandial
macrovascular complications are more common in type hypertriglyceridemia in patients with type-2 diabetes
2 DM it is also a major cause of morbidity and mortality mellitus with and without macrovascular diasease. Journal
in type 1 DM as well. Macrovascular disease has been of Associations of Physicians of India. 2010;58:603-60.
seen to forerun the development of hyperglycemia by 8. Agarwal RP, Ola V, Bishnoi P, Gothwal S, Sirohi P, Agrawal
R. Prevalence of micro- and macrovascular complications
decades suggesting a likelihood of atherosclerosis and
and their risk factors in Type-2 diabetes mellitus. Journal of
DM sharing a common soil for growth and development
Associations of Physicians of India. 2014;62:504-8.
in individuals.53 Amongst macrovascular complication 9. Chawla R. Pathophysiology of diabetes complications:
PVD is less common in Indians than Western diabetics. Indian perspective. In: Joshi SB (Ed). Medicine Update. The
Diabetes care in the Indian context has to start from Association of Physicians of India. 2014;24(2):1361-7.
the roots to prevent the complications. Identification of 10. Sosale A, Prasanna Kumar KM, Sadikot SM, Nigam A, Bajaj
S, Zargar AH, Singh SK. Chronic complications in newly
the high risk category for development of Type 2 DM like
diagnosed patients with type 2 diabetes mellitus in India
age > 40 years, positive family history of DM, increased (CINDI). Indian Journal of Endocrinology and Metabolism.
abdominal fat (waist circumference in males > 90 cm, 2014;18:355-60.
females > 85 cm), prediabetes and people with sedentary 11. Umamahesh K, Vigneswari A, Surya Thejaswi G, Satyavani
life style is important. Targeting the modifiable risk K, Viswanathan V. Incidence of cardiovascular disease
and associated risk factors among subjects with type-2
factors such as obesity, physical inactivity, dyslipidemia,
diabetes. A 11 year follow up study. Indian Heart Journal.
HTN and changing the dietary habits will be of immense 2014;66:5-10.
help in controlling DM and its complications. This has to 12. Agarwal AK, Singla Sweta, Singla S. Prevalence of coronary
be achieved through creating awareness regarding DM risk factors in type–2 diabetics without manifestations of
regular health checkups and catching them young and overt coronary heart disease. Journal of Associations of
Physicians of India. 2009;57:135-42.
treating them properly.
13. Davies TME, Millns H, Stratton IM, Holman RR, Turner RC.
Risk factors for stroke in type 2 diabetes mellitus. United
REFERENCES Kingdom Prospective Diabetes Study (UKPDS 29). Archives
1. Nam Han Cho, David Whiting, Nita Forouhi, et al. IDF Internal Medicine. 1999;159:1097-103.
Diabetes Atlas, 7th edn, Brussels, Belgium: International 14. Das S, Chakrabarty SK, Patnaik M, Roul L, Mohanty J,
Diabetes Federation; 2015. pp. 50-2. Singh SC. The relationship of carotid plaque, intima media
thickness (IMT), resistivity index (R1) and pulsatility index with diabetic microvascular complications. Journal of
(PI) in Asian-Indian patients with Acute ischemic stroke with Associations of Physicians of India. 2010;58:481-4.
and without type-2 DM. International Journal of Clinical 27. Rema M, Premkumar S, Anitha B, Deepa R, Pradeepa R,
Medicine. 2011;2:561-7. Mohan V. Prevalence of diabetic retinopathy in urban India:
15. Mohan V, Kumar RR, Shanthi Rani S, Deepa R. Intimal The Chennai Urban Rural Epidemiology Study (CURES) eye
medial thickness of the carotid artery in South Indian study-1. Investigative Ophthalmology and Visual Science.
diabetic and nondiabetic subjects: The Chennai Urban 2005;46:2328-33.
Population study (CUPS). Diabetologia. 2000;43:494-9. 28. Rajalakshmi R, Amutha A, Ranjani H, Ali MK, Unnikrishnan
16. Mohan V, Deepa R, Rani SS, Premalatha G. Prevalence R, Anjana RM, Narayan KM, Mohan V. Prevalence and risk
of coronary artery disease and its relationship to lipids in factors for diabetic retinopathy in Asian Indians with young
a selected population in south india. The Chennai urban onset type-1 and type-2 diabetes. Journal of Diabetes and
Population Study (CUPS NO 5). J American College of its complications. 2014;28(3):291-7.
Cardiology. 2001;38:682-7. 29. Rema M, Saravanan G, Deepa R, Mohan V. Familial
17. Sridhar GR. Diabetes in India. Snapshot of a Panorama. clustering of diabetic retinopathy in south Indian type-2
Current Science. 2002;83:791-2. diabetic patients. Diabetic Medicine. 2002;219:910-6.
18. Padma MV, Bajaj JS. Diabetes and stroke. In: Bansal BC 30. Mohan V. Epidemiology of complications of diabetes. In:
(Ed). Recent concepts in stroke. Medicine Update. The Chandalia HB (Ed). RSSDI Textbook of diabetes mellitus, 3rd
Association of physicians of India: Mumbai. 1999. pp. 79- edition, Jaypee Brothers Medical Publishers. 2014;169-83.
95. 31. Sahoo R, Gantayat M. Diabetic neuropathy in tropics. In:
19. Das S. Cerebrovascular Complication in NIDDM. Journal of Samal KC (Ed). Diabetes in the Indian Science 6 National
Associations of Physicians of India. 1993;41(Suppl 1):57- Congress on Diabetes, Cuttack. 1990. pp. 83-92.
65. 32. Das S. Introduction. In: Das S (Ed). Low body weight type
20. Premlatha G, Shanthirani S, Deepa R, Markovitz J, Mohan V. 2 diabetes mellitus Technical series. Academic wing of
Prevalence and risk factors of peripheral vascular disease Association of Physicians of India, Mumbai. 1999. pp. 1-4.
in a selected South Indian Population. The Chennai Urban 33. Jyostna VP, Singh SK, Gopal D, Unnikrishnan AG, Agrawal
Population Study (CUPS). Diabetes Care. 2000;23:1295- NK, Singh SK. Clinical and biochemical profiles of young
300. diabetics in North–Eastern India. Journal of Associations of
21. Mohan V, Premalatha G, Shastry NG. Peripheral vascular Physicians of India. 2002;50:1130-4.
disease in NIDDM in South India. Diabetes Research 34. Pradeepa R, Rema M, Vignesh J, Deepa M, Deepa R, Mohan
Clinical Practice. 1995;27:235-40. V. Prevalence and riks factors for diabetic neuropathy in
22. Pendsey S. Peripheral vascular diasease (PVD), in diabetics: an urban South Indian Population: The Chennai Urban
Indian Scenario. International Journal of Diabetes Rural Epidemiology Study (CURES–55). Diabetes Medicine.
Developing countries. 1998;18:31-3. 2008;25(4):407-12.
23. Eshcol J, Jebarani S, Anjana RM, Mohan V, Pradeepa R. 35. Viswanathan V, Kumpatla S. Pattern and causes of
Prevalence, incidence and progression of peripheral arterial amputation in diabetic patients. A multicentric study
disease in Asian Indian Type 2 Diabetic patients. Journal of from India. Journal of Associations of Physicians of India.
Diabetes and its Complications. 2014;28:627-31. 2011;59:148-51.
24. Surana SP, Shah DB, Gala. K, Susheja S, Hoskote SS, Gill 36. Viswanathan V, Thomas N, Tandon N. Profile of diabetic
N, Joshi SR, Panikar V. Prevalence of metabolic syndrome foot complications and its associated complications: A
in an urban Indian diabetic population using the NCEP ATP multicentric study from India. Journal of Associations of
III guidelines. Journal of Associations of Physicians of India. Physicians of India. 2005;53:933-6.
2008;56:865-8. 37. Rajapurkar M, Dobhi M. Burden of disease. Prevalence and
25. Hazra DK, Viswanathan V. Pathogenesis of microvascular incidence of renal disease in India. Clinical Nephropathy.
complications of diabetes. In: Chandalia HB (Ed). RSSDI 2010;74:9-12.
Text-book of Diabetes mellitus, 3rd edn, Jaypee Brothers 38. MV Chandrakanth, Das S, Rout SB, Mohanty R, SC Singh,
Medical Publishers. 2014. pp. 918-34. Pattnaik M, Sethy B. Study of markers of atherosclerosis
26. Madan R, Gupta B, Saluja S, Kansra UC, Tripathy BK, Guliani including insulin resistance in patients with chronic renal
BP. Coagulation profile in diabetes and its association failure. Journal of Diabetes Mellitus. 2012;2(2):208-13.
39. Agarwal N, Sengar NS, Jain PK, Khare R. Nephropathy in 51. Bhansali A, Chattopadhyaya A, Dash RJ. Mortality in
newly diagnosed type-2 diabetes with special stress on the diabetes: A retrospective analysis from a tertiary care
role of hypertension. Journal of Associations of Physicians hospital in North India. Diabetes Research and Clinical
of India. 2011;59:145-7. Practice. 2003;60:119-24.
40. Unnikrishnan RI, Rema M, Pradeepa R, Deepa M, 52. Mohanty SC, Indian Scenario: Infections, NIDUS 1999,
Shanthirani CS, Deepa R, Mohan V. Prevalence and risk Complications of Diabetes in Indian Scenario, S Das (Ed).
factors of diabetic nephropathy in an urban South Indian 53. Das S. Macrovascular disorders in diabetes: Determinants
population. The Chennai Urban Rural Epidemiology study and risk factors. In RSSDI Text Book of Diabetes Mellitus
(CURES 45). Daibetes Care. 2007;30(8):2019-24. 2014;57:749-55. 3rd edn, Jaypee Brothers Medical
41. Mukhopadhyaya J, Ray S. Cardiac autonomic neuropathy in Publication.
diabetes. Medicine Update. API. 2004;14:35-8. 54. Mohan V, Deepa M, Pradeepa R. Screening for diabetes
42. Joshi SR, Saboo B, Vadivale M, et al. Prevalence of and its complications and providing diabetes prevention
diagnosed and undiagnosed diabetes and hypertension and treatment to rural India through a combination of
in India: results from the Screening India’s Twin Epidemic telemedicine and personalized care. The Chunampet Rural
(SITE) study. Diabetes Technology and Therapeutics. Diabetes Prevention Project (CRDPP). Journal of Diabetes
2012;14(1):8-15. Science and Technology. 2012.
55. Ramachandran A, Snehalata C, Sathavani K, Latha E,
43. Amarpurkar D, Das HS. Chronic liver disease in diabetes
Sasikala R, Vijay V. Prevalence of vascular complications
mellitus. Tropical Gastroenterology. 2002;23:3-5.
and their risk factors in Type 2 diabetes. Journal of
44. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri
Associations of Physicians of India. 1999;47:1152-6.
BA. Nonalcoholic steatohepatitis: an expanded clinical
56. Ashok S, Ramu M, Deepa R, Mohan V. Prevalence of
entity. Gastroenterology. 1994;107:1103-9.
neuropathy in type2 diabetes patients attending a diabetes
45. Das S, Singh SP, Parida P, Mallik RN. Non-alcoholic fatty liver
centre in south India. Journal of Associations of Physicians
disease in subjects with type 2 diabetes mellitus and non-
of India. 2002;50:546-50.
diabetics with special reference to insulin resistance and
57. Chanda A, Ayyar V, Idiculla M, Bantwal G. Perception of foot
hepatic histopathological changes. Diabetes and Metabolic
problems among diabetic patients: A cross-sectional study.
Syndrome: Clinical Research & Reviews. 2010;4:226-9.
International Journal of Diabetes in Developing Countries.
46. United Nations, Department of Economic and Social Affairs, 2006;26(2):77-80.
Population division. World Population Prospects: The 2008
58. Vaz NC, Ferreira AM, Kulkarni MS, Frederick S Vaz, Pinto
revision; 2009.
NR. Prevalence of diabetic complications in Rural Goa,
47. Stevenson CR, Forouhi NG, Roglic G, Williams Bg, Lauer India. Indian Journal of Community Medicine. 2011;36(40):
JA, Dye C, Unwin N. Diabetes and tuberculosis: The impact 283-6.
of the diabetes epidemic on tuberculosis incidence. BMC 59. Dandona R, Dandona L. Review of findings of Andhra
Public Health. 2007;7:234. Pradesh Eye Disease Study: policy implications for eyecare
48. Bashar M, Alcabes P, Rom WN, Condos R. Increased services. Current ophthalmology. 2001;49(4):215-34.
incidence of multidrug resistant tuberculosis in diabetic 60. Narendran V, John RK, Raghuram A, Ravindran RD,
patients on the Bellevue Chest Service, 1987-1997-Clinical Nirmalan PK, Thulasiraj RD. Diabetic retinopathy among
investigations. Chest. 2001;120(5):1514-9. self-reported diabetics in southern India: a population
49. Viswanathan V, Kumpatla S, Aravindalochanan V, Rajan R, based assessment. British Journal of Opthalmology.
Chinasamy C, Srinivasan R, Selvam JM, Kapur A. Prevalence 2002;86:1014-8.
of diabetes and prediabetes and associated risk factors 61. Sadikot SM, Nigam A, Das S, Bajaj S, Zargar AH. The burden
among tuberculosis patients in India. PLoS One. 2012; of diabetes and impaired glucose tolerance in India using
7(7):e41367. the WHO 1999 criteria: prevalence of diabetes in India
50. Sridhar CB, Anjana S, Thomas MJ. Acute infections. In: sudy (PODIS). Diabetes Research and Clinical Practice.
Tripathy BB, DAs AK, Rao PV, Madhu SV, Mohan V (Ed). 2004;66:301-7.
RSSDI Text Book of Diabetes mellitus, 1st edn, Jaypee 62. Agrawal RP, Ranka M, Beniwal R, Gothwal SR, Jain GC,
Publishers. 2002. pp. 471-7. Kochar DK, Kothari RP. Prevalence of diabetic retinopathy
in Type 2 diabetes in relation to risk factors: Hospital Based 65. Phatak S, Gupta OP. Pandemic trends in prevalence of
Study. International Journal of Diabetes in Developing diabetes mellitus and associated coronary heart disease in
Countries. 2003;23:16-9. India: their causes and prevention. International Journal of
63. Rema M, Ponnaiya M, Mohan V. Prevalence of retinopathy Diabetes in Dveloping Countries. 2003;23:37-50.
66. Ahmad J, Ahmed F, Siddiqui MA, Khan AR, Katyal P, Hameed
in non insulin dependent diabetes mellitus at a diabetes
B, Ahmad I. Inflammatory markers, insulin resistance and
centre in southern India. Diabetes Research in Clinical
carotid intima media thickness in North Indian type 2
Practice. 1996;34:29-36. diabetic subjects. Journal of Associations of Physicians of
64. Raman R, Rani PK, Rachepalle SR, Gnanamoorthy P, Uthra India. 2007;55:693-8.
S, Kumaramanickavel G, Sharma T. Prevalence of Diabetic 67. Das S, Behera MR. Coronary artery disease in diabetes.
Retinopathy in India. 2009;116(2):311-8. World Clinics Diabetology. 2016;2(1):172-90.
CHAPTER
40
GLP-1 Analogs: Benefits
Beyond Glycemic Control
Rajeev Chawla, Shalini Jaggi
ABSTRACT to achieve stable glycemic control with various other

The global burden of diabetes is increasing exponentially. pleiotropic benefits of beta-cell preservation and
A better understanding of the etiopathogenesis improved insulin sensitivity. Availability of once-weekly
of type 2 diabetes has lead to a pathophysiology- formulations may also improve patient adherence. These
based management strategy with multiple agents to agents can effectively be used in type 2 diabetes patients
who are either uncontrolled on metformin or intolerant
manage hyperglycemia. A delicate balance needs to be
to metformin, and can be combined with most other
maintained to choose agents as per individual profile of
classes of diabetes therapies working on multiple other
each patient to maintain euglycemia while preventing
pathophysiological targets.
undesirable adverse effects of hypoglycemia and weight
gain. Glucagon-like peptide-1 (GLP-1) receptor agonists
INTRODUCTION
are novel agents with benefits extending beyond glucose
The “incretin effect”, described as an augmented insulin
control, including weight loss, reduction in blood
response to an oral glucose load than an isoglycemic
pressure and cholesterol levels, and improvement in
intravenous glucose challenge is attributed to gut-
beta-cell function. They work by mimicking the effects of
derived hormones released from intestines in response
the incretin hormone GLP-1 secreted from the intestine
to nutrient intake.1 Mainly two hormones- glucagon-like
in response to an oral meal intake. These agents not peptide-1 (GLP-1) and glucose-dependant insulinotropic
only augment insulin secretion and reduce glucagon peptide (GIP) —are responsible for the incretin effect.
release but also reduce appetite by increasing satiety and GLP-1 is secreted from intestinal L-cells located in the
slowing gastric emptying. Five GLP-1 receptor agonists distal ileum and also throughout the small intestine,
are presently approved in the United States: exenatide, the large intestine, and pancreatic α-cells, while GIP is
liraglutide, dulaglutide, albiglutide and lixisenatide. secreted from K-cells in the small intestine, primarily in
Though all of them are GLP-1 receptor agonists each agent the duodenum.
has its own unique pharmacodynamic, pharmacokinetic The fasting concentrations of GIP and GLP-1 are
and clinical effect.Commonly seen adverse effects with very low and rise steeply following meal ingestion. The
GLP-1 therapy include nausea, vomiting, and injection- enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades
site reactions. These agents may be avoided in individuals both GIP and GLP-1, cleaving the biologically active
with history of pancreatitis and thyroid cell carcinomas. forms of GLP-1 into inactive peptide fragments, resulting
GLP-1RAs offer an innovative and efficacious option in a very short half-life.
CHAPTER 40: GLP-1 Analogs: Benefits Beyond Glycemic Control 239
GLP-1 ANALOGS TABLE 1: Physiological properties of GLP-1
GLP-1 has a glucose-dependent effect on insulin Insulin secretion Stimulated

secretion and hence it does not stimulate insulin Glucagon secretion Inhibited
secretion when blood glucose concentrations fall Insulin biosynthesis Stimulated
below a critical level (80 mg/dL). It alsocauses glucose- Food intake Induces satiety
dependent suppression of glucagon secretion from Gastric emptying Slowed
α-cells in the pancreas besides various other effects on Insulinotropic effects in type 2 diabetes Preserved
glucose metabolism as shown in Table 1. GLP-1 levels
are significantly reduced in patients with type 2 diabetes. TABLE 2: Classification of GLP-1 analogs on the basis of their
structure
GLP-1 analogs are incretin mimetic agents that increase
the GLP-1 levels to supraphysiological levels and correct Human GLP-1 based Exendin-4 based
the incretin defect in the pathogenesis of type 2 diabetes. zz Liraglutide zz Lixisenatide
Figure 1 depicts the multiple effects of GLP-1 on different zz Taspoglutide zz Exenatide
organs besides its actions on the intestines and pancreas. zz Albiglutide zz Exenatide long-acting release
GLP-1 analogs (recombinant GLP-1 receptor Abbreviation: GLP-1, glucagon-like peptide-1
agonists) are resistant to cleavage by native dipeptidyl
peptidase-4 (DPP-4) and hence have a protracted
mechanism of action resulting in a relatively less
dosage frequency. Owing to their peptide structure,
they can currently be administered in injectable form
only. GLP-1 RAs as a class have been available for
management oftype 2 diabetes for almost a decade
now and hence have widespread clinical experience.
Agents such as liraglutide, exenatide, exenatide LAR,
albiglutide, lixisenatide, and dulaglutide are already in
market while few others are in the pipeline.2,3 Exenatide,
exenatide LAR, and lixisenatide are exendin-4 based
Fig. 1: Actions of glucagon-like peptide on various organs
synthetic peptides, which is a peptide discovered in the
Gila monster lizardsaliva. Exendin-4 has 53% homology efficacy and reduce HbA1c by 0.5–0.9% (5.5 mmol/
to the human GLP-1 and is resistant to degradation mol-10 mmol/mol). It is well known that both fasting
by the dipeptidyl peptidase-4 (DPP-4) enzyme.4 Other plasma glucose (FPG) and postprandial glucose (PPG)
GLP-1 RAs are synthetically modified forms of naturally contribute to high levels of HbA1c.10 The short-acting
occurring GLP-1, where modifications such as amino GLP-1RAs have pronounced effects in reducing PPG
acid substitution protect the GLP-1 molecule from partly by inhibition of gastric emptying. Lixisenatide also
inactivation by DPP-4.3 Exenatide and Liraglutide were delays gastric emptying11,12 and markedly reduces the
approved for use in adults with type 2 diabetes along with postprandial glucose response.13
dietary modification and exercise.5-9 The long duration GLP-1RAs may be administered
Various agents in these two groups are given in Table 2. either once daily-liraglutide or once weekly-exenatide
GLP-1 RAs are also segregated into short duration or LAR, albiglutide and dulaglutide. The prolonged half-life
long duration agents. Short-acting agents (exenatide and of these formulations is due to different modifications
lixisenatide) have half-lives of 2-3 hours with exenatide such as structural changes in formulation as in exenatide
needing twice daily administration while lixisenatide LAR or the conjugation with various other molecules
is given once daily. They both have moderate glycemic such as the acyl group (liraglutide) or human albumin
(albiglutide), or Fc fusion protein with immunoglobulin both as monotherapy and in combination with agents
G (dulaglutide), which increase their size and alters their such as metformin, sulfonylurea, and thiazolidinediones.
pharmacokinetic properties, efficacy as well as safety. It undergoes mainly renal elimination and does not seem
The prolonged half-life facilitates continuous stimulation to be significantly degraded in circulation. Exenatide
of the GLP-1 receptor and reduces fluctuations in peptide plasma concentrations increase in a dose-dependent
levels.14 Generallyliraglutide has demonstrable greater manner following subcutaneous injection.
efficacy than exenatide. On an average, liraglutide When used in above doses, exenatide monotherapy
reduces HbA1c by around 4 mmol/mol (0.33%) and leads to significant reduction in HbA1C. Significant
FPG about 1 mmol/L greater than exenatide.2,15-17 The reductions in HbA1C have been observed as monotherapy
other longer acting once-weekly formulations have as well as combination therapy of exenatide to a pre-
shown less potent reductions in HbA1c in comparison existing regimen of metformin, sulfonylurea, or both.
toliraglutide.2,16,18 Exenatide has demonstrated significant reduction in
HbA1C when used in combination with insulin glargine.
Liraglutide
Liraglutide is administered in daily doses of 1.2 or Extended Release Exenatide
1.8 mg subcutaneously. Its efficacy has been established The extended release formulation is prepared by
in the in LEAD (Liraglutide Effect and Action in Diabetes) incorporating the drug as extended-release microsphere
studies with more than 4400 patients. Liraglutide was formulation with D, L-lactide-co-glycolide polymer and
well tolerated, efficacious with average HbA1c reduction
sucrose in equal proportions. It is injected in doses of
of 1.5% and had a favorable weight profile with much
2 mg subcutaneously once a week irrespective of meals.
less hypoglycemia. Weight loss of about 2–4 kg were seen
The extended release preparation demonstrated a better
along with and slight improvements in systolic blood
improvement in glycemic control, similar reduction
pressure and β-cell function. Liraglutideis recommended
in body weight, and almost no increase in risk of
as monotherapy and in combination with glimepiride
hypoglycemia compared to the twice daily administered
and metformin.
exenatide preparation. The most common adverse
Liraglutide used alone or in combination therapy
event is mild-to-moderate nausea which generally
caused hypoglycemia in about 3–12% of the patients.
occurs at initiation of therapy and subsides eventually.
Most of these episodes were minor requiring no
There is no increase in hypoglycemia even when
assistance. However, the rate of hypoglycemia increased
taken with metformin due to the glucose-dependent
to 5–27% when it was combined with sulphonylureas.
Nausea occurred at initiation of liraglutide in 5–40% actions of exenatide. However, risk of hypoglycemia
patients but it gradually subsided within the first 4 weeks is slightly increased when used with a sulfonylurea.
of therapy. Although antibodies to liraglutide have been Rare occurrence of pancreatitis has been reported with
seen in few patients but there is no effect on its efficacy. exenatide use.
Exenatide Dulaglutide
Exenatide,a synthetic exendin-based GLP-1 analog has (Once Weekly; Sustained Release)
a 53% homology to native human GLP-1. It increases Dulaglutide is a long-acting GLP-1 analog that offers
glucose-stimulated insulin secretion, suppresses elevated convenient once weekly dosing. It demonstrated an
postprandial glucagon levels characteristic of T2DM, and HbA1c reduction of about 1.28–1.52% and weight loss of
slows gastric emptying. It is given subcutaneously in 1.40–2.51 kg in a randomized placebo-controlled double-
doses of 5–10 µg twice daily, within 60 minutes before blinded study involving 262 obese type 2 diabetics. The
meals and should not be taken after meals. It can be used commonly reported adverse events included upper
gastrointestinal symptoms like nausea (13%), diarrhea GLYCEMIC EFFICACY OF GLP-1

(9%), and abdominal distension (8%).19,20 RECEPTOR AGONISTS
A l l G L P- 1 R A s a r e i n j e c t e d s u b c u t a n e o u s l y
Lixisenatide and improve glucose control (as demonstrated by
Lixisenatide, a synthetic GLP-1 receptor agonist with marked improvements in glycated hemoglobin levels
extended biological activity, is a 44 amino acid peptide [HbA1c]).3,26,27 GLP-1 RAs increase insulin secretion and
manufactured by amidation at the C-terminal amino inhibit glucagon release in a glucose-dependent manner,
acid while sharing some structural homology with delay gastric emptying and increase satiety. An ideal type
exendin-4.21 2 diabetes therapy should not only reduce HbA1c levels
Lixisenatide has been shown in rats to protect but must also have minimum side effects, particularly
pancreatic β-cells from lipid and cytokine-induced hypoglycemia.26,27 GLP-1 RAs may fit this description
apoptosis. In humans lixisenatide prevents islet insulin due to their good glycemic efficacy and low chances of
depletion induced due to lipotoxicity thus preserving hypoglycemia. The glycemic targets set by the American
pancreatic β-cell function, insulin production and Diabetes Association/European Association for the Study
storage. 22 Furthermore, it demonstrates potential to of Diabetes and the American Association of Clinical
modify the progression of diabetes by enhancing insulin Endocrinologists for most type 2 diabetes patients are
biosynthesis and stimulation of β-cell proliferation in less than 53 mmol/mol (7.0%) and less than 47 mmol/
animal models. This increase in glucose-stimulated mol (6.5%) respectively.26,27 It is established that with a
insulin secretion (GSIS) by Lixisenatideis completely 11 mmol/mol (1%) reduction in HbA1c, cardiovascular
glucose-dependant, thus avoiding undesirable complications reduce by almost 40%.28 The glycemic
hypoglycemia. Additionally it slows gastric emptying and control achieved by pharmacological doses of GLP-1 RAs
decreases food intake that contribute to both its efficacy is superior to that achieved by most other antidiabetic
and weight loss.22 agents including the DPP-4 inhibitors and sulfonylureas
besides the pleiotropic benefits, most important being
Albiglutide weight loss. 14,15
Albiglutide is developed by fusing two human GLP-1
molecules to recombinant human albumin. 11 Being EXTRA GLYCEMIC BENEFITS OF GLP-1
relatively impermeable to the central nervous system12 ANALOGS
this may influence its GI tolerability. In nonclinical The GLP-1 receptors (GLP-1R) are present throughout
studies in vitro and in animal models, Albiglutide was the body, including in the cardiovascular system,
shown to stimulate cAMP production through the therefore accounting for the multiple metabolic actions
GLP-1 receptor and induce insulin secretion from INS- of GLP-1 on different organ systems extending beyond
1 cells.12,23 In rodents it delayed gastric emptying and their glycemic actions. Specific G-protein coupled
reduced food intake.12,24 GLP-1 receptors have been identified in tissues of the
Albiglutide, administered weekly or biweekly, showed gastrointestinal tract including pancreas and liver, lungs,
dose-dependant improvement in glucose control. blood vessels including coronary artery endothelium,
Though higher efficacy was seen with monthly doses of cardiac myocytes, macrophages, peripheral nerves and
Albiglutide, its use was limited due to higher frequency the central nervous system. Though GLP-1 RAs delay
of GI-related adverse events. Dose titrations or biweekly gastric emptying facilitating weight loss, most preclinical
scheduling could thus be studied in future studies as studies suggest that the major mechanism associated
options for patients who tolerate and respond to the with weight loss by GLP-1 RAs is due to their direct
initial weekly regimen.25 action on the brain in reducing appetite.29 Magnetic
resonance imaging in rats have demonstrated that healthy low risk BMI of 18.5–24.9 kg/m2.31 A dramatic
these anorexigenic effects of GLP-1 may be regulated improvement in T2DM and related comorbidities is
by the paraventricular and arcuate nucleus area of documented with a weight loss of 5–10% from baseline.32
the hypothalamus and the brain stem. 30 Presence The global pandemic of obesity and its comorbidities
of GLP-1 receptors in several regions of the brain, poses a significant economic burden besides hampering
predominantly the hypothalamus and brain stem, the quality of life. The expenditure on overweight and
which are the core regulators of food intake and satiety, obesity is projected to comprise 16–18% of total health
has been demonstrated. GLP-1 crosses the blood brain care expenses in the US by 2030.33 Most obesity treatment
barrier to activate these receptors and inhibits food guidelines recommend pharmacotherapy in adults
intake by promoting satiety resulting in weight loss. with BMI of 30 kg/m 2 or higher or adults with a BMI
GLP-1 RAs also interact with the heart and blood of 27 kg/m2 or higher with at least one weight-related
vessels independent of their glycemic action, and may comorbid condition (hypertension, dyslipidemia, insulin
contribute to cardioprotection through various direct resistance, type 2 diabetes mellitus).34 Though bariatric
and indirect mechanisms. Preclinical studies with surgery has been recommended as a viable treatment
natural GLP-1 as well as GLP-1 RAs (liraglutide and option for morbid obesity, the search is ongoing forless
exenatide) showed their cardioprotective effects, while invasive options.33 Inspite of tremendous efforts, the
various clinical trials have documented their beneficial development of effective pharmacotherapeutic agents
effects in hypertension and dyslipidemia in patients for obesity has not been very promising35 though a few
with type 2 diabetes.29 Preclinical studies with liraglutide weight-management agents are currently available.32
showed reduced infarct size and improved survival post- The focus has now shifted to using GLP-1RAs as potential
myocardial infarction in rats as well as improved cardiac antiobesity agents. 33 The longer-acting GLP-1 RAs
function in mice fed on high-fat diet.29 Exenatide, when including exendin-4 derivatives and liraglutide, that
administered 1 hour after oral fat load, showed reduced are resistant to degradation by DPP-IV enzyme, may be
secretion of TAG and ApoB, suggesting that its effect promising anti-obesity agents.35 Remarkable weight loss
on postprandial lipid metabolism was independent of seen with liraglutide therapy prompted using a higher
delayed gastric emptying. These findings suggest a key dose formulation specifically for its anti-obesity use,
role of GLP-1 in control of chylomicron secretion which with Liraglutide 3 mg/day (trade name Saxenda) being
is unrelated to gastric emptying.29 approved by the US Food and Drug Administration for use
Hence the pleiotropic benefitsof GLP1 RAs may be as an anti-obesity drug for adults.33,34 Significant weight
seen in the cardiovascular system; on lipid metabolism; loss was demonstrated in overweight and obese patients
in neurological disorders; on blood pressure (especially with T2DM with subcutaneous liraglutide 3.0 mg daily
systolic) and on body weight. It is also important here over 56 weeks compared to placebo.32 Though bariatric
to point out that because of their widespread actions, surgery has proven clinical superiority than liraglutide
there is also a possibility of some non-beneficial adverse for both weight loss and improvement in metabolic
effects, such as those in the gastrointestinal system or an parameters, many individuals where surgery may not
increased heart rate with this class of agents. be preferred may rather benefit from with liraglutide.
Additional research is warranted for its potential use in
WEIGHT LOSS ASSOCIATED WITH THE combination with other weight loss treatments to further
USE OF GLP-1 RECEPTOR AGONISTS potentiate as well as sustain weight loss.33 Liraglutide
The risk of developing diabetes is directly associated with in clinical use demonstrated delayed gastric emptying
increase in body weight, being three timesat a body mass that may partially contribute to reduction in meal
index of 25.0–29.9kg/m 2, and increasing dramatically intake seen with this drug.26 A potential mechanism for
to 20-fold at a BMI of 35 kg/m2 and higher vis-a-vis a weight reduction may be through its effect on energy
expenditure primarily proposed to be due to GLP-1 not documented owing to potential species-specific
action on peripheral (vagal) and central pathways differences in GLP-1 receptor expression in thyroid
influencing food intake and metabolism byactivation of tissue.
hindbrain, hypothalamic nuclei as well as certain brain
Renal effects: There is limited data on GLP-1RA use
areas associated with motivation and reward processes33
in chronic kidney disease (CKD) patients. Exenatide
noninvasive pharmacological treatment
undergoes renal elimination and hence should be
avoided.44 Though liraglutide has no renal excretion,
SIDE EFFECTS AND ASSOCIATED RISKS
it should be used with caution till more safety data
OF GLP-1 RECEPTOR AGONISTS emerges.45 Similarly, data on lixisenatide, long-acting
Gastrointestinal effects: The most commonly associated exenatide and other once-weekly drugs are still very
side effects with GLP-1RAs are gastrointestinal such limited.40,45
as nausea, vomiting and diarrhea, attributable to their
mechanism of action. In extreme cases patients may Hypoglycemia: Hypoglycemia is not a major concern
discontinue treatment in distress. 36 GI disturbances with GLP-1 agonists per se. It only occurs generally
were seen in 10–42% of patients, with different doses when used in combination with insulin or sulfonyl ureas
used in different trials. Increased incidence was seen especially when their doses are not readjusted when
in high-dose regimens, though they tend to remit with starting a new agent.46,47 Therefore, it is recommended
time.37 These can be reduced by starting with lower doses to down-titrate the dose of these hypoglycemic therapies
initially and gradual uptitration of dose over the next few when adding a GLP-1 RA.47
weeks of treatment as tolerability improves with time.
CONCLUSION
Acute pancreatitis: GLP-1 RAs in diabetic patients have
The wide spread presence of GLP-1 receptors in the
been associated with a slightly increased risk of acute
body accounts for numerous favorable effects of these
pancreatitis38 with few cases reported in animals as well
novel incretin-based therapies on various organs as well
as humans treated with this class of drugs. So far, cases
as metabolic mechanisms apart from glycemic control.
have been reported with both exenatide and liraglutide
GLP-1 receptor agonists not only enhance endogenous
and none with lixisenatide as yet.39 Studies show an
insulin secretion and inhibit glucagon secretion in
average incidence of 1.6 cases of acute pancreatitis
response to meal ingestion but also suppress appetite
per 1000 patients/years of exposure with liraglutide.40
and food intake. Besides, they help in weight loss with
Current guidelines recommend use of GLP-1 RAs with
beneficial effects on metabolic regulation. These extra-
extreme caution in patients with history of pancreatic
glycemic benefits extend to the cardiovascular system,
pathology and suspending therapy if acute pancreatitis
lipid metabolism, neurological disorders, systolic
presents during drug use. All patients on these agents
blood pressure and body weight. GLP-1 receptors are
should be informed of this risk,which essentially seems
also found in the central nervous system, mainly in the
to be a class effect.41
nucleus tractus solitarius (NTS) in the caudal brainstem.
Medullary thyroid carcinoma: GLP-1 receptor expression GLP-1 expressing neurons in the NTS send projections
has been validated in thyroid tissue, especially the C to varied brain regions mainly in the hypothalamus
cells. 38,42 Preclinical animal studies with liraglutide and regulate feeding behavior and energy homeostasis.
showed an increase in C cell hyperplasia frequency Thus, GLP-1 receptor antagonists manifest wide spread
and thyroid cancer in mice and rats.43 GLP-1 receptor metabolic effects extending far beyond glycemic control,
stimulation induces calcitonin release in rodents but emerging as novel and preferred agents in current
the involvement of GLP-1 RAs in increasing incidence diabetes management algorithms. With new data
of medullary thyroid carcinoma in humans is yet pouring in on their further benefits on metabolism these
are potential promising agents to be watched out for over Isolated Perfused Pancreas Study [Abstract]. Diabetologia.
the next few years with fast emerging extra-glycemic 2006;49:400-1.
11. Bush MA, Matthews JE, De Boever EH, Dobbins RL, Hodge
benefits and safety beyond glycemic control.
RJ, Walker SE, Holland MC, Gutierrez M, Stewart MW. Safety,
Tolerability, Pharmacodynamics and Pharmacokinetics of
REFERENCES Albiglutide, a Long-Acting Glucagon-Like Peptide-1 Mimetic,
1. Mudaliar S, Henry RR. The incretin hormones: from in Healthy Subjects. Diabetes, Obesity and Metabolism.
scientific discovery to practical therapeutics. Diabetologia. 2009;11:498-505.
2012;55(7):1865-8. 12. Baggio LL, Huang Q, Brown TJ, Drucker DJ. A Recombinant
2. Dungan KM, Povedano ST, Forst T, González JG, Atisso C, Human Glucagon-Like Peptide (GLP)-1-Albumin Protein
Sealls W, Fahrbach JL. Once-Weekly Dulaglutide versus (Albugon) Mimics Peptidergic Activation of GLP-1
Once-daily liraglutide in metformin-treated patients with Receptor-Dependent Pathways Coupled with Satiety,
Type 2 diabetes (AWARD-6): A Randomised, Open-Label,
Gastrointestinal Motility, and Glucose Homeostasis.
Phase 3, Non-inferiority Trial. The Lancet. 2014;384:1349-
Diabetes. 2004;53:2492-500.
57.
13. Meier JJ. GLP-1 Receptor Agonists for Individualized
3. Lund A, Knop FK, Vilsboll T. Glucagon-Like Peptide-1
Treatment of Type 2 Diabetes Mellitus. Nature Reviews
Receptor Agonists for the Treatment of Type 2 Diabetes:
Endocrinology. 2012;8:728-42.
Differences and Similarities. European Journal of Internal
14. Garber A, Henry RR, Ratner R, Hale P, Chang CT, Bode B.
Medicine. 2014;25:407-14.
Liraglutide, a Once-Daily Human Glucagon-Like Peptide 1
4. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD,
Analogue, Provides Sustained Improvements in Glycaemic
Fineman MS, Baron AD. Effects of Exenatide (Exendin-4)
Control and Weight for 2 Years as Monotherapy Compared
on Glycemic Control over 30 Weeks in Patients with Type
with Glimepiride in Patients with Type 2 Diabetes. Diabetes,
2 Diabetes Treated with Metformin and a Sulfonylurea.
Obesity and Metabolism. 2011;13:348-56.
Diabetes Care. 2005;28:1083-91.
15. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya
5. ADA. Standards of medical care in diabetes--2013. Diabetes
E, Brett JH, Zychma M, Blonde L. LEAD-6 Study Group
Care. 2013;36(Suppl 1):S11-66.
Liraglutide Once a Day versus Exenatide Twice a Day
6. Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type
2 diabetes mellitus. CMAJ : Canadian Medical Association for Type 2 Diabetes: A 26-Week Randomised, Parallel-
Journal = journal de l’Association medicale canadienne. Group, Multinational, Open-Label Trial (LEAD-6). Lancet.
2005;172(2):213-26. 2009;374:39-47.
7. Dicker D. DPP-4 inhibitors: impact on glycemic control and 16. Buse JB, Nauck M, Forst T, Sheu WH-H, Shenouda
cardiovascular risk factors. Diabetes Care. 2011;34(Suppl SK, Heilmann CR, et al. Exenatide Once Weekly versus
2):S276-8. Liraglutide Once Daily in Patients with Type 2 Diabetes
8. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini (DURATION-6): A Randomised, Open-Label Study. Lancet.
E, Nauck M, et al. Management of hyperglycemia in type 2 2013;381:117-24.
diabetes: a patient-centered approach: position statement 17. Wysham C, Blevins T, Arakaki R, Colon G, Garcia P, Atisso
of the American Diabetes Association (ADA) and the C, Kuhstoss D, Lakshmanan M. Efficacy and Safety of
European Association for the Study of Diabetes (EASD). Dulaglutide Added onto Pioglitazone and Metformin versus
Diabetes Care. 2012;35(6):1364-79. Exenatide in Type 2 Diabetes in a Randomized Controlled
9. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman Trial (AWARD-1). Diabetes Care. 2014;379;2159-67.
RR, Sherwin R, et al. Medical management of hyperglycemia 18. Pratley RE, Nauck MA, Barnett AH, Feinglos MN, Ovalle F,
in type 2 diabetes: a consensus algorithm for the initiation Harman-Boehm I, et al. HARMONY 7 Study Group. Once-
and adjustment of therapy: a consensus statement of Weekly Albiglutide versus Once-Daily Liraglutide in Patients
the American Diabetes Association and the European with Type 2 Diabetes Inadequately Controlled on Oral Drugs
Association for the Study of Diabetes. Diabetes Care. (HARMONY 7): A Randomised, Open-Label, Multicentre,
2009;32(1):193-203. Non-Inferiority Phase 3 Study. The Lancet Diabetes &
10. Haschke G, Haag-Diergarten S, Werner U, Kramer W, Endocrinology. 2014;2:289-97.
Herling AW. The GLP-1 Receptor Agonist AVE0010 Preserves 19. Seewoodhary J. Novel GLP-1 Mimetics in Diabetes:
Beta Cell Function and Insulin Secretion after a Week Lixisenatide and Albiglutide. Future Prescriber. 2011;12:
Treatment in Male Obese Zucker Diabetic Fatty Rats—An 20-22.
20. Barrington P, Chien JY, Showalter HD, Schneck K, Cui S, 30. Herzlinger S, Hor ton ES. Extraglycemic Ef fects of
Tibaldi F, et al. A 5-Week Study of the Pharmacokinetics and GLP-1 Based Therapautics: Adressing Metabolic and
Pharmacodynamics of LY2189265, a Novel, Long-Acting Cardiovascular Risks Associated with Type 2 Diabetes.
Glucagon-Like Peptide-1 Analogue, in Patients with Type 2 Diabetes Research and Clinical Practice. 2013;100:1-10.
Diabetes. Diabetes, Obesity and Metabolism. 2011;13:426- 31. Deacon CF, Hughes TE, Holst JJ. Dipeptidyl Peptidase
33. IV Inhibition Potentiates the Insulinotropic Effect of
21. Thorkildsen C, Neve S, Larsen BD, Meier E, Petersen JS. Glucagon-Like Peptide 1 in the Anesthetized pig. Diabetes.
Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases 1998;47:764-9.
Insulin mRNA Expression and Prevents Diabetic Progression 32. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A,
in db/db Mice. Journal of Pharmacology and Experimental Skjoth TV, Andreasen AH, Jensen CB, De Fronzo RA. Efficacy
Therapeutics. 2003;307:490-6. of Liraglutide for Weight Loss among Patients with Type 2
22. Werner U, Haschke G, Herling AW, Kramer W. Pharmacological Diabetes: The SCALE Diabetes Randomized Clinical Trial.
Profile of Lixisenatide: A New GLP-1 Receptor Agonist for JAMA. 2015;314:687-99.
the Treatment of Type 2 Diabetes. Regulatory Peptides. 33. Ladenheim EE. Liraglutide and Obesity: A Review of the
2010;164:58-64. Data So Far. Drug Design, Development and Therapy.
23. Bloom M, Bock J, Duttaroy A, Grzegorzewski K, Moore P, 2015;9:1867-75.
Ou YC, Wojcik S, Zhou X, Bell AC. Albugon Fusion Protein: A 34. Nuffer WA, Trujillo JM. Liraglutide: A New Option for the
Long-Acting Analog of GLP-1 That Provides Lasting Antidiabetic Treatment of Obesity. Pharmacotherapy. 2015;35:926-34.
Effect in Animals (Abstract). Diabetes. 2003;52:A112. 35. Kanoski SE, Rupprecht LE, Fortin SM, Jonghe BC, Hayes
24. Ou YC, Bloom M, Grzegorzewski KJ, Bock J, Duttaroy A, MR. The Role of Nausea in Food Intake and Body Weight
Moore P, Wojcik S, Zhou JX, Sung C, Bell AC. Pharmacokinetic Suppression by Peripheral GLP-1 Receptor Agonists,
and Pharmacodynamic Analysis of Albugon, a Long-Acting E xe n d i n - 4 a n d L i r a g l u t i d e . N e u ro p h a r m a c o l o g y.
Analog of Glucagon-Like Peptide-1, in Mice and Monkeys 2012;62:1916-27.
(Abstract). AAPS PharmSci. 2003;5:5263. 36. Tella SH, Rendell MS. Glucagon-Like Polypeptide Agonists
25. Rosenstock J, Reusch J, Bush M, Yang F, Stewart M. in Type 2 Diabetes Mellitus: Efficacy and Tolerability, a
Potential of Albiglutide, a Long-Acting GLP-1 Receptor Balance. Therapeutic Advances in Endocrinology and
Agonist, in Type 2 Diabetes: A Randomized Controlled Trial Metabolism. 2015;6:109-34.
Exploring Weekly, Biweekly, and Monthly Dosing. Diabetes 37. Sun F, Chai S, Yu K, Quan X, Yang Z, Wu S, Zhang Y, Ji L,
Care. 2009;32:1880-6. Wang J, Shi L. Gastrointestinal Adverse Events of Glucagon-
26. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Like Peptide-1 Receptor Agonists in Patients with Type 2
Bloomgarden Z, Bush M, et al. American Association Diabetes: A Systematic Review and Network Meta-Analysis.
of Clinical Endocrinologists’ Comprehensive Diabetes Diabetes Technology & Therapeutics. 2015;17:35-42.
Management Algorithm 2013 Consensus Statement— 38. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC.
Executive Summary. Endocrine Practice. 2013;19:536-57. Pancreatitis, Pancreatic, and Thyroid Cancer with Glucagon-
27. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini, Like Peptide-1-Based Therapies. Gastroenterology.
E, Nauck M, et al. Management of Hyperglycaemia in 2011;141:150-6.
Type 2 Diabetes: A Patient-Centered Approach. Position 39. Pappachan JM. Incretin-Based Therapies and Pancreatitis
Statement of the American Diabetes Association (ADA) and Risk: Myth or Reality. Endocrine. 2015;48:360-2.
the European Association for the Study of Diabetes (EASD). 40. Scheen AJ. Pharmacokinetics and Clinical Use of Incretin-
Diabetologia. 2012;55:1577-96. Based Therapies in Patients with Chronic Kidney Disease
28. Zoungas S, Chalmers J, Ninomiya T, Li Q, Cooper ME, and Type 2 Diabetes. Clinical Pharmacokinetics. 2015;54:1-
Colagiuri S, et al. ADVANCE Collaborative Group. Association 21
of HbA1c Levels with Vascular Complications and Death 41. AACE 2015 Guidelines Type 2 Diabetes.
in Patients with Type 2 Diabetes: Evidence of Glycaemic 42. Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh
Thresholds. Diabetologia. 2012;55:636-43. MW. Glucagon Like Peptide-1 Receptor Expression in the
29. Seufert J, Gallwitz, B. The Extra Pancreatic Effects of Human Thyroid Gland. The Journal of Clinical Endocrinology
GLP-1 Receptor Agonists: A Focus on the Cardiovascular, & Metabolism. 2011;97:121-31.
Gastrointestinal and Central Nervous Systems. Diabetes, 43. Bunck MC, Corner A, Eliasson B, Heine RJ, Shaginian RM,
Obesity and Metabolism. 2014;16:673-88. Taskinen MR, et al. Effects of Exenatide on Measures of Beta-
Cell Function after 3 Years in Metformin-Treated Patients 46. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin
with Type 2 Diabetes. Diabetes Care. 2011;34;2041-7. P, Hale PM, Zdravkovic M, Blonde L. The LEAD-4 Study
44. Brunton S. GLP-1 Receptor Agonists vs. DPP-4 Inhibitors Investigators. Efficacy and Safety of the Human Glucagon-Like
for Type 2 Diabetes:Is One Approach More Successful or Peptide-1 Analog Liraglutide in Combination with Metformin
Preferable than the Other? International Journal of Clinical and Thiazolidinedione in Patients with Type 2 Diabetes (LEAD-
Practice. 2014;68:557-67. 4 Met+TZD). Diabetes Care. 2009;32:1224-30.
45. Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, 47. Zinman B, Hoogwerf BJ, García SD, Milton DR, Giaconia JM,
de Boer AS, Drucker DJ, et al. Glucagon-Like Peptide-1 Kim DD, Trautmann ME, Brodows RG. The Effect of Adding
Receptor Agonists Activate Rodent Thyroid C-Cells Causing Exenatide to a Thiazolidinedione in Suboptimally Controlled
Calcitonin Release and C-Cell Proliferation. Endocrinology. Type 2 Diabetes: A Randomized Trial. Annals of Internal
2010;151:1473-86. Medicine. 2007;146:477-85.
CHAPTER
41
Gliptins versus Sulfonylureas:
Which is Better?
V Palaniappen
Estimated number of people with diabetes worldwide A1c Goals for Glycemic Control
in 2015 was 415 millions, in 2040 it will be 642 millions. A1c ≤ 6.5%: For patients without concurrent serious
In South East Asia in 2015 Diabetes incidence was 78.3 illness and at low hypoglycemic control
millions, in 2040 it will be 140.2 millions. A1c > 6.5%: For patient with concurrent serious
illness and at risk for hypoglycemia.

For better glycemic target achievement which is better oral
IMPORTANCE OF GLYCEMIC CONTROL
antihyperglycemic therapy (AHT)? DPP4i is better:
IN CURBING THE DIABETES BURDEN
Evidence from the UKPDS trial suggests that reduction Incretins and Glucoregulatory Mechanism
in HbA 1C is associated with a reduction in diabetic (Figs 1 to 8)
complications. If HbA1c is down by 1%—>deaths related GLP–1 secreted upon the ingestion of food, promotes satiety and
to diabetes down by 21%, myocardial Infraction down reduces appetite. α cells: ↓Postprandial glucagon secretion.
by 14%, microvascular complications down by 37%. Liver: ↓ glucagon and reduces hepatic glucose output.
Stomach: helps regulate gastric emptying. β cells: enhance
glucose-dependent insulin secretion (Tables 1 and 2).
A B
Figs 1A and B: The incretin effect. (A) Healthy controls; (B) Type 2 diabetes
Source: Adapted from Nauck M, et al. Diabetologia. 1986;29:46-52.
Fig. 2: Secretion of GLP-1 after meal

Source: Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-23.
Fig. 3: Gliptins—A unique dipeptidyl peptidase-4 (DPP-4) inhibitor mechanism of action

Source: Adapted from Drucker OJ Expert Opin Invest Drugs. 2003;12(1):87-100. Ahren B Curr Diab Rep. 2003;3:365-72.
Enhancing the Incretin Effect (Table 1) Oral (Fig. 9 and Table 3)

—— BLOCK DPP-4, the enzyme that degrades GLP – 1
GLP – 1 effect is diminished in type 2 diabetes
Natural GLP – 1 has short half life (1–22 minutes) and GIP
Injection i. Sidagliptin
—— Add GLP – 1 agonist with longer half life —— Sexagliptin
i. Exenatide —— Vildagliptin
ii. Liraglutide —— Linagliptin
iii. Exenatide weeks only

CHAPTER 41: Gliptins versus Sulfonylureas: Which is Better? 249
Fig. 4: Can DPP4 inhibitor prevent hypoglycemia? Fig. 5: DPP4-i: Consistently lesser hypoglycemia than SU
Source: Christensen MB, et al. J Clin Endocrinol Metabl. 2014;99(3):E418-26.
Fig. 7: DPP4i: Low free drug concentration

Source: Schernthamer, et al. Diabetes Obes Metab. 2012; Graefe
Mody et al. BJCP. 2012; Graefe Mody DOM 2011; Deacon CF.
Diabetes Obes Metabl. 2011;13(1):7-18.
Fig. 6: DPP4 association-dissociation grid of gliptin
Source: Schnapp G, et al. ADA 2014
TABLE 1: Low free drug concentration and high selectivity favours avoidance of off target effects
Sitagliptin Vildagliptin Saxagliptin Linagliptin
IC50 for DPP4 19 62 50 1
DPP4 vs DPP8 >2600 < 100 < 100 40,000
DPP4 vs DPP9 >5550 < 100 < 100 > 10,000
DPP4 vs DPP2 >5550 >100,000 >50,000 >100,000
Highest selectivity for DPP4 vs DPP2/8/9
TABLE 2: A good tissue distribution of DPP4i

Linagliptin Saxagliptin Sitagliptin Vildagliptin
Volume distribution, l 11101 151 198 71
Fraction bound to protein, % 70–80 Very low 38 9.3
Terminal half life, hours > 100 2.5 12.4 2–3
3.1 (active metabolite)
The prolonged elimination phase does not contribute to the accumulation of the drug. Binding to DPP4 is reversible and gets saturated at higher dose. The half-
life for accumulation (steady state) of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours.
TABLE 3: Various oral Gliptins pharmacological features

Linagliptin Sitagliptin Vildagliptin Saxagliptin
5 mg QD 100 mg QD 50 mg BD 5 mg QD
Metabolism Relevant organ for metabolism None None Liver Liver
Active metabolites No No No Yes
Excretion Proportion excreted unchanged 90 79 24 23
Main route of excretion Bile and gut Kidney Kidney Kidney
Share of renal excretion 5% 87% 85% 75%
Dosing and Dose adjustment and/or No Yes Yes Yes
monitoring limitations in RI
Drug-related monitoring No Kidney function Kidney and liver function Kidney function
1. Trials listed in US prescribing information, except for vildagliptin, for which data from EU summary of product characteristics is shown.
2. 18 weeks’ treatment duration.
3. 24 weeks’ treatment duration.
4. Between group difference vs placebo.
Fig. 8: DPP4 inhibitors: comparable efficacy in individual trials

Source: US prescribing information (linaglliptin, saxagliptin and sitagliptin), EU summary of product characteristics (vildagliptin).
2 year efficacy and safety of linagliptin compared with Linagliptin was associated with significantly fewer
glimipiride in patients with type 2 diabetes (Fig. 9): cardiovascular events (12 vs 26 patients; relative risk
Reductions in adjusted mean HbA
1c (baseline 7·69% 0·46, p=0·0213).
[SE 0·03] in both groups) were similar in the linagliptin
(−0·16% [SE 0·03]) and glimepiride groups (−0·36%
Conclusion
[0·03]); meeting the predefined non-inferiority
criterion of 0·35%. When metformin and lifestyle interventions fail
Fewer hypoglycemia (58 [7%] of 776 vs 280 [36%] to achieve glycemic control in a patient with type
p<0·0001) or severe hypoglycemia (1 [<1%] vs 12 [2%]) 2 diabetes, the optimum choice for an additional
with linagliptin compared with glimepiride. pharmacotherapy is unclear.
Fig. 9: Odds ratio of hypoglycemic events-safety margin Fig. 10: Liver disorder
Source: Adapted from Craddy P, Palin HJ, Johnson KI. Comparative
effectiveness of dipeptidylpeptidase-4 inhibitors in typ2 diabetes:
a systemic reviw and mixed treatment comparison. Diabetes Ther.
2014;5(1):1-41.
Although sulphonylureas are the most commonly

added oral antidiabetic drugs in this scenario,
the DPP-4 inhibitors offer noninferior glucose-
lowering efficacy with a reduced risk of
hypoglycemia and weight gain.
DPP4i has a good tissue distribution, is mainly bound
to protein, has a long terminal half life, and does not
accumulate.
Is Liver Disorder in T2DM a Concern?

Efficacy and Safety in Chronic Liver Disease (Fig. 10)
Patients included:
Chronic hepatitis on Rx* (n=25)
Chronic hepatitis not on Rx (n=13)
Liver cirrhosis (n=32)

Fig. 11: Similar efficacy (↓ A1c) over 24 weeks) in patients with/
without hepatobilary disorders
Study duration: 3 months
**Cirrhosis: Child-Pugh A (25), B(3) and C (4)
No change from baseline in AST, ALT, albumin,
bilirubin, prothrombin time after 3 months

*Antiviral and immunosuppressant drugs
Prescribing Characteristics of DPP-4
Inhibitors-Adherence to Therapy 50%
CKD in Diabetes and Importance of Dose Cardiovascular Safety in GLIPTINS? (Figs 17 to 20)
Adjustment (Figs 11 to 16) Cardiovascular safety of linagliptin in type 2 diabetes:
Linagliptin is the 1st and only DPP-4 inhibitor with a a comprehensive patient – level pooled analysis of
primarily nonrenal route of excretion (via bile and gut) prospectively adjudicated cardiovascular events
Fig. 12: Linagliptin reduces albuminuria in patients with diabetes on

top of stable dose of ACE/ARB
Source: Groop PH, et al. Diabetes. 2012;61(Suppl 1):A243.
*Significant change versus baselin after 24 weeks of Rx

The renoprotective effects of linagliptin may be due to the
• Inhibition of podocyte damage Fig. 13: Albuminuria lowering associated with linagliptin
• Inhibition of myofibroblast transformation independent of glucose and blood pressure reduction
• Increased GLP-1 receptor expression in the kidney Source: Groop PH, et al. Diabetes. 2012;61(Suppl 1):A243.
Composite of 6 renal endpoints:

• New Onset Micro-albuminuria,
• New Onset Macro-albuminuria,
• Increase in Serum Creatinine
(increase to 2.8 mg/dL),
• Loss of baseline eGFR >50%,
• Acute renal failure,
• Death from any cause
Fig. 14: Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of dipeptidyl
peptidase 4 inhibitor linagliptin in type 2 diabetes
Source: Cooper ME, et al. Am J Kidney Dis. 2015
Fig. 15: Linagliptin had greater adherence to therapy compared to Fig. 16: Cardiovascular safety in gliptins
other diabetes medications
Source: Patorno E et al. Poster# 1707-P – Presented at the American
Diabetes Association 75th Scientific Sessions , Boston, MA, June 7,
2015
Fig. 17: CV risk is not increased with linagliptin

Source: Rosenstock J et al. Cardiovasc Diabetol. 2015;21:14:57.
Fig. 18: Time to occurrence of primary compsite CV event

Source: Rosenstock J et al. Cardiovasc Diabetol. 2015;21:14:57.
~9400 patients, HR = 0.78 (95% CI 0.55-1.12)

(No significant difference vs comparator)
# 4P-MACE: All adjudicated CV events i.e. CV death, non-fatal MI, non-fatal

stroke, unstable angina, stable angina, and transient ischemic attacks (TIAs);
Pre-specified adjudicated cardiac events
Comparator arm comprised of patients on Glimepiride (n=775), Voglibose
(n=162) and placebo with background therapy (n = 2675)
Fig. 19: HR estimates for secondary composite CV endpoints
Source: Rosenstock J et al. Cardiovasc Diabetol. 2015;21:14:57. Fig. 20: Linagliptin CV safety meta-analysis, 2015
Source: Rosentock J et al. Cardiovascular Diabetology. 2015;14:57.
doi:10.1186/s12933-015-0215-2. Given the small number of
reported cases of CHF, this data should be interpreted with caution
Methods
Pooled analysis of 19 trials (9459 subjects) of
linagliptin versus placebo/active treatment
Primary end point: composite of prospectively
adjudicated CV death, non-fatal myocardial

infarction, non-fatal stroke, and hospitalization for
unstable angina (4P-MACE)
Total 5847 patients received linagliptin and 3612
comparator (glimepiride/voglibose/placebo)
To conclude DPP4i is the better choice on comparing
with SU in varies aspects & studies as discussed above.
For better glycemic target achievement which is better *Hypoglycemia: fingerstick blood glucose measurement £50 mg/dL
(2.75 mmol/L)
oral antihyperglycemic therapy (AHT)? Sulfonylurea is 1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;
2004. 2. UKPDS Group. Lancet1998; 352: 837–853. 3. Draeger KE, et al.
better: Horm Metab Res. 1996; 28: 419–425. 4. McGavin JK, et al. Drugs 2002;62;
1357–1364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb
Company; 2002
Best Responders to Sulphonylureas
Fig. 21: Hypoglycemia is common with SUs.
(Figs 21 to 24) Modern SUs have less hypoglycemic events
Duration of DM< 5 year (Sufficient reserve of Beta cell
TABLE 4: Sulphonylureas (SUs)
function) (Table 4)
CONS PROS
BMI<25 kg/m2
zz Hypoglycaemia zz Long track record
FPG 150–200 mg/dL
But not common zz Good evidence base
Insulin requirement <25 units/day zz Increase in beta-cell failure zz Safe
But not a contraindication to zz Well tolerated
early use zz Rapid efficacy
zz Weight gain zz OK in renal impairment
But often only in those of lower zz Economic
weight
Fig. 22: Advantages of early combination therapy in optimising

diabetes mellitus (DM) management
Source: 1. Phung OJ, et al. Diabetes Obes Metab. 2014;16(5):410-7;
2. Del Prato S, et al. Int J Clin Pract. 2005;59(11):1345-55; 3. Derosa
G, et al. Vasc Health Risk Manag. 2007;3(5):665-71.
Fig. 23: Complementary MOA of glimepiride and metformin

Abrreviations: HGO: Hepatic glucose overproduction; MOA:
Mechanism of action
Source: 1. Kalra S, et al. Diabetes Technol Ther. 2013;15(2):129–35;
2. Goroll AH, et al. Primary Care Medicine: Office Evaluation and
Management of the Adult Patient. 6th edn. Philadelphia: Lippincott
Williams and Wilkins, 2011.
Combination therapy was more efficient in reducing HbA1c than metformin or glimepiride monotherapy
Mean change in HbA1c at week 20 according to treatment
Fig. 24: Improved glycemic control with combination therapy

Abrreviations: HbA1C, Glycated haemoglobin; Met, Metformin; Glim, Glimepiride
Source: Charpentier G et al. Diabet Med. 2001;18:828-34.
IDF Recommend SUs as Second Line —— Affordability

Cost-effective alternative to newer OHAs
Treatment Options (Figs 25 to 30)
—— Adherence
Expected A1c reduction with SUs monotherapy is
Oral route of administration (vs injectable
1.0–2.0%
insulins and GLP-1 analogs) and once daily
Modern SUs are preferred DM management option in
dosing (vs 3 times daily for alpha-glucosidase
Indian/Asian context
inhibitors and glinides
In a recent population-based cohort study in

Denmark, real-world effectiveness of 2nd line
agents in DM treatment was assessed
HbA1C reduction with SU is better than with the use
of DPP-4i
Fig. 25: Efficacy of sulfonylureas: Reduction in HbA1C levels

Abbreviations: SU Sulfonylurea; HbA 1C, Glycated haemoglobin;
DPP-4, Dipeptidyl peptidase-4; GLP-1, Glucagon-like peptide-1;
GLD, Glucose-lowering drugs
Source: Thomson RW, et al. Diabetologia. 2015;58(10):2247-53.
Fig. 26: Unique characteristics of modern sulfoynylureas

Abbreviations: SUR, Sulfonylurea receptor; kD, kilo Dalton; KATP, Potassium adenosine triphosphate channel; K+, Potassium
Source: Kalra S, et al. Indian J Endocrinol Metab. 2015;19(5):577–96.
Fig. 27: Practical considerations in managing hypoglycemia with

SU use
Source: Kalra S, et al. Indian J Endocrinol Metab. 2015;19(5):577-
96.
Fig. 28: Glimepiride/metform FDC vs metformin UP therapy

Abbreviations: FDC, Fixed-dose combination; G/M, Glimepiride/metformin; Met UP, Metformin uptitration; FPG, Fasting blood glucose;
PPBG: Post-prandial blood glucose; HbA1C, Glycated haemoglobin
Source: Kim H, et al. J Diabetes Investig. 2014;5(6):701–8.
Fig. 29: Glimepiride vs DPP-4i as add-on with metformin

Abbreviations: HbA1c, Glycated haemoglobin; FPG, Fasting plasma glucose; DPP-4, Dipeptidyl peptidase-4
Source: Amate JM, et al. Int J Clin Pract. 2015;69(3):292–304.
Fig. 30: Durability of glycemic response among second-line treatment options, as add-on to metformin therapy
SUs versus DPP-4 Inhibitors as Add-on Agents with Myocardial Ischemic Preconditioning is NOT
Metformin Impaired by Modern SUs (Fig. 31)
DPP-4 inhibitors—Protects beta cell function similar Modern SUs do not inhibit the mitochondrial K ATP
to SUs channel opening in cardiac myocytes and thereby
SUs are more cost-effective. preserve myocardial ischemic preconditioning.
Is Weight Gain with SUs Correlated with Reduction Pleiotropic Benefits of Modern Sulfonylureas (Fig. 32)
in Glucotoxicity? (Figs 31 to 33) Antioxidative
Weight gain associated with SUs could be considered Angiogenesis
as in indicator for reduction in glucotoxicity Vascular health
Weight gain with SUs could be attributed to enhanced Ischemic preconditioning
utilization of ingested glucose and subsequent Insulin sensitisation
lowering in glycosuria Glucagon secretion
Weight gain is least with modern SU, glimepiride Insulin clearance.
when compared to other SUs.
Fig. 31: Myocardial ischemic preconditioning is NOT impaired by modern SUs

Source: Kalra S, et al. Indian J Endocrinol Metab. 2015;19(5):577–96.
Fig. 32: Methodological limitations in interpretation of

observational studies
Abbreviations: SU, Sulfonylurea; AHA, Anti-hypoglycemic agent
Source: Riddle MC. Modern Sulfonylureas: Dangerous or Wrongly
Accused? Diabetes Care. 2017 ;40(5):629-631.
Fig. 33: Time-lag bias is SU observational studies

Abbreviation: CV, Cardiovascular
Source: American Diabetes Association. Sulfonylureas and the
Risks of Cardiovascular Events and Death: A Methodological Meta-
Regression Analysis of the Observational Studies.2016.
Available at: http://care.diabetesjournals.org/content/40/5/706.
Accessed on 13July2017
TABLE 5: Glimepiride exhibits weight-neutralising effect in DM patients

Author Glimepiride iDPP4
Treatment BMI Weight ∆Weight ∆ Weight BMI (kg/ Weight ∆Weight ∆Weight
(weeks) (kg/m2) (kg) (kg) (%) m2) (kg) (kg) (%)
Forst (2010) 12 31.5 91 ± 15 0.73 I 0.81 31.7 91 ± 14 -0.57 -0.63
Arechavaleta (2011) 30 30.2 82 ± 17 1 1.2 11.46 29.7 81 ± 15 -0.8 -1
Ferrannini (2009) 52 31.7 89 1 1.56 11.76 31.8 89 -0.23 -0.26
Galwitz (2012) 104 30.3 86 ± 18 1.3 1.49 30.2 87 ± 17 -1.4 -1.63
In a systemic review of meta-analysis of clinical trials, the variation in weight difference in treatment groups treated with glimepiride and DPP4 was 2.1
kg and was considered nonsignificant.
DM IN ELDERLY RECOMMENDATION Gliclazide and Gliclazide MR [Grade B, level 2] and

Glimepiride [Grade C, level 3] should be used instead
Sulfonylureas should be used with Caution of Glyburide
with age [Grade D, Level 4] Meglitinides may be used instead of Glyburide
(Table 5 and Fig. 33) [Grade C level 2 for Repaglinide; Grade C, level 3 for
Initial doses of sulfonylureas in the elderly should Nateglinide], particularly in patients with irregular
be half of those used for younger people, and eating habits [Grade D, consensus]
doses should be increased more slowly [Grade D,
Consensus]
SU + Combinations: A Consensus with varying strength of SU + metformin should

Statement be made available, while SU + other drugs may be
considered. (Grade A; EL 4)
CONSENSUS RECOMMENDATIONS ON
Comparative assessment as dual therapy with
SULFONYLUREA (SU) and COMBINATIONS IN THE
metformin:
MANAGEMENT OF T2DM - INTERNATIONAL TASK
—— Compared to metformin up-titration beyond
FORCE
half-maximal dose, addition of SU to metformin
Taking it Forward: Safe and Smart Plus – 2017… demonstrates better glucose lowering efficacy,
safety, and tolerability. (Grade A, EL 1)
Safe and Smart Plus – A guidance on usage of SU in
—— Compared to DPP-4 inhibitors, SUs demonstrate
combination (with other OADs, as well as insulin)
better and more durable glucose lowering
to help physicians across the country and beyond in
efficacy; however, likelihood of body weight
effectively treating T2DM.
increase and hypoglycemia risk should be taken
An International Task force constituted with experts
into consideration. (Grade A, EL 1)
from Africa, Asia and Middle East
—— Compared to GLP-1 receptor agonists, SUs show
Task Force met in New Delhi, India on March 18–19,
similar glycemic efficacy, with acceptable safety
2017
at lower cost. (Grade A, EL 1)
September 2017 – Rollout of the consensus and
Use in special populations:
Publication of the consensus statement.
—— C o m b i n a t i o n s c o n t a i n i n g m o d e r n S U s
(Glimepiride and Gliclazide MR) can be used in

Executive Summary/Proposed
elderly patients as they are associated with low
Recommendations (Fig. 33) risk of hypoglycemia. (Grade A; EL 1)
Sulfonylureas (SUs) in oral combination therapy —— SUs (Glibenclamide) may be used in the glycemic
—— Modern SUs (Glimepiride and Gliclazide MR) are

control of neonatal diabetes (KCNJ11, ABCC8
effective and safe second line agents in patients gene mutations) and MODY 3. (Grade A; EL 3)
who have not achieved predecided glycemic —— The evidence base for the use of SUs in adolescents
targets with metformin monotherapy. (Grade A; with type 2 diabetes is limited. (Grade A; EL 4)
EL 1) —— There is insufficient evidence to recommend the
—— Modern SUs (Glimepiride and Gliclazide MR)

use of SUs , as monotherapy or in combination, to
are effective and safe as initial therapy if used be used during pregnancy and lactation. (Grade
in combination with lifestyle modification and A; EL 2)
metformin, in patients with a baseline HbA1c ≥ Use in comorbid conditions:
7.5%. (Grade A; EL 1) —— There is insufficient evidence to suggest that
—— SUs may be considered for use in combination

modern SUs (Glimepiride and Gliclazide MR)
with all classes of oral antidiabetic drugs except increase CV risk. Modern SUs (Glimepiride and
glinides. (Grade A, EL1) Gliclazide MR) are preferred over conventional
—— If not used earlier, modern SUs (Glimepiride and SUs in patients with diabetes and cardiovascular
Gliclazide MR) may be preferred as third line disease. (Grade A; EL 1)
agents for management of diabetes uncontrolled —— S h o r t e r a c t i n g d r u g s , e s p e c i a l l y t h o s e
with dual combination therapy, owing to better metabolized in the liver (glipizide), should be
safety profile than older SUs. (Grade A, EL 1) the preferred SU in patients with moderate/
—— Fixed dose combinations (FDCs) containing severe renal impairment. In mild/moderate
SUs reduce cost, offer convenience and improve renal impairment, modern SUs may also be used,
patient adherence (Grade B; EL 1); hence FDCs preferably at lower doses. (Grade A; EL 3)
—— Reduction of SU dose and/or longer intervals ‘Increased risk of cardiovascular mortality’ is the
between dosing are recommended in patients warning sign commonly seen in the labeling
with mild/moderate hepatic impairment. (Grade information on all SUs, despite favorable outcomes
B;EL 4) in UKPDS
Sulfonylureas in combination and Ramadan: Potential pitfalls in designing and interpreting
—— Modern SUs may be used in combination with analyzes were noted by epidemiologists in SU and
other drugs during Ramadan, with appropriate other AHA-related observational studies
counseling and dose modification. (Grade A; EL 3)
—— Individuals on once daily SU should take their POINTS IN FAVOR OF SU
medication at Iftar (EVENING MEAL AT sunset Intensification of diabetes therapy is crucial
after breaking fasting). (Grade A; EL 3) Sulfonylureas are an important component in all T2
—— Individuals on twice daily SU may shift the DM patients
morning dose to Iftar and half of the evening dose Tolerability is good
to Suhur. (MEAL CONSUMED EARLY MORNING Lower costs
BEFORE FASTING). (Grade A; EL 4) Rapid efficacy
Well-established efficacy and safety profile
NEGATIVE IS NOT ABSOLUTELY Long tract record
NEGATIVE IN SU USAGE Consistant durability in efficacy
SU Combinations have a definite place
Association between SUs and

Modern SUs have less CV risks.

Cardiovascular Mortality

Reports from meta-analysis with TSA of RCT’s

CONCLUSION
SUs are not associated with increased risk for all-
cause mortality, cardiovascular mortality, myocardial Selection of DPP4i or SU is purely depends upon patient
infarction and stroke centric. In affordable patients, if total cost per month is
SUs as an add-on to metformin was considered as not a problem, if duration of DM is less means definitely
safe in terms of overall mortality and cardiovascular DPP4i is a better choice than SU. In less affordable
mortality patients, if total cost per month is a problem, if duration
Among SUs, glipizide was associated with increased of DM is more means definitely SU is a better choice than
all-cause and cardiovascular mortality, while the risk DPP4i. In late uncontrollable patients to achive glycemic
was least with glimepiride (numerically, though did target both combinations of DPP4i and SU will be the
not achieve statistical significance). wiser choice.
ADA-2017 Renewed Interest in SUs BIBLIOGRAPHY

Reputations of All SUs Remain Undermined: Are SUs 1. AACE Guidelines 2017.
2. ADA Guidelines 2017.
Wrongly Criticized?
3. Bremer JP, et al. Diabetes Care. 2009;32(8):1513-7.
Risk/benefit ratio of SUs are still debated, more than 4 4. Canadian Guidelines 2017.
decades after UGDP trial, which showed that SUs are 5. Safe and smart plus consensus statement—2017.
associated with increased mortality 6. Standards of Medical Care in Diabetes—2017, ADA.
CHAPTER
42
Metformin—the Molecule of
the Decade: Old is Gold
Sanjay Dash
INTRODUCTION occurred in the 1980s and 1990s based on clinical studies

Diabetes is a chronic progressive disease with potentially demonstrating its efficacy and safety in T2DM, especially
devastating complications such as CVD and kidney with publication of the UKPDS.1 Metformin was shown to
disease, affecting all age groups, requiring lifelong have efficacy similar to that of sulfonylureas in reducing
treatment. A number of drugs are available to treat fasting plasma glucose (FPG) and PPG, but did not cause
T2DM; many of them may cause hypoglycemia, weight weight gain or hypoglycemia.
gain (e.g. Sulfonylureas) or they are quite expensive In India, metformin has been available for use since
(DPP4I, SGLT2I and GLP-RA). 1980s.
Metformin effectively reduce blood glucose levels,
does not cause hypoglycemia or weight gain, can be MECHANISM OF ACTION
safely used in T2DM with several comorbidities and is The principal glucoregulatory actions of metformin
quite affordable. occur primarily at the liver to reduce glucose output and
secondarily at the peripheral tissues (muscle, adipose
HISTORY tissue) to augment glucose uptake, particularly after
The glucose-lowering properties of guanidine derivatives meals (Table 1). Metformin has shown to inhibit hepatic
were recognized through the study of French lilac gluconeogenesis leading to reduced hepatic glucose
(Galega officinalis), but it had prohibitive gastrointestinal production (HGP). This action leads to reduced blood
side effects. Chemists found that they could make the glucose levels. Metformin also decreases intestinal
compound more tolerable by bonding two guanidines absorption of glucose.
together, forming a biguanide. Metformin is one such
biguanide, first synthesized in 1920s and then clinically TABLE 1: Major proposed mechanisms of action of metformin2
developed in 1950s by the French physician Jean Sterne.
zz Reduction in HGP
Out of the three biguanides having glucose-lowering
zz Enhanced release of GLP-1 and other gut peptides
properties, phenformin and buformin were withdrawn
zz Improvement in peripheral insulin sensitivity
from the market in most countries by 1978 because of an
zz Decrease in gut carbohydrate absorption
association with fatal lactic acidosis. Metformin, though
zz Increase in enteric glucose extraction
having a very low rate of fatal lactic acidosis, was guilty
zz Increased fatty acid oxidation
by association. Resurgence of interest in metformin
CHAPTER 42: Metformin—the Molecule of the Decade: Old is Gold 263
Metformin activates AMP-activated protein kinase Additional Therapeutic Potential

(AMPK), the energy sensor, in hepatocytes. Activation It should be noted that the goal of treatment of T2DM
of AMPK leads to down regulation of energy consuming is not only to reduce blood sugar but also improved
processes such as gluconeogenesis. AMPK also clinical outcomes and reduce complications. Metformin
suppresses lipogenesis and lowers cellular fatty acid probably fits the bill.
synthesis in liver and muscle. Metformin works through
LKB1 to regulate AMPK. LKB1 is a tumor anabolic Diabetes Prevention
suppressor and activation of AMPK through LKB1 may Over the 2.8 year study in Diabetes Prevention Program3
play a role in inhibiting cell growth. the incidence of diabetes was reduced by 58% with
There is also growing evidence that at least some of the intensive lifestyle modification and 31% with metformin
drug’s metabolic effects may involve the enteroendocrine treatment compared with the placebo treatment.
axis, including gut activation culminating in the release Metformin therapy led to improvements in indices
of GLP-1. of insulin sensitivity and caused weight loss, which
explained more than half of the effect on diabetes risk.
ROLE OF METFORMIN IN T2DM Reversion to normoglycemia just once during the
Pursuant to the UKPDS findings, and subsequent DPP intervention, measured by FPG or glucose tolerance
favorable recommendations by several professional testing, reduced the risk of developing diabetes by more
diabetes associations regarding its use, metformin, today than 50% in the DPPOS extension.4
is the most commonly used first line therapy and the
gold-standard in the treatment of T2DM with wide safety Lipid Profile
profile both as monotherapy and in combination with A meta-analysis of 41 randomized, controlled evaluation
other medications. of metformin showed significant reductions in total
cholesterol, LDL cholesterol and triglycerides in patients
Glycemic Control randomized to metformin relative to comparator
Metformin monotherapy reduces A1C by 1.0–2.0%; treatments 5 . HDL cholesterol was rarely improved
in combination with glimepiride by 0.7%, with by metformin treatment. It also lowers serum FFA
glibenclamide by 1.25% and with glitazones by 1.3% concentration.
(Table 2). Reductions in glycemic parameters by Further, metformin treatment is known to lower
metformin are dose-dependent allowing for incremental inflammation marker levels like PAI-1 concentrations
titration to effect. approximately 20% and the fibrinolytic response is
enhanced. Levels of tPA also are significantly reduced
TABLE 2: Comparison of antihyperglycemic drugs monotherapy with metformin therapy.
in lowering A1C These effects may contribute to the anti-
Drugs Decrease in Drugs Decrease in atherosclerotic properties of metformin.
A1C (%) A1C (%)
Metformin 1.0–2 .0 Sulfonylurea 1.0–2.0 METFORMIN AND BODY WEIGHT
Glitazones 0.5–1.4 Glinides 0.5–1.5 The mechanism of weight loss by metformin is thought
AGIs 0.5–0.8 DPP4-I 0.5–0.8 to be mainly mediated through reduced food intake.
SGLT2I 0.5–0.7 Insulin 1.5–3.5 Metformin acts on the central nervous system to reduce
GLP-RA 0.5–1.0 appetite by attenuating hypothalamic AMPK activity,
which decreases NPY (anorexigenic) and increases for any diabetes-related endpoint and a 25% risk
POMC (anorectic) expression. reduction for microvascular complications compared to
The mean weight loss is in the range of 1 to 5 kg, or a conventional therapy. A greater than expected benefit on
1% to 3% reduction from baseline. Weight loss is greatest macrovascular complications was seen for overweight
in the most obese patients and is durable for at least 10 patients on metformin; there were significant reductions
years in adherent patients from the DPPOS. Comparing in risk for all-cause mortality and stroke versus intensive
metformin with GLP-1 RA, it was shown that weight loss therapy with sulfonylureas or insulin.7 In a meta-analysis
at 52 weeks were similar in two groups ( -2.22 kg v/s -2.29 of 179 trials and 25 observational studies of head to head
kg, respectively)6 monotherapy or metformin based combinations on
cardiovascular mortality, it was found that metformin
CANCER BIOLOGY was associated with lower long-term CV mortality
Preclinical experiments have provided evidence that compared with sulfonylurea monotherapy.8
metformin can halt replication of cancer cell lines In two subsequent trials, HOME 9 and SPREAD-
(including breast, endometrium, ovarian, and prostate) DIMCAD,10 the risk reductions related to cardiovascular
in vitro. UKPDS has also shown metformin treatment endpoints were remarkably consistent at about 40%.
Reviewing 17 studies involving patients of DM with
reduced the risk of death from cancer by 29% relative to
CKD (eGFR <60 mL/mL/1.73m 2), CCF or CLD with
diet.
hepatic impairment , comparing treatment regimen
that includes metformin with those that did not include
PCOS
metformin, Crowley et al.11 found that metformin use
Insulin resistance leading to elevated free testosterone
was associated with lower all-cause mortality among
levels with resultant hyper androgenemia is one of
patients in each of the above noted three chronic
the key factors in pathogenesis of polycystic ovarian
conditions. Studies have shown that metformin is safe
syndrome (PCOS). Metformin reduce the insulin levels
in compensated cardiac failure and mild to moderate
by improving insulin sensitivity and thereby improve
kidney failure cases (eGFR >30 mL/mL/1.73 m2 ) as these
clinical manifestation of the disease.
individuals are not at significantly elevated risk for lactic
acidosis. As a result, many patients with comorbidities
Nonalcoholic Fatty Liver Disease can now safely take metformin.
In animal models, metformin has shown to improve fatty
liver, resolution of hepatomegaly and reversal of steatosis ADVERSE DRUG REACTIONS AND
in histology. However, human studies have shown CONTRAINDICATIONS
favorable results in weight and liver enzymes, but not in
The most common adverse effects of metformin are
histology. gastrointestinal disturbances in the form of recurrent
abdominal pain, loss of appetite, flatulence, and
Microvascular and Macrovascular diarrhea. These effects are usually transient and can be
Risk Reduction minimized by taking the drug with the meals and doing
The efficacy of metformin in improving glycemic gradual dose increments. 5% may not tolerate metformin
control and reducing microvascular complications of permanently. Upto 30% of metformin users have reduced
diabetes is similar to that of other oral hypoglycemic intestinal absorption of vitamin B12. Lactic acidosis, the
agents. Over a mean of 10 years of follow-up in UKPDS, dreaded complication of metformin may occur rarely
the improvement in the glycemic control with drug in presence of renal impairment, liver failure or hypoxic
therapy was associated with a 12% risk reduction conditions (MI, CCF, etc.).
CHAPTER 42: Metformin—the Molecule of the Decade: Old is Gold 265
Though there are fewer contraindications to or metformin. New England Journal of Medicine.
metformin now, a few still remain, including in acute 2002;346(6):393-403.
4. Perreault L, Pan Q, Mather KJ, et al. Effect of regression
medical illnesses like ARF, ALD, DKA, severe infection
from prediabetes to normal glucose regulation on long
and shock, decreased tissue perfusion, hemodynamic term reduction in diabetes risk: results from Diabetes
instability, advanced chronic liver disease, acute unstable Prevention Programme Outcomes Study. Lancet.
congestive heart failure and CKD with eGFR <30 mL/ 2012;379(9833):2243-51.
min/1.73 m2. 5. Wulffele MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort
RT. The effect of metformin on blood pressure, plasma
cholesterol and triglycerides in type 2 diabetes mellitus: a
Newer Antihyperglycemic Agents systematic review. J Int Med. 2004;256:1-14.
In the ever-expanding armamentaria of therapy for 6. Umpierrez G, ToféPovedano S, Pérez Manghi F, Shurzinske L,
T2DM newer agents are challenging the pole position of Pechtner V. Efficacy and safety of dulaglutide monotherapy
metformin as the first line of therapy. Two of the newly versus metformin in type diabetes in a randomized controlled
trial (AWARD-3). Diabetes Care. 2014;37(8):2168-76. Epub
introduced drugs, SGLT2I—empagliflozin and GLP-RA—
2014 May 19.
Liraglutide are now shown to have clear CV benefits and 7. UK Prospective Diabetes Study (UKPDS) Group. Effect
improved renal outcomes. Should they be able to replace of intensive blood glucose control with metformin on
metformin as the first line therapy? In the landmark complications in overweight patients with type 2 diabetes
trials EMPA-REG OUTCOME12 and LEADER13 showing (UKPDS 34). Lancet. 1998;352(9131):854-65.
8. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-
robust cardiovascular benefits, it is to be noted that more
Cuervo C, Berger Z, Chu Y, et al. Diabetes Medications as
than 70% of the subjects already had metformin as the
Monotherapy or Metformin-Based Combination Therapy for
baseline drug. Type 2 Diabetes: A Systematic Review and Meta-analysis.
Ann Int Medicine. 2016;164(11):740-51. Epub 2016 April
CONCLUSION 19.
Metformin, with the possible exception of insulin has 9. Kooy A, de Jager J, Lehert P, et al. Long-term effects
of metformin on metabolism and microvascular and
unsurpassed efficacy in A1C reduction with added
macrovascular disease in patients with type 2 diabetes
advantages of least side effects, clear CV benefits along mellitus. Arch Intern Med. 2009;169:616-25.
with its low cost, catapulted the drug in less than a decade 10. Hong J, Zhang Y, Lai S, et al. SPREAD-DIMCAD Investigators.
to be the most commonly used oral antihyperglycemic Effects of metformin versus glipizide on cardiovascular
agent throughout the world. outcomes in patients with type 2 diabetes and coronary
artery disease. Diabetes Care. 2013;36:1304-11.
11. Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB,
REFERENCES Stanifer JW, Mock CK, et al. Clinical outcomes of metformin
1. United Kingdom prospective diabetes study (UKPDS) group: use in population with chronic kidney disease, congestive
intensive blood glucose control with sulphonylureas or heart failure, or chronic liver failure. A systematic review.
insulin compared with conventional treatment and risk of Ann Intern Med. 2017;166:191-200.
complications in patients with type 2 diabetes (UKPDS 33). 12. Zinman B, Wanner C, Lachin JM, et al. EMPAREG OUTCOME
Lancet. 1998;352(9131):837-53. investigators. Empagliflozin, cardiovascular outcomes and
2. Silvio E Inzucchi. Is it time to change the type 2 diabetes mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-
treatment paradigm? No! Metformin should remain the 28.
foundation therapy for type 2 diabetes. Diabetes Care 2017; 13. Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER
40:1128-1132 | https://doi.org/10.2337/dc16-2372 Steering Committee; Leader Trial Investigators. Liraglutide
3. Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in and CV outcomes in type 2 diabetes N Engl J Med.
the incidence of type 2 diabetes with lifestyle intervention 2016;375:311-22.
CHAPTER
43
A Decade of RCTs in Diabetes:
Clinical Implications
Suhas Erande
PRELUDE diabetics was more rewarding, also in long term, to

As we understand, randomized controlled clinical trials reduce CV complications (metabolic memory/legacy).
are the Gold Standard of evidence based medicine, which It is worth noting that all these RCTs were analyzing the
all of us practice. In chronic diseases like T2DM, CAD, approach to management of diabetes and individual
hypertension, obesity, RCTs have been the mainstay to drug use was not the main point of interest.
form practice guidelines periodically. The last decade
has seen a flurry of RCTs in diabetes and they have had 2008: TIGHTER GLUCOSE
huge clinical impact-the way we think, plan, approach CONTROL (?MORE BENEFITS)
and manage T2DM. To see this impact, one must With the result of intensive control (HbA1c~7%) being
compare the 2008 and 2017 ADA standards of diabetes beneficial, it was thought that numerically lower targets
care guidelines. There are nearly 47 published guidelines (A1c~6.5% OR 6%) may be more so. ACCORD, ADVANCE
and 472 permutations/drug combinations to treat and VADT aimed at this target. However, it was seen
diabetes. This illustrates how extensive the viewpoints that intensive control (especially, if tried speedily), may
are and how complex the diabetes disease entity is!! prove harmful, increasing CV deaths! Taking lessons
from all these, ADA guidelines became more patient-
2007: WHAT DID WE KNOW?
DCCT/EDIC1 UKPDS2
UKPDS and DCCT/EDIC had equipped us with clear
understanding, that, the tighter the glycemic control,
better off were patients to reduce microvascular
complications (clearly) and macrovascular complications
(to certain extent) (Fig. 1). STENO 2 study had informed
us that multifactorial interventions reduced CV risk by
57% and delayed the 1st CV event by at least 8 years. We
were also wisened by these studies in that, lipid control
was the most beneficial, followed by BP control and then
glucose control—to reduce CV risk. We also understood Fig. 1: Impact of intensive therapy in diabetes
that intensive control approach in newly diagnosed summary of major clinical trials
CHAPTER 43: A Decade of RCTs in Diabetes: Clinical Implications 267
Fig. 2: Primary major adverse cardiac event in cardiovascular Fig. 3: Cardiovascular death in cardiovascular outcome trials
outcome trials
centric (2011). Age, diabetes duration, life expectancy, 2015—empagliflozin reduces CV (38%) and all-
presence/absence of organ complications, patient’s cause mortality (32%) and HF by 35%, it also reduces
preparedness, family support were considered before microalbuminuria and renal end-points. Helps
opting for intensive (A1c<6.5 or 6%)/lenient (A1c~7.5 or weight and BP reduction and does not increase risk of
8%) approach. hypoglycemia. Small increase in risk of stroke noted
Later on, after 2008, came the era of CVOT in EMPAREG trial.8
(Cardiovascular Outcome Trials). The USFDA mandate 2016—liraglutide reduces CV composite end points
in 2008, asked the trialists to prove CV safety of diabetes by 13%-also helps wt and BP reduction—renal end-
medication before acquiring their license to market them points improved in LEADER trial.9 Stroke risk not
(This was preceded by the controversial meta-analysis increased. No risk of hypoglycemia. ADA guidelines
suggested earlier use of empagliflozin/liraglutide
on Rosiglitazone, which drew attention to harmful CV
(next add on to metformin) if high CV risk.
effects of this drug). Hence, CVOT studies became the
norm and various studies (essentially of newer drugs for
CENTRALITY OF RCTs IN
T2DM) followed.
These studies differ from the previous3-6 ones, in that
CLINICAL PRACTICE
If a clinician wants to know about a particular drug/
the focus is not on the approach conventional vs intensive
therapy/procedure/approach to treat a given patient,
with whatever established diabetes medication), but
he would be seeking details of the same. These details
to demonstrate CV safety of the new diabetes drug. CV
would be the efficacy, safety, the mechanism it works,
death, nonfatal MI or stroke (3 point MACE) and CV as
the limitations of its use, other drugs or therapies to treat
well as all-cause mortality were the primary end-points
the same patient and the relative/comparative merits/
in such studies (Figs 2 and 3).
demerits of it. Various tools are available to do the same.
All of these methodologies have their own strengths
IMPACT OF RECENT CVOT and limitations, but, to paraphrase Churchill on
IN DIABETES ON PRACTICE democracy, RCTs are far from perfect/infallible—the
2008—only metformin had proved CV safety (32% only good thing going with them is they are better
reduction in MI-UKPDS trial) than the other methods. In diabetes RCTs, patients
2013—saxagliptin may increase risk of hospitalization recruited follow treatment protocols and related
for HF (SAVOR TIMI 53 Study).7 periodic investigations rigorously-which may not
2014—sitagliptin neutral CV effects (TECOS Study). happen in real world practice. Hence, RWE (real world
judge their relevance/applicability to a given patient in

clinic, may be an arduous task. Costs or adverse effects
of newer diabetes drugs, may prove to be challenging
irrespective of robust RCT evidence (viz. empagliflozin/
liraglutide) favoring their utility. In the real world (beyond
RCTs), costs, side-effects, availability may prove more
decisive. Longstanding diseases like diabetes may not be
adequately managed by algorithmic solutions. Hence,
the pathway of RCTs→practice guidelines→clinical
practice may not be straightforward.
Fig. 4: Medical research pyramid
evidence) synthesized from many observational studies

Factors Which Affect Influences
(retrospective) is gaining ground. High costs incurred of RCTs on Clinical Practice
in conducting RCTs especially to observe CV outcomes Timing of the RCT with regard to the technology’s (or
in diabetes, is a limiting factor. It is logical to expect that drug’s) development and diffusion.
The constituency supporting this technology/drug
longer the trial duration, more reliable would the CVOTs
be-but-costs would also spiral with the time duration. prior to the RCT.
Quality of the trial—statistical and other design
IMPORTANCE OF CLINICAL features.

Whether the RCT is conducted through one or
PRACTICE GUIDELINES
multiple centers.
Research, practice and policy in healthcare sector focus
The form of dissemination of results.
on improving the organization, delivery and outcomes
Other relevant important factors.
of care, while optimizing efficacy. Critical to achieving
It would be interesting to note that the famous (sic),
these goals, is the compliance with best practice based
UGDP trial of yesteryears (1961), which ultimately
on currently available knowledge, gathered through
found tolbutamide to be harmful (CV effects), was
research (Fig. 4). Knowledge syntheses such as practice
scrutinized by various agencies, viz. NIH (validity),
guidelines provide the evidence base for healthcare
biometric society (statistics), FDA (2 year audit of all
decision making. Their development, dissemination
trial sites) and finally the Supreme Court of USA (legal)
and implementation are intended to improve the quality
and no violation was found. The use of hypoglycemic
of care. Guideline adoption or implementation may be agents did not stop immediately-but-only over next 8
ridden with issues which are beyond the scope of this years. Probably, the influence of old virtues of inference
discussion. and clinical judgment prevailed over these results of
the RCT. Closer in timeframe, the rosiglitazone ban in
FACTORS WHICH INFLUENCE many countries still has not affected it is use in some
PHYSICIAN PRACTICE countries such as China todate and for completing this
Results from research/RCTs, physician’s behavior/ statement, one cannot overlook Sri Lanka-which still
discretion, marketing by manufacturers, the drug uses tolbutamide!! Assessing impact of RCTs on diabetes
(product) features, public knowledge are important clinical practice may be difficult, however, physician
factors which influence physician’s practice. In our interviews (prescription habits, perceived efficacy of
medical education, analysis/interpretation/critical the drug or its place in protocol, level of knowledge and
reviews of published literature are some areas which information) or sales figures of the related drug can be
generally are not emphasized on. Analysing RCTs to evaluated to peep into it.
CHAPTER 43: A Decade of RCTs in Diabetes: Clinical Implications 269
HAVE RCTs IN DIABETES HELPED It is worthy of note that McKinsey and Company
CLINICAL PRACTICE IN LAST DECADE? has observed that integrated diabetes care (patient
Indian diabetes practice has its own peculiar education and empowerment, care coordination,
challenges and demands which cannot be resolved by multidisciplinary team and individual care plans)
non-Indian solutions. We have started our approach is able to reduce (at least) HbA1c by 0.5% and also
in that direction. RSSDI guidelines of 2015 is an reduce hospitalizations. This analysis is based on
indicator. RCTs in diabetes in the last decade!11
We have started to address global risk and we are
trying not to be glucocentric in our thinking. We are REFERENCES
also trying to look at the early detection of diabetes 1. DCCT EDIC Study Research Group. NEJM. 2005;353:2643-
53.
and increasing mass awareness on diabetes.
2. UKPDS Group Lancet. 1998;252:837-53.
We are trying to assert intensive control approach
3. Holman RR, et al. NEJM. 2008;359:1577-89.
in newly detected diabetics, to reduce long-term 4. ADVANCE Collaborative Study Group. Lancet. 2007;370:829-
complications. We realize centrality of patient 40.
education and empowerment. 5. ACCORD NEJM. 2008;358:2545-59.
We have started looking for patient features so as 6. Duckwor th W, Abraira C, Monitz T, et al. For VADT
to select relevant diabetes medication (SES, age, investigators. Glucose control and vascular complications
in Veterans with type 2 diabetes NEJM. 2009;360:129-39.
BMI, WHR, other comorbidities, duration of DM,
7. Seirica BM, Bhatt DL, Braunwald E,Steg PG,Davidson J,
psychological preparedness, family support, etc.
Hirshberg B, et al. Saxagliptin and cardiovascular outcomes
Use and acceptance of glucometers and injectable in patients with type 2 diabetes. NEJM. 2013;369:1317-26.
therapies is increasing-though slowly. Use of social 8. Zinman B, Waner C, Lachin JM, Fitchett D, Hantel S, et al.
media, other gadgets to improve patient awareness- Empagliflozin, Cardiovascular outcomes and mortality in
education-compliance is increasing. type 2 diabetes NEJM. 2015;373:2117-28.
We are encouraged to be updated through CMEs 9. Marso SP, Daniels GM,Brown Frandsen,Kristiansen P,
and various academic activities happening around Mann JF, Nauck MA, et al. Liraglutide and cardiovascular
outcomes in type 2 diabetes. NEJM. 2016;375:311-22.
publication of diabetes RCTs.
10. Recent cardiovascular outcome trials of antidiabetic drugs:
In days to come, if we design a simple diabetes a comparative analysis. AK Singh, Ritu Singh (Eds). Indian
practice audit to have an introspection of impact of Journal of Endocrinology abd Metabolism. 2017;21:1.
RCTs and other knowledge syntheses on our own 11. The evidence for integrated care, Healthcare Practice,
practices, it can throw some light on this subject. 2015.
CHAPTER
44
Insulin Pumps in India
Narendra Pal Jain, Rishu Bhanot
INSULIN PUMPS IN TYPE 2 IN INDIA What is an Insulin Pump?

Patients with Type 2 Diabetes mellitus (T2DM) have Its a biomedical device used for the administration of
decline in B cell function with progression of disease and insulin in diabetics (Figs 1 to 3).
often require insulin therapy. Components of a traditional pump are :
The place of CSII or insulin pump therapy has been —— Pump (including controls, processing module,
studied and evaluated as an alternative to multiple daily and batteries)  

injections in patients with DM. The insulin pump infuses —— Disposable reservoir for insulin (inside the
the insulin at a continuous basal rate and correction pump)  

boluses at meal time and out of range glucose values —— Disposable infusion set, including a cannula for
respectively. Thus CSII or insulin pump mimics the subcutaneous  insertion (under the skin) and a
insulin provided by a normal functioning pancreas. tubing system to interface the insulin reservoir to
T2DM patients with advanced age are less likely to the cannula. 
adapt to complex CSII technology than younger people
with T1DM. Initiation of CSII requires expenses born by
the user or insurance company. These challenges can be
overcome (for people with T2DM) by effectively reducing
glucose levels, simple and cost effective insulin pumps/
CSII.
Continuous subcutaneous insulin infusion (CSII,
also known as insulin pump therapy) has become an
established and recognized treatment for type 1 diabetes
mellitus (T1DM) since 1970’s, especially in those who
have inadequate glycemic control on multiple insulin
injections. Despite the insulin pumps being in the
market for over 40 years, its use in type 2 diabetes has
been doubted. Fig. 1: Medtronic insulin pump
CHAPTER 44: Insulin Pumps in India 271
Fig. 2: Basal-bolus insulin treatment: matching insulin

administration to insulin needs
CSII has been found to be superior to commercially

available insulin pens and multiple dosing of insulin Fig. 3: Some insulin pumps, like the one in this picture, connect to the
body through a thin tube and needle inserted under the skin, usually
using syringes in the abdomen
The insulin deliver is achieved in two ways:
1. Basal dosage: The glucose level is maintained by TYPES
delivering small amounts of insulin continuously. The insulin pumps in India are manufactured and
2. Bolus: Extra dosage of insulin is delivered as per marketed by various companies. The pumps currently
insulin to carbohydrate ratio. available in India are manufactured by Medtronic which
An insulin pump is worn all through the day but can markets various models such as the 722, 640G and 754
be removed for activities like swimming and playing for
upto 2 hours. INDICATIONS FOR AN INSULIN PUMP
The superiority of the insulin pump over MDI has The American Association of Clinical Endocrinologists
been established because of recommends considering an insulin pump for following
Consistency of basal delivery.
group of patients:
Adjustable basal rates. Those who are not able to achieve target HBA1C
Low insulin depots allowing the reduction of glycemic despite of being on basal-bolus injections and full
variability adherence to treatment.
With the availability of new MDI regimens which Wide and abberant glycemic variations  
use long acting insulin analogues have posed a fresh Frequent hypoglycemic episodes
challenge to the insulin pumps. So now the physicians “Dawn phenomenon” (early morning spike in blood
have to decide whether the patient will benefit with CSII glucose) 
or MDI and make sure that proper patient selection is Pregnancy or planning for pregnancy
done. Erratic lifestyle  
Various randomized and nonrandomized studies Personal preference
have shown the efficacy of CSII across all age groups. Which DM-2 patient is a good candidate for CSII?
The face of CSII is being changed by the availability of Patients with type 2 diabetes who:
continuous glucose sensors which allow for improved Patients who need the same multiple-daily injection
glucose control by decreasing glycemic variations and self-monitoring requirements as for type 1 diabetes
and manipulate insulin delivery to avoid incidence of and those who have evidence of beta-cell failure with low
asymptomatic hypoglycemia. C- peptide levels.
CURRENT SCENARIO OF INSULIN 3. Didangelos T, Iliadis F. Insulin pump therapy in adults.

Diabetes Res Clin Pract. 2011;93(Suppl 1:):S109-13.
PUMPS IN INDIA 4. Grunberger G, Bailey TS, Cohen AJ, et al. Statement by
There are 62 million diagnosed patients of Type 2 the American Association of Clinical Endocrinologists
Diabetes in our country. Since 2000, India has (31.7 Consensus Panel on insulin pump management. Endocr
million) topped the world with the highest number of Pract. 2010 16(5):746-62. [Medline].
5. Hanaire H, et al. Treatment of diabetes mellitus using an
people with diabetes mellitus followed by China (20.8
external insulin pump: the state of the art. Diabetes Metab.
million), the United States (17.7 million) in second and
2008;34:401-23.
third place respectively. The International Diabetes 6. Hauge C. Insulin Pumps: Evolution of an Industry. Medtronic
Federation (IDF) estimates the total number of diabetic MiniMed Europe. Switzerland: Business Briefing: European
subjects to be around 40.9 million in India and this is Pharmacology, 2003.pp.1-3.
further set to rise to 69.9 million by the year 2025. The 7. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA:
10-year follow-up of intensive glucose control in type 2
pumps available in the market are complex and designed
diabetes. N Engl J Med. 2008;359:1577-89.
for type 1 patient with a bolus-basal regimen deigned 8. Kaveeshwar SA, Cornwall J. The current state of diabetes
to be used with U-100 insulin. The need of the hour is mellitus in India. Australas Med J. 2014;7:45-8.
simpler pumps with concentrated U 500 insulin and 9. Kesavadev J, Das AK, Unnikrishnan R, 1st, Joshi SR,
simpler dosing regimens. These pumps will bring down Ramachandran A, Shamsudeen J, et al. Use of insulin pumps
the cost factor and also that simple pumps will by-pass in India: Suggested guidelines based on experience and
cultural differences. Diabetes Technol Ther. 2010;12:823-
the learning curve of an average individual as education
31.
is also a limiting factor about the usage of the pumps. 10. Pfeiffer E, Thum C, Clemens A (1974) The artificial beta cell-
In India, insurance companies need to reimburse for -a continuous control of blood sugar by external regulation
insulin pumps so that more people are attracted towards of insulin infusion (glucose controlled insulin infusion
it as a viable option. system). Hormone and Metabolic Research, 6, 339–342.
11. Pickup JC, Keen H, Parsons JA, Alberti KG (1978a)
CONCLUSION Continuous subcutaneous insulin infusion: an approach to
achieving normoglycaemia. British Medical Journal, 1, 204-
There is no consistent clinical evidence available on CSII
207.
for T2DM. RCTs have compared MDI verses CSII and 12. Scheiner G, Sobel RJ, Smith DE, Pick AJ, Kruger D, King
both have shown equivalent reduction in glucose and J, et al. Insulin pump therapy: guidelines for successful
HbA1c. Thus more data is needed to speculate the use of outcomes. Diabetes Educ. 2009 Mar-Apr. 35 Suppl
simpler, cost-effective insulin pumps and concentrated 2:29S-41S; quiz 28S, 42S-43S.
13. Sherr J. and Tamborlane WV, “Past, present, and future of
insulin formulations (U- 500). As such, patients of T2DM
insulin pump therapy: better shot at diabetes control,”Mount
with uncontrolled glycemic status, CSII or insulin pumps Sinai Journal of Medicine, vol. 75, no. 4, pp. 352-361,
may be a suitable option. 2008.
14. WHO; country and regional Date on Diabetes GENEVA
BIBLIOGRAPHY :WHO 2016The Diabetes Control and Complications Trial
1. Anonymous (2007c) Megans Insulin Pump Comparison, Research Group: The effect of intensive treatment of
1–3. Available at: http://dfw-iug.org/pump_compare3.pdf diabetes on the development and progression of long-term
2. Cobelli C, Renard E, Kovatchev B. Artificial Pancreas: Past, complications in insulin-dependent diabetes mellitus. N
Present, Future. Diabetes. 2011 60(11):2672-82. Engl J Med. 1993;329:977-86.
CHAPTER
45
Newer Insulins and Art of Insulin Therapy
Mangesh Tiwaskar
INTRODUCTION The Diabetes Control and Complications Trial (DCCT)

Diabetes has reached epidemic proportions worldwide. and the United Kingdom Prospective Diabetes Study
The long-term complications of diabetes form more (UKPDS) conducted in Type 1 diabetes (T1D) and Type
than half of the cost related to diabetes. Hyperglycemia 2 diabetes(T2D) patients, respectively. DCCT results
associated with diabetes has been linked to cardiovascular revealed the tight blood glucose control minimizes
disease and other complications like retinopathy, complications by nearly 60%. 4 Similarly results from
nephropathy and neuropathy. Many of these conditions UKPDS confirmed that every percentage point drop in
are exclusively related to the presence of diabetes. 1 HbA1c levels (e.g. from 9 to 8%) reduced complications
Data from the International Diabetes Federation 2014 by 35%.5
shows that India has more than 6.6 crore people living Though insulin therapy is mandatory for all T1D
with diabetes and nearly half that number remain patients, it is slowly being understood that most of the
undiagnosed. Diabetes is also responsible for more than T2D patients will need insulin therapy.6 The basis for
10 lakh deaths in our country.2 this reasoning stems from the progressive nature of the
Better knowledge about Type 1 and Type 2 diabetes disease. Data from UKPDS confirmed that β-cell failure
has paved the path of newer options for treatment. in T2D is progressive in nature. 50% of β-cell loss usually
However, it is the advent of improved insulin therapy exists at diagnosis with a gradual decline of around 5%
which has heralded a new era in diabetes management. over the years, leading to restrained virtue of insulin
Insulin therapy in Type 1 and Type 2 diabetic patients secretagogues and insulin sensitizers. 7, 8
tries to match the normal pattern of insulin secretion to Prompt use of insulin in T2D may help in minimizing
offer optimal blood glucose control. glucotoxicity, resulting in reduced β-cell apoptosis and
the decline of β-cell function.3 Moreover, insulin therapy
SCIENCE OF INSULIN has also delineated augmentation in insulin sensitivity
THERAPY: THE NEED and, occasionally, reversal of insulin resistance.9 In a
Since hyperglycemia is the key manifestation of diabetes, 6 year sub-study by Wright A et al. (UKPDS 57),10 insulin
the therapeutic goal of diabetes management is to safely therapy was instantly added to type 2 diabetic patients
achieve and maintain normal or near normal glucose on sulfonylurea monotherapy if maximal doses failed to
levels, to delay or inhibit the onset of complications.3 sustain fasting plasma glucose levels at <108 mg/dL. This
This aspect has been validated by large studies like timely addition of insulin resulted in improved glycemic
control without heightened hypoglycemia or weight respectively. These are chiefly injected at mealtimes,
gain. In fact, the additional 0.5% decrease in HbA1c levels hence are also called “prandial” or “bolus” insulins.
seen in the combination group correlated with an 11.5% They reach their peak at 30–90 min and their duration
risk reduction for diabetes-related complications. At the of action is for 3–5 hours. They are also used in insulin
end of this study, nearly 53% patients on sulphonylurea pumps (subcutaneous insulin infusion systems or
therapy needed additional insulin to maintain glycemic SCII). Severe hypoglycemia is less frequent with these
control. formulations as compared to regular insulin.7,11,13,14
These viewpoints are reflected in the latest Short-acting insulin: Regular insulin is an example
American Diabetes Association (ADA) guidelines of short-acting insulin. Due to its delayed onset of
which recommend insulin therapy (in combination action, it must be injected 30–60 min before meals,
with or without other agents) in newly-diagnosed T2D which is inconvenient. Intravenous administration,
patients who are markedly symptomatic and/or present however, reduces its onset of action. It reaches its
with high blood glucose or A1C. Addition of insulin to peak in 2–4 hrs with a duration of action of 5–8
metformin as a second step of diabetes management is hrs.7,13,14
also recommended if HbA1c remains ≥9%.6 Intermediate-acting insulin: Represented by Neutral
Protamine Hagedorn (NPH) insulin which is regular
INSULINS AT A GLANCE insulin combined with protamine, to form a poorly
The three main components of insulin therapy are soluble complex. Its action kicks off in 1–3 hrs and
prandial (bolus) insulin, basal insulin and a correction- peaks at 8 hrs with duration of action being 12–16
dose or insulin supplement. Prandial insulin covers hrs. Lente insulin is synthesized by adding zinc with
postmeal requirement whereas the basal insulin takes regular insulin in an acetate buffer making it poorly
care of the constant levels of insulin present in blood. soluble compound. NPH and lente insulins are
The correction-dose or supplemental insulin rectifies commonly used as twice daily basal insulins. The
premeal or between-meal hyperglycemia, independent premixed formulations, e.g. insulin lispro protamine
from prandial insulin. 11 Refinement of the insulin and insulin aspart protamine (available as a part
manufacturing process and formulations have led to the of premixed solutions) have a similar time action
availability of several commercial preparations which profile as NPH, but has better prandial coverage and
vary in their pharmacokinetics and give the physician hypoglycaemia safely.7,13,14
and the patient a better chance to customize insulin Long-acting insulins: Ultralente is a very stable
therapy.12 insulin which is absorbed very slowly in its zinc
Insulin preparations are divided on the basis of their crystalline form. Insulin glargine is an analogue
onset of action into rapid, short, intermediate and long- with modifications made to make it more stable
acting types. The main types of insulin are: with increased solubility at an acidic pH of 4 and
Rapid-acting insulin: These are insulin analogs with reduced solubility at physiological pH. Subcutaneous
slightly modified amino acid sequences to prevent injection leads to the formation of a microprecipitate,
aggregation in solution. Their onset of action is resulting in slow dissolution from the injection site
very rapid (15 min) as they dissociate very quickly and consistent peakless delivery over 24 hrs. Detemir
into monomers in subcutaneous tissue. In case of is one more long-acting insulin which is acylated
insulin lispro, lysine at position 29 is switched with with fatty acid moiety at position 29 on lysine, which
proline at position 28, and insulin aspart has proline augments its albumin binding leading to gradual
at position 28 which is replaced with aspartic acid absorption from injection site. Its large size may also
while in insulin glulisine, aspart at B3 and lysine hamper trans-endothelial transport. These insulins
at B29 positions is replaced by lysine and Glucine have an onset of action of 1 hr with duration of acting
CHAPTER 45: Newer Insulins and Art of Insulin Therapy 275
lasting for 20–26 hrs. Insulin degludec is the newly associated comorbid conditions and available resources.
available novel long-acting basal insulin which The insulin therapy aims to achieve the glycemic targets
forms soluble multi-hexamer aggregates after being with minimal adverse effects especially hypoglycaemias.
injected subcutaneously leading to an ultralong Type 2 diabetics, in whom insulin therapy may
action profile of more than 24 hours. 7,13-15 prove beneficial, include those with symptomatic
Premixed insulin: Premixed analogues contain a hyperglycemia, failure of oral agents, pregnancy, acute
combination of a rapid-acting analog (for prandial medical or surgical emergency and in ICU/CCU. 6,16,17
coverage) and an intermediate or long-acting
analogue to cover basal needs. The advantages of Hospitalized Patients18
these analogs include absence of self-mixing and Based on available evidence, the American College of
reduction in the number of injections. It can be used Endocrinology (ACE) and the American Association of
to initiate insulin therapy, especially in Type 2 diabetic Clinical Endocrinologists (AACE) released a consensus
individuals with regular eating habits, in whom oral statement for the management of hyperglycemia in
agents have proved inadequate. Their onset of action the hospitalized patients. The key recommendations
varies depending upon the combination but their include:
duration of action is for 10–16 hrs.8,14
Critically Ill Patients
7
MODES OF INSULIN DELIVERY Insulin therapy must be inducted at blood glucose
The three main modes of insulin delivery include: >180 mg/dL
1. Syringe: Allows the patient to “freemix” insulin as per For most of the patients, maintain glucose levels at of
his/her needs. However, it includes a need for better 140–180 mg/dL once insulin therapy is initiated
doctor and patient education. Also, living daily life Prefer intravenous (IV) insulin infusions for achieving
with vials, syringes, etc. might become cumbersome. and maintaining glycemic goals
Insulin absorption might also change depending Validated protocols for Insulin infusion must be
upon the injection site. Insulin lispro and glargine followed with proven safety and efficacy, and with
are both clear solutions, so a great caution has to be minimal rates of hypoglycemia
exerted by the patients and they must be trained to Repeated monitoring of glucose is must to earn
read the labels very carefully before usage. optimal glucose control and to curtail incidence of
2. Pen: Convenient to carry, easy to use and distinguish hypoglycemia.
due to colour coding/size. The dose can be delivered
more accurately, and now 33 G needles are generally Noncritically Ill Patients
used for injections. It is however more expensive than For rest of the indoor patients on insulin, the
vialed insulins. preprandial glucose goal should be <140 mg/dL with
3. Pump: Involves fewer injections, removes site- random blood glucose level of <180 mg/dL. These
dependant absorption variability and ensures targets should be achieved safely.
physiological delivery with better control/lesser Tighter glucose control may be needed in steady
hypoglycaemia. Drawbacks include cost and the patients with previous tight glucose control.
special training needed to operate it along with Conversely, targets may be more flexible in mortally
likelihood of technical problems. ill patients or in patients with dismal brittleness.
Appropriate subcutaneous insulin injection, with
INITIATING INSULIN THERAPY prandial, basal, and correction boluses if needed,
Insulin treatment regimens depend upon the patient’s is the endorsed method for accomplishing and
location, educational status and willingness to learn, preserving glucose control.
Sliding scale insulin as the solo regimen is neither 3. Insulin NPH twice a day or nocturnal and premeal
approved nor encouraged or advocated. regular human insulin 3 times per day (no missed
Antihyperglycemic agents other than insulin are not meals): Insulin NPH can be given before breakfast
preferred in most of the indoor patients and again at bedtime along with regular insulin
injection before all meals. Since regular insulin has
Type 1 Diabetes Patients 7,16,19 comparatively longer duration of action, its use at all
In T1D patients confined to critical care units, the mealtimes might make even once daily bedtime NPH
ideal therapeutic protocol includes initiation of an as a viable option for most patients.
IV insulin infusion (only regular human insulin to be
used) with repeated monitoring and titration of the Type 2 Diabetes Patients 6,7
insulin dose. Patients with new-onset type 1 diabetes Initial therapy of type 2 diabetes begins with lifestyle
respond favorably to a combination of background basal changes, then typically moves onto monotherapy with a
insulin and short-acting insulin taken before meals. The noninsulin agents. When switching from monotherapy
total daily insulin dosage in these adults and children to dual therapy, the 2015 ADA guidelines recommend
immediately postdiagnosis is normally 0.2–0.6 unit/ that basal insulin can be added for all patients in whom
kg/day. Initial basal insulin could be insulin glargine HbA1c is ≥9%, to achieve target levels more quickly. This
or degludec, although NPH insulin or insulin detemir combination results in similar control with less weight
may also be given twice a day. Overall, patients using gain, lower insulin doses and fewer hypoglycemic
insulin analogues (lispro, aspart, glargine) in regimens episodes than insulin alone or insulin used along
which mimic physiologic insulin release present with with sulfonylureas. Moreover, ADA recommends
fewer hypoglycemic episodes than patients using insulin initiation (with or without additional agents)
traditional insulins (regular and NPH). Prandial insulin even in newly detected T2D patients with remarkably
can be matched to carbohydrate intake/meal, premeal symptomatic and/or high blood glucose levels or A1C.
blood glucose and expected physical activity. One of Alternatively, if non-insulin therapy proves
the programs which helps in understanding this better inadequate, basal insulin can be added as the next step.
is Dose Adjustment For Normal Eating (DAFNE). This In patients who seem to require increasing doses of
program trains type 1 diabetic individuals to estimate the insulin due to poor control, thiazolidinediones (TZD)
carbohydrate in each meal and to inject the right dose of or sodium-glucose transporter 2 (SGLT2) inhibitors can
insulin.20 be added to enhance control. Conversely, combination
Three suggested options, in order of preference, for therapy, with basal and mealtime insulin, can be started
this patient category include: when glucose is ≥300 mg/dL and/or HbA1C is ≥10% or if
1. Glargine and premeal rapid-acting insulin: This is triple therapy inadequate to achieve targets.
one of physiological insulin regimens which offers Initiating insulin therapy in a stepwise, flexible
basal and prandial coverage over 24 hrs. Once-daily fashion by involving the patient in making dose
glargine given at bedtime with aspart/lispro/aspart adjustments based on self-monitored blood glucose
(in a 50:50 ratio) given at mealtimes allows patients levels might enhance patient compliance. Basal insulin
to skip meals or change mealtimes. Glargine achieves can be initiated at 10 U or 0.1–0.2 U/kg (based on blood
steady state in 2 hrs. This regimen is easier to use glucose levels). This can be used in combination with
since it has separate basal and prandial insulins. metformin and another non-insulin agent, if required.
2. Insulin NPH or detemir twice a day and premeal If fasting blood glucose reaches acceptable levels with
rapid-acting insulin: NPH or lente is given before this regimen but HbA1c levels remain elevated, a second
breakfast and at bedtime with lispro/aspart given injection can be added to provide prandial coverage.
before meals. This regimen is less flexible since NPH Prandial coverage can be achieved by adding a glucagon
can act as both a basal and a prandial insulin. like peptide (GLP-1) receptor agonist or prandial insulin.
TABLE 1: Approach to starting and adjusting insulin in type 2 diabetes

Step 1 If FBG traget Step 2a Step 2b Step 3
Basal insulin is achieved Add a rapid-acting Switch to premixed Add 2 or more rapid
(normally with but HbA1c insulin before the insulin twice a day insulin injections
metformin ± another goals are not largest meal before meals
noninsulin drug) attained (or if
dose exeeds
Starting dose 10 U/day or 0.1– 0.2 0.5 U/kg/day) Start with 4 U/0.1 U Divide basal dose Start with 4 U/0.1 U
U/kg/day per kg or 10% of the into appropriate per kg or 10% of the
basal dose portions* basal dose/meal. If
HBA1c<8% reduce
If not basal insulin by the
controlled, same amount
move to
Step 3
Adjustment 10–15% or 2–4 U Treat with a Increase dose by Increase dose by Increase dose by 1–2 U
dose 1 or 2 times/wk to GLP-1-RA 1–2 U or 10–15% 1–2 U or 10–15% or 10–15% 1–2 times/
attain FBG goals one-two times/ 1–2 times/week till week till target is
or week till target is target is achieved achieved
achieved
Combating Identigy the cause Move to step Identify the cause Identify the cause Identify the cause and
hypoglycemia and decrease dose by 2a or 2b and decrease and decrease decrease equivalent
4 U or by 10–20% equivalent does by equivalent does by does by 2–4 U or by
2–4 U or by 10–20% 2–4 U or by 10–20% 10–20%
*70/30 aspart mix, 75/25 or 50/50 lispro mix
Abbreviation: FBG, fasting blood glucose; GLP-1RA, GLP-1 receptor agonist
Source: Adapted from American Diabetes Association 6; Inzucchi SE et al.21
As a less flexible option, basal insulin can be replaced Usage of insulin supplements before or between
by premixed analogues (30/70 or 50/50 aspart mix, 25/75 meals should be done carefully since it might lead to
or 50/50 lispro mix). Yet another expensive option to the “insulin stacking.” To avoid this, supplements injected
“basal–bolus” therapy could be using a CSII or an insulin <3 hours after a previous insulin dose, can be given at
pump. half the dose. In physically active patients who exercise
Overall, a 50:50 ratio can be used to provide the 1-3 hours after meals, the dose of rapid-acting insulin
complete insulin dose required in a day i.e. 50% basal analogues may have to be reduced substantially to avoid
and 50% prandial, where the prandial can be split hypoglycaemia.22
equally between three meals. The approach to initiating/ “Adjustments” of insulin dosage are done on basis of
adjusting insulin treatment, suggested by the ADA a persistent change in blood glucose levels. In case of a
guidelines, is given in the Table 1. patient receiving bedtime NPH insulin and presenting
with frequent fasting hypoglycaemia, the adjustment
Fine-tuning Insulin Therapy 7,11 would be to decrease the bedtime insulin dose. Timely
Self-monitoring of blood glucose (SMBG) helps to and precise adjustments in the insulin regimen in
refine insulin therapy to ensure adequate control. accordance to the patients’ meal/activity levels are the
Supplemental insulins are fixed doses of rapid- or short- key to effective long-term glucose control.
acting insulin used to correct hyperglycemia. They are
typically injected with the usual prandial dose of insulin. OVERCOMING THE PSYCHOLOGICAL
A ballpark dose for patients with T1D is an additional 1U BARRIERS TO INSULIN THERAPY
per 50 mg/dL. For patients with T2D, 1U of supplemental Though the benefits of insulin therapy are well-studied,
insulin may be given per 30 mg/dL above the target many fears and misconceptions exist both in the minds of
glucose level. the patient and the physician making therapy initiation a
challenge in type 2 diabetes patients. Some tactics which like hypoglycemia and weight gain might also worry
can be adopted by physicians to overcome their patients’ them. Each of these aspects can be dealt with separately.
fears include listening patiently, acknowledging their In many cases, asking the patient to interact with another
fears, probing gently to get to the root of the problem who is already on insulin therapy may do wonders for
and imparting adequate knowledge. The physicians their morale. It is also important for the physician to
are advised to decline use insulin therapy as a “threat”. constantly guide and monitor the patients to ensure
Some questions which might give some insight into the that the treatment regimen is being followed correctly.
patient’s fear include “What problems do you think will Please give positive feedback whenever necessary and
occur if you begin insulin therapy?” “What do you feel is if required enlist the help of family members or other
the most negative point about insulin?” Upon receiving caregivers to keep the patient motivated.9,23,24
answers to these questions, gently ascertain the real Some of main patient barriers to insulin therapy are
cause for concern by asking questions such as “Why do outlined in Table 2 along with possible solutions.
you feel like that?” or “Can you tell me more about that?” Physician-related inhibitions stem from a lack
Some of the patient fears stem from a dislike for of experience, an idea that it will be a burden to the
needles, social stigma, seeing insulin as a personal failure, patient, fear of inducing side-effects or inexperienced/
a last resort, a feeling that the regimen is complex and unwilling staff. However, delaying insulin therapy till it is
will interfere with their daily routine. Some other aspects “absolutely necessary” might result in the disease having
TABLE 2: Overcoming patient barriers to insulin therapy

Patient's fear Suggested strategies for the physician
Insulin is a personal failure/have not zz Stress that they have not failed, other treatment options have failed them.
manged their condition properly/ zz Explain the progressive nature of diabetes and the eventual need for insulin.
stigma/the last thing the doctor thought zz Present insulin as a logical treatment step.
of since there is no other cure

Insulin is not effective zz Most patients feel that diabetes is a "sugar" problem. Point out that diabetes occurs due to
lack of insulin, ergo replacement is the best way to deal with it and insulins available today are
very similar to that made by the body.
Might interfere with their daily lives zz Ascertain their precise fears and design regimens which will enmesh with their daily routine.
(exercise traveling, work, etc.) For example, Insulin pens can be used to afford ease of travel, ease of injection (can be
injected discreetly at work or at functions) or prescribe morning only or bedtime only
regimens to curb embarrassment
Insulin causes complications and death zz Acknowledge their fears and assure them that your experience with several patients has
(they might have observed others who shown you otherwise
have suffered in spite of insulin therapy) zz Explain that complications result due to lack of insulin; not because of its appropriate use
Insulin injections are painful (may zz Clarify that insulin needles are smaller and thinner and less painful
be based on antibiotic injections/ zz Give a dry injection to yourself in front of the patient or ask the patient to give themselves a
vaccinations) dry injection
zz Insulin pens can help overcome inhibitions
zz Genuine "needle phobia" can be overcome by counselling
Fear of hypoglycemia zz Acknowledge their fear and assure them that you will help them and their family members/
caregivers to recognise, combat and devise ways to avoid hypoglycaemic episodes
zz Inform them and include long-acting insulins in their regimen where hypoglycemia is less of a
problem
Insulin causes weight gain zz Tailor regimens to limit weight gain. For example, use of newer analogs like glargine, detemir,
addition of metformin, glucagon like peptide 1 receptor agonists
zz Involve a nutritionist to identify strategies to combat weight gain
Source: Adapted from Funnell MM,23 Stotland NL,24 Alkhaifi M et al.25; Haslam D26
progressed to an advanced stage where the patient might 5. American Diabetes Association. Implications of the United
be burdened by significant complications.25,27,28 kingdom prospective diabetes study. Diabetes Care.
2003;26(Suppl 1):S28-32.
6. American Diabetes Association. Approaches to glycemic
CONCLUSION treatment. Sec.7. In Standards of Medical Care in
More than 17% of the world’s diabetic population lives Diabetes-2015. Diabetes Care. 2015;38(Suppl 1):S41-8.
in India. 2 The discovery of insulin in 1921 and the 7. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type
giant strides made in the development of commercial 1 and type 2 diabetes mellitus: scientific review. JAMA.
preparations of insulin and its analogs have helped 2003;289(17):2254-64.
in making control of blood glucose in diabetes a 8. Freeman JS. Insulin analog therapy: improving the match
with physiologic insulin secretion. J Am Osteopath Assoc.
manageable goal.12 Insulin therapy for type 1 diabetes
2009;109(1):26-36.
can be carefully calibrated in accordance to the meal
9. Marrero DG. Overcoming patient barriers to initiating insulin
patterns and physical activity of the patient to achieve therapy in type 2 diabetes mellitus. Clin Cornerstone. 2007;
optimal blood glucose levels. Though insulin was 8(2):33-43.
considered as “last resort” till not very long ago for type 10. Wright A, Burden AC, Paisey RB, Cull CA, Holman RR.
2 diabetes, ADA now recommends the use of insulin as UK Prospective Diabetes Study Group. Sulfonylurea
an adjunct to metformin when HbA1c remains ≥9% and inadequacy: efficacy of addition of insulin over 6 years in
also in selected newly diagnosed patients. Similarly, patients with type 2 diabetes in the UK Prospective Diabetes
Study (UKPDS 57). Diabetes Care. 2002;25(2):330-6.
combination insulin regimens are also being advocated
11. H i r s c h I B . I n s u l i n a n a l o g u e s . N E n g l J M e d .
for swift and accurate attainment of blood glucose 2005;13;352(2):174-83.
targets. 6 Though insulin therapy is a must in type 1 12. History of diabetes. American Diabetes Association ADA
diabetes and becomes essential during the course of [Internet] 2015 [cited 2015 July 16] Available from:
type 2 diabetes, misconceptions and fears regarding its http://www.diabetes.org/research-and-practice/student-
usage exist till date. Effective communication between resources/history-of-diabetes.html?referrer=https://www.
the physician and the patient can help overcome google.co.in/.
13. Herbst KL, Hirsch IB. Insulin strategies for primary care
barriers to insulin therapy. Self-monitoring of glucose
providers. Clin Diabetes. 2002;20:11-7.
levels, judicious use of the different types of insulin with 14. Insert C: Types of Insulin. The National Institute of Diabetes
meticulous refinement of insulin regimens as the disease and Digestive and Kidney Diseases. [Internet] [year
progresses will make management of T1D and T2D a unknown] [cited 2015 July 15] Available from: http://www.
much easier goal to attain for all patients of diabetes. niddk.nih.gov/health-information/health-topics/Diabetes/
diabetes-medicines/Pages/insert_C.aspx.
REFERENCES 15. Kalra S, Unnikrishnan AG, Baruah M, Kalra B. Degludec
1. Pozzilli P, Strollo P, Bonora E. One size does not fit all insulin: A novel basal insulin. Indian J Endocrinol Metab.
glycemic targets for type 2 diabetes. J Diabetes Invest. 2011;15 (Suppl 1):S12-6.
2014;5:134-41. 16. Mooradian AD, Bernbaum M, Albert SG. Narrative review:
2. IDF Diabetes Atlas 6 th Edition [Internet]. International a rational approach to starting insulin therapy. Ann Intern
Diabetes Association, 2014 [updated 2014;cited:2015;16]. Med. 2006;18;145(2):125-34.
Available from: http://www.idf.org/sites/default/files/ 17. American Diabetes Association. Glycemic targets. Sec. 6. In
Atlas-poster-2014_EN.pdf Standards of Medical Care in Diabetes-2015. Diabetes Care
3. Sorli C, Heile MK. Identifying and meeting the challenges 2015;38(Suppl.1):S33-S40.
of insulin therapy in type 2 diabetes. J Multidiscip Healthc. 18. Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D,
2014;7:267-82. Hellman R, Hirsch IB et al. American Association of Clinical
4. American Diabetes Association. Implications of the Endocrinologists and American Diabetes Association
diabetes control and complications trial. Diabetes Care. consensus statement on inpatient glycemic control. Endocr
2003;26(Suppl 1):S25-7. Pract. 2009;15(4):353-69.
19. Hirsch IB, Type 1 diabetes mellitus and the use of flexible 23. Funnell MM. Overcoming barriers to the initiation of insulin
insulin regimens. Am Fam Physician. 1999;15;60(8): therapy. Clin Diabetes. 2007;25(1):36-8.
2343-52, 2355-6. 24. Stotland NL. Overcoming psychological barriers in insulin
20. DAFNE. What is DAFNE? [Internet] 2015 [updated 2012 therapy. Insulin. 2006;1:38-45.
March 23; cited 2015 July 16] Available from: http://www. 25. Alkhaifi M, Alkhussaib G, Theodorson T, Ward MA, Al
dafne.uk.com/What_is_DAFNE_-I293.html. Mazrou’I A. Barriers in initiating insulin treatment in type 2
21. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini diabetes mellitus among physicians in Wilayat of Bowsher in
E, Nauck M, et al. Management of hyperglycemia in type 2 Oman. J Family Med Community Health. 2015;2(3):1034.
diabetes, 2015: a patient-centered approach: update to a 26. Haslam D. Should we Fear Insulin Therapy in the Treatment
position statement of the American Diabetes Association of type 2 diabetes? The Open Obesity Journal. 2014;6:70-7.
and the European Association for the Study of Diabetes. 27. Maharaj S, Pirie F, Paruk I, Motala A. How to start and
Diabetes Care. 2015;38(1):140-9. optimise insulin therapy. Starting insulin therapy in type 2
22. Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL. diabetes can be challenging. CME. 2010;28(10):458-64.
Guidelines for premeal insulin dose reduction for 28. Brod M, Alolga SL, Meneghini L. Barriers to initiating insulin
postprandial exercise of different intensities and durations in type 2 diabetes patients: development of a new patient
in type 1 diabetic subjects treated intensively with a basal- education tool to address myths, misconceptions and
bolus insulin regimen (ultralente-lispro). Diabetes Care. clinical realities. Patient. 2014;7:437-50.
2001;24(4):625-30.
CHAPTER
46
Individualization of Diabetes Care
TREATMENT APPROACHES FOR T2 To achieve the target HbA1c level in patient with
DIABETES HbA1c > 8.0–8.5%, multiple anti-diabetes agents
There are two general treatment approaches for T2 DM. should be considered.
AACE guideline recommends multiple antidiabetes
1. Guideline approach: Antidiabetes agents such as
Metformin followed by Sulfonulurea addition with agents for newly diagnosed diabetic subjects with
subsequent (UPKDS) addition of insulin. This HbA1c >7.5%.
approach is known as treat to failure approach, and Treat to fail algorithm, the 2009 American Diabetes
has many challenges. Association/European Association of Study of Diabetes
2. Pathophysiology approach: Preferred combination (ADA/EASD) algorithm recommended metformin as
therapy according to defects in T2DM. The therapy initial therapy to achieve HbA1c <7–0%, followed by,
should consider patient’s overall health status sequential addition of SU, and if SU fails basal insulin
and co-morbid condition. This individualized should be added. The revised 2012 ADA/EASD algorithm
approach, which we refer to as the ABCD(E) of included newer antidiabetes agents such as GLP-1
diabetes treatment.
receptor agonists, DPP4i, and TZDs as potential choices
A - Age
if metformin fails (Fig. 1 and Table 1).
B - Body weight
The ADA/EASD 2012 does not consider initial
C - Complications (microvascular and macrovascular)
combination therapy in most newly diagnosed T2DM
D - Duration of diabetes
E - Life expectancy patients in achieving goal of HbA1c goal <6-0–6-5%.
F – Expense Diabetes care delivery should include strategies such
as shared-decision making motivational interviewing
Therapy in Newly Diagnosed T2DM techniques, shared medical appointments and
Patients multidisciplinary team collaboration which helps in
Goal is to achieve the targeted level of glycemic achieving glycemic targets and improving patients
control. HbA1c should be <60% in newly diagnosed quality of life.
diabetic patients without CVD. Long-term glycemic control:
Monotherapy will not reduce HbA1c <6.5–7.0%, hence Combination therapy is initiated with drugs targeting
ideally combination therapy should be preferred. pathogenic defects (additive effect).

Fig. 1: Non-insulin therapy for hyperglycemia in type 2 diabetes, treating defronzo’s octet match
patient characteristics to drug characteristics
TABLE 1: Pathophysiological detects and drugs

Metabolic Insulin Insulin Beta-cell Increased free Loss of Increased Increased Insulin resistance
defects resistance resistance (decrease in fatty acid levels incretin activity of absorption in tired brain
in muscle in liver insulin in the blood function alpha-cells in the of glucose
secretion from fat cell from pancreas (higher by kidneys,
by the breakdown the blood levels result in
pancreas) (more insulin gut of glucagon higher blood
resistance toxic (GLP1, increase blood glucose
to beta-cell) GLP) glucose level)
Drugs to Metformin Metformin Sulfonylurea, TZS’s GLP1 GLP.DPP GLP1, amylin SGLT2 GLP1
treat TZD’s TZD’s insulin, TZD’s analogs, inhibitor analogs,
DPP4 insulin insulin
The therapy should not only reduce HbA1c in long- Factors deciding treatment strategy:
term glycemic control but also reverse the pathogenic Patients attitude and efforts
defects. Hypoglycemia
Early thearpy prevent/slow progressive beta-cell Duration
failure. Life expectancy
Drug therapy should reduce in HbA1c with significant Complications
glucose lowering ability. Vascular complications (Fig. 2)

CHAPTER 46: Individualization of Diabetes Care 283
Fig: 2 Choosing tight or losse target?
Patient characteristic: Short duration of diabetes, long Metformin is first line agent for T2DM
expectancy and significant CVD Insulin therapy is considered in newly diagnosed
Less stringent A1C goals, i.e. <8% T2DM patient with markedly symptomatic and/or
Advanced microvascular or macrovascular compli elevated glucose levels and higher A1C.
cations In noninsulin monotherapy if the A1C target is not
Extensive comorbid conditions. achieved over 3–6 months, add a second oral agent, a
GLP-1 receptor agonist, or insulin
A patient-centered approach should be considered
Individualized Goal Based on
which include efficacy, cost, potential side effects,
Duration effects on weight, comorbidities, hypoglycemia risk,
Age expectancy and patient preferences
Co-morbid conditions DSME should focus on psychosocial problems, since
CVD/ microvascular complications emotional well-being is associated with positive
Unaware of hypoglycemia outcomes.
Consider bariatric surgery for adults with BMI >35 IMPLEMENTATION STRATEGIES
kg/m2 Initial therapy
After surgery, life-long lifestyle support and medical Advancing to dual combination therapy
monitoring is necessary Advancing to triple combination therapy
Transitions to and titrations of insulin
PATIENT–CENTERED APPROACH
Antihyperglycemic Therapy OTHER CONSIDERATIONS (TABLE 2)
Glycemic targets Old age
—— HbA1C <7.2% (mean PG ~ 150–160 mg/dL [8*3– —— Decreased life expectancy
—— Higher CVD burden

8–9 mmol/L]
—— Preprandial PG < 130 mg/dL (7.2 mmol/L) —— Reduced GFR
—— Postprandial PG <180 mg/dL (10.0 mmol/L) —— At risk for adverse events from polypharmacy
—— Individualization is key : —— More likely to be compromised from hypo
Tighter targets (6.0–6.5%) - younger, healthier) glycemia

L ooser targets (7.5–8.0%) - older, co Weight
—— Metformin
morbidities, hypoglycemia prone, etc.
—— Avoidance of hypoglycemia —— GLP-1 receptor agonists
—— Less ambitious targets —— Bariatric surgery
—— Consider LADA in lean patients

HbA1c <7.5–8.0 % if tighter targets not easily
achieved Sex/ethnic/racial/genetic differences-Gender may
drive concerns about adverse effects (e.g. bone loss
Focus on Drug Safety from TZDs)
Therapeutic options Comorbidities
—— Lifestyle modifications —— Coronary disease metaformin: CVD benifit
—— Reducing weight (UKPDS)

—— Healthy diet —— SGLT2 inhibitors
—— Increase physical exercise —— Avoid hypoglycemia
—— SUs and ischemic preconditioning

Oral agents and noninsulin injectables
—— Metformin: Meglitinides —— Pioglitazone and CVD events
—— Sulfonylureas: glucosidase inhibitors
—— Thiazolidinediones: Bile acid sequestrants TABLE 2: Elements of decision-making in glycemic target-setting

—— DPP-4 inhibitors: Dopamine-2 agonists Biological zz General health related
—— GLP-1 receptor agonists: Amylin mimetics zz Life expectancy
zz Comorbid conditions
—— SGLT2 inhibitors
zz Diabetes-related
zz Disease duration
Insulin zz Vascular complications
Neutrapeutic options: Insulin Psychological zz Risk of hypoglycemia/adverse events

—— Neutral protamine Hagedorn (NPH) zz Expected treatment efforts on part of patient
zz Patient attitude
—— Regular
—— Basal analogs (glargine, detemir, deglu-dec) Social zz Available resources

—— Rapid analogs (lispro, aspart, glulisine)
zz Available support system
CHAPTER 46: Individualization of Diabetes Care 285
—— Heart failure metformin: May use unless condi THERAPEUTIC PATIENT

tion is unstable of severe EDUCATION
—— SGLT2 inhibitors
Our focus on newer drugs alone puts us at risk of
—— Avoid TZDs
forgetting traditional clinical wisdom
—— Renal disease increased risk of hypoglycemia
Inherent power of traditional wisdom has served
—— Metformin and lactic acidosis
preceding generations of physicians (and their
US : stop @ %Cr > 1 . 5 (1–4 women)
patients) fairly well
UK : dose @ GFR < 45 and stop @ GFR < 30
One such treatment for diabetes is thera peutic
Caution with SUs (esp. glyburide)
patient education (TPE)
—— DPP-4i’s–dose adjust for most liver dysfunction
TPE encompasses various strategies
Most drugs not tested in advanced liver disease
—— Face-to-face counseling and group education
—— Pioglitazone decreases steatosis hypoglycemia
—— Ut i l i z e d t o c o nve y m e s s ag e s o f va r y i ng
emerging concerns regarding association with
increased mortality. importance, which can be grouped as primary,
secondary or tertiary education
How do We Ascertain this TPE is administered as formal structured programs
Patient Centered Care?
KEY POINTS
Patient centered care (PCC)
—— Care that is respectful of and responsive to
1. Glycemic targets and glucose lowering therapies
individual patient preferences, needs and values must be individualized.
—— Ensures that patient values guide all clinical
2. Glycemic target should not be viwed as fixed goals
decisons but flexible and be adopte d according to patients
Improve communication skills of the doctors health and living conditions.
Guideline emphasized upon 3. Passive to active role of patient in setting goals.
—— Patient involvement 4. Diet, exercise and education is the basic of all diabetic
—— Decision aids treatment program.
—— Shared decision making 5. After metformin, there are limited data to give us
—— Adherence combination therapy with add itional 1–2 oral or
Components of patient-centered professionalism injectible agents is reasonable aiming to minimize
—— C: compassionate competence side effects where possible.
—— A: authentic accessibility 6. An intensive lifestyle interventions in obese patients
—— R: reciprocal respect with particular consideration given to drug therapy.
—— E: expressive empathy 7. In the older, more infirm patient a more conservative
—— S: straightforward simplicity less aggressive approach may be best.
CHAPTER
47
Diabetes and Immunity
INTRODUCTION prediabetes stage in its staging. The histopathology of

Diabetes mellitus is a group of conditions with T1D is defined by a decreased β-cell mass with infiltration
heterogeneous pathogenetic mechanisms characterized of mononuclear cells into the islets of Langerhans, which
by hyperglycemia and involvement of multiple organ was described in 1901 by Opie.
system especially the vasculature. Type 2 and type 1 The autoimmune response involve both the cellular
diabetes mellitus are the two major types. The immune and humoral immune pathways. Inflammatory cells
system provides immunity through a collection of infiltrate pancreatic the islets leading to insulitis. The
cells, tissues and molecules that protects the body pathophysiologic mechanisms in include two distinct
from numerous pathogenic microbes and toxins in stages in genetically susceptible individuals: i) Triggering
the environment. While it is an established fact that of autoimmunity resulting in one or multiple islet cell
type 1 diabetes mellitus is a disease characterized by autoantibodies associated with gradual β-cell killing.
autoimmune destruction of the β cells of the pancreas; CD8 + T lymphocytes are responsible for selective and
recent understanding suggests that disturbances in specific killing of β-cells; ii) Loss of β-cell mass and
immune system could be involved in type 2 diabetes function leading to hyperglycemia.
mellitus causation. Moreover there is defective immune A complex interaction of genetic, epigenetic and
response to microbial and other toxic insults in diabetes environmental factors is involved in its pathogenesis.
Maternal factors suggested to play a role in its development
mellitus necessitating enhanced care in patients with
include gestational infections; higher maternal age; ABO
diabetes mellitus suffering from infections; and the
incompatability; higher birth order and stress. Genetic
adopting measure to prevent infections like appropriate
susceptibility could be HLA based or non-HLA based.
vaccinations.
HLA risk include DQ8, DQ2, or both; whereas DQ6
is believed to be protective. Non-HLA based genetic
IMMUNITY IN THE PATHOGENESIS
factors include INS-VNTR, PTPN22 and IL2RA (CD25).
OF DIABETES MELLITUS
Autoimmunity could be triggered by environmental
Type 1 Diabetes Mellitus toxins and nutritional factors. They include infection
Autoimmune β-cell destruction begins before clinical (virus), vitamin D deficiency, diet (bovine milk), toxins
presentation of hyperglycemia in type 1 diabetes (T1D) (alloxan, streptozotocin, vacor). Markers of autoimmune
and recent classification have therefore introduced a process is measured through auto-antibodies such
CHAPTER 47: Diabetes and Immunity 287
as GAD65Ab, IAAb, IA-2Ab, ZnT8Ab. There are also that are seen in diabetes mellitus. It is a known fact
candidate minor antigens like ICA12, VAMP2, NPY, etc. that low birth weight increases the risk of metabolic
The accelerating factor for β-cell loss are again infection, syndrome in the future. One of the mechanisms is
worsening insulin resistance such as puberty and weight heightened inflammation. Early life stress and low
gain. birth weight increases the stress response through the
activation of the hypothalamopituitary adrenal (HPA)
Type 2 Diabetes Mellitus axis causing hypercortisolemia resulting in an insulin
In recent decades, there has been prolific discussions resistant states. These early life changes are programmed
on the role of immune disturbances such as chronic in such a way that there is a chronic activation of the HPA
low-grade inflammation in type 2 diabetes mellitus axis in the life of the individual. Innate immunity aims to
causation and atherosclerotic cardiovascular diseases. restore homeostasis in the short-term conferring survival
The association of inflammation with carbohydrate advantage in the face of an environmental insult, but
metabolism can be traced back to historical reviews by in type 2 diabetes it is prolonged. Thus the adaptations
Shoelson et al. in the 19th century. They cited reports developed early in life becomes maladaptive. In the same
from over a century ago in which high-dose salicylates vein, there are suggestions that chronic psychological
decreased glycosuria in individuals classified as diabetic. stress is associated with risk of diabetes or worsening
The postulated mechanisms linking diabetes of diabetes outcomes in those already diagnosed. In
pathogenesis and immunological reactions are diverse. the Hoorn Study in the Netherlands, stressful life events
There are scientific reports suggesting that the innate in the previous 5 years predicted the development of
immunity is activated in type 2 diabetes resulting in the diabetes in people (aged 50–74 years) who did not have
release of inflammatory cytokines that worsen insulin diabetes mellitus.
resistance, promotes β-cell failure, alters T-cell mediated Cytokines such as TNF-α cause insulin resistance
immunity and even increases the risk for autoimmunity. by activation of the stress-induced kinase, c-Jun NH2-
The possible players in the predisposition to terminal kinase, serine phosphorylating signalling
enhanced innate immunity in type 2 diabetes are genetic proteins such as insulin receptor substrate-1 and 2 (IRS-1
and racial factors, nutrition, aging, chronic stress and and IRS-2). This inhibits insulin signalling and stimulates
early life programming. Polymorphisms in the TNF-α of expression of SOCS proteins which cause degradation
gene promoter, TNF-α receptor gene and IL-6 gene of IRS-1 and -2 by binding them. TNF-α, IL-1β, and IL-6
are variously associated with insulin sensitivity or downregulate PPAR-g expression. PPAR-g is involved in
resistance. Dietary factors have been postulated to be insulin sensitivity by promoting adipogenesis.
involved in type 2 diabetes causation via calorie excess, There are other smaller evidences that the adaptive
inflammation and alteration of the gut microbiota. immune response may also be impaired in type 2 diabetes.
High fat diet induces inflammation in the gut lining It was shown by Lindsay et al. elevated g-globulin, a non-
resulting in ‘leaky gut’ where bacterial products such specific marker of adaptive immunity increases the risk
as lipopolysaccharides (LPS) are easily absorbed and for type 2 diabetes mellitus development in American
transported in the circulation to organs including the Indians. The concept if type 2 diabetes is a slowly
adipose tissue. This induces inflammation in the adipose evolving autoimmune disease is a topic of significant
tissue resulting in the release of inflammatory cytokines debate. So far the existing signal is inadequate to
that cause insulin resistance. The alteration in the gut prove or disprove this idea. Obesity associated insulin
microbiota seen in obesity induced insulin resistance also resistance suggests the possibility of an activated innate
increases the efficiency of fat and LPS absorption further immune response mainly at central adipose tissue.
worsening insulin resistance. Aging is accompanied by Isolated T-and-B cells and/or antibodies from obese
an inflammatory cytokine profile mirroring the changes can transfer disease; and therapies targeting them have
been shown to slow disease advancement. Also there response in bactericidal activity probably play an
has been demonstration of specific autoantibodies important role. These impairments can be worsened
linked to the insulin resistant or type 2 diabetes state like by hyperglycemia and acidosis. However, reversing
antibodies to Golgi SNAP receptor complex member 1 hyperglycemia and acidosis may not show immediate
(GOSR1) transcript variant 1, suggesting an autoimmune benefit, thereby suggesting that chronic processes such
pathophysiologic mechanism. GOSR1 transcript as accumulation of advanced glycation end products and
variant 1 is a protein involved in trafficking between other structural changes could contribute. Host factors
the endothelial reticulum and Golgi compartments. play an equally important role in the predisposition
Autoantibody against these proteins are seen in 30–70% to poor outcomes with infection in diabetes. These
of insulin-resistant individuals. include vascular insufficiency (microangiopathies
and macroangiopathies), peripheral neuropathy
DEFECTIVE IMMUNE RESPONSE (motor, sensory and autonomic) and skin and mucosal
IN DIABETES MELLITUS colonization with pathogens; among others. Infection
Immune function study in diabetes mellitus and obese and diabetes have a bidirectional relationship in that
humans and experimental animals have suggested that diabetes predisposes to increased risk of infections and
infection outcomes; and infection worsens diabetes
they are associated with impairments in host immune
status.
mechanisms. Patients with diabetes have been reported
to have a greater incidence of infections as well as
greater infection-related morbidity and mortality.
CONCLUSION
Understanding the association between diabetes and
Thus colonization by Staphylococcus aureus and
immunity is an important area for enhanced research;
Candida species; more severe infection with organisms
as immune disturbances have been suggested and
such as Klebsiella species; urinary tract infection and
shown to be involved both in the pathogenesis and
asymptomatic bacteriuria; risk of tuberculosis infection
complications of diabetes. Envisaging diabetes mellitus
and treatment failure; hepatitis C infection are increased
from an immunological perspective can help fill some
in diabetes mellitus. Infections such as rhinocerebral
of the lacunae we have in our understanding of diabetes
mucormycosis, malignant otitis externa, Fournier
and in the care of those who suffer from the disease.
gangrene and emphysematous cystitis, pyelonephritis
and cholecystitis occur almost entirely in diabetes.
BIBLIOGRAPHY
The infections in a diabetic patient are unique in that 1. Antonio Hernandez-Mijares, et al. Human Leukocyte/
they are recurrent, more severe, frequently require Endothelial Cell Interactions andMitochondrial Dysfunction
hospitalization, and also have higher mortality than in Type 2 Diabetic Patients and Their Association With Silent
controls. Myocardial Ischemia. Diabetes Care. 2013;36:1695-702.
Therefore on one hand there is heightened 2. Barbara Menart-Houtermans, et al. Leukocyte Profiles Differ
Between Type 1 and Type 2Diabetes and Are Associated
immunological response in diabetes resulting in its
With Metabolic Phenotypes: Results From the German
pathogenesis, on the other hand, impaired immune Diabetes Study (GDS). Diabetes Care. 2014;37:2326-33.
response seen in the condition is associated with DOI: 10.2337/dc14-0316.
increased risk of and worse outcomes with infections. 3. Clive S. Cockram, et al. Diabetes and Infections. In. Textbook of
Many aspects of neutrophil function are affected Diabetes. 4th edn. Oxford. Wiley-Blackwell. 2010. pp. 835-58.
4. John C Pickup. Inflammation and Activated Innate Immunity
in diabetes. Neutrophil function such as chemotaxis,
in the Pathogenesis of Type 2 Diabetes. Diabetes Care.
adherence to endothelium, phagocytosis, bactericidal 2004;27:813-23.
activity and opsonization are impaired in diabetes. The 5. Lício A Vellos, et al. Type 2 diabetes mellitus-an autoimmune
disturbance in the balance of oxidant and antioxidant disease? Nature Reviews Endocrinology. 2013;9:750-5.
CHAPTER 47: Diabetes and Immunity 289
6. Marc Y Donath, Steven E Shoelson. Type 2 diabetes as 8. Paul A Davis, et al. Obesity and Immunity. In: Nutrition and
an inflammatory disease. Nature Reviews Immunology. Immunology. New York. Humana Press. 2000. pp. 295-301.
2011;11:98-107. 9. Sue Tsai, et al. Are Obesity-related Insulin Resistance
7. Marc Y Donath. Targeting inflammation in the treatment and Type 2 Diabetes Autoimmune Diseases? Diabetes
of type 2 diabetes: time to start. Nature Reviews Drug 2015;64:1886-97. DOI: 10.2337/db14-1488.
Discovery. 2014;13:465-76. 10. William T Cefalu. Inflammation, Insulin Resistance, and Type
2 Diabetes: Back to the Future? Diabetes. 2009;(58):306-7.
CHAPTER
48
Novel Therapeutic Approaches to
Preserve Beta Cell Function
in Diabetes Mellitus
Vijay Negalur
INTRODUCTION PANCREATIC BETA CELL MASS

Diabetes is a chronic metabolic disorder characterized by FUNCTION IN DIABETES
hyperglycemia due to defect in insulin activity or insulin In general, the adult human pancreas weigh between
secretion or both. Diabetes is further related to long 60 g and 100 g and beta cell mass is roughly 2% of the
term complications that affect the eyes, nerves, kidneys pancreatic weight.6 Beta cell mass is regulated through
as well as an increased risk for cardiovascular disease.1 a delicate balance between beta cell expansion or
Over the last few years, there has been an alarming rise formation and beta cell apoptosis. Disturbances in
in number of diabetic patients. Recent IDF estimates beta cell formation or increased beta cell apoptosis can
show that globally, there are 425 million people suffering reduce beta cell mass (Fig. 1).7
from diabetes and by 2045, this number will reach an Although etiologically different, beta cell dysfunction
estimated 628.6 million. India has 72.9 million people and decline occurs in both T1D and T2D. In both
suffering from diabetes and by 2045; and it is estimated forms, apoptosis of beta cell and impaired proliferation
this number will reach to 134.3 million.2 following hyperglycemia are observed. 8 Both forms
Diabetes is mainly categorized into Type 1 diabetes
(T1D), Type 2 diabetes (T2D), diabetes during pregnancy
or gestational diabetes and other specific types which
may occur due to genetic defects, pancreatic diseases,
infections or drugs like glucocorticoids.3 T1D mainly
involves autoimmune destruction of pancreatic beta
cells that produce insulin resulting into progressive
insulin deficiency and hyperglycemia. 4 T2D mainly
involves insulin resistance, reduced insulin production
and eventual pancreatic beta cell failure.5 Irrespective of
the clinical form, loss of beta cell number and function
is the main underlying pathology of both T1D and T2D.3
This aspect of physiology is being intensively studied to
design newer therapeutic options with an aim to restore
and preserve beta cell functionality. Fig. 1: Dynamics of pancreatic β-cell mass7
CHAPTER 48: Novel Therapeutic Approaches to Preserve Beta Cell Function in Diabetes Mellitus 291
involve intra-islet inflammatory mediators mainly and function. It is still a matter of debate whether decline
cytokine interleukin [IL]-1β that trigger a common in beta cell mass or beta cell dysfunction is the major
pathway causing beta-cell apoptosis.9 underlying reason for beta cell failure.17 It is believed
In Asian Indians, this beta cell decline occurs more that considerable beta cell failure occurs at an early stage
rapidly. Staimez et al. used oral disposition index before diagnosis. Once beta cell failure is initiated, the
(DIO) to measure beta cell function and found a highly decline towards overt diabetes accelerates.18 In a study
significant difference between NGT and IFG or IGT by Butler AE et al., it was observed that obese individuals
even after adjustment for variables known to impact with IFG and T2D had 40% and 63% respectively
disease development. It was observed that Asian Indians lesser beta cell mass and volume when compared
with mild dysglycemia have marked reduction in beta- with non-diabetic individuals.19 Thus, owing to insulin
cell function which is independent of their age, family resistance and metabolic overload, the beta cells initially
history, adiposity or insulin sensitivity.10 try to compensate by increasing insulin secretion
T 1 D i s a n au t o i m mu n e d e s t r u c t i o n o n t h e but then eventually commence several pathological
pancreatic beta cells characterized by insulitis (beta-cell processes like glucotoxicity, lipotoxity and oxidative
inflammation) which leads to loss of most beta cells.11 It stress that synergistically achieve beta cell dysfunction
was common assumption in the past that 90% of beta cells and apoptosis.20
are destroyed from the time of clinical onset of disease
and as a rule less than 10% normal cells remained.12 THERAPEUTIC APPROACHES TO
However, there are accumulating data available to negate PRESERVE BETA CELL FUNCTION IN T1D
this assumption. In a recent study by Oram R et al., it was The ultimate aim in the course of T1D is to prevent
observed that, for more than 5 years, 73% of T1D patients autoimmunity or to prevent hyperglycemia in individuals
had detectable serum C-peptide 90 minutes post meal; whose beta cell destruction is already underway. This
indicating that majority of patients with T1D still retain a objective can be attained by preserving beta cell function.
some amount of functioning beta cells long after disease
onset.13 This amount of functional beta cells seem to Vitamin D Supplementation
correlate with the age of diagnosis of T1D. Massive beta Although numerous preclinical studies have shown
cell depletion at onset is only observed in children. A that Vitamin D supplementation has a beneficial effect
lesser decline in beta cells is observed when the age on insulin secretion and sensitivity, mixed results
of onset is above 15 years and this pattern remains have been observed in clinical trials. 21 Studies by
consistent through the subsequent years.14 The DiMelli Walter et al. on adult population and Bizzari et al. on
study by Thümer et al. also showed that a there exists adolescent population were unsuccessful in showing
a positive correlation between fasting C-peptide levels any beneficial effect of Vitamin D supplementation on
and age of onset of diabetes. Thus, it can be concluded beta cell function preservation.22,23 In a study by Gabbay
that more aggressive beta-cell destruction, and a higher et al., oral cholecalciferol 2000 IU/day for 18 months in
rate of metabolic decompensation is observed mainly in patients (6–16 years) with new onset T1D (<6 months)
younger patients.15 demonstrated slower decline of beta cell function after
T2D is a consequence of two main pathological vitamin D supplementation.24 One of the underlying
defects; impaired insulin activity caused by insulin mechanisms to preserve beta cells is by increasing the
resistance and dysfunction of pancreatic beta number of regulatory T cells (Tregs). Tregs are known
cells.16Although insulin resistance was assumed to be to secrete immune-modulatory cytokines and thus
the most important factor in T2D pathogenesis, recent suppress the process of autoimmune destruction of
evidences have highlighted that T2D mainly develops T1D.21In a recently published randomized controlled
due to deficiency and impairment in the beta cell mass trial, oral cholecalciferol 70 IU/kg/day for 12 months in
patients (6–16 years) with new onset T1D (<3 months) improved stimulated C-peptide responses compared
was shown to lower the insulin needs and also improve with placebo group. This effect was strongest in patients
the suppressive capacity of the Tregs.25 that were randomized ≤6 weeks after diagnosis. 32
Although efficacious; it does not represent a cure for
Intensive Insulin Therapy patients. Thus, significant advances are required to halt
It has been observed that aggressive control on disease progression towards absolute insulin deficiency
glucose levels at the time of diagnosis preserves beta and reduce the dependence on exogenous insulin.31
cell function. 26 Shah et al. randomly assigned newly
diagnosed adolescents with T1D to receive conventional Anti-CD20
treatment or a glucose controlled insulin infusion Many diseases mediated by T-lymphocytes have a
system. After one year it was observed that, the mean B-lymphocyte constituent which plays a vital role as
plasma C peptide levels were significantly higher in the antigen presenting cells. Rituximab is an anti-CD20
insulin infusion system group than the control group.27 monoclonal that selectively depletes B-lymphocytes. A
Similar results were obtained in the DCCT study in phase II trial involving 87 patients with newly diagnosed
which T1D patients receiving intensive insulin therapy T1D, randomized to four weekly rituximab infusions
(IIT) had higher C-peptide levels and lower HbA1c levels or placebo showed that after one year, the rituximab
than patients receiving conventional therapy. Fewer group resulted in 20% elevation in C-peptide levels as
microvascular and macrovascular complications were compared with the placebo group. Significantly lower
observed in the IIT group compared to those receiving HbA1c levels were also observed in the rituximab group.
conventional therapy.28 Patients taking rituximab also required lesser insulin
to achieve better glycemic control.33 However, in a 30
Anti-CD3 month follow-up study, it was observed that C-peptide
Owing to the key role of T-cells in the pathogenesis of fall rate paralleled the fall observed in the control group.
T1D, T-cell directed therapies are extensively studied to This suggests that rituximab delayed that reduction
prevent or stop the progress of autoimmune processes in C-peptide levels but failed to alter the fundamental
involved in beta cell destruction. The anti-CD3 antibodies pathophysiology of the disease.34
treatment not only removes pathogenic T cells but can
also induce a state of operational tolerance by their CTLA-4
effects on regulatory T cells.29 Apart from the main antigen-driven signal, immune
Otelixizumab is one such anti-CD3 antibody that T-cells also require a costimulatory signal for complete
has shown been extensively studied. The phase I and activation. Abatacept is a CTLA-4-immunoglobulin
phase II trials showed positive safety and efficacy results fusion protein that modulates co stimulation and
for Otelixizumab, but the phase III trial results were prevents complete T-cell activation. A multicentric,
contradictory. Otelixizumab at high doses has shown randomized placebo controlled trial evaluated the
improvement in beta cell function but was accompanied efficacy of abatacept in recent onset T1D. Abatacept
with adverse effects. On the contrary, lower doses of the group had 59% higher levels of stimulated C-peptide
drug tested to avoid the associated adverse effects were than the placebo group; thus indicating that abatacept
not effective in beta cell preservation.30 slowed reduction in β-cell function over 2 years. HbA1c
Another anti-CD3 monoclonal antibody, Teplizumab, values were lower in the treatment group but insulin
has shown to preserve the C-peptide levels and reduce use was similar in both the groups.35 Similar results were
the need for exogenous insulin. 31 Results from the obtained post 1 year cessation of treatment implying that
Protégé Trial showed that after 2 years, patients who the effect of abatacept on beta cell function continued for
received a 14 day full dose of teplizumab significantly at least 1 year after cessation of therapy or 3 years from
T1D diagnosis. However, as observed in anti-CD3 and 1RAs may have a role in increasing proliferation and
anti-CD20 antibodies, the rate of C-peptide fall in the differentiation of beta cell and in decreasing the rate
treatment group paralleled the decline in the placebo of beta cell apoptosis as an add-on to insulin therapy.
group after 9 months.36 However, long term randomized clinical trials are
required to further evaluate the application of GLP-1RAs
TUMOR NECROSIS FACTOR-α in TID.41
(TNF-α) AGONIST
Evidences from in vitro studies and animal models THERAPEUTIC APPROACHES TO
indicate that Tumor necrosis factor-α (TNF-α) play a PRESERVE BETA CELL FUNCTION IN T2D
role in the autoimmune process leading to pancreatic Declining beta cell function coupled with hyperglycemia
destruction. A pilot study was carried out to study the and insulin resistance characterizes T2D. However, early
efficacy and feasibility of etanercept therapy to extend metabolic control may help improve and preserve beta
endogenous insulin production in new onset pediatric cell function.
T1D patients. It was observed that, at week 24, etanercept
group had significantly lower HbA1c levels than the Early Short-term Intensive
placebo group. Etanercept group also had 39% higher Insulin Therapy
C-peptide levels. On the other hand, a 20% reduction The objective of providing early short-term intensive
in C-peptide levels was observed in the placebo group. insulin therapy (IIT) in T2D is to induce a state glycemic
Although the data suggests that etanercept preserves remission, wherein the patients maintain normal
beta cell function, larger studies may be required to glycemic levels without any antidiabetic drugs after
further assess the efficacy and safety.37 stopping IIT. Most studies involve a short term IIT for 2–5
weeks in newly diagnosed T2D patients. It was observed
Interleukin 2 that major proportion of newly diagnosed patients
Various immunological Interleukin 2 (IL-2) studies have achieved remission with this therapy.42
implied that deficiencies in receptor and its signaling A meta-analysis of 7 studies involving 899 patients
pathway deficiency may play an important role in T1D showed that post IIT, an increased beta-cell function and
pathogenesis.38 NOD mouse studies have also shown decreased insulin resistance was observed. Four of those
that combining IL-2 with sirolimus prevents and reverse studies showed that, after the glycemic remission rates
T1D by augmentation of IL-2 signaling.39 However, the were 66·2%, 58·9%, 46·3% and 42.1% after 3,6,12 and 24
results obtained in the phase I study that involved IL-2 months respectively. Thus, short term IIT can improve
and sirolimus were conflicting. It was observed that the insulin resistance as well as beta cell function (Fig. 2).43
IL-2-sirolimus combination demonstrated a decrease
in C-peptide levels for the first 3 months. Surprisingly, Dipeptidyl Peptidase-4 Inhibitors
the C-peptide levels eventually increased in almost all Dipeptidyl peptidase-4 inhibitors (DPP4i) are a
subjects indicating that decrease in C-peptide levels was promising therapeutic option for T2D. DPP4i prevent
only temporary.40 incretin hormone degradation (mainly GLP-1) which
results in reduced glucose and glucagon levels and
Glucagon-like Peptide-1 Receptor increased insulin levels.44 More and more evidences have
Agonist (GLP-1RA) now suggest that DPP4i may play a part in preservation of
Although approved for only T2D, glucagon like peptide-1 beta cell function.
receptor agonist (GLP-1RA) could have beneficial effects In a recent meta-analysis involving 52 clinical trials,
in both new onset and longstanding T1D patients. From it was observed that, DPP4i as a monotherapy and as an
various preclinical studies, it is observed that GLP- add-on therapy to other drugs had significantly improved
study was the first to demonstrate that troglitazone was

effective in delaying or preventing the onset of type 2
diabetes in high-risk hispanic women and this effect was
attributed to beta cell preservation and reduced insulin
resistance.49 Similar results were obtained in the PIPOD
study which showed that TZDs as a class improved
insulin sensitivity, reduced insulin secretory demands,
and preserve beta-cell function.50 The ACT-NOW study
also showed that pioglitazone prevents the onset of T2D
in high risk patients by improving insulin sensitivity and
beta cell function.51
Fig. 2: Drug-free remission rate after intensive insulin therapy in
early T2D patients43
Sodium-Glucose Cotransporter
beta cell cell function compared to placebo. However, 2 Inhibitors (SGLT2i)
no significant improvement in insulin resistance was Sodium-glucose cotransporter 2 Inhibitors (SGLT2i)
observed following DDP4i monotherapy or as an are novel anti-diabetic agents that suppress glucose
add-on therapy. Stratification analysis for each type absorption from kidneys which result in increased
of DPP4i revealed that, all DPP4i except linagliptin glucose excretion via urine. 52Although the primary
improved beta cell function. A significant improvement action of SGLT2i is on the kidneys, there are data that
in insulin resistance was also additionally observed in have indicated that inducing glucosuria in T2D patients
the sitagliptin treatment group.45 can improve beta cell function. Phase III trials have
indicated that canagliflozin improves beta cell function
GLP-1RA in patients with T2D.53 In a study by Merovci A et al;
Evidences from various randomized controlled studies significantly lower fasting and 2-hour plasma glucose
and post-hoc analysis have indicated that GLP-1RA concentrations were observed with Dapagliflozin in
improve beta cell function. Both exenatide and liraglutide T2D patients. There was also an incremental C-peptide
improved insulin secretory responses in T2D patients.
concentration observed in the dapagliflozin group as
Reductions in proinsulin-to-insulin ratio were also
compared with the placebo group and the beta cell
observed implying the favorable effect of GLP-1RA on
function was improved by 2 fold in the dapagliflozin
beta cells. However, improvement in beta cell function
treated group.54
with GLP1RA is generally reversed upon cessation of
treatment suggesting that functional intensification of
Other Novel Agents under Research
secretory capacity of β-cells may not reproduce into
long-term modulation of this system.46 Imeglimin
Imeglimin is a first in class tetrahydrotriazine containing
Thiazolidinediones glucose lowering agent with a distinct mechanism that
Thiazolidinediones (TZDs) are PPAR-γ agonist insulin is involved in regulation of mitochondrial energetics. In
sensitizers that are approved for use in T2D.47Although a double blind, randomized, placebo controlled trial;
the clinical use of TZDs is limited owing to its adverse it was observed that imeglimin treatment for 7 days
effects, they have shown to prevent beta cell apoptosis increased the insulin secretory response to glucose
and improve beta cell function. Consistent data from by 112%. A 36% increment in beta cell function and a
various trials have shown that TZDs can prevent T2D 13% decrease in hepatic insulin extraction were also
onset in high risk patients by ~50–75%.48 The TRIPOD observed. This indicates that the glucose-lowering effect
observed with imeglimin may be due to improves β-cell delay disease progression. In this context, this review
function.55 tries to throw light on the various therapeutic approaches
aimed to preserve beta cell function in Type 1 diabetes
AS1842856 and Type 2 diabetes.
AS1842856 is a forkhead transcription factor forkhead A multimodality approach appears to be necessary
box O1 (Foxo1) inhibitor that has been orally effective to slow or arrest the progression of beta cell destruction
in diabetic db/db mice by causing a marked decrease in TID. Vitamin D supplementation has shown to slow
in fasting plasma glucose level. Foxo1 is essential in down the decline of beta cell function. However, early
mediating the effect of insulin on gluconeogenesis aggressive glucose control via IIT at the time of disease
in liver. It is suggested that suppressing the Foxo1 diagnosis has only resulted in temporary restoration
activity reduces hepatic gluconeogenesis and thus of endogenous insulin production. Several immune-
improves hepatic insulin action and peripheral glucose modulatory agents like otelixizumab, teplizumab,
metabolism.56 rituximab, abatacept, etanercept and IL-2 have also
been evaluated and have shown to slow down the rate
Anakinra of beta cell destruction. However, these effects waned
Anakinra is an interleukin-1b receptor antagonist that off over time and insulin secretion was parallel in both
has shown to improve glyemia and beta cell function. placebo-treated groups. Although a new therapy has
IL-B2 is a proinflammatory cytokine that is produced not been recognized that can be clinically applied for
as a result of hyperglycemia and it is implied that IL- T1D treatment, a lot of progress has been made towards
B2 inhibits beta cell function and promotes beta cell achieving the goal of beta cell preservation.
apoptosis. In a study by Larsen CM et al., it was observed In T2D, early IIT based therapy is one of the
that once daily anakinra significantly reduced HbA1c approached to cause temporary remission. This concept
values, increased C-peptide secretion and reduced the have yielded a new therapeutic strategy, wherein we first
proinsulin to insulin ratio.57 provide ‘induction’ therapy for early improvement in beta
cell function and then ‘maintenance’ therapy intended
Sinogliatin to preserve this beneficial beta-cell effect. Various oral
Sinogliatin or dorzagliatin is a novel fourth generation antidiabetic drugs like incretin based analogues, TZDs
glucokinase activator that has shown a potential role in and SGTL2i have shown to prevent or delay the onset of
the treatment of T2D. Glucokinase is a critical enzyme disease by preserving beta cell function. There are also
that involved in the regulation of both hepatic glucose newer molecules such as imeglimin, AS1842856, anakinra
production and insulin secretion. Thus, glucokinase and sinogliatin that have shown promise but large scale
is an attractive target T2D treatment. Preclinical study randomized trials are essential to confirm these claims.
by Wang P et al., suggested that sinogliatin displays its To conclude, the onset of both T1D and T2D involve
antidiabetic effects by improving glucokinase activity significant loss of functional β-cell mass. A better
and insulin resistance via liver and pancreas.58 Although understanding of β-cell mass and the various protective
mechanisms for improving β-cell function will help
Sinogliatin is currently in Phase III trial, the results of
develop newer therapeutic approaches that will be
the Phase 1 and II trials are unavailable in the public
helpful for modulating the natural progression of these
domain.59
diseases in the future.
DISCUSSION
REFERENCES
Today, the goals of diabetes treatment has shifted from
1. Definition, Classification and Diagnosis of Diabetes,
merely reducing blood glucose levels to reversing or Prediabetes and Metabolic Syndrome. Canadian Journal of
slowing down the decline of beta cell function and thus, Diabetes. 2013; 37:S294.
2. IDF Diabetes Atlas [Internet]. Idf.org. 2017 [cited 30 Type 2 diabetes. Diabetes Care. 2013;36 (Supplement
November 2017]. Available from: https://www.idf.org/e- 2):S113-S9.
library/epidemiology-research/diabetes-atlas.html 18. Leahy J, Hirsch I, Peterson K, Schneider D. Targeting
3. Tesemma C, Getnet A. Recent advance in diabetes therapy: β-cell function early in the course of therapy for Type 2
pancreatic beta cell regeneration approaches. Diabetes diabetes mellitus. The Journal of Clinical Endocrinology &
Manag. 2016;6(6):108-18. Metabolism. 2010;95(9):4206-16.
4. Gregory J, Moore D, Simmons J. Type 1 Diabetes Mellitus. 19. Butler A, Janson J, Bonner-Weir S, Ritzel R, Rizza R, Butler P.
Pediatrics in Review. 2013;34(5):203-15. β -cell deficit and increased β -cell apoptosis in humans with
5. Olokoba A, Obateru O, Olokoba L. Type 2 Diabetes Mellitus: Type 2 diabetes. Diabetes. 2003;52(1):102-10.
A Review of Current Trends. Oman Medical Journal. 2012; 20. Halban P, Polonsky K, Bowden D, Hawkins M, Ling C,
27(4):269-73. Mather K et al. β-cell failure in type 2 diabetes: postulated
6. Weir G, Bonner-Weir S. Islet β cell mass in diabetes and how mechanisms and prospects for prevention and treatment.
it relates to function, birth, and death. Annals of the New Diabetes Care. 2014;37(6):1751-8.
York Academy of Sciences. 2013;1281(1):92-105. 21. Dayal D, Sachdeva N. Preservation of residual beta cell
7. Jung K, Kim K, Lim S. Therapeutic approaches for preserving function with vitamin D Supplementation in type 1 diabetes.
or restoring pancreatic β-cell function and mass. Diabetes & Immunoendocrinology. 2015;2:e1093.
Metabolism Journal. 2014;38(6):426. 22. Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E,
8. Donath M, Halban P. Decreased beta-cell mass in diabetes: Ziegler A. No Effect of the 1 ,25-Dihydroxyvitamin D3
significance, mechanisms and therapeutic implications. on β -Cell Residual Function and Insulin Requirement in
Diabetologia. 2004;47(3):581-9. Adults With New-Onset Type 1 Diabetes. Diabetes Care.
9. Donath M, Størling J, Maedler K, Mandrup-Poulsen T. 2010;33(7):1443-8.
Inflammatory mediators and islet ?-cell failure: a link 23. Bizzarri C, Pitocco D, Napoli N, Di Stasio E, Maggi D, Manfrini
between type 1 and type 2 diabetes. Journal of Molecular S, et al. No protective effect of calcitriol on β-cell function in
Medicine. 2003;81(8):455-70. recent-onset Type 1 diabetes: The IMDIAB XIII trial. Diabetes
10. Staimez L, Weber M, Ranjani H, Ali M, Echouffo-Tcheugui Care. 2010;33(9):1962-3.
J, Phillips L, et al. Evidence of reduced β-cell function 24. Gabbay M, Sato M, Finazzo C, Duarte A, Dib S. Effect
in asian indians with mild dysglycemia. Diabetes Care. of cholecalciferol as adjunctive therapy with insulin on
2013;36(9):2772-8. protective immunologic profile and decline of residual β-cell
11. Cnop M, Welsh N, Jonas J, Jorns A, Lenzen S, Eizirik D. function in new-onset Type 1 diabetes Mellitus. Archives of
Mechanisms of pancreatic-cell death in type 1 and type Pediatrics & Adolescent Medicine. 2012;166(7).
2 Diabetes: Many differences, few similarities. Diabetes. 25. Treiber G, Prietl B, Fröhlich-Reiterer E, Lechner E, Ribitsch A,
2005; 54(Supplement 2):S97-S107. Fritsch M, et al. Cholecalciferol supplementation improves
12. Gepts W. Pathologic anatomy of the pancreas in juvenile suppressive capacity of regulatory T-cells in young patients
diabetes mellitus. Diabetes. 1965;14(10):619-33. with newonset type 1 diabetes mellitus - A randomized
13. Oram R, Jones A, Besser R, Knight B, Shields B, Brown R, clinical trial. Clin Immunol. 2015;161:217-24.
et al. The majority of patients with long-duration type 1 26. Gallagher M, Goland R, Greenbaum C. Making progress:
diabetes are insulin microsecretors and have functioning preserving beta cells in type 1 diabetes. Annals of the New
beta cells. Diabetologia. 2013;57(1):187-91. York Academy of Sciences. 2011;1243(1):119-34.
14. Pipeleers D, Ling Z. Pancreatic beta cells in insulin- 27. Shah S, Malone J, Simpson N. A Randomized trial of
dependent diabetes. Diabetes/Metabolism Reviews. intensive insulin therapy in newly diagnosed insulin-
1992;8(3):209-27. dependent diabetes mellitus. New England Journal of
15. Thümer L, Adler K, Bonifacio E, Hofmann F, Keller M, Milz Medicine. 1989;320(9):550-4.
C, et al. German new onset diabetes in the young incident 28. Effect of intensive therapy on residual β-cell function
cohort study: DiMelli Study Design and First-Year Results. in patients with Type 1 diabetes in the diabetes control
The Review of Diabetic Studies. 2010;7(3):202-8. and complications Trial. Annals of Internal Medicine.
16. Ozougwu C, Obimba C, Belonwu D, Unakalamba B. 1998;128(7):517-23.
The pathogenesis and pathophysiology of type 1 and 29. Sprangers B, Schueren B, Gillard B, Mathieu C. Oletixizumab
type 2 diabetes mellitus. Journal of Physiology and in the treatment of Type 1 diabetes mellitus. Immunotherapy.
Pathophysiology. 2013;4(4):46-57. 2011;3(11):1303-6.
17. Meier J, Bonadonna R. Role of reduced β-Cell mass 30. Guglielmi C, Williams S, Del Toro R, Pozzilli P. Efficacy
versus impaired -cell function in the pathogenesis of and safety of otelixizumab use in new-onset type 1
diabetes mellitus. Expert Opinion on Biological Therapy. 43. Kramer Caroline Kaercher, et al. Short-term intensive
2016;16(6):841-6. insulin therapy in type 2 diabetes mellitus: a systematic
31. Vudattu N, Herold K. Treattment of new onset type 1 review and meta-analysis. Lancet Diabetes Endocrinol.
diabetes with teplizumab: successes and pitfalls in 2013;1(1):28-34.
development. Expert Opinion on Biological Therapy. 44. Gothwal S, Khosya S. DPP 4 (dipeptidylpeptidase-4)
2014;14(3):377-85. inhibitors: beyond glycemic control. Iosr Journal of
32. Hagopian W, Ferry R, Sherry N, Carlin D, Bonvini E, Johnson Pharmacy. 2013;3 (3):81-5.
S et al. Teplizumab preserves c-peptide in recent-onset Type 45. Lyu X, Zhu X, Zhao B, Du L, Chen D, Wang C et al.
1 diabetes: two-year results from the randomized, placebo- Effects of dipeptidyl peptidase-4 inhibitors on beta-cell
controlled protege trial. Diabetes. 2013;62(11):3901-8. function and insulin resistance in type 2 diabetes: meta-
33. Pescovitz M, Greenbaum C, Krause-Steinrauf H, Becker analysis of randomized controlled trials. Scientific Reports.
D, Gitelman S, Goland R, et al. Rituximab, B-lymphocyte 2017;7:44865.
depletion, and preservation of beta-cell function. New 46. Grandy S, Shaunik A,Hardy E. Effects of glucagon-like
England Journal of Medicine. 2009;361(22):2143-52. peptide-1 receptor agonists on β-cell function in patients
34. Pescovitz M, Greenbaum C, Bundy B, Becker D, Gitelman with Type 2 diabetes. Journal of Diabetes & Metabolism.
S, Goland R et al. B-lymphocyte depletion with rituximab 2016;7:643.
and β-cell function: two-year results. Diabetes Care. 47. Gupta D, Kono T, Evans-Molina C. The role of peroxisome
2013;37(2):453-9. proliferator-activated receptor γ in pancreatic β cell function
35. Orban T, Bundy B, Becker D, DiMeglio L, Gitelman S, Goland and survival: therapeutic implications for the treatment of
R, et al. Co-stimulation modulation with abatacept in type 2 diabetes mellitus. Diabetes, Obesity and Metabolism.
patients with recent-onset type 1 diabetes: a randomised, 2010;12(12):1036-47.
double-blind, placebo-controlled trial. The Lancet. 48. Page K, Reisman T. Interventions to preserve beta-cell
2011;378(9789):412-9. function in the management and prevention of Type 2
36. Orban T, Bundy B, Becker D, DiMeglio L, Gitelman S, Diabetes. Current Diabetes Reports. 2013;13(2):252-60.
Goland R, et al. Costimulation modulation with abatacept 49. Buchanan T, Xiang A, Peters R, Kjos S, Marroquin A,
in patients with recent-onset type 1 diabetes: Follow- Goico J. et al. Preservation of pancreatic-cell function and
up 1 year after cessation of treatment. Diabetes Care. prevention of Type 2 diabetes by pharmacological treatment
2013;37(4):1069-75. of insulin resistance in high-risk hispanic women. Diabetes.
37. Mastrandrea L, Yu J, Behrens T, Buchlis J, Albini C, Fourtner 2002;51(9):2796-803.
S et al. Etanercept treatment in children with new-onset 50. Xiang A, Peters R, Kjos S, Marroquin A, Goico J, Ochoa C,
Type 1 diabetes: Pilot randomized, placebo-controlled, et al. Effect of pioglitazone on pancreatic β-cell function
double-blind study. Diabetes Care. 2009;32(7):1244-9. and diabetes risk in hispanic women with prior gestational
38. Hulme M, Wasserfall C, Atkinson M, Brusko T. Central role for diabetes. Diabetes. 2006;55(2):517-22.
interleukin-2 in Type 1 diabetes. Diabetes. 2011;61(1):14- 51. DeFronzo R, Banerji M, Bray G, Buchanan T, Clement
22. S, Henry R, et al. Determinants of glucose tolerance in
39. Shapiro A, Suarez-Pinzon W, Power R, Rabinovitch impaired glucose tolerance at baseline in the Actos Now
A. Combination therapy with low dose sirolimus and for Prevention of Diabetes (ACT NOW) study. Diabetologia.
tacrolimus is synergistic in preventing spontaneous and 2009;53(3):435-45.
recurrent autoimmune diabetes in non-obese diabetic mice. 52. Singh H, Thangaraju P, Singh J, Kaushal S. Canagliflozin:
Diabetologia. 2002;45(2):224-30. A novel SGLT2 inhibitor for type 2 diabetes mellitus. North
40. Long S, Rieck M, Sanda S, Bollyky J, Samuels P, Goland R, American Journal of Medical Sciences. 2014;6(3):107.
et al. Rapamycin/IL-2 combination therapy in patients with 53. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium
type 1 diabetes augments tregs yet transiently impairs-cell glucose co-transporter 2 inhibitor, improves model-based
function. Diabetes. 2012;61(9):2340-8. indices of beta cell function in patients with type 2 diabetes.
41. Popovic D, Stokic E, Popovic S. GLP-1 receptor agonists Diabetologia. 2014;57(5):891-901.
and Type 1 diabetes - where do we stand? Current 54. Merovci A, Mari A, Solis C, Xiong J, Daniele G, Chavez-
Pharmaceutical Design. 2015;21(36):5292-8. Velazquez A. et al. Dapagliflozin lowers plasma glucose
42. Retnakaran R. Emerging strategies for the preservation concentration and improves β-cell function. The Journal
of pancreatic beta-cell function in early Type 2 diabetes. of Clinical Endocrinology and Metabolism. 2015;100(5):
Clinical and Investigative Medicine. 2014;37(6):414. 1927-32.
55. Pacini G, Mari A, Fouqueray P, Bolze S, Roden M. Imeglimin 2 diabetes mellitus. New England Journal of Medicine.
increases glucose-dependent insulin secretion and 2007;357(3):302-3.
improves β-cell function in patients with type 2 diabetes. 58. Wang P, Liu H, Chen L, Duan Y, Chen Q, Xi S. Effects of
Diabetes, Obesity and Metabolism. 2015;17(6):541-5. a novel glucokinase activator, hms5552, on glucose
56. Nagashima T, Shigematsu N, Maruki R, Urano Y, Tanaka metabolism in a rat model of Type 2 diabetes mellitus.
H, Shimaya A, et al. Discovery of Novel Forkhead Box Journal of Diabetes Research. 2017;2017:1-9.
O1 Inhibitors for Treating Type 2 Diabetes: Improvement 59. Long-term efficacy and safety of HMS5552 in T2D
of Fasting Glycemia in Diabetic db/db Mice. Molecular - Full Text View - ClinicalTrials.gov [Internet]. Clinical
Pharmacology. 2010;78(5):961-70. t r i a l s . g o v . 2 0 17 [ c i t e d 3 0 N o v e m b e r 2 0 17 ] .
57. Larsen CM1, Faulenbach M, Vaag A, Vølund A, Ehses JA, Available from: https://clinicaltrials.gov/ct2/show/
Seifert B, et al. Interleukin-1–receptor antagonist in type NCT03173391?term=HMS5552&phase=2&rank=1
CHAPTER
49
Management of Diabetes in
Resource Crunch Countries
G Prakash
INTRODUCTION More than 80% of people with Diabetes live in low

Diabetes mellitus and its complications remain a health income and middle-income countries and communities.
threat not only to the individual but to the society.
The disease is a burden to the health economies of all CHALLENGES AND THE WAY AHEAD
countries throughout the globe. Diabetes ranks high on EPIDEMIOLOGICAL DATA
the international health agenda as a global pandemic. There are limited population based multicenter
Diabetes is the primary concern in 21st century. A prevalence studies in resource crunch countries. It is
study reported that, 31% of total outpatient costs is due difficult in countries like India to generalize results
to the treatment of diabetes complications which is of one part of India to others due to diversities in the
around 19% more than the treatment cost of individual geographical, cultural, socioeconomic, educational and
patient per year. 1 Diabetes had been neglected by dietary habits. The global epidemiology of Diabetes is
various International health agencies and National changing. Type-2 Diabetes has become more common
Governments, which resulted into low research funding not only in young adults but also in adolescents and
for the prevention and control of diabetes. Health care children which was traditionally thought of as a disorder
systems in developing countries are much more geared of middle aged and elderly people. Besides T2DM,
towards treatment of acute symptomatic presentation gestational diabetes is becoming more prevalent and
of single acute disease rather than management of could further fuel the increase in diabetes prevalence.
asymptomatic chronic diseases. The data of GDM is again lacking due to lack of uniform
global consensus for screening GDM. There is an
PREVALENCE inadequate populace level information from health
The International Diabetes Federation Atlas state that registries or surveys, specifically related to the prevalence
there are around 415 million people living with Diabetes and the access to therapeutic services of diabetes in rural
in 2015 throughout the world (a number previously areas.3
forecast for 2030). 2 Of the top 10 countries with the
largest Diabetes population, four are in Asia (China, SCREENING
India, Indonesia and Japan). Asia is the Center of the The adverse outcome is indicated by the duration of
global epidemic of Diabetes as a result of rapid economic glycemic burden. Hence, early screening helps to lower
development, urbanization and nutritional transition. the burden of complications. Due to epidemiological
issues and health economic factors, there is difficulty poor socioeconomic condition, the most common cause
in diagnosis of disease in developing world. Population of death in type 1 diabetes is lack of access to insulin.6
diagnosis is not practical across the entire rural areas Educating diabetic patient is the effective and integrated
particularly in India which represent a large population. part of diabetes therapy.
Involve health care providers in free medical camp both
in government and nongovernment sectors. Encourage PHARMACOLOGIC MANAGEMENT:
nondiabetic subjects to report for medical check-up and ORAL ANTIDIABETIC DRUGS
screening for Diabetes. Simple, noninvasive diabetes risk International guidelines recommend that the treatment
score is also available for identifying people with high of the diabetes should be individualized based on the
risk of diabetes. safety, efficacy, tolerability and economical condition
Indian Diabetes Risk Score (IDRS) is one among of patient. Currently, there are no ideal drug which can
the numerous risk scores and other low-cost tools for achieve required glycemic target. The ideal agent should
screening diabetes in the general population which has be inexpensive, effective, potent and safe.
been shown to be a cost-effective method of screening
for undiagnosed diabetes in the community.4 Metformin
American Diabetes Association also recommend Metformin is the first line therapy for treatment of
an assessment tool. ADA risk test for screening5 of type diabetes. Metformin is the oldest drug which provided
2 DM. Hence, it is reasonable to screen asymptomatic effective glycemic control and prevents further
individual for prediabetes or diabetes. cardiovascular and diabetes associated complications.
DIABETES MANAGEMENT Sulfonylureas

The challenges include: All the International recommendation approves use of
Lack of awareness any class of drug next to Metformin therapy if glycemic
Cost of therapy control is not achieved. WHO recommends sulfonylurea
Lack of specialized facilities to patients who have contraindications to Metformin or
Superstitions and beliefs in whom Metformin does not improve glycemic control.
Multilingual population The evidence on similar levels of glycemic control
High rate of illiteracy (Hba1c) achieved with Metformin and sulfonylurea is
Faith in alternative systems of treatment of high quality.8 In a meta-analysis comparing glyburide
Hesitancy to go to doctors or hospitals. with other sulfonylurea, Glyburide was associated with
1.4 times relative risk of increase in overall hypoglycemic
DIABETES EDUCATION events. 9 Educating hypoglycemic symptoms and
Diabetes is chronic disease with rising prevalence, management help to curtail the problem. Sulfonylureas
hence there is a need for education for medical care are CV safe drugs.7 Sulfonylurea in combination with
and patient self-management for the prevention of Metformin targets two pathways, efficacious, cost
complication and minimizing long term complications. effective and had long safety history, no effect on body
Patient education on life style modifications and medical weight when combining with Metformin.10
nutrition therapy helps not only in prevention of diabetes In comparison to addon therapy, the combination
but also in reduction of complications that occur tablets improve patient’s adherence, effective and is cost
due to diabetes. Despite reports that a well-designed effective.
community health insurance scheme can improve access Modern sulfonylurea when compared to older ones
to medical care even for people with diabetes living in has the following advantages.11
CHAPTER 49: Management of Diabetes in Resource Crunch Countries 301
Has lower risk of hypoglycemic events. if there is no sustainable and affordable intervention in
Exhibit a higher exchange rate and lower binding Diabetes Management. The effective treatment should
affinity to beta cells. also consider political, cultural and social issues with
Secrete smaller amounts of insulin in fasting and the patient population. Diabetes is emerging as 21st
postprandial state. century challenge. This has to be fought with greater
understanding of the disease pathophysiology, proper
Pioglitazone diagnosis and easy access to available therapies.
The only other drug besides Metformin reduces insulin
resistance. It improves CV risk factors like ↑ HDL, ↓ TGL, REFERENCES
↓ inflammatory mediators beyond glycemic control. The 1. World Health Organization Care health indicators; the
increased incidence of bladder cancer with pioglitazone latest data from multiple WHO sources. United Republic of
in diabetic patients is still a debatable.12 Tanzania. Geneva, WHO 2006.
2. International Diabetes Federation IDF. Diabetes Atlas, 2015.
3. Paul Grant P. Management of Diabetes in resource poor
Insulin settings. Clinical Medicine. 2013;13(1):27-31.
Insulin is the mainstay for treatment of Type-1 DM, 4. Sharma KM, Ranjani H, Ngujen Ha, Shetty S, Dutta M, et al.
secondary drug failure in T2DM, acute metabolic Indian Diabetes Risk Score helps to distinguish Type-1 from
decompensation and diabetic pregnancies. The Non-Type 2DM Journal of Diabetes Science and Technology.
challenges in Type-1 DM are affordability, self- 2001;5:419-25.
5. American Diabetes Association. 2. Classification and
monitoring of blood glucose, storage of insulin and
Diagnosis of Diabetes. Diabetes Care. 2017;40(Suppl
cultural issues regarding self-injection. The need
1):S11-S24.
for consumables such as clean needles and insulin 6. Misra P, Upadhyay RP, Misra A, Anand KA. A review of the
syringes is a major problem. The barriers can be solved epidemiology of Diabetes in rural India. Diabetes Res Clin
by providing patient education utilizing health care Pract. 2011;92(3):303-11.
workers and educators. Landmark studies DCCT and 7. Abrahamson MJ. Should Sulfonylureas remain an
UKPDS done with conventional insulin alone highlights acceptable first line add on to Metformin therapy in patients
with Type 2 diabetes? Yes, they continue to serve as well!
the importance of glycemic control in prevention of
Diabetes Care. 2015;38:166-9.
complication. The government can provide insulin free 8. Prevention and Control of Non-Communicable Diseases:
of cost to poor needy patients who require insulin as Guidelines for Primary health Care in low resource settings
that is being followed by government of Tamil Nadu. WHO – 2012.
The government and various welfare organizations can 9. Ganji AS, Cukierman J, Gestein HC, Goldsmith CH, Clase
help in providing newer antidiabetic drugs like DPP4 CM. A systematic review and meta-analysis of hypoglycemia
inhibitors, SGLT-2 inhibitors and insulin analogs which and cardiovascular event: a comparison of glyburide with
other secretogogues and with Insulin. Diabetes Care.
had been highlighted for its cardio-vascular benefits
2009;30: 389-94.
besides glycemic control. 10. Lim PC, Chong CP. What next after Metformin? Focus on
therapy, Pharm Pract (Granada). 2015;13(3):606.
CONCLUSION 11. Van Dalem J, et al. Risk of hypoglycemia in users of
There is increasing prevalence of diabetes worldwide. Sulfonylureas compared with Metformin in relation to renal
Owing to the diverse factors in the resource crunch function and sulfonylurea metabolite group: Population
based cohort study. BMJ. 2016;354:3625.
countries, the disease management in challenging.
12. Balaji V, Seshiah V, Astalakshmi S, Ramanan SG,
Current research is focused on expensive new antidiabetic
Janar thinakani M. A retrospective study on finding
drugs which is unaffordable for majority of patients in correlation of pioglitazone and incidences of bladder
poor countries. The frequency of both microvascular cancer in Indian population. Indian J Endocrinol Metab.
and macrovascular complications will increase globally 2014;18(3):425-7.
CHAPTER
50
Exercise Prescription for Lifestyle
Diseases: A Cornerstone
Anil Kumar Virmani
LIFESTYLE DISEASES Studies have shown that high levels of cardio

respiratory fitness are associated with a lower mortality,
Sedentary lifestyle is a very important risk factor for the
in both men and women. On the other hand, lower levels
common noncommunicable lifestyle diseases (NCD)
of cardiorespiratory fitness, are responsible for a greater
such as metabolic syndrome, diabetes and cardiovascular
risk of mortality than the traditional risk factors.
disease. There is now sufficient clinical evidence that
Findings from the Newcastle Heart Project has
physical exercise can ameliorate most of these ailments,
shown that South Asians are less physically active than
both as a primary and secondary prevention. In fact,
Europeans. The prevalence of T2DM and IGT has been
prescription of physical exercise to all patients with
shown to be significantly lower in higher quartiles of
diabetes has become a global health initiative.
physical activity i.e. 16.8%, 13.2%, and 11% for sedentary,
It is important to distinguish physical activity from moderately heavy, and heavy workers in South India,
physical exercise. Physical activity has been defined as respectively. (Vishwanathan M, et al.). Asian Indians,
“any bodily movement produced by the contraction of because of their sedentary lifestyle are more prone to
skeletal muscles that increases energy expenditure above various noncommunicable diseases.
the basal level”. Whereas, physical exercise is a planned,
structured, repetitive and purposeful activity with the KEY POINTS
objective of improving or maintaining the physical At least 30 min exercise in daily routine is essential
fitness. Physical fitness has been defined as “the ability to improve the physical and mental health of an
to carry out daily tasks with vigor and alertness, without individual
undue fatigue, and with ample energy to enjoy leisure- Sedentary time is defined as the time spent sitting
time pursuits and meet unforeseen emergencies.” during the nonexercising wake hours—Associated
It was Galen (131–200 AD), who first discovered the with obesity, diabetes, CVD, and other NCD
power of exercise. Yet, today it is the “billion dollar drug” The health authorities are trying to promote the
that never gets prescribed ! According to Robert N Butler, awareness to increase the leisure time physical
Former Director, National Institute on Aging, “If exercise activity as a strategy to prevent the spread of the NCD
could be packed in a pill, it would be the single most The recent ADA guidelines on physical activity and
widely prescribed and beneficial medicine in the nation”. exercise for people with diabetes recommend that
CHAPTER 50: Exercise Prescription for Lifestyle Diseases: A Cornerstone 303
after every thirty minutes of sedentary activity, they oxygen, improves cardiorespiratory fitness, increases the
should undertake atleast three minutes of some light threshold for lactic acid accumulation, and decreases
activity. The focus is to increase the physical activity blood pressure and body fat (Brisk walking, jogging,
during the office hours, traveling time, and also 15–20 minutes of continuous activity).
during the leisure time
Even, those who perform at least 150 minutes of Flexibility Exercise Like Yoga
moderate-intensity activity or 75 minutes of vigorous-
Recommendations for Asian Indians
intensity activity weekly during one or two sessions
Be active as far as possible and cut down on your
have 30% DECREASE in all-cause, CV and cancer
sedentary time, like reducing time to watch television,
mortality. They are also known as “weekend warriors”.
or working on computer, etc.
The health benefits of exercise are enormous, ranging
In presence of any cardiovascular disease or diabetes,
from low risk of noncommunicable diseases, colon and
always consult your doctor for medical advice
breast cancers, cognitive impairment, depression to
overall mortality, in both adolescents and adults. regarding type, duration and intensity of exercise.
Asian Indians require atleast one hour of exercise
Regular physical exercise releases a myokine
called Irisin, decreases visceral fat, increases cortisol daily, inclusive of all types of exercise, in comparison
and adrenaline and decreases expression of Toll-like to the ADA guidelines of 30 minutes.
Duration of exercise can be spread throughout the
receptors. These lead to a decrease in the proinflammatory
cytokines production and acute decrease in IL-6, leading day, with at least 10 minutes of exercise at one time.
Brisk walking is the best form of exercise, as it can be
to reduced systemic inflammation. Moreover, Irisin
promotes “browning” of mature adipocytes and scWAT done by everyone.
Physically intensive Yoga exercises should be
and increases cellular thermogenesis of adipocytes, but
inhibits adipogenesis and promotes osteogenesis during encouraged but more research is required in this
lineage-specific differentiation. area.
Exercise also increases noninsulin dependent It should be a structured, graded and individualized
glucose uptake of glucose called contraction-mediated exercise training depending on the needs of an individual.
uptake (CMGU), with the ultimate result that along with
Measures to increase physical activity:
insulin-signalling pathways, it leads to additive effects,
Reduce the screen/TV time to < 30 m/day
thus increasing glucose uptake by skeletal muscle. The
Take stairs instead of Lift/Escalator
types of exercise are:
Walk in the office for atleast 5 min every hour
Anaerobic exercise: In this, oxygen is not used for energy. Avoid prolonged sitting
It is a form of intense physical activity in which the Use cycle for nearby activities
body’s supply of oxygen to produce energy does not meet Park your car a distance from the shopping venue
demand.It increases muscular strength, endurance and Daily physical activity.
flexibility. It can be: (a) Isometric–little or no movement No patient should leave a physician’s practice
(muscle tension; pushing against wall); (b) Isotonic– without: An assessment of current physical activity
repeated movements using weights (push-ups); (c) levels—and—a physical activity prescription and/or
Isokinetic–resistance is moved through entire range of referral to qualified resources for further counseling.
motion; (hydraulic).
Aerobic exercise: Continuous activity that uses oxygen. It Exercise is a Medicine
increases blood supply to muscles and ability to utilize Physicians should prescribe it, patients should take it!
BIBLIOGRAPHY 4. Effects of yoga on cardiovascular disease risk factors: A

1. Blair SN. Br J Sports Med. 2009;43:1-2. systematic review and meta-analysis. Holger Cramer, et al.
2. Consensus Physical Activity Guidelines for Asian Indians; International Journal of Cardiology. 2014;173(2):170-83.
Misra A, Nigam P, Hills AP, Chadha DS, Sharma V, Deepak 5. Misra A. Prevention of type 2 diabetes: the long and winding
KK, Vikram NK, Joshi S, Chauchan A, Khanna K, Sharma road. Lancet. 2009;374(9702):1655-6.
R, Mittal K, Passi SJ, Seth V, Puri S, Devi R, Dubey AP, and 6. O’Donovan G, et al. Association of “weekend warrior” and
Gupta S for Physical Activity Consensus Group, Diabetes other leisure time physical activity patterns with risks for all-
Technol Ther. 2012;14(1):83-98. cause, cardiovascular disease and cancer mortality. JAMA
3. de Rezende LF, Rey-López. JP, Matsudo VK, do Carmo Intern Med. 2017;9.
Luiz O. Sedentary behavior and health outcomes among 7. Viswanathan M, et al. Familial aggregation of type 2
older adults: A systematic review. BMC Public Health. (non-insulin-dependent) diabetes mellitus in south India;
2014;14:333. absence of excess maternal transmission. Diabet Med.
1996;13(3):232-7.
CHAPTER
51
Nonhigh–Density Lipoprotein Cholesterol:
Primary Target for Lipid Lowering
SN Narasingan
INTRODUCTION intermediate density lipoprotein (IDL), etc. Non-HDL

Of all the lipoproteins, it is the LDL which plays the contributes for a significant proportion of CVD risk in
central role in atherogenesis, right from its initiation patients with hypertriglyceridemia and in patients who
in the form of endothelial dysfunction, to its eventual lowered their LDL levels with statins, but burdened with
manifestation as clinical atherosclerotic cardiovascular residual risk. These non-LDL lipoprotein may account
disease (ASCVD). Accordingly, reduction of LDL-C for a significant proportion of ASCVD risk, particularly
results in substantial reduction of ASCVD risk. There is in patients who have elevated TG levels or those in
robust evidence from large scale randomized clinical whom LDL-C has already been lowered with statins. The
trials, mostly using statins, to this effect. Many primary large scale statin trials have shown that despite marked
prevention trials, secondary prevention trials and trials ASCVD risk reduction, the residual risk of ASCVD in
conducted in high risk of population have clearly proven statin- treated patients remains as high as 55–70%.1-4 It is
the role LDL-C in causation of ASCVD and the potency of thus evident that in order to reduce ASCVD-effectively,
statins in reducing this ASCVD risk. LDL plays a crucial we need to concentrate on all atherogenic lipoproteins,
role in patients with familial hypercholesterolemia and and not just LDL alone.
it is found that other CV risk factors like hypertension
and smoking have no role in these patients for premature NON-HDL-C AS AN INDICATOR
CHD. The dominant role of LDL is further exemplified OF ASCVD RISK
by patients of Familial Hypercholesterolemia, who NonHDL-C is defined as total cholesterol minus HDL-C.
commonly develop premature atherosclerosis and HDL is the only protective antiatherogenic lipoprotein
clinical ASCVD even in the absence of any other risk which contains apo-A . All other lipoproteins such as
factor. Based on these evidences, our prime focus for LDL, IDL, VLDL, Chylomicron remnants including
prevention of ASCVD must be on lowering LDL-C and lipoprotein (a) are considered to be atherogenic and
keeping it low throughout life. now designated as nonHDL cholesterol. Hence, nonHDL
However, there are several other atherogenic seems to be the best predictor of ASCVD risk than LDL
lipoproteins in blood and LDL accounts for only about alone. Since, HDL is the only antiatherogenic lipoprotein,
75% of them. The other significant contributors are nonHDL-C effectively measures all atherogenic
cholesterol-enriched remnant of TG-rich lipoproteins lipoprotein in blood, including LDL, VLDL IDL, Lp(a),
su ch a s ve r y l ow - d e n si t y l i p o p ro te i n ( VL D L ) , etc. (Fig. 1). For this reason, it is expected to be a more
Plasma lipoproteins
Apo A-1
Apo B48 chylomicrons Apo B100 Apo B100 Apo B100 Apo B100 HDL
and remnants VLDL IDL LDL LP(a)
Non-HDL-C
Fig. 1: Plasma lipoproteins
accurate predictor of ASCVD risk as compared to to be the most common lipid abnormality in T2DM
LDL-C. Several large scale studies have indeed proven patients with CV events. Non-HDL-C was the most
this hypothesis 5-9 showing that non-HDL-C is a much common lipid abnormality among T2DM patients with
stronger predictor of all-cause and ASCVD mortality as CV events. Elevated non-HDL-C was 21.6% among
compared to LDL-C. For example, in the lipid Research patients who were on statin therapy with optimal LDL-C
Clinics Program, 4462 middle aged individuals who levels. Despite an optimal LDL-C level, 47% of the T2DM
were free from ASCVD were followed up for an average patients with CV events had elevated non-HDL-C.10
of 19 years.5 It was found that non-HDL-C was a much Non-HDL-C seems to predict ASCVD risk equally
stronger predictor of ASCVD outcomes as compared well regardless of TG levels. Though , EPICNORFOLK
to LDL-C (chi-square 24.3 for non-HDL-C and 5.0 for [European Prospective Investigation into Cancer and
LDL-C). A 30 mg/dL increase in non-HDL-C resulted in Nutrition–Norfolk] Study projected predictive accuracy
19% increase in mortality in men and 11% increase in of NON-HDL-c in patients with relatively low TG [200
women compared to 15 and 8% respectively for LDL-C, mg/dL], the SHEP [Systolic Hypertension in the Elderly
In other studies, non-HDL-C has been shown to correlate Program] study confirmed the same relationship in
well with subclinical atherosclerosis also, detected either patients with elevated TG levels [400 mg/dL]. Thus,
by imaging studies or assessed during autopsy. while the EPICNORFOLK (European Prospective
Non-HDL-C is particularly informative in diabetics Investigation into Cancer and nutrition–Norfolk)
who tend to higher TG levels, and thus have a greater study confirmed predictive accuracy of non-HDL-C in
difference between LDL-C and non-HDL-C. A post-hoc patient with relatively low TG (<200 mg/dL), the SHEP
analysis of 4 large prospective studies – The Framingham (Systolic Hypertension in the elderly Program) study11
Cohort Study, The Framingham off Spring study, The documented the same in those who had elevated TG
lipid research Clinics Program follow-up study and (>400 mg/dL). In contrast, in the SHEP study, LDL-C
Multiple Risk factor intervention trial—that included a lost its predictive value when TG levels exceeded
total of 19381 individuals showed that compared to non- 400 mg/dL.
diabetics, the diabetic subjects had significantly higher Non-HDL-C has also been compared with Apo B for
non-HDL-C levels. On multivariate analysis, ASCVD risk its ability to predict ASCVD risk, Since all atherogenic
in diabetics increased with elevation in non-HDL-C but lipoproteins, whether LDL, VLDL or Lp (a), contain one
not LDL-C. molecule of Apo B, Apo B is considered to be the most
Presence of elevated non-HDL among patients with accurate predictor of ASCVD risk. This was confirmed
T2DM with CV events despite of optimal LDL-C has by the INTERHEART study which showed that the ratio
been reported recently from South India. Conclusion of of Apo B to Apo A-I (the protein moiety present in HDL)
this research letter: Non-HDL in this study was found was the strongest determinant of MI risk in the studied
CHAPTER 51: Nonhigh–Density Lipoprotein Cholesterol: Primary Target for Lipid Lowering 307
Risk of major cardiovascular events by LDL and non-HDL cholesterol categories
Target level
LDL-C Non-HDL-C Number of major Total number HR

cardiovascular of participants (95% Cl)
events
≥100 mg/dL ≥130 mg/dL 1877 10419 1.21 (1.13–1.29)
≥100 mg/dL <130 mg/dL 467 2873 1.02 (0.92–1.12)
<100 mg/dL ≥130 mg/dL 283 1453 1.32 (1.17–1.50
<100 mg/dL <130 mg/dL 2760 23426 1.00 (Reference)
0.5 1.0 2.0
Meta-analysis of data obtained from 62,154 statin treated HR (95% Cl)
patients enrolled in 8 trails published between 1994 and 2008
Boekholdt SM et al. JAMA. 2012;307(12):1302-1309
Fig. 2: Meta-analysis of 8 trials: 4S, AFCAPS, LIPID, CARDS, TNT, IDEAL SPARCL, JUPITER
individuals.12 Since, non-HDL-C measures cholesterol analysis is strongly associated with increased risk of
component of all Apo B containing lipoprotein, it future CV events even if LDL is brought under control
correlate with the circulating level of Apo B. In the with statins. 100 mg/dL Non-HDL-C is associated with
Women Heart Study, the highest quintile on non-HDL-C increased risk of future CV events, even if LDL is under
had similar relative risk for major ASCVD events as control with statins.14
the highest quintile of Apo B. However, in the Health
Professionals follow-up study, non-HDL-C was found OTHER ADVANTAGES OF NON-HDL-C
to be an inferior predictor of CV events as compared to Apart from being a wholesome ASCVD risk marker, non-
Apo B.13 Nevertheless, it is important to that in both these HDL-C offers several other advantages that are relevant
studies, non-HDL-C was a better predictor of ASCVD risk to clinical practice:
than LDL-C. Estimation of non-HDL-C does not require any
Finally, there is robust evidence to show that non- additional testing. It can be easily calculated by
HDL-C is an accurate predictor of residual ASCVD risk subtracting HDL-C from total cholesterol.
in patients already on statin therapy. A meta-analysis of Unlike LDL-C, measurement of non-HDL-C does
62154 statin treated patient in 8 trials published between not need fasting blood sampling because both total
1994 and 2008 revealed that one standard deviation cholesterol and HDL-C are not acutely affected by
increase in LDL-C, Apo B and non-HDL-C increased feeding.
the risk of CV event by 13%, 14% and 16% respectively Since non-HDL-C includes both LDL-C and the
indicating that the strength of association with ASCVD TG rich non-LDL lipoproteins, using a non-HDL-C
was greater for non-HDL-C than for LDL-C or even based approach obviates the need to look at TG
Apo B. The results of this meta-analysis are depicted in levels separately. Furthermore, focusing on non-
Figure 2. People who had LDL levels < 100 mg/dL with HDL-C simplifies the management of LDL and other
Non-HDL level of ≥ 130 mg/dL had hazard ratio of 1.32 lipoproteins which are atherogenic. Furthermore,
indicating CV risk of 32% when compared to people as LDL-C is the major component of non-HDL-C,
who had uncontrolled LDL levels of > 100 mg/dL with focusing on non-HDL-C maintains focus on LDL-C
Non HDL level of ≤ 130 mg/dL who had hazard ratio of Non-HDL includes the risk created by small dense
1.02 indicating CV risk of 2%. Non-HDL-C in this meta- LDL-C which are more atherogenic than large
buoyant LDL particles. When there is increase in TG HDL-C as the primary target for therapy.21 The primary
there is always an increase in small dense LDL-C. reason for this is that these guidelines have focused
The values of LDL which we normally get from on ASCVD-risk based approach rather than lipid-level
Labs do not provide information on small dense based approach for initiation and follow-up of statin
LDL-C. Elevated Non-HDL C is now considered as a therapy. Now 2016 ACC Expert consensus decision
surrogate for an elevated TG which indirectly covers pathway on the role of non-statin therapies for LDL-C
small dense LDL-C also covers, to some extent, the lowering management of ASCVD risk changed the
excess ASCVD risk imparted by the small dense form recommendations: Due to the frequency of elevated
of LDL, which is significantly more atherogenic than non-HDL-C despite near normal levels of LDL-C in
the normal large buoyant particles. Small dense LDL diabetics, non-HDL-C thresholds are included in
is the dominant form of LDL particles in patients high-risk patients. Ezetimibe is preferred as the initial
with elevated TG levels.15-17 Unfortunately, LDL-C non-statin therapy due to its tolerability, convenience,
levels do not provide any information about the LDL and single-tablet daily dose. Colesevelam has a modest
particle size but an elevated non-HDL-C, being a hypoglycemic effect that may be of benefit in some
surrogate for elevated TG, indirectly suggests greater diabetic patients with fasting triglycerides <300 mg/dL
proportion of the small dense variety of LDL particles. or in patients who are ezetimibe intolerant.22 2016 ESC/
EAS Guidelines for the management of dyslipidemias
What do the Guidelines Suggest? emphasized on non-HDL-C. The secondary targets
Based on the accumulated and emerging evidence, it is are 100,130 and 145 mg/dL for very high, high, and
being increasingly recognized by most experts worldwide moderate-risk subjects, respectively. If the goal is
that non-HDL-C would be a better target for lipid lowering not reached, statin combination with a cholesterol
therapy than LDL-C alone. Most of the current guidelines absorption inhibitor should be considered. If the goal
have incorporated this in their recommendations. The is not reached. Statin combination with a bile acid
JBS3 consensus recommendations for the prevention sequestrant may be considered.23
of ASCVD state that non-HDL-C should be used in
preference to LDL-C as the treatment goal for lipid What should be Recommended
lowering therapy.18 Following the same concept, the 2014 for Indians?
National Institute for Health and Clinical Excellence Several studies have shown that Indian have high
(NICE) lipid management guidelines recommend –“… prevalence of diabetes, obesity and metabolic syndrome,
before starting lipid modification therapy for the primary all of which are characterized by high TG levels,
prevention of ASCVD, take at least 1 lipid sample low HDL-C and higher prevalence of small dense
to measure a full lipid profile. This should include LDL particles, which is also known as atherogenic
measurement of total cholesterol, HDL-C, non-HDL-C dyslipidemia. High prevalence of elevated TG and low
and TG concentrations. A fasting sample in not needed”. HDL-C has been documented in various epidemiological
Similarly, the U.S National Lipid Association guidelines studies conducted in Indian subjects.24 For this reason, it
have also placed a greater emphasis on non-HDL-C than appears that non-HDL-C is likely to be an important
LDL-C.19 The International Atherosclerosis Society has target for the therapy for Indians. Furthermore, even
also recommended non-HDL-C alongside LDL-C as a though most of the trials have shown ASCVD risk
target for therapy.20 reduction mainly with statins, there is evidence from
However, the recently published ACC/AHA guidelines other studies that addition of a fibrate to statin therapy
for lipid management, in 2013, have not provided any leads to incremental ASCVD risk reduction in patients
specific recommendation about using LDL-C or non- with atherogenic dyslipidemia . Accordingly the lipid
CHAPTER 51: Nonhigh–Density Lipoprotein Cholesterol: Primary Target for Lipid Lowering 309
Association of India recommends non-HDL-C as a co- non-HDL after LDL goal will be appropriate approach in
primary target, as important as LDL-C, for lipid lowering managing lipids at this point of time.
therapy in indians. In all Individuals, the non-HDL-C
level should be kept within 30 mg/dL of LDL-C levels. REFERENCES
Lipid Association of India Expert Consensus 1. Davidson MH. Reducing residual risk for patients on statin
Statement on Management of Dyslipidemia in Indians therapy; The potential role of combination therapy. Am J
cardiol 2005; 96:3k-13k; discussion 34k-35k.
2016 .Part I 25
2. Kastelein JJP, van der steeg WA,Holme I, et al. Lipids,
Non-HDL-C, which is equal to total cholesterol –
apolipoprotein, and their ratios in relation to cardiovascular
HDL-C, includes all atherogenic lipoprotein in blood events with statin treatment. Circulation. 2008;117:3002-
and is therefore a more accurate predictor of ASCVD 9.
risk, particularly in patients who have elevated TG 3. Lloyds-Jones D, Adams RJ, Brown TM, et al. Executive
(e.g diabetics, obese persons, those with metabolic summary: Heart disease and stroke statistics -2010
update: A report from the American Heart Association.
syndrome) and those already on statin therapy.
Circulation. 2010;121:948-54.
The lipid association of India recommends non-
4. Libby P. The forgotten majority: Unfinished business
HDL-C as a co-primary target, as important as in cardiovascular risk reduction. J Am coll Cardiol.
LDL-C, for lipid lowering therapy. 2005;46:1228-55.
Monitoring of non-HDL-C will provide a simple 5. Cui Y. Blumenthal RS, Flaws JA, et al. Non-high density
practical tool for treatment decisions relating to lipid- lipoprotein cholesterol level as a predictor of cardiovascular
disease mortality . Arch Intern Med. 2001;161:1413-9.
lowering therapy since it does not require a fasting
6. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy
blood sample and takes care of both LDL-C and TG
SM. Non-high density lipoprotein and very low density
targets. lipoprotein cholesterol and their risk predictive valued in
In all individuals, the non-HDL-C levels should be
coronary heart disease. Am J Cardiol. 2006;98:1363-8.
kept within 30 mg/dL of LDL-C levels 7. Liu J, Sempos, Donahue RP, Dorn J, Trevisan M, Grundy
Statins remain in the first line agent for lipid lowering, SM. Joint distribution of non-HDL and LDL cholesterol and
regardless of whether LDL-C is the target for therapy coronary heart disease risk prediction among individuals
with and without diabetes. Diabetes Care. 2005;28:1916-
or non-HDL-C
21.
Increasing the dosage of statins or switching to a
8. Bittner V, Hardison R, Kelsey SF, Weiner BH, Jacobs AK, sopko
more potent statin and intensifying lifestyle measures G. Non-high-density lipoprotein cholesterol levels predict five
should be the first step to achieve further non-HDL-C –year outcome in the bypass angioplasty revascularization
lowering when LDL-C target has already been investigation (bari). Circulation. 2002;106:2537-42.
reached. Adding a non-statin drug such as ezitimibe 9. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-
HDL cholesterol, apolipoproteins a-I and b100 standard
or a fibrate should be considered when above
lipid measures, lipid ratios, and crp as risk factors for
measures prove inadequate. cardiovascular disease in women. JAMA. 2005;294:326-
33.
CONCLUSION 10. Satyavani Kumpatla, Anju Soni, SN Narasingan, Vijay
Non-HDL should be considered as a primary target in Viswanathan. MV Hospital for Diabetes and Prof. M.
view of huge body of evidence. Non-HDL also covers Viswanathan Diabetes Research Centre. Available online 19
April 2016 CSI Science Direct Indian Heart Journal.
LDL and hence, both are considered atherogenic
11. Frost PH, Davis BR,Burlando AJ, et al. Serum lipids and
lipoproteins. Moderate to high dose statins will help incidence of coronary heart disease Findings from the
to bring down non-HDL levels. Residual risk requires systolic hypertension in the elderly program [SHEP].
concentration on non-HDL and reaching the target of Circulation 1996;94:2381-8.
12. Yusuf S Hawken S, Ounpuu S, et al. Effect of potentially 20. An International Atherosclerosis society position
modifiable risk factors associated with myocardial infarction paper. Global recommendation for the management of
in 52 countries the [INTERHEART study]: Case – control dyslipidemia. Available at www.Athero.Org/download/
study. Lancet. 2004;364:937-52. iasppguidelines_full report_20131011.Pdf.Last accessed
13. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, may 7, 2015 .
Rimm EB. Non-high-density lipoprotein cholesterol and 21. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/
apolipoprotein b in the prediction of coronary heart disease AHA guideline on the treatment of blood cholesterol to
in men. Circulation. 2005;112:3375-83. reduce atherosclerotic cardiovascular risk in adults: A
14. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL report of the American College of Cardiology/American
cholesterol, non-HDL cholesterol and apolipoprotein b levels Heart Association Task Force on Practice Guidelines.
with risk of cardiovascular events among patients treated Circulation. 2014;129:S1-45.
with statins: A Meta analysis. JAMA. 2012;307:1302-9. 22. Lloyd-Jones DM, et al. 2016 lipid pathway 2016 ACC Expert
15. Maki KC, Bays HE, Dickin MR. Treatment options for the Consensus Decision Pathway on the role of Non-Statin
management of hypertriglyceridemia: Strategies based on therapies for LDL-Cholesterol lowering in the Management
the best-available evidence. J Clin Lipidol. 2012;6:413-26. of Atherosclerotic Cardiovascular Disease Risk. A report of
16. Austin MA,king MC,Vranizan KM, Krauss RM. Atherogenic the American College of Cardiology Task Force on Clinical
lipoprotein phenotype. A proposed genetic marker for Expert Consensus Documents. Endorsed by the National
coronary heart disease risk. Circulation. 1990:82:495-506. Lipid Association.
17. Brewer HB Jr. Hypertriglyceridemia: Changes in the 23. European Heart Journal Advance Access published August
plasma lipoproteins associated with an increased risk of 27, 2016. European Heart Journal doi:10.1093/eurheartj/
cardiovascular disease. AM J Cardiol. 1999;83:3F-12F. ehw272. ESC/EAS Guidelines.
18. Joint British Societies, Consensus recommendations for the 24. Joshi SR, Anjana RM,Deepa M, et al. Prevalence of
prevention of CVD. JBS 3. Heart 2014;100(Suppl 2):ii1-ii67. dyslipidemia in urban and rural india : The ICMR – INDIAB
19. Jacobson TA, Ito MK, Maki KC, et al. National lipid association Study .PLos One 2014:9:e96808 .
recommendations for patient centered management of 25. SS Iyengar, Raman Puri, SN Narasingan. Journal of the
dyslipidemia: Part 1-full report J Clin Lipidol. 2015;9:129- Association of Physicians of India, Supplement copy.
69. 2016;64(3):19-21.
SECTION
4
Endocrinology
Growth Hormone Replacement Therapy: Current Primary Hypoparathyroidism and its Management
Recommendations Ajay Aggarwal, Roopak Wadhwa
Minal Mohit
A New Look at Testosterone Therapy in Aging
Vitamin D Therapy: Hope or Hype Males
PK Sasidharan DC Sharma
Approach to a Patient with Short Stature Lipohypertrophy Secondary to Insulin Injection
Indira Maisnam Therapy
Sunil Gupta
Logical Approach to Thyroid Nodule
CHAPTER
52
Growth Hormone Replacement Therapy:
Current Recommendations
Minal Mohit
INTRODUCTION TABLE 1: Congenital and acquired causes of growth hormone

deficiency
Adult Growth Hormone Deficiency (GHD) is a recognized
Genetic Transcriptional factor defect
clinical syndrome associated with abnormal body
Dysplasia/aplasia
composition, reduced physical performance, altered
Hypothalamic- Tumors
lipid metabolism, decreased bone mass, increased pituitary disease zz Pituitary adenomas, secreting or non-
insulin resistance, and reduced Quality Of Life (QOL), secreting

zz Craniopharyngioma, meningioma,
even when all other pituitary hormones are intact or
germinoma, cyst, glioma, hamartoma,
adequately replaced. It is also likely that the syndrome of metastases
GHD per se contributes to the increase in morbidity and Infiltrative/Inflammatory diseases
mortality rates among patients with hypopituitarism.1-7 zz Lymphocytic hypophysitis, sarcoidosis,
histiocytosis X, granulomatous hypophysitis

Infections
ETIOLOGY zz Tuberculosis, fungal, toxoplasmosis,
GHD in adults may be of either adult-onset GHD pneumocystis carinii

(AOGHD) or childhood onset (COGHD) and may occur Vascular
zz Pituitary apoplexy, Sheehan’s syndrome,
as isolated GHD or as multiple hormone deficiencies. subarachnoidal hemorrhage

Of all the new cases of adults with GHD diagnosed each Iatrogenic Hypothalamic-pituitary damage by surgery/
year, 15–20% cases represent the continuation of COGHD irradiation
into maturity; the remainder is AOGHD acquired from Drug induced, e.g. somatostatin analogs,
monoclonal antibody therapies, interferons
damage to the pituitary gland or hypothalamus. Such
Other Traumatic brain injury, blast injury
damage is most often caused by pituitary or peripituitary
tumors, or by treatment for them with surgery and/or Source: Adapted from Feldt-Rasmussen and Klose
radiotherapy, 8 or it may be traumatic brain injury or
aneurysmal subarachnoid hemorrhage (Table 1).9-13 In annually, while its incidence rate is approximately 2 per
COGHD, the etiology is usually hypothalamic in origin 100,000 when COGHD patients are considered.16 The
because of impaired GHRH secretion,14 with the most incidence rate appears to be significantly higher in males
common diagnosis being isolated idiopathic GHD. 15 in the COGHD group and in the AOGHD group above 45
AOGHD has been estimated to affect 1 per 100,000 people years of age.16
314 SECTION 4: Endocrinology
DIFFERENCES BETWEEN COGHD and low high-density lipoprotein cholesterol. 28 Adults

AND AOGHD with GHD also have reduced skeletal muscle and
GHD occurring in children is mainly idiopathic and is lean body mass and increased fat mass with central
usually recognized because of growth failure. Acquiring distribution of fat mostly in the visceral compartment.2
GHD as an adult as a result of hypothalamic-pituitary GHD cases have fasting insulin levels above the normal
damage leads to the development of clinical features reference range.27 Central fat distribution in adults with
of GHD after the attainment of final height. Therefore, GHD predisposes these patients to insulin resistance
there are phenotypic differences between adults with and altered lipid metabolism,2 all of which contribute
COGHD and those with AOGHD. Compared with to the increased cardiovascular morbidity and mortality
patients with AOGHD, patients with COGHD have lower rates of these patients. Therefore, in treating adults
BMI, waist-to-hip ratio, serum IGF-I and IGF binding with GHD, physicians should consider evaluating the
protein (IGFBP-3) levels, and better QOL scores. Also, fasting glucose, hemoglobin A1C, fasting lipid profile,
patients with COGHD have more severe consequences body composition through the measurements of BMI,
than patients with AOGHD in reduced muscle mass, waist circumference, waist-to-hip ratio, and lean and fat
bone mass and cardiac function.17-19 Furthermore, in mass quantification using DEXA scans at baseline and
many cases of adults with COGHD, only GH secretion is periodically during GH treatment.
impaired. When other anterior pituitary hormones are
also deficient in patients with COGHD, the differences
OSTEOPENIA/OSTEOPOROSIS
between adults with COGHD and AOGHD are less COGHD and AOGHD are associated with reduced bone
pronounced. Older patients secrete less GH, thus making mass compared with age- and sex-matched normal
it more difficult to discern any differences between older
TABLE 2: Typical symptoms and signs of the adult growth
patients with GHD and older normal subjects.20-23
hormone deficiency syndrome
Body composition
CONSEQUENCES OF UNTREATED GHD zz Increased body fat, particularly central adiposity
See Table 2. zz Decreased muscle mass
zz Decreased muscle function
Cardiovascular Complications Cardiovascular and metabolism

zz Decreased sweating and poor thermoregulation
Hypopituitary GH-deficient adults have an increased
zz Decreased insulin sensitivity and increased prevalence of
number of atheromatous plaques in carotid and impaired glucose tolerance

femoral arteries, compared with control individuals.24 zz Increased total and LDL cholesterol and Apo B. Decreased HDL
These patients have a greater intima media thickness, cholesterol

zz Accelerated atherogenesis
increased stiffness of carotid arteries and reduced aortic zz A variable decrease in cardiac muscle mass
distensibility, reduced left ventricular mass, decreased zz Impaired cardiac function
ejection fraction, and abnormal left ventricular diastolic zz Decreased exercise capacity
zz Decreased total and extracellular fluid volume

filling.5,25,26 Cardiovascular parameters to consider while
zz Increased concentration of plasma fibrinogen and plasminogen
evaluating GHD subjects include systolic and diastolic activator inhibitor type I
blood pressure, heart rate, and electrocardiogram Bones
results. More expensive and complex examinations Decreased bone density, associated with an increased risk of
(echocardiogram, carotid echo-Doppler) should be fracture
performed only if clinically indicated. Quality of life
zz Depressed mood
zz Increased anxiety
METABOLIC COMPLICATIONS zz Lack of energy levels
Patients with GHD have elevated levels of total and low zz Social isolation
zz Lack of positive well-being

density lipoprotein-cholesterol,27 high serum triglycerides
CHAPTER 52: Growth Hormone Replacement Therapy: Current Recommendations 315
controls,29-32 COGHD results in reduced bone mass in GH is traditionally stopped. Retesting of the GH reserve
adult life33,34 and patients with AOGHD have an increased is appropriate to consider for most children once they
prevalence of fracture rates. GH replacement improves have attained final height. Re-evaluation of GH status at
radial BMD in 12 months and at trabecular sites in 18–24 final height is advised after GH has been discontinued
months, also reducing fracture risk.34-38 Measurement of for at least 1 month. ITT is recommended as a first-line
bone mineral content and BMD in GH-deficient patients stimulation test, many other stimulation tests have been
is therefore recommended before starting GH therapy. proposed as alternatives, including GHRH combined
Bone remodels slowly; therefore, the first DEXA scan with arginine (GHRH+ARG), glucagon, or ARG tests
after initiation of GH replacement should be conducted alone. A substantial proportion of children with isolated
about 2 years later, and could be repeated at 2- to 3-year idiopathic GHD recover normal GH reserve by the time
intervals thereafter. Long-term beneficial skeletal effects final height is attained.47,48 This is particularly likely in
of GH in combination with bisphosphonates or GH alone those previously diagnosed with partial GHD (i.e. peak
on BMD of up to 7 years’ duration have been shown in GH between 9 μg/L and 16.5 μg/L) on dynamic testing.
various studies.39,40 Patients with multiple pituitary hormone deficits, with
or without structural pituitary or peripituitary disease,49
QUALITY OF LIFE and/or previous cranial radiation therapy are more likely
Adults with COGHD and AOGHD experience to have ongoing GHD.48 However, there clearly exists a
diminished QOL in comparison with the normal group of patients with isolated GHD in childhood who
population.2 Reductions in physical and mental energy, subsequently satisfy the criteria for severe GHD when
dissatisfaction with body image, and poor memory retested as adults, and rarely, a group of children with
have been reported. 41,42 Previous studies using self- multiple pituitary hormone deficits who have normal
rating questionnaires such as the Hopkins Symptom GH reserve on retesting.50 On attainment of final height,
Check List, 45 the Nottingham Health Profile 43,44 the GH retesting is not necessary for individuals with a high
Psychological General Well-Being index43,44 and the QOL- likelihood of GHD such as severe GHD in childhood due
AGHDA (Assessment of Growth Hormone Deficiency in to a genetic cause, structural hypothalamic-pituitary
Adults)45,46 have shown improvements in QOL following disease, or central nervous system tumors, or as the
as early as 6 months of GH replacement. More recently, presence of at least 3 pituitary hormone deficiencies
a new QOL-specific questionnaire (QLS-H [Questions on or severe GHD and the receipt of high-dose cranial
Life Satisfaction-Hypopituitarism]) has been developed radiation therapy and serum IGF-I levels below the
for adults with GHD.42 Data derived from 576 patients given laboratory reference range (<2.5 percentile or <–2
with GHD enrolled in a phase 4 surveillance study of SDS in the absence of conditions that may lower serum
adults with GHD have shown that such patients have a IGF-1 levels). Radiologic evaluation of the hypothalamic-
baseline QLS Z-score significantly lower compared with pituitary region using magnetic resonance imaging
that of normal subjects. After 4 years of GH replacement, (MRI) showing ectopic posterior pituitary at the median
the QLS-H Z-score improved significantly.42 Therefore, eminence (rather than along the pituitary stalk), absence
the evaluation of QOL using self-rating questionnaires42-46 of a visible stalk, and diagnosed case of multiple pituitary
can become part of the clinical management of GH- hormone deficits (rather than isolated idiopathic GHD)
deficient patients, complementary to the measurement are all predictors of severe GHD on retesting.
of other surrogate biologic markers and other clinical
end points. DIAGNOSIS OF GHD IN ADULTS
The mainstay of a diagnosis of GHD in adults is the
TRANSITIONAL CARE OF GHD performance of a GH stimulation test. In the context of
The goal of GH treatment in childhood is primarily panhypopituitarism caused by organic destruction and
statural growth. When final adult height is achieved, associated with low serum IGF-I levels, no further testing
Flow chart 1: Treat if peak GH 11.0 µg/L in patients with BMI <25 kg/m2, peak GH 8.0 µg/L in patients with BMI 25 and <30 kg/m2 and
peak GH 4.0 µg/L in patients with BMI 30 kg/m2
is necessary. ITT is the gold standard GH stimulation TABLE 3: Factors that may affect GH dosing
test and the GHRH+ARG test is the alternative test of Increase GH dose Decrease GH dose
choice.51-53 Low serum IGF-I levels alone are not sufficient
Young patients regardless of Elderly patients
to make the diagnosis, since there are several reasons for onset type
decreased hepatic production of IGF-I other than GHD, Low serum IGF-I levels High serum IGF-I levels
and these include hepatic or renal failure, untreated
Addition of oral estrogen Discontinuation of oral estrogen
hypothyroidism and protein or calorie malnutrition.
Change from transdermal to Change from oral to transdermal
Flow chart 1 as a guideline for clinicians to diagnose
oral estrogen estrogen
GHD in adults.
To induce lipolysis Addition of testosterone
FACTORS AFFECTING GH DOSING Worsening glucose tolerance Side effects
See Table 3.
equivalent clinical and biochemical response compared
Physiologic Factors with men. With decreasing GH secretion across the
During puberty and pregnancy higher GH dosing lifespan after puberty, clinical features and therapeutic
is required. 54,55 Pubertal girls require more GH than end-points differ with patient age. Sensitivity to side
pubertal boys.56,57 GH-deficient women require higher effects of exogenous GH is greater in elderly GH-deficient
GH doses during the initiation and maintenance phases patients; therefore, the starting dose, size of dose
specially in those with intact hypothalamic-pituitary- increments, and target serum IGF-I levels should all be
gonadal axis and in those on oral estrogens to achieve an reduced when GH replacement is considered.20, 21
Obesity and Glucose Tolerance Compliance

Obesity is characterized by marked decreases of both Occasionally patients may find it difficult to comply
spontaneous and stimulated GH secretion, yet normal or with daily injections. As an alternative, the patient can
low-normal serum IGF-I levels are observed.68-60 administer his or her injections on an alternate-day
basis or three times a week using the same total weekly
Concomitant Medications dose. Studies have shown that daily versus thrice-weekly
Women using oral estrogen as replacement therapy or for injections of GH are equally effective in GH-deficient
contraceptive purposes are more GH-resistant than men adults in increasing serum IGF-I levels and improving
because of the attenuation of GH action by estrogen.61-63 lipid and bone metabolism, BMD, and body composition
Growth hormone replacement can lower serum free T4 and in reversing cardiac abnormalities.67,68
and increase T3 levels by increasing the extrathyroidal
conversion of T4 to T3.64 In addition, serum cortisol DOSING STRATEGIES
levels may decline because GH can inhibit the enzyme The strategy proposed by the GH Research Society52 and
11 β-hydroxysteroid dehydrogenase type 1 resulting Endocrine Society Clinical Practice Guidelines53 involves
in a shift in cortisol metabolism favoring cortisone dosing GH independent of body weight, starting with a
production. These effects might cause unmasking of low dose, then gradually increasing this to the minimal
central hypothyroidism 65 and hypoadrenalism. 66 In dose that normalizes serum IGF-I levels without causing
contrast, patients started on testosterone-replacement unacceptable side effects (Table 4). Low GH dosages
therapy may require their GH doses to be decreased as (0.1–0.2 mg/day) might be safer in GH-deficient patients
the co-administration of testosterone can potentiate GH with concurrent diabetes, obesity, and in those with
actions and exacerbate GH induced adverse effects. previous gestational and family history of diabetes.
TABLE 4: AACE 2009 recommendations for GH replacement therapy in adults with GHD (Grade A; BEL 1)
Starting dose:
zz Age <30 years: 0.4–0.5 mg/day (may be higher for patients transitioning from pediatric treatment)
zz Age 30–60 years: 0.2–0.3 mg/day
zz Age >60 years: 0.1–0.2 mg/day
Use lower GH doses (0.1–0.2 mg/day) in all patients with diabetes or who are susceptible to glucose intolerance.
Dose titration: At 1- to 2-month intervals, increase dose in increments of 0.1–0.2 mg/day based on clinical response, serum IGF-I levels, side
effects, and individual considerations such as glucose intolerance. Longer time intervals and smaller dose increments may be necessary in
older patients.
Goal: Aim for serum IGF-I levels in the middle of the normal range appropriate for age and sex, unless side effects are significant. Consider a
trial of higher GH doses to determine whether this provides further benefit as long as the serum IGF-I levels remain within the normal range
and the patient does not experience side effects.
Monitoring: At 6-month intervals once maintenance doses are achieved. Monitoring should include clinical evaluation and assessment of side
effects, serum IGF-I, and fasting glucose levels. The lipid profile should be assessed annually, and QOL measurements may be done every 6 or
12 months. If the initial bone DEXA scan is abnormal, repeat evaluations at 2- to 3-year intervals are recommended. If pituitary microadenomas
or postsurgery residual pituitary tumor is still present, periodic MRIs should be undertaken. Patients on concurrent thyroid, glucocorticoid, and
gonadal hormone replacement may need dose adjustments after starting GH replacement therapy.
Special situations: It is important to retest patients transitioning from pediatric to adult care, especially those who had isolated GHD, and
consideration should be given to minimizing lengthy interruptions in their GH therapy.
Length of GH therapy: The appropriate length of GH therapy is unclear. If benefits are achieved, treatment should continue, but if no apparent
or objective benefits of treatment are achieved after at least 2 years, discontinuing GH therapy may be considered. If patients decide to
discontinue GH replacement therapy, a 6-month follow-up appointment should be offered, because a substantial number of patients may
wish to resume therapy, noting in retrospect that they did feel better on treatment.
Subcutaneous injections are usually administered in levels in the middle of the age- and sex-appropriate
the evening to mimic physiologic GH secretion.69 Once reference range quoted by the laboratory utilized (50th
maintenance doses are achieved, fasting glucose, IGF-I, percentile or 0 SDS). Ongoing monitoring of glucose
serum-free T4, and assessment of the hypothalamic- metabolism in the form of fasting blood glucose levels
pituitary-adrenal axis clinically or via early morning and hemoglobin A1c in patients receiving long-term GH
cortisol or cosyntropin stimulation test (in patients not replacement is highly recommended.
already taking glucocorticoid replacement), testosterone
and lipid levels, and overall clinical status should be Tumor Regrowth/Recurrence
assessed at 6- to 12-month intervals. If the initial bone The growth promoting effects of GH and IGF-I provide
DEXA scan is abnormal, repeat bone DEXA scans are a plausible theoretical basis by which GH treatment
recommended at 2- to 3-year intervals to assess the need could increase cancer risk and promote tumor regrowth/
for additional bone-treatment modalities. If patients recurrence. The published data so far, however, do not
taking replacement GH report significant QOL benefits suggest that GH therapy is associated with causing or
and/or there are objective improvements, such as in accelerating recurrences of pituitary-region tumors,
cardiovascular risk markers, BMD, body composition, although adult GH replacement is contraindicated in
or physical activity tolerance, then GH treatment active malignancy. The GH Research Society consensus
should be continued throughout life, like other pituitary statement advocates clinical screening for neoplasia in
replacement hormones, with the exception of estrogen, these patients to be based on current recommendations
which is stopped after the menopause. If there are for early detection and cancer prevention in the general
neither subjective nor objective benefits of treatment, population.52
some clinicians and patients might decide to consider
stopping GH treatment altogether. Cardiovascular Morbidity
Although it is well known that there is increased
SAFETY ISSUES WITH GH atherosclerosis and cardiovascular mortality in untreated
REPLACEMENT THERAPY GH deficient adults, there are scarce data regarding
cardiovascular morbidity in GHD per se. There are
Diabetes Mellitus many studies showing improvement in cardiovascular
There is no evidence to date that long-term GH risk markers with GH replacement. A meta-analysis of
replacement therapy increases the risk of diabetes 37 blinded, placebo-controlled GH replacement trials
mellitus in adults.70 The incidence of diabetes mellitus showed that overall beneficial effects are observed on
in GH-treated hypopituitary patients with normal BMI is lean and fat mass with no changes in weight, improved
same as that in the normal population. In normal subjects total and low density lipoprotein-cholesterol, and
as well as GH-deficient adults, not only obesity but also improved diastolic blood pressure, but with reduced
advanced age and decreased insulin sensitivity71 of other insulin sensitivity.71 Another meta-analysis of 16 trials
causes are risk factors for the development of diabetes (9 blinded, 7 open) showed positive effects on a number
mellitus. It is therefore important that hypopituitary of morphologic and functional cardiac parameters
patients with high risk of developing diabetes mellitus evaluated by echocardiography in GH-deficient adults
(obese patients or patients with previous history of on GH replacement therapy. 72 Therefore, annual
gestational diabetes) are given a very low dose of GH at measurements of BMI, waist circumference, waist-to-hip
initiation of therapy (i.e. 0.1–0.2 mg/day), and that the ratio and cardiovascular risk markers is recommended
dose of GH then is slowly increased based on the clinical in all patients, with the cardiovascular treatment targets
response, with less emphasis on achieving serum IGF-I being similar to the general population.
UNAPPROVED USES OF GH IN ADULTS age-related cognitive changes with GH treatment. There

Growth hormone is on the list of substances banned for is presently no “magic-potion” that will arrest or reverse
competitive sports by the World Anti-Doping Agency.73 aging.
There are no reliable tests to detect GH abuse; therefore,
the prevalence of this abuse can be surmised only CONCLUSION
through anecdotal evidence. Growth hormone should only be prescribed for adults
with a history of hypothalamic pituitary disease and
Growth Hormone Abuse in Sports biochemically proven GHD, while the unapproved use of
There are no clinical trials in healthy humans that GH for nonmedical conditions such as sports and aging is
demonstrate that GH has a performance-enhancing strongly discouraged. Before GH replacement is started,
effect. Anecdotal evidence suggests that GH is widely clinicians should consider baseline assessment of
abused for its anabolic and lipolytic properties. The clinical features of GHD, optimal dose of other hormone
anabolic actions of GH are mostly mediated through replacement therapy, and the clinical features that
IGF-I and include increases in total body protein turnover impact GH dosing. This evaluation should then guide
and muscle synthesis, as seen in adults with GHD and the clinician in selecting the initial GH dose and the
endurance-trained athletes. 74 Growth hormone alone pace of dose titration, as well as which clinical variables
stimulates proliferation of cartilage in the growing to be used to monitor treatment. Responsiveness to
epiphyseal plate, stimulates linear growth, increases GH therapy is determined by many variables such
bone mass and mineral content, and induces lipolysis as age, sex, adiposity, and concomitant medications.
in adipose tissue, leading to a reduction in fat mass.75-77 Controlled trials, using stepwise dose titration regimes
When combined with testosterone, GH can exert and measuring clinical end points such as body
synergistic effects on anabolism, and athletes combine composition and insulin sensitivity have shown that GH
these hormones to gain maximal effects to enhance dosing should be individualized, with close attention to
performance. avoiding side effects, and the induction or worsening of
glucose intolerance. Low GH doses are recommended at
Growth Hormone is No “Fountain of Youth” initiation of GH therapy, with gradual upward stepwise
Prescribing and administering GH for “antiaging” has titration. Low starting doses may not only be beneficial
become a routine intervention in an industry that has for glucose metabolism, particularly in overweight and
made claims about GH being a remedy for aging, or obese patients who are more prone to glucose intolerance,
a so-called “fountain of youth”. 78 The use of GH for but also may have cost and possibly safety implications.
antiaging and for athletic enhancement accounts for During follow-up of GH replacement, the clinician
approximately 30% of GH prescriptions79 though neither should be mindful of factors such as side effects, glucose
of these indications is approved by the FDA. In theory, intolerance, oral estrogen and oral contraceptive use,
the use of GH is logical to consider because aging is concomitant thyroid, glucocorticoid and testosterone
associated with the gradual reduction in GH secretion, replacement therapy, and weight changes that may
and therefore it was reasonable to hypothesize that GH dictate dose adjustments. Although present data support
supplementation might safely arrest or reverse aging.78 the safety and efficacy of long term GH replacement
A recent meta-analysis of 31 studies evaluating varying in adults, continued follow-up and monitoring by an
doses and duration of GH therapy in the elderly reported endocrinologist experienced in treating pituitary-related
small changes in body composition but significantly disorders, with special emphasis on safety assessments
increased rates of adverse events,80 while animal studies and perceived and objectively measured benefits, should
have shown reduced life spans and premature onset of still be undertaken.
Guidelines issued by AACE to summarize the current R7: In patients with hypothalamic GHD, e.g. idiopathic
knowledge regarding GH replacement therapy in GH- isolated GHD of childhood, the GHRH+ARG test may
deficient adults, to offer practical recommendations for be misleading; hence, an ITT or glucagon stimulation
clinicians, and to describe briefly the misuse of GH in test should be used (Grade A; BEL 1).
sports and aging. R8: Similar cut points for GH stimulation testing in
the transition patients coming off GH therapy are
SUMMARY OF RECOMMENDATIONS applicable as for adults (Grade B; BEL 2).
R1: GHD is a well-recognized clinical syndrome in R9: On restarting GH therapy, the starting dose of GH
adults that is associated with significant comorbidities in transition patients should be approximately 50%
if untreated (Grade A; BEL 1). of the dose between the pediatric doses required for
R2: GH should only be prescribed to patients growth and the adult dose (Grade C; BEL 3).
with clinical features suggestive of adult GHD and R10: Patients with irreversible hypothalamic-
biochemically proven evidence of adult GHD (Grade pituitary structural lesions and those with evidence
A; BEL 1). of panhypopituitarism (at least 3 pituitary hormone
R3: No data are available to suggest that GH has deficiencies) and serum IGF-I levels below the age-
beneficial effects in treating aging and age-related and sex appropriate reference range when off GH
conditions and the enhancement of sporting therapy are deemed to be GH deficient and do not
performance (Grade A; BEL 1). require further GH stimulation testing (Grade A;
R4: Patients with childhood-onset GHD (COGHD) BEL 1).
previously treated with GH replacement in childhood R11: The ITT remains the gold-standard test for
should be retested after final height is achieved diagnosing adult GHD. Acceptable alternative
and GH therapy discontinued for at least 1 month stimulation tests to diagnose adult GHD include the
ascertaining their GH status before considering GHRH+ARG test, the glucagon test, and, rarely, the
restarting GH therapy. Exceptions include those ARG test alone (Grade A; BEL 1).
with known mutations, those with embryopathic/ R12: Appropriate GH cut points based on body mass
c o ng e n i t a l d e f e c t s, t h o s e w i t h i r re v e r s i b l e index (BMI) should be used with the GHRH+ARG
hypothalamic-pituitary structural lesions, and those test, because BMI has a well-validated effect on GH
with evidence of panhypopituitarism (at least 3 responses to GHRH and ARG stimulation (Grade A;
pituitary hormone deficiencies) and serum IGF-I BEL 1).
levels below the age- and sex-appropriate reference R13: In patients where the ITT is not desirable
range off GH therapy (Grade A; BEL 1). and when recombinant GHRH is not available, the
R5: For childhood GH treatment of conditions other glucagon test is a reliable alternative, but not the
than GHD, such as Turner’s syndrome and idiopathic levodopa and clonidine tests (Grade C; BEL 3).
short stature, there is no proven benefit to continuing R14: Patients w ith hypothalamic GHD may
GH treatment in adulthood; hence, there is no demonstrate false-negative responses to the
indication to retest these patients when final height is GHRH+ARG test. If the peak GH level is above the
achieved (Grade B; BEL 2). cut point in such patients, then these patients should
R6: The preferred GH stimulation test to establish the be retested, if possible, with the ITT, glucagon test,
diagnosis of adult GHD in patients with COGHD is the or, rarely, the ARG test alone (using appropriate cut
insulin tolerance test (ITT). Acceptable alternative points) (Grade A; BEL 1).
stimulation tests include the GHRH+arginine (ARG) R15: Traumatic brain injury and aneurysmal
test, the glucagon test, and, rarely, the ARG test alone subarachnoid hemorrhage are now recognized
(Grade A; BEL 1). conditions causing GHD. However, in patients with
these conditions, GHD may be transient; therefore, R24: After initiating GH therapy, physicians should
it is recommended GH stimulation testing to be follow up on patients at 1- to 2-month intervals, and
performed at least 12 months after the event (Grade the GH dosage should be increased in steps of 0.1–0.2
B; BEL 2). mg/day based on clinical response, serum IGF-I
R16: Dosing of GH replacement therapy in all patients levels, side effects, and individual considerations.
should be individualized (Grade A; BEL 1). Longer time intervals and smaller dose increments
R17: As GH-deficient women with an intact may be needed for older patients (Grade A; BEL 1).
hypothalamic- pituitary-gonadal axis and women R25: When maintenance doses are achieved, serum
on oral estrogens are generally more GH resistant IGF-I, fasting glucose levels, hemoglobin A1c, BMI,
than men, these patients will require higher initiation waist circumference, waist-to-hip ratio, serum-free
and maintenance doses of GH than their male T4, and assessment of the hypothalamic-pituitary-
counterparts to achieve an equivalent clinical and adrenal axis clinically or via early morning cortisol
biochemical response (Grade B; BEL 2). or cosyntropin stimulation test (in patients not
R18: There are insufficient data regarding its safety to on glucocorticoid replacement), testosterone and
make recommendations about the use of GH during fasting lipid panel, and overall clinical status should
pregnancy (Grade D).
be performed at 6- to 12-month intervals (Grade B;
R19: The sensitivity to side effects of exogenous GH
BEL 2).
is greater in elderly GH-deficient patients; therefore, R26: Adults with GHD have an increased risk of
the starting dose, size of dose adjustments, and target
cardiovascular morbidity and mortality; therefore,
serum IGF-I levels should be reduced when GH
cardiovascular parameters to consider monitoring
replacement is considered (Grade B; BEL 2).
during follow-up include fasting lipid profile,
R20: For patients with compliance issues, clinicians
systolic and diastolic blood pressure, heart rate, and
may consider administering GH injections on
electrocardiogram results, while more expensive
alternate days or three times per week using the same
and complex examinations such as echocardiogram
total weekly dosage (Grade C; BEL 3).
and carotid echo-Doppler examinations should
R21: There is no evidence that one GH product
be performed only if clinically indicated (Grade C;
is more advantageous over the other, apart from
BEL 3).
differences in pen devices, dose increments and
decrements, and whether or not the product requires
R27: Adults with GHD have an increased risk of
refrigeration; therefore, we do not recommend the developing osteopenia and osteoporosis; therefore,
use of one commercial GH preparation over another we recommend measurement of bone mineral
(Grade D; BEL 4). content and bone mineral density (BMD) in GH-
R22: GH dosing regimens should be individualized deficient patients before starting GH therapy. If
independent of body weight, starting with a low dose, the initial bone dual energy X-ray absorptiometry
and then gradually increasing this to the minimal (DEXA) scan is abnormal, repeat bone DEXA
dose that normalizes serum IGF-I levels without scans are recommended at 2- to 3-year intervals
causing unacceptable side effects (Grade A; BEL 1). to assess the need for additional bone-treatment
R23: Initiating and maintaining GH therapy using modalities.
low GH dosages (0.1–0.2 mg/day) may be more R28: In GH-deficient adults on GH replacement
appropriate in GH-deficient patients with concurrent therapy with pituitary microadenomas or postsurgery
diabetes, obesity, and in those with previous residual pituitary tumor, periodic magnetic resonance
gestational and family history of diabetes so as not to imaging should be undertaken to assess the size of
aggravate blood glucose levels (Grade A; BEL 1). the tumor (Grade C; BEL 3).
R29: Adults with GHD have diminished quality continued long-term surveillance of patients with
of life (QOL); therefore, we recommend a specific pituitary-region tumors regardless of whether or not
questionnaire be administered to adults with GHD these patients are treated with GH therapy (Grade D;
before they begin GH treatment; subsequently, these BEL 4).
adults should be evaluated annually to determine
whether there is a change or sustained impact of GH REFERENCES
therapy on QOL (Grade C; BEL 3). 1. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The
R30: No data are available regarding titrating the GH growth hormone deficiency syndrome in adults. Clin
dose to the ideal target serum IGF-I level; therefore, Endocrinol (Oxf). 1992;37:387-97.
2. Simpson H, Savine R, Sönksen P, et al. Growth hormone
we recommend targeting the serum IGF-I level to
replacement therapy for adults: into the new millennium.
the middle of the age- and sex-appropriate reference
Growth Horm IGF Res. 2002;12:1-33.
range quoted by the laboratory utilized (50th 3. Svensson J, Bengtsson BA, Rosen T, Oden A, Johannsson
percentile or 0 standard deviation score [SDS]). This G. Malignant disease and cardiovascular morbidity in
decision should be based on the circumstances of hypopituitary adults with or without growth hormone
each individual patient (Grade D; BEL 4). r e p l a c e m e n t t h e r a py. J C l i n E n d o c r i n o l M e t a b .
R31: Interaction of GH with other pituitary hormone 2004;89:3306-12.
4. Abs R, Feldt-Rasmussen U, Mattsson AF, et al. Determinants
axes may influence thyroid, glucocorticoid, and
of cardiovascular risk in 2589 hypopituitary GH-deficient
testosterone requirements that may necessitate dose
adults–a KIMS database analysis. Eur J Endocrinol.
adjustments of these hormones (Grade C; BEL 3). 2006;155:79-90.
R32: No data are available regarding the optimal length 5. McCallum RW, Petrie JR, Dominiczak AF, Connell JMC.
of GH replacement; therefore, we recommend that if Growth hormone deficiency and vascular risk. Clin
patients on GH replacement report significant QOL Endocrinol (Oxf). 2002;57:11-24.
benefits and objective improvements in biochemistry 6. Stochholm K, Gravholt CH, Laursen T, et al. Mortality
and body composition, then GH treatment should be and GH deficiency: a nationwide study. Eur J Endocrinol.
2007;157:9-18.
continued indefinitely. However, if the patient reports
7. Stochholm K, Laursen T, Green A, et al. Morbidity and
neither subjective nor objective benefits, then it is GH deficiency: a nationwide study. Eur J Endocrinol.
reasonable to consider discontinuing GH treatment 2008;158:447-57.
altogether (Grade D; BEL 4). 8. Feldt-Rasmussen U, Abs R, Bengtsson BA, et al. Growth
R33: If diabetes mellitus is diagnosed during GH hormone deficiency and replacement in hypopituitary
therapy, or if GH therapy is considered for patients patients previously treated for acromegaly or Cushing’s
with concurrent diabetes mellitus, adjustments in disease. Eur J Endocrinol. 2002;146:67-74.
9. Kelly DF, Gonzalo IT, Cohan P, Berman N, Swerdloff R,
anti-diabetic medications and treatment with low-
Wang C. Hypopituitarism following traumatic brain injury
dose GH therapy may be necessary. Alternatively, it and aneurysmal subarachnoid hemorrhage: a preliminary
is reasonable to withhold or discontinue GH therapy report. J Neurosurg. 2000;93:743-52.
and to optimize the treatment of the diabetes before 10. Lieberman SA, Oberoi AL, Gilkison CR, Masel BE, Urban
reconsidering later resumption of low-dose GH RJ. Prevalence of neuroendocrine dysfunction in patients
replacement in these patients (Grade D; BEL 4). recovering from traumatic brain injury. J Clin Endocrinol
R34: Growth hormone treatment is contraindicated Metab. 2001;86:2752-6.
11. Aimaretti G, Ambrosio MR, Di Somma C, et al. Residual
in patients with a previous history of malignancy or in
pituitary function after brain injury-induced hypopituitarism:
the presence of active malignancy (Grade D; BEL 4).
a prospective 12-month study. J Clin Endocrinol Metab.
R35: No data are available to suggest that GH therapy 2005;90:6085-92.
is associated with causing or accelerating recurrences 12. Aimaretti G, Ambrosio MR, Di Somma C, et al. Traumatic
of pituitary-region tumors; therefore, we recommend brain injury and subarachnoid haemorrhage are conditions
at high risk for hypopituitarism: screening study at 3 months 24. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides
after the brain injury. Clin Endocrinol (Oxf). 2004;61:320-6. AN, Johnston DG. Detection of premature atherosclerosis
13. Kreitschmann-Andermahr I, Hoff C, Saller B, et al. Prevalence by high-resolution ultrasonography in symptom-free
of pituitar y eficiency in patients af ter aneur ysmal hypopituitary adults. Lancet. 1992;340:1188-92.
subarachnoid hemorrhage. J Clin Endocrinol Metab. 25. Colao A, Di Somma C, Rota F, et al. Common carotid
2004;89:4986-92. intima-media thickness in growth hormone (GH)-deficient
14. Gelato MC, Malozowski S, Caruso-Nicoletti M, et al. Growth adolescents: a prospective study after GH withdrawal
hormone (GH) responses to GH-releasing hormone during and restarting GH replacement. J Clin Endocrinol Meta.
pubertal development in normal boys and girls: comparison 2005;90:2659-65.
to idiopathic short stature and GH deficiency. J Clin 26. Colao A, Di Somma C, Rota F, et al. Short-term effects
Endocrinol Metab. 1986;63:174-9. of growth hormone (GH) treatment or deprivation on
15. Maghnie M, Triulzi F, Larizza D, et al. Hypothalamicpituitary cardiovascular risk parameters and intima-media thickness
dysfunction in growth hormone-deficient patients at carotid arteries in patients with severe GH deficiency. J
with pituitary abnormalities. J Clin Endocrinol Metab. Clin Endocrinol Metab. 2005;90:2056-62.
1991;73:79-83. 27. Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of
16. Stochholm K, Gravholt CH, Laursen T, et al. Incidence treatment with recombinant human growth hormone on
of GH deficiency - a nationwide study. Eur J Endocrinol. body composition and metabolism in adults with growth
2006;155:61-71. hormone deficiency. N Engl J Med. 1989;321:1797-03.
17. Ogle GD, Moore B, Lu PW, Craighead A, Briody JN, Cowell
28. Cuneo RC, Salomon F, Watts GF, Hesp R, Sonksen PH.
CT. Changes in body composition and bone density after
Growth hormone treatment improves serum lipids and
discontinuation of growth hormone therapy in adolescence:
lipoproteins in adults with growth hormone deficiency.
an interim report. Acta Paediatr Suppl. 1994;399:3-7;
Metabolism. 1993;42:1519-23.
discussion 8.
29. Hyer SL, Rodin DA, Tobias JH, Leiper A, Nussey SS. Growth
18. Johannsson G, Albertsson-Wikland K, Bengtsson BA.
hormone deficiency during puberty reduces adult bone
Swedish Study Group for Growth Hormone Treatment
mineral density. Arch Dis Child. 1992;67:1472-4.
in Children. Discontinuation of growth hormone (GH)
30. Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M.
treatment: metabolic effects in GH-deficient and GH-
Bone mineral status in growth hormone-deficient males
sufficient adolescent patients compared with control
with isolated and multiple pituitary deficiencies of childhood
subjects. J Clin Endocrinol Metab. 1999;84:4516-24.
onset. J Clin Endocrinol Metab. 1992;74:118-23.
19. Longobardi S, Cuocolo A, Merola B, et al. Left ventricular
31. Degerblad M, Bengtsson BA, Bramnert M, et al. Reduced
function in young adults with childhood and adulthood
onset growth hormone deficiency. Clin Endocrinol (Oxf). bone mineral density in adults with growth hormone (GH)
1998;48:137-43. deficiency: increased bone turnover during 12 months of
20. Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative GH substitution therapy. Eur J Endocrinol. 1995;133:180-8.
adiposity are specific negative determinants of the 32. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet
frequency and amplitude of growth hormone (GH) secretory SM. Reduced bone mineral density in patients with adult
bursts and the half-life of endogenous GH in healthy men. J onset growth hormone deficiency. J Clin Endocrinol Metab.
Clin Endocrinol Metab. 1991;73:1081-8. 1994;78:669-74.
21. Zadik Z, Chalew SA, McCarter RJ Jr, Meistas M, Kowarski 33. Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas
AA. The influence of age on the 24-hour integrated G, Bengtsson BA. Increased fracture frequency in adult
concentration of growth hormone in normal individuals. J patients with hypopituitarism and GH deficiency. Eur J
Clin Endocrinol Metab. 1985;60:513-6. Endocrinol. 1997;137:240-5.
22. Bulow B, Hagmar L, Mikoczy Z, Nordstrom CH, Erfurth 34. Wuster C, Abs R, Bengtsson BA, et al. The influence of growth
EM. Increased cerebrovascular mortality in patients with hormone deficiency, growth hormone replacement therapy,
hypopituitarism. Clin Endocrinol (Oxf). 1997;46:75-81. and other aspects of hypopituitarism on fracture rate and
23. Tomlinson JW, Holden N, Hills RK, et al. West Midlands bone mineral density. J Bone Miner Res. 2001;16:398-405.
Prospective Hypopituitary Study Group. Association 35. Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson
between premature mortality and hypopituitarism. Lancet. BA. Two years of growth hormone (GH) treatment increases
2001;357:425-31. bone mineral content and density in hypopituitary patients
with adult-onset GH deficiency. J Clin Endocrinol Metab. demographic and clinical characteristics, dosing and safety.
1996;81:2865-73. Clin Endocrinol (Oxf). 1999;50:703-13.
36. Snyder PJ, Biller BM, Zagar A, et al. Effect of growth 47. Juul A, Kastrup KW, Pedersen SA, Skakkebaek NE. Growth
hormone replacement on BMD in adult-onset growth hormone (GH) provocative retesting of 108 young adults
hormone deficiency. J Bone Miner Res. 2007;22:762-70. with childhood-onset GH deficiency and the diagnostic
37. Baum HB, Biller BM, Finkelstein JS, et al. Effects of value of insulin-like growth factor I (IGFI) and IGF-binding
physiologic growth hormone therapy on bone density and protein-3. J Clin Endocrinol Metab. 1997;82:1195-201.
body composition in patients with adult-onset growth 48. Nicolson A, Toogood AA, Rahim A, Shalet SM. The prevalence
hormone deficiency: a randomized, placebo-controlled trial. of severe growth hormone deficiency in adults who received
Ann Intern Med. 1996;125:883-90. growth hormone replacement in childhood. Clin Endocrinol
38. Hansen TB, Brixen K, Vahl N, et al. Effects of 12 months of (Oxf). 1996;44:311-7.
growth hormone (GH) treatment on calciotropic hormones, 49. Toogood AA, Shalet SM. Diagnosis of severe growth
calcium homeostasis, and bone metabolism in adults hormone (GH) deficiency in young adults who received GH
with acquired GH deficiency: a double blind, randomized, replacement therapy during childhood. Acta Paediatr Suppl.
placebo-controlled study. J Clin Endocrinol Metab. 1997;423:117-20.
1996;81:3352-9. 50. Shalet SM, Toogood A, Rahim A, Brennan BM. The diagnosis
39. Biermasz NR, Hamdy NA, Pereira AM, Romijn JA, Roelfsema of growth hormone deficiency in children and adults. Endocr
F. Long-term skeletal effects of recombinant human Rev. 1998;19:203-23.
growth hormone (rhGH) alone and rhGH combined with 51. Growth Hormone Research Society. Consensus guidelines
alendronate in GH-deficient adults: a seven-year follow-up for the diagnosis and treatment of adults with growth
study. Clin Endocrinol (Oxf). 2004;60:568-75. hormone deficiency: summary statement of the Growth
40. Drake WM, Rodriguez-Arnao J, Weaver JU, et al. The Hormone Research Society (GHRS) Workshop on Adult
influence of gender on the short and long-term effects of Growth Hormone Deficiency. J Clin Endocrinol Metab.
growth hormone replacement on bone metabolism and 1998;83:379-81.
bone mineral density in hypopituitary adults: a 5-year study. 52. Ho KK. Consensus guidelines for the diagnosis and
Clin Endocrinol (Oxf). 2001;54:525-32. treatment of adults with GH deficiency II: a statement of
41. Badia X, Lucas A, Sanmarti A, Roset M, Ulied A. One year the GH Research Society in association with the European
follow-up of quality of life in adults with untreated growth Society for Pediatric Endocrinology, Lawson Wilkins Society,
hormone deficiency. Clin Endocrinol (Oxf). 1998;49:765-71. European Society of Endocrinology, Japan Endocrine
42. Rosilio M, Blum WF, Edwards DJ, et al. Long-term Society, and Endocrine Society of Australia. Eur J Endocrinol.
improvement of quality of life during growth hormone 2007;157:695-700.
(GH) replacement therapy in adults with GH deficiency, as 53. Molitch ME, Clemmons DR, Malozowski S, et al. Evaluation
measured by questions on life satisfaction-hypopituitarism and treatment of adult growth hormone deficiency: an
(QLS-H). J Clin Endocrinol Metab. 2004;89:1684-93. Endocrine Society Clinical Practice Guideline. J Clin
43. Burman P, Broman JE, Hetta J, et al. Quality of life in adults Endocrinol Metab. 2006;91:1621-34.
with growth hormone (GH) deficiency: response to treatment 54. Martha PM Jr, Gorman KM, Blizzard RM, Rogol AD, Veldhuis
with recombinant human GH in a placebo controlled JD. Endogenous growth hormone secretion and clearance
21-month trial. J Clin Endocrinol Metab. 1995;80:3585-90. rates in normal boys, as determined by deconvolution
44. Gilchrist FJ, Murray RD, Shalet SM. The effect of long term analysis: relationship to age, pubertal status, and body
untreated growth hormone deficiency (GHD) and 9 years of mass. J Clin Endocrinol Metab. 1992;74:336-44.
GH replacement on the quality of life (QoL) of GH-deficient 55. Lonberg U, Damm P, Andersson AM, et al. Increase in
adults. Clin Endocrinol (Oxf). 2002;57:363-70. maternal placental growth hormone during pregnancy and
45. Monson JP, Abs R, Bengtsson BA, et al. Growth hormone disappearance during parturition in normal and growth
deficiency and replacement in elderly hypopituitary adults. hormone-deficient pregnancies. Am J Obstet Gynecol.
KIMS Study Group and the KIMS International Board. 2003;188:247-51.
Pharmacia and Upjohn International Metabolic Database. 56. Leung KC, Johannsson G, Leong GM, Ho KKY. Estrogen
Clin Endocrinol (Oxf). 2000;53:281-9. regulation of growth hormone action. Endocr Rev.
46. Abs R, Bengtsson BA, Hernberg-Stahl E, et al. GH replacement 2004;25:693-721.
in 1034 growth hormone deficient hypopituitary adults: 57. van den Berg G, Veldhuis JD, Frolich M, Roelfsema
F. An amplitude-specific divergence in the pulsatile
mode of growth hormone (GH) secretion underlies the low normal circulating IGF-I concentrations and reverse
gender difference in mean GH concentrations in men cardiac abnormalities associated with adult onset GH
and premenopausal women. J Clin Endocrinol Metab. deficiency (GHD). J Endocrinol Invest. 2003;26:420-8.
1996;81:2460-7. 69. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age
58. Magiakou MA, Mastorakos G, Gomez MT, Rose SR, on the 24-hour profile of growth hormone secretion in man:
Chrousos GP. Suppressed spontaneous and stimulated importance of endogenous estradiol concentrations. J Clin
growth hormone secretion in patients with Cushing’s Endocrinol Metab. 1987;64:51-8.
disease before and after surgical cure. J Clin Endocrinol 70. Monson JP, Bengtsson BA, Abs R, Feldt-Rasmussen U,
Metab. 1994;78:131-7. Wuster C. Can growth hormone therapy cause diabetes?
59. Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson KIMS Strategic Committee. Lancet. 2000;355:1728-9.
ML, Lizarralde G. Dual defects in pulsatile growth hormone 71. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau
secretion and clearance subserve the hyposomatotropism B, Chanson P. Impact of growth hormone (GH) treatment
of obesity in man. J Clin Endocrinol Metab. 1991;72:51-9. on cardiovascular risk factors in GH-deficient adults: a
60. Yamamoto H, Kato Y. Relationship between plasma insulin- metaanalysis of blinded, randomized, placebo controlled
like growth factor I (IGF-I) levels and body mass index (BMI) Trials. J Clin Endocrinol Metab. 2004;89:2192-9.
in adults. Endocr J. 1993;40:41-5. 72. Maison P, Chanson P. Cardiac effects of growth hormone
61. Kelly JJ, Rajkovic IA, O’Sullivan AJ, Sernia C, Ho KK. Effects in adults with growth hormone deficiency: a meta-analysis.
of different oral oestrogen formulations on insulin-like Circulation. 2003;108:2648-52.
growth factor-I, growth hormone and growth hormone 73. World Anti-Doping Agency. The 2005 prohibited list:
binding protein in post-menopausal women. Clin Endocrinol international standard. Available at: http://www.wadaama.
(Oxf). 1993;39:561-7. org/r tecontent/document/list_book_2005_en.pdf.
62. O’Sullivan AJ, Ho KK. Route-dependent endocrine and Accessed March 2005.
metabolic effects of estrogen replacement therapy. J 74. Healy ML, Gibney J, Russell-Jones DL, et al. High dose
Pediatr Endocrinol Metab. 2000;13(Suppl 6):1457-66. growth hormone exerts an anabolic effect at rest and during
63. Ho KK, Gibney J, Johannsson G, Wolthers T. Regulating of exercise in endurance-trained athletes. J Clin Endocrinol
growth hormone sensitivity by sex steroids: implications for Metab. 2003;88:5221-6.
therapy. Front Horm Res. 2006;35:115-28. 75. Pasarica M, Zachwieja JJ, Dejonge L, Redman S, Smith SR.
64. Porretti S, Giavoli C, Ronchi C, et al. Recombinant human Effect of growth hormone on body composition and visceral
GH replacement therapy and thyroid function in a large adiposity in middle aged men with visceral obesity. J Clin
group of adult GH-deficient patients: when does L-T(4) Endocrinol Metab. 2007;92:4265-70.
therapy become mandatory? J Clin Endocrinol Metab. 76. Franco C, Brandberg J, Lonn L, Andersson B, Bengtsson
2002;87:2042-5. BA, Johannsson G. Growth hormone treatment reduces
65. Agha A, Walker D, Perry L, et al. Unmasking of central abdominal visceral fat in postmenopausal women with
hypothyroidism following growth hormone replacement abdominal obesity: a 12-month placebo-controlled trial. J
in adult hypopituitary patients. Clin Endocrinol (Oxf). Clin Endocrinol Metab. 2005;90:1466-74.
2007;66:72-7. 77. Arwert LI, Roos JC, Lips P, Twisk JW, Manoliu RA, Drent ML.
66. Toogood AA, Taylor NF, Shalet SM, Monson JP. Modulation Effects of 10 years of growth hormone (GH) replacement
of cortisol metabolism by low-dose growth hormone therapy in adult GH-deficient men. Clin Endocrinol (Oxf).
replacement in elderly hypopituitary patients. J Clin 2005;63:310-6.
Endocrinol. 2000;85:1727-30. 78. Lyle WG. Human growth hormone and anti-aging. Plast
67. Amato G, Mazziotti G, Di Somma C, et al. Recombinant Reconstr Surg. 2002;110:1585-9.
growth hormone (GH) therapy in GH-deficient adults: a 79. Vance ML. Can growth hormone prevent aging? N Engl J
long-term controlled study on daily versus thrice weekly Med. 2003;348:779-80.
injections. J Clin Endocrinol Metab. 2000;85:3720-5. 80. Liu H, Bravata DM, Olkin I, et al. Systematic review: the
68. Pincelli AI, Bragato R, Scacchi M, et al. Three weekly safety and efficacy of growth hormone in the healthy elderly.
injections (TWI) of low-dose growth hormone (GH) restore Ann Intern Med. 2007;146:104-15.
CHAPTER
53
Vitamin D Therapy: Hope or Hype
PK Sasidharan
VITAMIN D BASIC FACTS only by regular consumption of a well balanced diet

Though it is considered as a vitamin, vitamin D is and by adequate sunlight exposure. Whatever may
unique because it functions as a hormone and is also be the source it has to be activated in the liver by a 25
produced in the body. It has crucial roles in calcium hydroxylation and in the kidneys by a 1-hydroxylation
homeostasis, bone mineral metabolism, cellular growth to produce the active 1,25 dihydroxy vitamin D.7,9 The
and differentiation and immunomodulation. Vitamin D daily dietary requirement is around 400 IU to 1000
is required for growth and differentiation of macrophages IU, previously it was taken as 200 IU.7,9 The generally
and hence it is involved in limiting the growth and accepted normal level of vitamin D now is between
survival of intracellular microbes like Mycobacterium 30–60 ng/mL.9 When the levels are less than 20 ng/ml
tuberculosis, Salmonella and viruses.1-6 Evidences now link it is taken as deficiency and between 20 to 30 ng/mL is
Vitamin D deficiency with all noncommunicable diseases considered now is insuffienciency.7,9,11,12 It was strongly
like hypertension, diabetes, cancers, autoimmune believed once that India, being a tropical country, would
disorders and dyslipidemia. 8,9,15 Vitamin D acts by not have deficiency of Vitamin D. But, that belief was
modifying gene expressions in target tissues by binding to disproved first by our landmark study.1 The same study
specific receptors (VDR) which is expressed in almost all had also brought out the reasons for the deficiency but
organs, and even today we do not know everything about due to reasons unknown these are not widely known or
its actions in the human body.2,3,4,7,8 accepted.1
There are two natural sources of Vitamin D; one is
through biosynthesis in skin and the other through diet.7 LANDMARK STUDY ON
Ultraviolet light mediated cutaneous biosynthesis can VITAMIN D DEFICIENCY1
occur only on direct exposure of the skin to sunlight. But The very first original study on vitamin D deficiency in
the higher content of melanin and use of obstructive India was initiated following the incidental observation
clothing could be interfering with adequate exposure of of its deficiency in a 14-year-old boy with skeletal
the skin to ultraviolet light mediated synthesis of vitamin tuberculosis in the year 1993. He had low calcium, low
D. When it comes to dietary source, for a vegetarian diet phosphate and elevated alkaline phosphatase and
the sources for vitamin D are the pulses (Dhal) and for low Vitamin D level in the absence of a malabsorption
the nonvegetarians it is egg, fish, curd and meat. It is state. Lack of balanced diet was the only cause we
possible to get adequate amounts of vitamin D precursor could find in him as the cause of vitamin D deficiency.
CHAPTER 53: Vitamin D Therapy: Hope or Hype 327
Subsequently, similar finding was noticed in a few more low cut of value of <200 IU/day). If we had kept 400 IU per
patients with active tuberculosis. It appeared thus that day as the cut for normal dietary intake the percentage
vitamin D deficiency was probably linked to the cause would have been much higher. Among the cases there
of tuberculosis as it was already known to be associated was one patient with tuberculous arthritis of the ankle
with malnutrition.1 In 1999 a controlled study was done joint, who looked perfectly normal but for the arthritis,
to look for the association between tuberculosis, Vitamin had the lowest level of vitamin D (less than 1 ng/mL).14
D and nutrition.1 Because of the firm belief that vitamin D This patient did not have symptoms of hypocalcemia
deficiency did not exist in India, there was a discouraging and the serum calcium and phosphorus and alkaline
attitude from all the quarters and hence the study got phosphatase values did not suggest deficiency (Table 1,
delayed till 1999. The study enrolled 35 new cases of patient no. 13). It was also observed that the mean levels
pulmonary and extrapulmonary tuberculosis, before of calcium, phosphorus and alkaline phosphatase were
starting anti-tuberculous treatment and comparison in the normal range in the study subjects1.
was done with 16 age and sex matched healthy controls.
Their clinical features, details regarding intake vitamin Review of the Landmark Study
D containing foods, details of sunlight exposure, serum We had a relook at the original study after the consensus
25 hydroxy vitamin D levels and other biochemical regarding normal levels of vitamin D became available.
characteristics were compared with the controls. 1 It is now well accepted that 20–100 ng/mL is the normal
Those who were otherwise likely to develop vitamin D range and less than 20 ng/mL indicates deficiency.9,11
deficiency due to causes other than sunlight exposure and On application of these values to the original data we
dietary inadequacy were excluded. Sunlight exposure observed that all the study subjects with tuberculosis had
was estimated based on the number of hours they spent vitamin D deficiency and there was only one case with
outdoors in daylight. An exposure more than ten hours even 30 ng/mL. Just three cases out of 35 had vitamin
a week was considered adequate.1 Besides these, the D level above 20 ng/mL and the mean value of 10.7/
necessary investigations for diagnosing tuberculosis, mL got in the study subjects suggested gross deficiency
calcium, phosphorus, alkaline phosphatase, renal and in patients with tuberculosis.9,11 It was observed that
liver function tests and were done.1 there was significant deficiency even among the healthy
25 hydroxy vitamin D3 in the cases ranged from controls, 10 of them out of 16 had vitamin level below
1 ng/mL to 30 ng/mL and the mean value was 10.7 20 ng/mL (Table 2). Only two out 16 healthy controls had
ng/mL. Vitamin D levels in the controls ranged from a value of more than 25 ng/mL, and above 30 ng/mL only
9–58 ng/mL with mean of 19.4 ng/mL, the difference in just one subject. In spite of the small sample size the
being statistically significant (p<0.005). The study was land mark study itself had thrown light on the existence
completed in 2000, but there was no consensus then on of widespread deficiency and its probable causes in the
the normal levels of Vitamin D. The lowest value of vitamin population of Kerala and thus the whole of India.
D obtained in the healthy control group (9 ng/mL) was
arbitrarily taken as normal. There were 16 cases out of REASONS FOR WIDESPREAD
35 who had values below 9 ng/mL. The 72% of the cases DEFICIENCY OF VITAMIN D
had adequate exposure to sunlight. The serum levels The primary reasons for the widespread deficiency
of Vitamin D between those who got adequate sunlight of vitamin D in India are lack of balanced diet,
exposure and those who did not get was not significantly hyperpigmentation of the skin and partly reduced
different, and we concluded that inadequate sunlight sunlight exposure. On closer observation of the problem,
exposure was not the cause of vitamin D deficiency in it becomes clearer that it is due to combination of several
the study subjects. But it was observed that the dietary other problems as well and is indeed a complex issue,
intake was inadequate in 54% of the cases (even with a interlinked to diet and lifestyle habits. The research tools
TABLE 1: 25 hydroxy D3 levels in patients with tuberculosis

Study Age Sex Religion Level of Study Age Sex Religion Level of
subjects with 25 OH D3(ng/mL) subjects with 25 OH D3
tuberculosis tuberculosis (ng/mL)
1. 13 F H 21.0 19 17 F M 10.0
2. 22 F M 9.6 20 23 F M 8.5
3. 33 F M 8.2 21 28 M H 11.0
4. 35 F M 8.2 22 40 M H 13.5
5. 46 M M 30.0 23 27 M H 6.6
6. 20 M H 5.8 24 50 M M 7.0
7. 18 F M 4.6 25 18 F H 2.0
8. 60 M H 18.0 26 20 M M 2.5
9. 38 M M 5.8 27 28 F H 20.0
10. 55 M H 12.0 28 50 M H 5.4
11. 58 F H 13.5 29 55 M H 23.0
12. 40 F H 12.0 30 65 M H 10.0
13. 30 F H <1.0 31 21 F M 12.0
14. 54 M H 3.7 32 29 F H 18.0
15. 32 F H 9.5 33 69 M H 13.5
16. 36 F M 7.0 34 28 F M 5.0
17. 40 N H 14.0 35 20 M C 17.0
18 56 F M 8.5
Abbreviations: M, Male, F, Female, M, Muslim, H, Hindu

Source: Medicine Update 201217
TABLE 2: 25 hydroxy D3 levels in control samples (in ng/mL)

S. no. Age Sex Religion Vit D level S. no. Age Sex Religion Vit D level
1 31 M M 17.0 9 30 M H 26
2 45 M H 58.0 10 40 M H 15
3 65 F M 20.0 11 25 M H 12
4 42 F M 9.5 12 14 M M 14
5 53 F H 9.0 13 24 F M 17
6 19 M M 22.0 14 28 M M 22
7 21 F M 14.0 15 28 M H 17
8 35 F H 18.0 16 45 M H 20
17
Source: Medicine Update 2012
that we employ now are not enough to find out root environment of people who get diseases and of those
causes of such problems; but the root causes can always who remain healthy without any diseases even after
be traced by close observations of the diet, lifestyle and eighty or ninety years.
What is Good Lifestyle and What is from taking dietary items, which contain Vitamin D.
Wrong with Lifestyle? In Kerala for example, several people avoid pulses
Good lifestyle include several habits like regular intake believing that it produces gas or dyspepsia, even as
of a balanced diet, drinking adequate water, ensuring the diet does not contain adequate nonvegetarian
safety of food and water, cleaning teeth in morning items as a source of protein. The gas or dyspepsia
and before bedtime, washing hands before eating or is due to disordered motility of the gastrointestinal
after visiting toilet. People with good lifestyle also avoid tract due to reduced fiber in the diet resulting
smoking, alcohol, overeating, fried food, fast food and from decreased intake of vegetables and fruits.
all the junk foods. Good lifestyle also involves doing Urgent attention from all quarters, to empower the
some kind of physical exercise regularly, avoiding undue society for regular consumption of balanced diet is
mental stress or of managing stress through relaxation absolutely essential to solve the problem of Vitamin D
techniques. Adopting the right posture while working, deficiency and for fighting all diseases, because “food
sitting, travelling or while using computers, and even is the primary medicine”.
the practice of good waste disposal habits all are good Second larger issue behind Vitamin D deficiency is
lifestyle habits. Thus it becomes obvious that absence defective 25 hydroxylation of dietary or cutaneously
of good lifestyle practices lead to weight gain or obesity, synthesised Vitamin D, due to clinical and subclinical
hypertension, diabetes, fatty liver, heart attacks, strokes liver diseases. The incidence and prevalence of liver
and cancers. All abnormal lifestyle practices can be diseases is steadily increasing every year due to
traced to unchecked and unhealthy promotion of changed lifestyle habits. Overeating and development
consumerism and lack of social empowerment. The of fatty liver is the most common reason for liver
observations on the causes of vitamin D deficiency in disease now. The growing acceptance of alcohol and
relation to lifestyle are given below. the increased consumption of it is another cause
Lack of regular consumption of balanced diet is for liver disease. Besides these two often there is
the most common cause of Vitamin D deficiency. exposure to other hepatotoxic substances through
Majority do not even have the chance to get a diet and as medicines and health preparations
balanced diet even by accident due to the lack of (including indigenous medicine) is common among
social empowerment. Balanced diet should contain all groups including the poorer ones. Almost all of
one source of calories (e.g. any one cereal in the these coexist often in most individuals and cause
Indian diet-no cereal is superior in that), adequate clinical and subclinical liver dysfunction.
protein (any one of the pulses/curd/fish/egg or meat) Another important cause for the deficiency is
vegetables-preferably raw or steamed only and never defective metabolism of vitamin D in the kidneys (the
overcooked-and fresh whole seasonal fruits and 1-hydroxylation). Kidney diseases are increasing due
adequate safe drinking water. Therefore, vegetarians to increasing prevalence of diabetes, hypertension
should always eat a combination of “anyone cereal and due to toxins in diet and environment, high
+ any one of the pulses + vegetables + fruits” in the protein diet in the affluent, nephrotoxic drugs
right proportions every time we eat (nonvegetarians like NSAID as over the counter medications and
should take egg, fish or meat instead of the pulses). If the reduced water intake. Toxins in the diet and
we are using roots and tubers as a source of calories, as environment that are potentially damaging to the
in a western diet, the source of protein should always kidneys could be cadmium, mercury, lead, copper
be nonvegetarian or at least curd should be used as a from electronic equipment or from some indigenous
source of protein. Lack of awareness about balanced preparations. Adequate water (approximately two
diet, some beliefs and wrong concepts about diet liters per day) is absolutely essential to prevent renal
and lack of social empowerment prevent people damage from hyperuricemia, high blood pressure
and urinary tract infections. In controlling high sample of the people of Kerala and could indicate
blood pressure salt restriction alone is stressed often similar situation in the rest of the country. The author’s
ignoring the role of adequate water intake, which has observation spanning three decades is that vitamin D
several other benefits as well. Hypomagnesemia as a deficiency is only an indicator sign of malnutrition or
result of clinical and subclinical renal damage, also it shows only the tip of the iceberg of malnutrition and
indirectly contributes to vitamin D deficiency. wrong lifestyle habits in a society. It is malnutrition
Hypomagnesemia is an important reason for Vitamin which initiates or perpetuates diseases like Tuberculosis
D deficiency. The 1-hydroxylation of vitamin D in the and even progression HIV infection to AIDS, since proper
kidneys is parathyroid hormone (PTH) dependent nutrition and Vitamin D has decisive role in maintaining
and PTH secretion in turn is magnesium dependent. cell mediated immunity. 1-5 The most common cause
Hypomagnesemia is primarily due to poor intake of for low CD4 count is malnutrition. Thus Vitamin
vegetables and fruits, besides the renal and GI losses. D deficiency is only an indicator of the subclinical
Sometimes there is poor absorption of magnesium and clinical malnutrition, which is widely prevalent.
from the intestine due to parasites and infections like Malnutrition is the most important cause for the higher
tuberculosis of intestine. Thus an individual could prevalence of HIV and tuberculosis in India, Africa and
have multiple reasons for hypomagnesemia, which other developing countries. It is a common observation
is always subclinical and is often overlooked. Thus that those with advanced AIDS have severe malnutrition
magnesium deficiency, due to multiple causes, would as well, and it could be a cause rather than the effect.
lead to reduced parathyroid hormone (PTH) secretion Besides, there are several examples of persons living
and the consequent reduction of 1-hydroxylation of with HIV for long periods if they follow a healthy diet and
vitamin D in the kidneys is an important and is an lifestyle. What is common to the people affected severely
unrecognized cause of Vitamin D deficiency.7,12,13 by tuberculosis and AIDS anywhere is malnutrition. The
Decreased sunlight exposure—Even if there is enough results of the study supported the already known link
sunlight in India, the habit of exposing our body to between tuberculosis and malnutrition. Randomized
sunlight, even by accident, is becoming very rare due controlled studies are not effective or feasible for
to changed lifestyle and lack of empowerment. The establishing the link between all aspects of nutrition,
preference for indoor jobs alone and not doing any lifestyle and diseases. The observations also suggest that
outdoor activities or outdoor exercise is a lifestyle tuberculosis and other infections control or all disease-
disorder resulting in reduced cutaneous biosynthesis control programmes, to succeed, need to incorporate
of vitamin D. dietary intervention and education and empowerment
The increasing use of obstructive clothing due to of the people for regular intake of balanced diet and
imitation of the western culture or for religious exercise in sunlight. This observation is particularly
reasons could be contributing to reduced sunlight relevant since, even relatively affluent section of society
exposure. do not really know of or consume a balanced diet but
Even if we expose our skin to sunlight, the increased they consume all kinds of fast foods, junk foods and
melanin content in the skin of our people, could be many of them are exposed to overeating, sedentary
interfering with ultraviolet light mediated vitamin D habits, alcohol and tobacco smoking and develop organ
synthesis.7,11 damages, which lead to defective vitamin D metabolism.
The very same people are confining to indoor activities
Social Relevance of the Landmark Study or do white-collar jobs only with hardly any sunlight
The landmark study itself had suggested that vitamin D exposure.
deficiency is very common in the subjects, including the It is also interesting to note the recently recognized
apparently healthy controls, who were representative role of Vitamin D in decreasing the risk of many chronic
illnesses, including common cancers, autoimmune etc. and people should be made aware of and empowered
diseases, other infectious diseases, hypertension, to make use of all these. If exercise is done in natural
diabetes and cardiovascular diseases all indicating setting we would get enough sunlight as well or else sun
the role of balanced diet and avoiding overeating in exposure by plan should be included in good lifestyle
controlling all these diseases. 8,9,11-13,16 It is reported habit. In short, all our people should be empowered to
that raising the serum 25(OH)D level to 40–60 ng/mL take a balanced diet in moderation and to do regular
would prevent breast, prostate and colorectal cancers. exercise in the open as a part of their lifestyle to solve the
There are no risks from intake of 1000–2000 IU per day problem of Vitamin D deficiency in the society rather
of vitamin D 3. 9-11 Vitamin D deficiency is also found than just focusing only on Vitamin D therapy.
to be associated with low HDL, high triglyceride and
high total cholesterol.15 Thus, it is obvious that etiology REFERENCES
of all diseases is converging finally to wrong diet and 1. Sasidharan PK, Rajeev E, Vijayakumari V. Tuberculosis and
lifestyle. The focus should be on empowering the Vitamin D deficiency. Journal of Association of Physicians of
India (JAPI). 2002;50.
people to practise balanced diet and other good lifestyle
2. Henry HL, Norman AW. Vitamin D: Metabolism and biological
habits rather than on Vitamin D therapy alone, which is actions. Annual Review of Nutrition. 1984. pp. 493-520.
certainly hype. As the person who originally opened this 3. Denis M. Killing of Mycobatcerium tuberculosis within
Pandora’s box of Vitamin D deficiency in India, I feel I human monocytes, activation by cytokines and calcitriol.
have the moral responsibility for settling the issue as well. Clin Exp Immunol. 1991;84:200-6.
4. Abu-Amer Y, Bar-Shavit Z. Imapired bone marrow derived
macrophage differentiation in vitamin D deficiency. Cell
RECOMMENDATIONS
Immunol. 1993;151(2):356-68.
There is an urgent need to provide the basic health 5. Kreutz M, Anderson R. Induction of human monocyte to
needs and improve the dietary habits and other lifestyle macrophage maturation in vitro by 1,25 DH D3. Blood.
habits in India rather than allowing unregulated vitamin 1990;15:2457-61.
D supplements and focusing on treatment of diseases 6. Crowle AJ, Salfinger M, May MH. 1,25 DH D3 synergizes
alone. Vitamin D supplements in mega doses are to with pyrazinamide to kill tubercle bacilli in cultured human
macrophages. Am Rev of Res Dis. 1989;139:549-62.
be regulated and the maximum dose to be used as
7. Richard FB, Marie DB, Krane SM, Kronenberg HM.
supplement is to be settled. My personal view is to use only Disorders of bone and mineral metabolism in health and
1000 IU per day indefinitely in those who have deficiency disease; Harrison’s Principles of Internal Medicine. McGraw
rather than giving massive doses intermittently. It is Hill, 17th edn. 2008;2:346.
unfortunate that Vitamin D therapy is the only thing 8. Garland CF, Gorham ED, Mohr AR, Garland FC. Vitamin D
happening to tackle the issue of vitamin D deficiency. for Cancer Prevention: Global Perspective. Ann Epidemiol.
2009;19(7):468-83.
All sections of people should get balanced diet and
9. Holick MF. Vitamin D deficiency medical progress.
adequate exposure to sunlight by suitable social reforms Review article: The New England Journal of Medicine.
and empowerment of the people. Tuberculosis control or 2007;357:266-81.
all disease control program should focus on empowering 10. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D,
the people for regular intake of balanced diet by the ethnicity and blood pressure in the Third National Health
necessary social, educational, financial and agricultural and Nutrition Examination Survey. American Journal of
Hypertension. 2007;20:713-9.
reforms. As an interim measure fortification of foodstuffs
11. P a u l L . V i t a m i n D d e f i c i e n c y a n d s e c o n d a r y
like oil or wheat-flour also may be tried till such time hyperparathyroidism in the elderly: Consequences for bone
that all sections of the society are empowered for taking loss and fractures and therapeutic implications. Endocrine
balanced diet regularly. To get sunlight exposure there Reviews. 2001. pp. 477-501.
must be facilities for doing physical exercise in the open 12. Stechschulte SA, Kirsner RS, Federman DG. Vitamin D:
like adequate play grounds, footpaths, cycle paths, parks, Bone and beyond, rationale and recommendations for
supplementation. The American Journal of Medicine. 15. Vitamin D levels and dyslipidemia-Population-based study
2009;122:793-802. in Finland. Journal of Internal Medicine. 2010;268(6):604-
13. Standing committee on scientific evaluation of dietary 10.
reference intakes, Inst. of Medicine. Dietary reference 16. Velayudhan G, Sasidharan PK. Vitamin D status in
intakes for Calcium, Phosphorus, Magnesium, Vitamin D hypertension. American International Journal of Research
and Fluoride: Washington DC, National Academy press: in Formal, Applied and natural Sciences. 2014;8(1):28-30.
1997. 17. Sasidharan PK, Rajeev E, Vijayakumari V. Vitamin D
14. Sasidharan PK. Tuberculous Osteomyelitis and Vitamin D deficiency in Kerala, India, Medicine Update. 2012;22.
deficiency. Journal of Calicut Orthopedic Association: Jan-
March 2004;2(1) (indexed online journal)
CHAPTER
54
Approach to a Patient with Short Stature
Indira Maisnam
INTRODUCTION hormones promote growth via direct and indirect

Growth begins from the fertilization of an ovum to the effects. It is required for the normal GH response to
fusion of the metaphysis and epiphysis of long bones. growth hormone releasing hormone and normal GH
It is associated with changes in the weight, height, head actions. Gonadal steroids account for pubertal growth
circumference, body proportions and body composition. spurt. Indirectly they stimulate the GH-IGF. Estrogens
result in epiphyseal closure in both genders by causing
PHYSIOLOGY OF NORMAL GROWTH chondrocyte apoptosis. Adequate GH is needed for the
Intrauterine growth depends on nutrients from the growth promoting effect of sex steroids. Glucocorticoids
mother and is influenced by genetic factors and hormones inhibit growth.
like insulin like growth factors and insulin. Sex steroids
may affect intrauterine growth as levels reach pubertal
levels in mid-gestation. Growth in this period is less
PATTERNS OF NORMAL GROWTH
dependent on growth and thyroid hormones, but thyroid Growth is divided into 4 phases: intrauterine, infantile,
hormone is required for neurological development. childhood and adolescence. The upper segment: lower
Infants with congenital growth hormone deficiency and segment is 1.7 at birth; at 3 years it is 1.3 and by 7–10 years
congenital thyroid deficiency have normal length but it is 1.
bone age is delayed in congenital hypothyroidism.
Intrauterine growth phase: Growth is fastest in this period
Postnatal grow th is a complex interplay of
and the rate is 1.2–1.5 cm per week.
environmental and hormonal influences on genetic
potential. Growth of the axial and appendicular skeletal Infantile phase (birth to 2 years): Infants grow about
system accounts for statural growth. Growth hormone 30–35 cm during this period. At around 2 years the infant’s
(GH), IGF-I, androgens, thyroid hormone, sex steroids and growth ‘crosses percentiles’, when the intrauterine
glucocorticoids affect chondrogenesis and chondrocyte influences on growth are gradually lost.
apoptosis in different ways. Inflammatory cytokines
adversely affect growth by promoting chondrocyte Childhood phase (2 years to onset of puberty): Growth
apoptosis. rate is slowest here and rate at 2–4 years is 5.5–9 cm/year;
GH stimulates postnatal growth by increasing IGF1 4–6 years is 5–8.5 cm/year; 6 years to puberty is 4–6 cm/
and IGF binding protein 3 and via direct effects. Thyroid year for boys and 4.5–6.5 cm/year for girls.
Adolescence phase (onset to completion of puberty): is a cause of short adult height. These children have early
Growth spurt starts at 10 years in girls and 12 years in height acceleration and epiphyseal fusion (Table 1).
boys. Growth rate is around 8–14 cm/year. In assessing a child presenting with short stature, the
following need to be answered. They are:
DIAGNOSTIC APPROACH TO A CHILD how short is the child?
WITH SHORT STATURE what is the height velocity (HV)?
what is the target and projected height?

Short stature is defined as a height standard deviation
what is the bone age?
score (SDS) or Z-score ≤ 2 standard deviations (SD)
below the mean height for individuals of the same Linear growth is assessed as supine length until 2–3
gender and chronologic age in a given population. years. The child should be relaxed with the legs fully
The two most common causes of short stature extended; and the head positioned in the Frankfurt
are FSS and CDGP. Family history of short stature plane, with the line connecting the outer canthus of the
(FSS) and family history of slow growth (CDGP) are eyes and the external auditory meatus perpendicular
helpful. Malnutrition and systemic illnesses are the to the long axis of the trunk. After 2 (or 3) years erect
next important group. Endocrine causes are growth height is measured by stadiometers like the Harpenden
hormone deficiency and insensitivity, hypothyroidism, stadiometer with the child standing in the Frankfurt
Cushing’s syndrome, pseudohypoparathyroidism and plane. Height ≤2 SD (≤2.3rd percentile) diagnoses
hypogonadism (after 10–12 years of age). Endocrine short stature. Children with height ≤2.25 SD have
causes are typically associated with obesity. There may extreme short stature. Percentiles and SDS (Z-score)
be poor academic performance, goiter and short stature can be calculated by online calculators or manually.
in hypothyroidism. Children with congenital GHD could For calculation of Z-score mean height for the age and
have micropenis, neonatal hypoglycemia and midline gender is subtracted from child’s height and divided by
facial defects. Cushing’s syndrome have central obesity, the standard deviation.
purple striae and proximal muscle weakness. Genetic Serial measurement measures the height velocity.
causes like Turner’s present with webbing of neck, Measurement should be done at least at 6 months
cubitus valgus and nonappearance of secondary sexual interval and recorded as cm/year.
characters. Skeletal dysplasias like achondroplasia Target height (TH) represents the child’s genetic
is characterized by short limb dwarfism, prominent potential. It is approximated by calculating the
forehead and mid-face hypoplasia. Precocious puberty midparental height and adding 6.5 cm for boys or
TABLE 1: Causes of short stature

Normal variants Systemic disorders Endocrine causes Genetic Skeletal dysplasia
zz Familial short stature zz Undernutrition zz Growth hormone deficiency zz Turner zz Achondroplasia
zz Constitutional zz Glucocorticoid therapy (GHD) zz Noonan zz Hypochondroplasia
delay of growth and zz Gastrointestinal (e.g. zz Growth hormone insensitivity zz Russell-Silver zz Spondyloepiphysial
puberty (CDGP) Crohn’s and celiac) zz Hypothyroidism zz SHOX dysplasia

zz Small for gestational zz Rheumatologic zz Cushing’s syndrome mutations
age (SGA) with ‘catch- zz Chronic kidney disease zz Hypogonadism (after 10–11 years zz Idiopathic
up growth’ zz Renal tubular acidosis of age) short stature

zz Idiopathic short zz Pulmonary disease (e.g. zz Precocious puberty
stature cystic fibrosis) zz Pseudohypoparathyroidism
zz Cardiac disease
zz Immunologic diseases
zz Idiopathic short stature
zz Psychosocial short stature

CHAPTER 54: Approach to a Patient with Short Stature 335
TABLE 2: Different patterns of growth

Type of growth Bone age Height velocity Examples
pattern approximates
Intrinsic Chronologic age Normal Familial short stature, genetic syndromes, skeletal dysplasias
(BA=CA > HA)
Delayed Height age Low normal/subnormal CDGP, early stages of chronic disease, early stages of malnutrition
(BA=HA < CA)
Attenuated Height age Subnormal Endocrinopathies: GH deficiency; GH insensitivity; hypothyroidism;
(BA=HA < CA) Hypogonadism after 10–12 years; Cushing’s syndrome
Chronic disease (severe), Malnutrition
subtracting 6.5 cm for girls. Projected height (PH) for a electrolytes, creatinine, bicarbonate, calcium, phosphate,
child >2 years is determined by extrapolating the child’s alkaline phosphatase and albumin.
growth along the current channel to the 18- to 20-year Karyotype is done in all girls with short stature.
mark. If bone age is advanced or delayed the PH should Thyroid function tests are done in most cases of short
be plotted based on the bone age. stature. Children with features of GHD should be
Bone age is determined from X-rays of the left screened for IGF1 and IGFBP-3. If screening suggests
hand and wrist. It is calculated by comparing with the GHD, then stimulation tests are done to confirm.
Greulich and Pyle Atlas and the Tanner-Whitehouse Exogenous steroid is an important cause of Cushing’s
(TW2) method. Delayed or advanced bone age is syndrome. Suppressed 8am cortisol with physical
defined as a bone age 2 SD ≤ or ≥ the mean, respectively. features of Cushing’s establishes the diagnosis of
This translates to a difference between bone age and exogenous Cushing’s. Tests for endogenous Cushing’s
chronological age of approximately 12 months between include overnight dexamethasone suppression test,
2 and 4 years, 18 months between 4 and 12 years, and 24 24-hour urinary free cortisol, low dose dexamethasone
months after 12 years. suppression test and midnight salivary (or serum)
Growth parameters are described as follows : cortisol. Further testing and imaging is directed by the
chronologic age → calendar age; bone age → age for biochemical results of the initial tests.
which bone maturation is average, and height age → age Tests to detect systemic illness are done based on
at which height is average. history and clinical examination. Skeletal survey are
The disturbances of linear growth can be categorized helpful in skeletal dysplasias.
broadly into three growth patterns: intrinsic shortness,
delayed growth and attenuated growth (Table 2). CONCLUSION
Intrinsic short stature is intrinsically determined like A detailed history and clinical examination along with a
familial and genetic factors; and skeletal dysplasias. In systematic approach helps establish the cause of short
delayed growth there is slow growth and delayed puberty stature in most cases. Physiological variants like FSS
but normal final height. CDGP is an important cause. and CDGP are the most common causes. A scientific
Attenuated growth is a more severe form of delayed approach is cost-beneficial by helping identify children
growth. Growth velocity is low; bone age and height age needing further evaluation and treatment, and avoiding
are low; and are lesser than chronologic age. Endocrine extensive evaluation in children who have physiological
causes, chronic illnesses and malnutrition are the causes. variants. Timely diagnosis and treatment is important
The algorithm guides the extent of testing (Flow because most endocrine causes of short stature and many
chart 1). Tests include complete blood count and secondary causes respond satisfactorily to treatment
erythrocyte sedimentation rate, C-reactive protein, when proper treatment is instituted at the right time.
Flow chart 1: Algorithmic approach to short stature
Abbreviations: HV, Height velocity; PH, projected height; TH, Target height; BA, Bone age; GDPP, gonadotropin-dependent precocious puberty
BIBLIOGRAPHY 3. http://www.uptodate.com/contents/diagnostic-approach-
1. Cooke DW, et al. Normal and aberrant growth. Shlomo to-children-and-adolescents-with-short-stature. Accessed
Melmed, Kenneth Ed. S. Polonsky, P. Reed Larsen, Henry M. on 18th August 2017.
Kronenberg. In. Williams Textbook of Endocrinology. 12th 4. Hussain K, et al. Applied physiology: Understanding growth.
Edition. Philadelphia. WB Saunders. 2011;935-1053. Current Paediatrics. 2006;16:430-3.
2. Cuttler L, et al. Somatic growth and maturation. JL Jameson, 5. Oostdijk W, et al. Diagnostic approach in children with short
LJ De Groot (Eds). In: Endocrinology adult and paediatric, stature. Horm Res. 2009;72:206-17.
7th Edition. Philadelphia: Elsevier Saunders. 2016;382-
417.
CHAPTER
55
Logical Approach to Thyroid Nodule
INTRODUCTION While majority of the nodules being benign, only

Nodular goiter is one of the common clinical problems 5–10% of them are malignant. Since most thyroid cancers
in thyroidal illness encountered in 5–10% of adult are curable by surgery if detected early, the focus should
population with a higher prevalence in iodine deficient be to follow standard evidence based approach in the
areas, hilly regions and foothills. As in other thyroidal diagnosis and management. And as elsewhere, this
illnesses, females outnumber males by a ratio of 8:1. With would involve a battery of investigations after a thorough
increasing usage of high-resolution ultrasonography clinical assessment.
(USG) of the neck, its detection is being reported much
more frequently now, adding to patient’s anxiety and Pointers to Malignancy
physicians responsibility to arrive at a diagnosis and to Clinical
plan an appropriate therapy.
zz Sex: Men >> Women zz Age < 20 years and > 60 years
CLINICAL PRESENTATION zz Positive family history of zz History or radiation – head,
malignancies neck, thorax
Morphologically nodular goiter may be solitary or
zz Post bone marrow transplant zz Recent rapid increase in size
multinodular (MNG) involving the isthmus and either
zz Cystic enlargement more zz Hard fixed nodule
one or both lobes and may present in different ways:
than 4 cm
Detected on routine physical palpation of the neck
zz Cervical adenopathy zz Hoarseness of voice
or an USG done for a nonthyroidal problem—
“Incidentalomas.”
Patient, usually a female for a cosmetic problem - as
Less Likely to be Malignant
an obvious swelling over the front of neck. “HOT” nodule with thyrotoxicosis
With pressure symptoms of dysphagia, dyspnea or
Contrary to the earlier belief, the multinodular goiters
hoarseness of voice. are less likely to be malignant
Clinical or laboratory evidence of hypo- and
hyperthyroidism. Investigational Steps

With cervical adenopathy. Laboratory
With a metastatic lesion in the lung, bone, brain or —— Thyroid function tests—T3, T4, TSH (serum)
liver. —— Anti-TPO antibody (serum)

USG neck1 all cases except when it is a hot nodule. It is an OPD

—— Size, location, number and consistency (solid, procedure, safe, accurate, does not require any special
cyst, mixed) equipment and is cost effective. The only prerequisite
Isotope thyroid scan/scintiscan is the availability of a cytopathologist experienced in
Fine needle aspiration cytology (FNAC) interpreting the aspirate. It is important to note that
the follicular and Hurthle cell carcinomas cannot be
Analysis of Diagnostic Aids distinguished cytologically unless there is capsular or
TFT will confirm the clinical diagnosis of functional vascular invasion.
status of hypothyroid or hyperthyroid or as euthyroid. There are several systems of histological classification,
Anti-TPO will point towards an autoimmune but the one followed worldwide including most centers
etiology—Hashimoto’s. in India is Bethesda System of reporting thyroid cytology
S erum calcitonin : A routine measurement of (TBSRTC), which aims to standardize international
calcitonin is controversial, it is prudent to measure terminology.5
the calcitonin levels only if there is a family history Most, about 85% of the specimens reported as
of multiple endocrine neoplasia (MEN) or medullary satisfactory contain at least six groups of cells with ten or
more loci of well-preserved thyroid epithelial cells
thyroid carcinoma.
Of the above, the reported cytology is as follows:
USG neck: While sonography cannot differentiate
Benign 83–87%
lesions from being benign or malignant, the following
Malignant 3–5% (papillary, follicular, medullary or
features are pointers towards malignancy.2
anaplastic)
zz Hypogenecity with irregular zz Infiltration into surrounding 8–12% (indeterminate-follicular lesion,
shape and ill defined borders structure
Hurthle cell cytology)
zz Microcalcification of the nodule zz Interrupted rim calcification
Mixed or pure cysts measuring Cervical adenopathy
zz
more than 4 cm
zz
MANAGEMENT
Based on the above inputs—clinical, laboratory, USG,
roadly speaking, the chances of malignancy
B
scintiscan and FNAC, decision-making regarding
depending on the gross features of nodule are3
management has to be undertaken (Flow charts 1A
—— Solid lesions about 20% risk of being malignant
and B). If there is a definite evidence of thyrotoxicosis
—— Cystic lesions measuring less than one centimeter
low TSH with high T3/T4 and a hot nodule on scintiscan
the risk is 0.1% and if the lesion is more than then the patient is started on antithyroid drug (ATD),
4 centimeter the risk is about 2% consisting of tab carbimazole (CMZ) or methimazole or
—— With mixed lesions the malignancy risk is about
propylthyouracil along with tab propranolol 60–80 mg/
7% day and reassessed once in 8–12 weeks both clinically
Isotope scan: Radio-nucleotide scan with either and hormonally, with the dosage of ATDs readjusted
iodine [I131/125] or 99m Technetium (cheaper and accordingly. ATD is continued for 12–18 months unless
lesser in vivo retention) will reveal increased uptake there is drug hypersensitivity or toxicity (agranulocytosis
by the nodule (Hot nodule), diminished or no uptake hepatitis) and then stopped keeping a watch for relapse
(Cold nodule) or similar uptake as the rest of the either clinical or hormonal.6 If there is a relapse, ATD is
gland (Warm). Probability of malignancy is 10–15% restarted till toxicity is controlled and definitive therapy
on cold nodules, while in case of the ‘hot’ nodule it is with either I-131 ablation or partial thyroidectomy (only
about 1–4%, and 5% in ‘warm’ nodules. if there are pressure symptoms) is offered. Patient has
FNAC: FNAC is considered as the gold standard in to be followed up and put on thyroxin supplements for
the evaluation of thyroid nodule4 and is indicated in hypothyroidism and continued for life.
CHAPTER 55: Logical Approach to Thyroid Nodule 339
Flow charts 1A and B: Work-up thyroid nodule
B
On the other hand, if the patient is euthyroid or The full work up of thyroid nodule besides a Physician
hypothyroid and the nodule is reported as malignant, or an Endocrinologist, involves the Radiologist, the
total thyroidectomy with block dissection of lymph Nuclear Medicine Specialist and most importantly a
nodes is the usual treatment. The follow up, will involve a Cytopathologist. Fine needle aspiration and the expert
watch for recurrence – a six monthly TBG estimation with opinion on the aspirate has become an essential requisite.
a careful clinical evaluation. Thyroxin replacement in a We do not have many centers with cytopathology but
high dose is obligatory with due considerations about a good histopathologist with practice and experience
radiotherapy. should be able to help.
The third scenario is a hypothyroid or euthyroid The stepwise approach in this write up is evidence
patient with a nodule reported as suspicious either in based and practiced in most large centers all over the
USG or scintiscan and FNAC yield no definite diagnosis. world. It will be possible to practice in any setting, if one
Surgical excision with the assistance of frozen section has the aptitude and initiative to organize teamwork.
facility should be the choice – rather than repeat FNAC.7
The repeat FNAC may not be acceptable to the patient REFERENCES
1. Accuracy of thyroid nodule ultrasound to predict thyroid
and also in the absence of cytopathologist we may not
cancer—Systematic review and metanalysis. JCEM. 2014;
get a definitive diagnosis. Our protocol involves a frozen 99(4):1253-63.
section biopsy. In this procedure, patient is prepared 2. Cibas ES, Ali ZS, The Bethesda System for reporting Thyroid
as for any thyroid surgery in consultation with the cytopathology: Thyroid 2009;19:1151-65. (PubMed)
histopathologist. After an incision along the crease of 3. Garg S, et al. To establish Bethesda system for diagnosis
of thyroid nodules on the basis of FNAC with histologic
the neck, lobectomy with the nodule is done and sent to
correlation. J Clin Diagnosis Res. 2015;EC. 17-21. (PMC
the laboratory–the histopathology report will usually be Free article in Pub Med).
available within few minutes. Depending upon this the 4. Hegedus L. Thyroid ultrasound and features and risk of
surgeon will proceed either to do a total thyroidectomy or carcinoma. Thyroid 2015. Endocrinology and Metabolism
carry out only lobectomy.8-10 This process has helped us Clin North Am. 2015;30:339-60, viii–x.
5. Shrikant J, et al. Thyroid nodule—update on diagnosis and
to reduce unnecessary morbidity of total thyroidectomy
management. Clinical Diabetes and Endocrinology. 2016;
in some centers (including the one in which the authors 2:17.
are associated with). 6. Likay K. The evaluation of thyroid nodules. Thyroid disorders
Despite all measures about 5% of nodules may and therapy. 2015;4:2.
remain nondiagnostic and after careful consideration, a 7. Regi S, Bajaj S. ITS clinical manual of thyroid disorders. Find
needle aspiration cytology, Elsevier. First edition. Jayakumar
surgical option should be considered.
RV (Ed). 2012;161:171-82.
8. Kannan S, et al. Improving Bethesda reporting in thyroid
CONCLUSION cytology: A team effort goes a long way and still Miles to
In the present scenario, in our practice we need to go… Indian Journal of Endocrinology and Metabolism.
develop a systematic approach to evaluate a thyroid 2017;2:277-81.
9. Unnikrishnan AG. Nontoxic thyroid goiters. Indian Thyroid
nodule. These patients are seen by or referred to different
Society - Clinical manual of thyroid disorder edition Ed.
specialists Surgical, ENT, Oncologist and at times the 2012.
Gynecologist or Obstetrician—if diagnosed initially for a 10. Yoon YH, et al. Diagnostic accuracy of US guided fine needle
gynecological problem or during pregnancy.9,10 aspiration biopsy. Thyroid. 2011. pp. 993-1000.
CHAPTER
56
Primary Hypoparathyroidism
and its Management
Ajay Aggarwal, Roopak Wadhwa
Parathyroid hormone (PTH) deficiency, a key hormone of primary hypoparathyroidism in India, given the total
essential for calcium homeostasis, causes primary population of 1.3 billion. Clark BL et al reported the
hypoparathyroidism. It is an uncommon disorder, prevalence rate of 37 and 22 per 100,000 personyears in
characterized by low serum calcium, high phosphorus US and Denmark respectively. Another study from US
and low or low-normal PTH. It can be divided into, reported 74% hypoparathyroid patients to be in the age
primary hypoparathyroidism due to intrinsic defects group of 45 years or more and occurrence of 75% cases
within parathyroid glands, primarily due to genetic in females. Cipriani et al in an Italian study reported
causes, and secondary or acquired forms due to hospitalizations rate of 72.2% and 27.8% among women
etiologies affecting parathyroid function. The diagnosis and men respectively due to hypoparathyroidism.
is easy once serum calcium, phosphorus and PTH levels
are known, but determining the cause of nonsurgical PATHOPHYSIOLOGY
hypoparathyroidism may be challenging. The extracellular fluid (ECF) concentration of ionized
Pseudohypoparathyroidism (PHP), even less common calcium remains nearly constant. Its maintenance in
disease, is characterized by low serum calcium, high both intra- and ECF is highly regulated and modulates
phosphorus but high PTH level due to PTH resistance. the functions of bone, renal tubular cells, adhesion
Autoimmunity, which affects either the parathyroid molecules, clotting factors, excitable tissues, etc. A
glands alone or multiple endocrine glands, is the most G-protein coupled receptor, extracellular calcium-
common cause in adults. Primary hypoparathyroidism sensing receptor (CSR), has been isolated from
may also be caused by rare genetic disorders, due to gene parathyroid, kidney and brain cells. Mutations in this
mutations involving the development of the parathyroid receptor may lead to disturbance in serum calcium
glands and synthesis or secretion of PTH. status. The secretion of PTH is regulated by this receptor
in parathyroid cells. Activating mutations of this receptor
EPIDEMIOLOGY causes hypocalcemia, due inhibition of PTH exocytosis,
KVS Hari Kumar et al estimated burden of parathyroid the intracellular mechanism(s) of which remains
disorders in India. They reported incidence rate unknown.
of primary hypoparathyroidism as 2.6 per 100,000 Normally, exocytosis of PTH occurs when there
personyears thereby giving a prevalence rate of 15.6 per is fall in ECF ionized calcium, which restores normal
100,000 population and approximately 200,000 patients range of ECF ionized calcium, by its effects on the
kidneys and skeleton. PTH causes bone resorption and dental abnormalities, brittle nails, dry, rough skin, raised
releases ionized calcium into the ECF by activating intracranial pressure with papilloedema, and hyper-
osteoclasts. The proximal tubular reabsorption of reflexia are other important signs.
phosphate from the lumen is also inhibited by PTH. So, The etiologies like DiGeorge’s syndrome (recurrent
in hypoparathyroidism, the phosphate concentration infections, congenital heart disease, micrognathia,
in plasma is elevated and in conditions of primary PTH speech delay, cleft palate and ear abnormalities),
excess, hypophosphatemia occurs. Familial APS-I (mucocutaneous candidiasis, adrenal
PTH retains calcium by its effect on the distal renal failure, vitiligo and dental enamel hypoplasia) may cause
tubules. This effect in hypoparathyroidism leads to other symptoms and signs.
calcium wastage through kidneys, which increases
the urinary calcium excretion and decreases the ECF INVESTIGATIONS
ionized calcium. PTH, by stimulating renal 1-alpha- S e r u m ca lc iu m, ph o sphate, P T H a n d alkalin e
hydroxylase, also plays important role in the synthesis of phosphatase levels are the blood tests required for
1,25-dihydroxy vitamin D. It allows better dietary calcium diagnosis. The results suggestive of hypoparathyroidism
absorption. Thus, both 1,25-dihydroxy vitamin D and include low serum calcium, high phosphate, low PTH
PTH contribute to a rise in the ECF ionized calcium. and normal alkaline phosphatase. Serum magnesium
The P TH deficienc y negatively affects bone may be low, CKD also needs to be excluded. The
resorption, phosphaturic effect, renal distal tubular measurement of vitamin 25(OH)D3 and its active
calcium reabsorption, and 1,25-dihydroxy vitamin D metabolite (1,25(OH)2D3) helps to rule out vitamin D
mediated dietary calcium absorption, thereby causing deficiency as a cause of hypocalcemia. 25(OH)D3 levels
hypocalcemia. are normal in hypoparathyroidism, but 1,25(OH)2D3 is
low due to PTH deficiency.
SIGNS AND SYMPTOMS The thyroid and adrenal insufficiency should
The patients present with the symptoms of hypocalcemia. ruled out, if autoimmune process is suspected. The
This may ranges from just an asymptomatic laboratory measurement of serum TSH, T4, thyroid autoantibodies,
finding to severe metabolic disturbance. Symptoms ACTH and adrenal antibodies helps. Ultrasound
include muscle pains, bone pains, abdominal pain, abdomen may detect renal calculi and brain MRI scan
paresthesia of the face, fingers, facial twitching, may reveal basal ganglia calcification, suggestive of long-
carpopedal spasm, stridor and convulsions. The other standing disease.
symptoms include syncope, emotional lability, anxiety,
depression, confusion, memory impairment, lethargy, TREATMENT
headaches, dry hair, skin and painful menstruation. Past Careful evaluation and consideration of the treatment
history of neck surgery, family history of hypoparathyroid options other than calcium supplementation are required
disorders are important points to be included in the to treat hypoparathyroidism. A diet rich in calcium and
history. vitamin D should be emphasized. Severe hypocalcemia
Clinical signs include Chvostek’s sign which detects with symptoms, such as tetany needs urgent IV calcium
latent tetany. It involves contraction of the facial muscles infusion.
caused by tapping of the facial nerve at the angle of the jaw. The primar y goals of management includes
The positive response in 25% of the normal population symptoms control, to maintain serum calcium in the
makes this sign nonspecific. Another important sign is low-normal range (8–8.5 mg/dL) and serum phosphorus
Trousseau’s sign which involves induction of carpopedal within normal range with calcium and vitamin D
spasm by occluding arterial circulation of the forearm supplementation. It helps to prevent hypercalciuria, renal
for three minutes using a blood pressure cuff. Cataracts, stones or calcium phosphate deposition in soft tissues.
CHAPTER 56: Primary Hypoparathyroidism and its Management 343
Vitamin D analogs such as calcitriol or alfacalcidol are to calcium and vitamin D, Natpara (rhPTH[1-84]), a
helpful. Calcitriol 0.5 μg or alfacalcidol 1 μg daily are usual parathyroid hormone is indicated.
starting doses. Dose is titrated every 4–7 days to achieve a The active ingredient in Natpara is produced by
low-normal serum calcium level. Calcitriol is preferred as recombinant DNA technology using a modified strain
it is more potent, has rapid onset of action and short half- of E.coli. Parathyroid hormone has 84 amino acids and
life. The patients with gain-of-function mutations of the a molecular weight of 9425 daltons. It raises plasma
calcium-sensing receptors when on vitamin D treatment calcium levels by increasing intestinal absorption and
may suffer from hypercalciuria, nephrocalcinosis, and renal reabsorption of calcium and increasing bone-
renal impairment. The asymptomatic patients can turnover rates to release calcium from bone. It may
simply be followed. Thiazide diuretics increase distal increase the risk of osteosarcoma. It is initiated at
renal tubular calcium reabsorption, thereby decreasing 50 mg daily as subcutaneous injection. The dose may be
urinary calcium excretion. Diuretics in combination with increased every four weeks in 25 mg increments up to a
low-salt, low-phosphate diet and phosphate binders are maximum dose of 100 µg daily.
beneficial. Serum calcium, phosphorus, and creatinine
should be measured at regular intervals initially for dose CONCLUSION
adjustments and then periodically once the therapy The management of primary hypoparathyroidism
protocol has stabilized. requires to diagnose the etiology of hypocalcemia,
Unfortunately, due to the limitations of therapy followed by supplementation with calcium and vitamin
patients with hypoparathyroidism may have poor quality D. Further enhancement of treatment by introducing
of life. The property to correct hypercalciuria and reduce thiazide diuretics and other options can help to treat
the risk of nephrocalcinosis, nephrolithiasis, and renal hypocalcemia and prevent symptoms. The results with
insufficiency makes replacement therapy with PTH, a current treatment are suboptimal and are associated
viable option. It reduces the wide fluctuation in serum with increased risk of wide fluctuations in serum
calcium and also helps to decrease the large doses of calcium, hypercalciuria, renal impairment. The patient
calcium and vitamin D required to maintain serum should be treated aggressively and monitored regularly,
calcium in normal range. To control hypocalcemia after evaluation and determination of the etiology of
in patients with hypoparathyroidism, as an adjunct hypocalcemia.
CHAPTER
57
A New Look at Testosterone
Therapy in Aging Males
DC Sharma
As the age advances the concentration of serum There have been three large longitudinal studies also
testosterone and to a greater extent free testosterone showing a decline in serum testosterone with aging.2
decline in men, this decrease is also described as Around 20, 30, and 50% men in their 60s, 70s, and 80s
andropause or “late onset hypogonadism”. Unlike respectively had total serum testosterone levels in
menopause in women where there is a complete serum hypogonadal range.3
estrogen deficiency the decrease in serum testosterone is Serum sex hormone binding globulin(SHBG)
modest and the possible clinical effects thereof have not increase with age resulting in a decrease in serum free
been well understood. testosterone levels by 2.8% per year.
Several physical and phenotypical changes in The sperm production does not appear to change
body function in aging men are similar to the clinical significantly with age. However, there is a small decline
picture seen in hypogonadism suggesting that these in the size of testes with age. There is a small increase in
changes could be because of testosterone deficiency. the level of gonadotropins, follicle stimulating hormone
However, whether these changes could be reversed with (FSH) rises more than luteinizing hormone (LH), but
testosterone supplementation and the long term safety of the change is not so large as one would expect from
testosterone at this age are not clearly answered. the decrease in testosterone, suggesting a role of both
primary and secondary hypogonadism contributing to a
CHANGES IN REPRODUCTIVE fall in serum testosterone.4
HORMONES WITH AGE
Several cross sectional and longitudinal studies have EFFECTS OF DECREASE IN
shown a decrease in serum testosterone concentration, TESTOSTERONE
an increase in sex hormone binding globulin (SHBG), Several changes taking place in parallel with a decrease
and a decrease in free testosterone with aging. in serum testosterone are observed suggesting a possible
The European Male Aging Study (EMAS), the largest causal relationship of these changes to falling levels of
cross sectional study to date, showed a decline of serum serum testosterone.
total testosterone concentration by 0.4 percent a year and The sexual symptoms (poor morning erection,
so a large number of older men have testosterone level decrease in libido, and erectile dysfunction) are
sufficiently low to be considered hypogonadal in young significantly correlated with a decline in serum
men.1 testosterone with aging.
CHAPTER 57: A New Look at Testosterone Therapy in Aging Males 345
With the advancing age, there is a decrease in testosterone treatment was not associated with increased
bone mineral density (BMD) and risk of bone fracture. risks of clinical cardiac events or prostate cancer, these
However, the risk of nonvertebral fracture increases in data suggested requirement of more scientific evidences
those who have low serum concentration of bioavailable to clarify these observations.8
estradiol, or free testosterone and high sex hormone
binding globulin (SHBG) concentration. SUGGESTED APPROACH
There is decline in muscle mass and increase in fat If men presents with suggestive symptoms of testosterone
mass with increasing age. In hypogonadal males, these deficiency such as decreased libido, energy, or mood, or
changes are reversed with testosterone replacement. osteoporosis or anemia, measure serum total testosterone
Some studies have shown improvement in several in the morning. If it is below 300 ng/dL, measure it twice
group of muscles with testosterone therapy in hypo since testosterone concentration fluctuate.
gonadal males but the effect in elderly males with Free testosterone should be measured only in obese
low testosterone have not been consistent. Similarly subjects.
inconsistent improvement in mood and cognitive function If the total serum testosterone is found to be less than
have been reported with testosterone replacement in 200 ng/dL, evaluate for known causes of hypogonadism.
elderly patients with low serum testosterone. Testosterone Consider treatment only in those who have been
treatment improves hemoglobin level in this population. documented to have consistently low testosterone in the
morning sample and after having a clear discussion and
Does a State of Hypogonadism explanation to the patients of potential benefits and risk
in Older Men Exist? of the therapy.
The studies have shown that a small population of elderly If the decision is made to treat an older men with
men shows clinical manifestations of hypogonadism, like testosterone, the target serum concentration should be
symptoms of sexual dysfunction, low muscle mass, bone lower than that for younger men, for example 300 to 400
density, energy, anemia, and impaired glucose tolerance. ng/dL, rather than 500 to 600 ng/dL, to minimize the
These features are more frequent in those with lower potential risk of testosterone dependent diseases.9
serum testosterone.5-7 Before initiating treatment a thorough evaluation
be done to rule out testosterone dependent conditions
Status of Testosterone Administration like sleep apnea, abnormally low HDL, marked benign
Although clinical observations suggest a relation prostate hyperplasia and prostate cancer. A digital rectal
of declining testosterone with age and its adverse examination should be performed and serum prostate
consequences, the effect of testosterone replacement in specific antigen (PSA) be ensured. If a nodule is detected
older men with low serum testosterone and hypogonadal or serum PSA is found to be raised, appropriate urology
symptoms has been unclear. evaluation should be undertaken periodic monitoring
A recent multicenter testosterone trial enrolling 790 like blood counts, lipid profile, digital rectal examination
men who were given testosterone gel therapy over one and serum PSA be carried out.
year confirmed that testosterone treatment of older men
with unequivocally low testosterone levels is efficacious SUMMARY
in improving sexual function, walking, mood, depressive Serum testosterone concentration decline with
symptoms, anemia, and bone density, all to a modest increasing age and free testosterone concentrations
degree. Testosterone treatment, however, did not fall even more. This decline might have adverse
improve vitality or cognition and was associated with consequences on energy, sexual function, muscle
an increase in coronary artery plaque volume. Although mass and strength, erythropoiesis, and bone.
Conditions which are known to decrease serum REFERENCES

testosterone like obesity and diabetes mellitus should 1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone
be evaluated and appropriately managed. therapy in men with androgen deficiency syndromes:
Aging men with established low serum testosterone an Endocrine Society clinical practice guideline. J Clin
Endocrinol Metab. 2010;95:2536.
level (below 200 ng/dL) should be evaluated to rule
2. Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone
out other causes for it as is recommended for a young
treatment and coronary artery plaque volume in older men
men with hypogonadism. with low testosterone. JAMA. 2017;317:708.
In the absence of known causes of hypogonadism, 3. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al.
consider testosterone thereby in only those with Testosterone treatment and sexual function in older men
unequivocally low serum testosterone concentration with low testosterone levels. J Clin Endocrinol Metab.
2016;101:3096.
(<200 ng/dL) associated with suggestive symptoms
4. Feldman HA, Longcope C, Derby CA, et al. Age trends in the
and only after conveying to the patients about the
level of serum testosterone and other hormones in middle-
potential risks and benefits of this therapy. aged men: longitudinal results from the Massachusetts
To minimize the potential risk of testosterone therapy male aging study. J Clin Endocrinol Metab. 2002;87:589.
the target range of serum testosterone be lower than 5. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects
that for younger men (300–400 ng/dL). of aging on serum total and free testosterone levels in
healthy men. Baltimore Longitudinal Study of Aging. J Clin
Before initiating testosterone treatment to older
men a thorough risk evaluation be undertaken
6. Nguyen CP, Hirsch MS, Moeny D, et al. Testosterone and
to screen for testosterone dependent diseases. A “Age-Related Hypogonadism”--FDA Concerns. N Engl J Med.
digital rectal examination should be performed and 2015;373:689.
serum prostate specific antigen (PSA) measured 7. Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al.
before initiating treatment, at 3 monthly interval and Testosterone treatment and cognitive function in older
men with low testosterone and age-associated memory
annually thereafter.10
impairment. JAMA. 2017;317:717.
After initiating treatment, the outcomes for success
8. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of
of therapy be assessed. If the symptoms or condition testosterone treatment in older men. N Engl J Med.
that led to measuring testosterone is not corrected in 2016;374:611.
the expected period of time (symptom relief in few 9. Tajar A, Huhtaniemi IT, O’Neill TW, et al. Characteristics of
month and improvement in bone mineral density androgen deficiency in late-onset hypogonadism: results
from the European Male Aging Study (EMAS). J Clin
(BMD) in two years), consider discontinuing the
treatment.
10. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset
The potential risk of testosterone therapy on hypogonadism in middle-aged and elderly men. N Engl J
cardiovascular complication remain unclear, more Med. 2010;363:123.
data and research is required.11 11. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-
testicular axis disruptions in older men are differentially
linked to age and modifiable risk factors: the European
Male Aging Study. J Clin Endocrinol Metab. 2008;93:2737.
CHAPTER
58
Lipohypertrophy Secondary to Insulin
Injection Therapy
Sunil Gupta
INTRODUCTION using insulin for more than six months as 77.4% and 36%
Insulin is the only treatment for people with type 1 respectively.
diabetes and most of the person with type 2 diabetes
sooner or later in their life needs insulin therapy for DEFINITION OF LIPOHYPERTROPHY
control of hyperglycemia. Weight gain and hypoglycemia Lipohypertrophy is a thickened ‘rubbery’ tissue
are two commonly discussed complications of insulin. swelling which is usually firm but may sometimes
Insulin injection therapy is also associated with few of the present as a soft lesion, and thus it may easily be missed
common but less addressed skin related complications, during a standard clinical medical examination2.
such as lipoatrophy, lipohypertrophy, insulin edema
or allergy. Lipohypertrophy (LH) is the one of the most CAUSES OF LIPOHYPERTROPHY
common cutaneous complication amongst them which The exact etiology of LH is not known. Studies have
is characterized by a tumor-like swelling of fatty tissue at observed several local factors, which may play an
the subcutaneous area in insulin injection sites.1 important role in causation of LH. Insulin molecule has a
strong growth-promoting properties and repeated trauma
PREVALENCE due to poor injection practices, such as infrequent/
The reported prevalence of LH in patients receiving missed injection site rotation, repeated injections at the
insulin injections varies widely in published studies, same site and/or frequent reuse of needle. As LH areas
possibly due to the lack of a well-structured diagnostic are relatively painless, patients tend to inject at the same
flow-chart. Fujikura J et al1 reported LH prevalence as site repeatedly rather than moving to a new injection site
29% in people with type 1 diabetes, while Vardar and which may be little painful. Other possible risk factors
Kizilci2 found it to be 48.8% in 215 Turkish patients who in type1 DM is longer duration of insulin therapy, and
had been using insulin for at least 2 years. Similarly, high number of insulin injections per day. The risk of
Seyoum and Abdulkadir 3 found 31% of 100 insulin LH significant increases if the needle is being used for
injectors in Ethiopia to have LH, while Hauner et al4 more than five times. Development of insulin antibodies
reported that 28.7% of 233 German T1D patients had the is also suggested as a possible underlying mechanism.
condition. The prevalence of LH was found to be 76.4% in LH is thought to be the direct anabolic effect of insulin
T1DM as noted by M. Blanco.5 Indian study6 has shown on local skin leading to fat and protein synthesis.
the prevalence of LH amongst type 1diabetics and T2 DM However, a large body of evidence also lends support
to a significant association between LH and many other increases. This imposes an extra economic burden of
factors, including female sex, low socioeconomic level, the disease for both patients and the healthcare system.
high body mass index, as well as long-standing disease Therefore, it is crucial to identify LH so as to educate
and/or insulin treatment.7 patients on good insulin injection habits. Hence, the
diagnosis of LH at all insulin injection sites should be
DIAGNOSIS implemented.7
Clinical Findings Blanco et al 5 in their study on 430 subjects those
Lipohypertrophy usually present as soft dermal nodules were injecting insulin. They filled a detail questionnaire
like lipomas or fibrocollagenous scar in subcutaneous regarding their insulin injection technique. The study
tissue and can vary in size from golf balls to an orange. was to assess the frequency of lipohypertrophy (LH) and
If large areas are involved, then the appearance can be its relationship to site rotation, needle reuse, glucose
unsightly. Initial skin changes can be subtle and manifest variability, hypoglycemia and use of insulin. 64.4% of
only as thickening of skin. This can be easily missed by studied subjects (Both T1DM and T2DM) had LH. He
visual inspection and so areas should be palpated. It is showed a strong relationship between the presence of LH
recommended that, in order to feel subtle skin thickening, and nonrotation of sites. More so, he demonstrated that
the hand should be stroked firmly in a sweeping motion correct rotation technique have the strongest protective
rather than using traditional techniques of light and deep value against LH. Of the patients who correctly rotated
palpation. LH is most commonly seen on either side of sites, only 5% had LH while, of the patients with LH, 98%
the umbilicus and mid thigh as these are commonly used either did not rotate sites or rotated incorrectly. Also,
sites for injection and are easily reached and convenient 39.1% of patients with LH had unexplained hypoglycemia
for patients. and 49.1% had glycemic variability compared with only
5.9% and 6.5%, respectively, in those without LH. The
CLINICAL CONSEQUENCES OF LH risk increased significantly when needles were used
LIPOHYPERTROPHY > 5 times. Total daily insulin doses for patients with and
A missed diagnosis of LH may have major clinical without LH averaged 56 and 41 IU/day, respectively.
consequences. In ultrasound examination, these lesions appeared as
homogeneous hyperechogenic densities filling part or
Glycemic Oscillations all of the SC tissue at injection sites, and could clearly be
The injection of insulin into LH may cause wide glycemic distinguished from adjacent normal subcutaneous tissue.
variability, including inappropriately high glucose levels Correct injection site rotation appears to be the critical
and a high rate of unexplained hypoglycemic episodes. in preventing LH and associated glycemic variability,
Thus patient may require large frequent changes in unexplained hypoglycemia, insulin consumption and
insulin doses. Proper insulin injection techniques the costs (Tables 1 and 2).5
related education programs aimed specifically for people
with LH have proven to be effective and have shown Bruising
significant reduction in glucose oscillations.7 Bruising is another complication of insulin injection-
Most studies suggest that insulin absorption at areas related skin lesions at the injection site. Bruising disturbs
affected by LH may be both delayed and erratic, leading to diabetic patients due to the resulting blemishes, for which
increase in doses of insulin and deteriorating metabolic there are as yet no solutions. Unfortunately, injection-
control. This causes undesirable glucose fluctuations related problems negatively affect the overall compliance
causing serious hypoglycemic episodes. Similarly, of diabetic patients for insulin therapy. It is important
whenever patients suddenly switch from affected to note that injection site-related adverse events, such
injection sites to normal ones, risk of hypoglycemia as pain, redness, bruising, and bleeding, are significant
CHAPTER 58: Lipohypertrophy Secondary to Insulin Injection Therapy 349
TABLE 1: Data for patient according to diabetes (DM) type and presence of lipohypertrophy (LH)5
Total T1D T2D LH present LH absent
Patient (n) 430 177 253 277 153
Gender (M/F) 221/202 89/86 132/116 142/130 79/72
Age (years, mean ±SD ) 49 ± 22.8 41 ± 23.2 55 ± 20.7 47 ± 23.8 54 ± 20.1
Since DM diagnosis (years, range) 6–15 6–15 6–15 6–15 6–15
(% in range) (43.7) (39.0) (47.0) (41.2) (48.4)
Insulin treatment (years, range) 1–5 6–13 1-5 6–13 1–5
(% in range) (44.2) (37.3) (54.9) (35.0) (64.1)
Frequent unexplained HG (n) 117 71 46 108 9
(%) (27) (40) (18) (39) (6)
Glycemic variability (n) 146 89 57 136 10
(%) (34) (50) (23) (49) (7)
TABLE 2: Data for diabetes patient according to injection site rotation and needle reuse5
Total Site rotation Needle reuse
None or Claimed and Never reuse Reuse at least
incorrect correct once
Patient (n) 430 288 100 190 240
Gender (M/F) 221/202 141/142 56/43 102/87 119/115
Age (years, mean ± SD ) 49 ± 22.8 47 ± 23.7 50 ± 21.5 47 ± 24.2 50 ± 21.6
Since DM diagnosis (years, range) 6–15 6–15 6–15 6–15 6–15
(% in range) (43.7) (44.1) (48.0) (46.8) (41.3)
Insulin treatment (years, range) 1–5 6–13 1–5 1–5 1–5
Reuse needle (at least once. n) 240 172 33 190 240
(%) (56) (60) (33) (0) (100)
Rotation claimed (n) 287 145 100 143 144
(%) (67) (50) (100) (75) (60)
Rotation correct (n) 106 6 100 69 37
(%) (25) (2) (100) (36) (15)
Rotation claimed and correct (n) 100 288 100 67 33
(%) (23) (0) (100) (35) (14)
Rotation correct and no reuse (n) 69 2 67 69 37
(%) (16) (1) (67) (100) (0)
Presence of lipohypertrophy (n) 277 264 5 109 168
(%) (64) (92) (5) (57) (70)
Skin cleansed with antiseptic (n) 69 50 12 30 39
(%) (16) (17) (12) (16) (16)
Frequent unexplained HG (n) 117 104 5 37 80
(%) (27) (36) (5) (19) (33)
Glycaemic variability (n) 146 134 7 55 91
(%) (34) (47) (7) (29) (38)
barriers to patient adherence to treatment regimens injection technique (IT). The nurse then examined the
involving multiple daily injections. Surprisingly, in few patient’s injection sites for the presence of LH, followed
of the studies one-half of the patients reported that by an individualized training session in which sub-
injection-related problems are due to their healthcare optimal IT practices highlighted in the questionnaire
providers who were unable to resolve the associated were addressed. All patients were taught to rotate sites
pain and bruising.7 Thus, it is important that physicians correctly to avoid LH and were begun on 4 mm pen
and/or healthcare providers should have sufficient needles to avoid intramuscular (IM) injections. They
experience, training and should possess sufficient
were instructed not to reuse needles. The purpose of the
knowledge to provide assistance to all patients taking
study was to assess whether proper injection technique
insulin therapy.7
(IT) is associated with improved glucose control over a
Glucose Control three-month period. Nearly 49% of patients were found
During the visit of insulin-injecting patients in clinician’s to have LH at study entry. After three months, patients
chamber, most of the discussions goes for blood glucose had mean reductions in HbA1c of -0.58% (0.50–0.66%,
control and dose adjustments, while very little time is 95% CI), in fasting blood glucose of -14 mg/dL (10.2–17.8
spent on improving Injection Technique (IT). However, mg/dL, 95% CI) and in total daily insulin dose of -2.0
IT may in certain cases be just as important to diabetes IU (1.4–2.5 IU, 95% CI) all with p < 0.05. 7 Follow-up
management as the type of insulin or dosage used.8 questionnaires showed that significant numbers of
In a cross-sectional study, conducted on 174 patients patients acknowledged the implication of IT and were
with T1DM (aged 13–18 years) taking multiple daily executing the injection technique more correctly.
insulin injections for a minimum duration of 1 year, it was Most of them found the 4 mm needle more convenient
shown that nearly 46% of patients were found to reuse
and comfortable. The study concluded that targeted
needles, while 42.5% failed to rotate the injection site and
individualized training in IT is associated with improved
23% revealed unexplained hypoglycemic events. 47%
glycemic control, better satisfaction with therapy,
of patients showed grade 1 LH, followed by 33.7% with
improved and simpler injection practices and possibly
grade 2 and 19.3% with grade 3 LH. A higher frequency of
lower consumption of insulin after a 3-month period.8
LH was observed in the thigh region (n = 28, 33.7%) than
in the arm (n = 23, 27.7%). People with uncontrolled DM
had a greater likelihood of having LH (59.5%) than those
with controlled diabetes (20.8%). Significant differences
in LH were observed based on needle length, needle
reuse, and rotation of the injection sites.9
MANAGEMENT (FIGS 1A AND B)

It is important that complications of lipohypertrophy are
recognized and managed appropriately.
Proper Insulin Injection Technique

Awareness of proper insulin injection technique is
important. In an Italian multicentric study amongst 346 A B
people with diabetes who had been injecting insulin Figs 1A and B: (A) Insulin injection induced lipohypertrophy on
for four years answered a questionnaire about their abdomen; (B) Insulin injection induced lipohypertrophy on thigh
CHAPTER 58: Lipohypertrophy Secondary to Insulin Injection Therapy 351
Clinical Pearls but precautions may be recommended for all other

Individuals on insulin therapy should also be trained subcutaneously injected drugs as well. In particular, local
to examine their own injection sites and how to detect damage may be minimized through the use of very short
LH. and thin needles and a careful injection site rotation
They should be counseled not to inject into areas of method. Insulin has a much higher chance to penetrate
LH until abnormal tissue returns to normal, which into the subcutaneous muscle tissue when injected
will take several months or even years. into areas thus eventually causing more hypoglycemic
While switching injections from LH areas to normal events as observed with LH. Prevention of wide glycemic
tissue often requires a decrease in the dose of insulin variations and the risk of unexplained hypoglycemia is
injected. This amount of change varies from one primarily based on patient education with respect to the
person to another and should be guided by frequent need for regular injection site rotation and avoidance of
blood glucose monitoring. areas affected by LH. Patients be educated so as to be
The best current preventative and therapeutic able to identify LH themselves in order to avoid damaged
strategies for LH include proper rotation of injection areas as much as possible.
sites with each injection and nonreuse of needles.
Patients should be taught self examination for early REFERENCES
recognition of skin changes and to avoid these areas. 1. Fujikura J, et al. Insulin induced Lipohypertrophy: Report
of a case with Histopathology. Endocrine Journal.
Changing insulin to rapid acting humanized insulin
2005;52(5):623-8.
has been shown to decrease this side effect as
2. Vardar B, Kizilci S. Incidence of lipohypertrophy in diabetic
adipocytes are in contact with insulin for short periods patients and a study of influencing factors. Diabetes Res
and thus local lipogenic effects are minimized. Clin Pract. 2007;77:231-6.
If conservative steps fail, then liposuction is an 3. Seyoum B, Abdulkadir J. Systematic inspection of insulin
effective alternative. injection sites for local complications related to incorrect
Switching to continuous subcutaneous insulin injection technique. Trop Doct. 1996;26:159-61.
4. Hauner H, Stockamp B, Haaster t B. Prevalence of
infusion and/or short acting insulin analogues are
lipohypertrophy in insulin-treated diabetic patients and
alternative methods. predisposing factors. Exp Clin Endocrinol Diabetes.
These lesions can sometimes spontaneously regress. 1996;104:106–10.
5. M. Blanco, et al. Prevalence and risk factors of
CONCLUSION lipohypertrophy in insulin-injecting patientswith diabetes.
In conclusion, even today little information is available Diabetes & Metabolism. 2013;39:44-53.
6. Gupta K, Gupta S, Fulwani M. Hospital based prevalence
on possible clinical consequences of local injection-
of lipohypertrophy in type 1 DM and type 2 DM on insulin
related side-effects of subcutaneous medications in therapy, poster No 631 PD, Poster Discussion, Vancouver,
diabetes. Screening of LH by examination of injection site IDF Dec 2015.
during all hospital visits should be implemented in all 7. Gentile E, et al. Lipodystrophy in insulin-treated subjects and
patients taking insulin therapy. The treatment of insulin- other injection-site skin reactions: Are we sure everything is
induced lipohypertrophy is to change injection sites with clear? Diabetes Ther. 2016;7:401-9.
8. Grassi G, et al. Optimizing insulin injection technique and
the hope that regression will occur. However when the
its effect on blood glucose control. Journal of Clinical &
excessive fat tissue does not decrease, an invasive surgical
Translational Endocrinology. 2014;1:145e150.
procedure may be done for cosmetic reason. Based on 9. Al Hayek A, et al. Frequency of lipohypertrophy and associated
the available evidences, multiple insulin injections at the risk factors in young patients with type 1 diabetes: A cross-
same site may be associated to LH and other skin lesions sectional study. Diabetes Ther. 2016l7:259-67.
SECTION
5
Neurology
Headache: Headache for Physician Changing Scenario in Management
Gurubax Singh of Status Epilepticus
Rajesh Shankar Iyer
Approach to Multiple Cranial Nerve Palsy
K Mugundhan Present Status of Thrombolysis in Acute Ischemic
Stroke: Indian Scenario
Nocturia: Evaluation and Management
V Shankar
Anish Kumar Gupta
Immunomodulation in Neurological Disorders
Neuromyelitis Optica: A Physician’s Perspective
Vertigo: Clinical Approach and Management
First Seizure: Should or Should not be Treated?
Lakshmi Narasimhan Ranganathan, Thamil Pavai N,
PK Maheshwari, A Pandey, Akhilesh Kumar Singh Guhan R, Arun Shivaraman MM, Mugundhan Krishnan
An Overview and Practical Clinical Hints in the
Diagnosis of Temporal Lobe Epilepsy
CHAPTER
59
Headache: Headache for Physician
Gurubax Singh
EVERY HEAD HAS ITS OWN HEADACHE overuse headache). So we would deal with these
An old Arabian proverb sums it all. Headache is one of the problems one by one.
Challenges in the headache:
common complaints in the primary outpatient setting
—— First severe headache
and if not correctly diagnosed and treated, may indeed
—— Chronic daily headache/Medication overuse
become a headache for the physicians. Newer insights
into the pathophysiology and treatment necessitate the headache
—— Headache in pregnancy
physician to be aware of the different types of headaches
—— Headache in elderly
so that a proper treatment protocol is initiated. One
—— Headache with comorbidities
needs to understand that cure rate for headache is not
—— Status migranosus
100% and a large number of patients have psychiatric
—— Menstrual migraine
comorbidity.
To make it easier to manage the headache patients,
ICHD came up with a classification system to bring FIRST SEVERE HEADACHE
uniformity in coding and choice of treatment plan. Although majority of patients coming to outpatient
However, the diagnostic criteria might be useful for setting would have a prior headache history but with
research purpose but would pose a challenge in the ease of availability of medical facilities, patients present
outpatient practice. Even the ICHD beta version early to the medical facility even when they have their
specialists do not expect the general practitioners to first headache. The purpose of the evaluation is to
remember it by heart but to use it as a guiding tool. Since correctly diagnose the type of headache
a large number of headaches would be treated initially to screen for potential secondary causes
by a general physician and not a headache specialist, to look for red flag signs
this article would focus on the main challenges faced The history and examination is of paramount
by a physician in the outpatient or emergency setting. importance in leading to a correct diagnosis in majority
Such problems if not treated appropriately in the nascent of patients. First ever headache in general requires
stage would lead to bigger therapeutic dilemmas later investigations to rule out secondary causes. However, the
on (especially chronic daily headache and medication cost and constraints of availability may limit investigating
356 SECTION 5: Neurology
all the patients. However, there are certain subsets of need to be taken into confidence and psychiatric
patients when investigations need to be emphasized. comorbidities need to be looked into. Patient should
These groups are have a sleep hygiene improvement, detoxification
first or worst headache of life (withdrawl of offending overuse drug), a proper diet plan
progressively worsening headache and prevention of dietary and environmental triggers.
age more than 50 years The patient needs to understand that there might be
atypical history for a primary headache worsening of the headache severity and frequency
headache getting worsened with cough, sneezing, initially but withdrawl of overuse drugs would pay
valsalva maneuvers dividends in the long run. Regular exercises (especially
s p e c i a l m e d i c a l c o n d i t i o n s ( p a t i e n t o n low load cervical exercises) and acupuncture may
anticoagulation, contraceptives, recent head trauma) also help in the treatment program. Biofeedback and
thunderclap headache (headache reaching peak relaxation techniques would help in improvement in
within one minute) quality of life indices. Certain prophylactic drugs such as
autonomic symptoms (all autonomic cephalalgias gabapentine, divalproex and Topiramate have efficacy in
need exclusion of a secondary cause) reducing the headache frequency. Beta blockers efficacy
associated signs (fever, neck stiffness, autonomic is uncertain. Botulinum toxin and use of occipital nerve
symptoms, unilateral Horner’s) stimulation have shown promising results. Recently, a
short neck (for craniovertebral junctional anomalies, portable external trigeminal nerve stimulator (CEFALY)
Arnold Chiari malformation) has shown good results in chronic migraine.
Asymmetric pulses
Tender temporal artery Headache in Pregnancy

Unilateral soft pyramidal signs Headache in pregnancy poses special therapeutic
The patient needs a symptomatic treatment, challenge due to limitation of studies on available
reassurance if it appears to be benign and evaluation remedial options. The frequency of headache may alter
and referral to higher center if secondary cause variably during pregnancy although in migraineurs,
(like subarachnoid hemorrhage or cerebral venous overall the frequency reduces. The fear of teratogenicity
thrombosis is suspected). Pituitary lesions might be is overwhelming both in the patient’s and physician’s
missed on routine evaluation. Hence, a thorough clinical mindset. There is a TERIS (teratogen information system;
examination comes handy in minimizing the chances of with categorization of risk as undetermined, none, none
misdiagnosis. Also patients and the caregivers need to to minimal, minimal, minimal to small and high) to judge
be taken into confidence if investigations are not being the propensity of the drug to cause fetal malformation
undertaken. in addition to the FDA categorization (A, B, C, D or X)
in descending order of safety. ACETAMENOPHEN is
CHRONIC DAILY HEADACHE category B and is one of the safest options. NSAIDs are
A headache which occurs on 15 days or more per month category B but should be avoided in the third trimester
for at least three months is defined as chronic daily due to potential effects on labor and amniotic fluid
headache. Investigations are required if you notice an volume. Among the prophylactic drugs, beta blockers,
abnormal clinical finding or a change in the type of calcium channel blockers, gabapentine, SSRIs are
headache. Majority of these are attributable to either a category C while amitriptyline and nortriptyline are
medication overuse and/or incorrect use of medicines. category D. Ergotamine, valproic acid and lithium are
Abortive drugs (like triptans and NSAIDs) are the most category X and are contraindicated. Non pharmacologic
frequent culprits. Nonpharmacologic therapies are measures (like biofeedback, relaxation therapy, local
crucial in the management of such patients. Patients heat or ice) may be helpful. Other options include
CHAPTER 59: Headache: Headache for Physician 357
antiemetics (prochlorperazine, metoclopramide), low Rule out secondary or complicating factors (fever,
dose corticosteroids and NSAIDs. Only prophylactic neck stiffness)
agents which may be used are low dose propranolol and Since sleep disruption and dehydration frequently
probably gabapentine. perpetuate the headache, hydration and sleep aids
may help. Intravenous antiemetics and sumatriptan
HEADACHE IN ELDERLY may help if not already given. The analgesic abuse
In elderly, one needs to understand that the pattern of requires detoxification process by withdrawl and
headache might be different and that the secondary substitution with alternate drug; and/or initiation of
causes are to be particularly looked for. Also, certain appropriate prophylactic therapy
headache types are unique to elderly (e.g. temporal If patient continues to have headache, intravenous
arteritis, hypnic headache, TIAs masquerading as aura valproate or a short term course of steroids
or headache). Also, comorbid illnesses and change (prednisolone or dexamethasone) may help.
in the hepatic function may require a modification of
the dosages of drugs. Migraine in elderly may appear
MENSTRUAL MIGRAINE
with visual or sensory symptoms without headache Large numbers of women report an association between
(migraine accompaniments). Tension type headache is migraine and menstrual periods. Menstrual migraine
could be pure menstrual migraine (that occurring only
more frequently seen than in younger age group. Hypnic
during menstruation, i.e. 1+/–2 days of menstruation, and
headaches occur only in elderly and awaken patients
at no other times of cycle. The first day of menstruation
from sleep. Medication used for comorbid illnesses
is day 1 and the preceding day is –1. By definition, no
(like nitroglycerine for CAD) should be screened as
day zero exists) or menstrually related migraine in which
a cause of headache. One needs to rule out cardiac
attack occurs on days 1+/-2 of menstruation in at least 2
cephalalgias, subdural hematomas, TIAs, etc. in elderly
out of three menstrual cycles and additionally at other
with a thorough history taking and clinical examination
times of cycle. Majority of women have menstrually
(especially focal signs, temporal artery tenderness,
related migraine than pure menstrual migraine. Acute
papillary asymmetry, etc.). Poor cognitive capacity
treatment stays the same. There is an additional
may pose hindrance to accuracy of history. Hence, one
option of perimenstrual prophylaxis depending on the
should have a low threshold for investigations. Certain severity of migraine and regularity of cycles. Options
medications may not be used in elderly (e.g. triptans, include perimenstrual NSAIDs, e.g. naproxen 550 mg/
dihydroergotamines, amitryptiline). One should try to day, estradiol supplementation during luteal phase,
minimize the use of drugs for above mentioned reasons perimenstrual triptan prophylaxis and continuous
and ensure lifestyle modification and adjustment of 84/168 days of contraceptive prophylaxis for women
other drugs to an optimal level. requiring contraception. Important point to consider is
that combined hormonal contraceptive should not be
STATUS MIGRANOSUS given to women with migraine with aura due to risk of
A migraine attack lasting longer than 72 hours, regardless stroke.
of treatment, is labeled as status migranosus. It may
occur in both types of migraine (i.e. with and without HEADACHE WITH COMORBIDITIES
aura). Possible mechanism could be an inflammation of It is not unusual to have patient with migraine who
the intracranial blood vessels. For an effective treatment has other illnesses. One needs to take advantage of the
Underlying triggers or perpetuating factors should be therapeutics of the antimigraine prophylaxis to choose
looked for (sleep disruption, dehydration, overuse of the drug. Below is the table showing the choice of drugs
analgesics, anxiety) for migraine in the presence of comorbid illnesses.
TABLE 1: Contraindicated drugs for specific comorbidities BIBLIOGRAPHY

Comorbid illness Choice of drug 1. Ahmad F, Par thasarathy R, Khalil M. Chronic daily
Anxiety, tremors Beta blockers headaches. Ann Indian Acad Neurol. 2012;15(Suppl
Hypertension Beta blockers 1):S40-S50. doi 10.4103/0972-2327.100002
Sleep problems Amitryptiline 2. Ahmed F. Headache disorders: Differentiating and managing
Seizure disorder Valproate the common subtypes. Br J Pain. 2012;6(3):124-32. doi
Mood disorder Valproate 10.1177/2049463712459691
Neuropathic symptoms Gabapentine 3. Clinch RC. Evaluation of acute headaches in adults. Am Fam
Obesity Topiramate Physician. 2001;63:685-92.
Depression Amitryptiline 4. Forbes RB. Acute headache. Ulster Med J. 2014;83(1):3-9.
5. Gelfand AA, Goadsby PJ. A neurologist’s guide to acute
migraine therapy in the emergency room. Neurohospitalist.
TABLE 2: Prophylactic agents and diseases requiring caution 2012;2(2):51-9. doi:10.1177//1941874412439583.
Prophylactic agents Diseases requiring caution 6. Gilmore B, Michael M. Treatment of acute migraine
Beta blockers Asthma, oral hypoglycemic use, heart headache. Am Fam Physician. 2011;83(3):271-80.
blocks, hypotension 7. Goadsby PJ, Goldberg J, Silberstein DS. Migraine in
Tricyclics Glaucoma, cardiac arrhythmias, urinary pregnancy. BMJ. 2008;336(7659):1502-4. doi:10.1136/
retention, constipation bmj.39559.675891.AD.
Valproate Pregnancy, obesity, liver disorder, 8. Hershey LA, Berdnarczyk EM. Treatment of headache in the
pancreatitis Elderly. Curr Treat Options Neurol. 2013;15(1):56-62. doi:
Topiramate Renal stones 10.1007/s11940-012-0205-6.
Flunarizine Hypotension, sick sinus syndrome, 9. MacGregor EA . Menstrual migraine: Therapeutic
bradycardia approaches. Ther Adv Neurol Disord. 2009;2(5):327-36.
doi: 10.1177/1756285609335537
Similarly, in presence of certain comorbidities, pro- 10. Modi S, lowder DM. Medications for migraine prophylaxis.
Am Fam Physician. 2006;73:72-8, 79-80.
phylactic agents may deserve caution. Table 1 depicts
11. Morey SS. Guidelines on migraine: part 3. Recommendations
the relatively contraindicated drugs for specific for Individual Drugs. Am Fam Physician. 2000;62(9):2145-
comorbidities. 8, 2151.
Hence, a judicious choice of prophylaxis would 12. Pfaffenrath V, Rehm M. Migraine in pregnancy: What are the
optimize the outcome with minimum of drugs (Table 2). safest treatment options? Drugs Saf. 1998;19(5):383-8.
To conclude, headache management is much more 13. Silberstein SD. Preventive migraine treatment. Continuum
(Minneap Minn). 2015;21(4 Headache):973-89. doi:
than a prescription of analgesics. A thorough assessment
10.1212/CON.0000000000000199.
would avoid failure in treatment and a satisfaction to 14. Weatherall MW. The diagnosis and treatment of chronic
physician. Migraine. Ther Adv Chronic Dis. 2015;6(3):115-23. Doi:
“He Who Comforts Never Has A Headache” 10.1177/2040622315579627.
(Danish Proverb)
CHAPTER
60
Approach to Multiple Cranial Nerve Palsy
K Mugundhan
INTRODUCTION Asymmetrical involvement

Multiple cranial neuropathies are common entity in Sequential involvement of cranial nerves
Simultaneous involvement of 2 distal cranial
neurologic practice. Diagnosis and evaluation of these
patients is difficult because of various etiologies and very nerve (e.g. III and XII cranial nerve) indicates a
poor outcome. They pass through different structures diffuse neoplastic extrinsic brainstem lesion like
of cranium and superficial soft tissue, meninges and nasopharyngeal carcinoma
subarachnoid space. Cranial nerves can be affected in More likely to cause erosion of bone or enlargement
their course and present as single cranial neuropathy of foramina of exit of various cranial nerves.
or multiple cranial neuropathies. The complete work Features favoring INTRINSIC lesion (within the
up to reach a conclusion while dealing with cranial brainstem)
neuropathiesis a difficult task and a real challenge for Symmetric or asymmetrical
the treating physician. Correct localization is the initial Simultaneous involvement of multiple cranial nerves
step in the diagnosis. Multiple cranial nerves get involved Early involvement of motor neuronal and long
during their intramedullary or extramedullary course. sensory pathways

Chronic meningitis is one of the common causes of Crossed paralysis involving cranial nerves on one
multiple cranial neuropathies.1 side and sensory motor involvement on opposite side
Horner’s syndrome, internuclear ophthalmoplegia
INTRINSIC VS EXTRINSIC Vertigo, gait unsteadiness, ataxia, discoordination,
BRAINSTEM LESIONS nausea, and vomiting may be present due to rich

A history aimed at eliciting these symptoms and a vestibular and cerebellar connections.
careful complete neurologic examination looking for
the associated signs is necessary to localize a process to
Causes of Extramedullary Multiple Cranial
the brainstem.Majority of brainstem syndromes are a
result of vascular insults, mainly brainstem infarctions
Nerve Palsy
and hemorrhages, often involving the lateral pons and Carcinomatous and lymphomatous meningitis,
medulla. idiopathic pachymeningitis
Features favoring EXTRINSIC lesion (outside the Metastasis of solid tumor or lymphomatous in
brainstem) filtration
Local spread from nasopharyngeal tumor, chordoma, common cause of cavernous sinus syndrome are
sarcoma tumors. These may be metastatic disease, a result of
Trauma, carotid artery dissection, jugular vein local tumor extension (nasopharyngeal carcinoma,
thrombosis pituitary adenoma or craniopharyngioma) or a primary
Paget disease, basilar invagination, Arnold-chiari and tumor (meningioma, lymphoma). The other causes are
bony disorders sarcoidosis, Wegener’s granulomatosis, or polyarteritis
Perineural invasion of spindle cell, basal cell, parotid nodosa. Painful ophthalmoplegia is the most common
and squamous cell cancer clinical feature of Tolosa-Hunt syndrome which is an
Granulomas and infectious diseases (sarcoid, idiopathic inflammatory granulomatous disease and
Wegener granulomatosis, Lyme disease, CMV) the most common cause of cavernous sinus syndrome
(Table 1). Spontaneous remission occurs in up to a third
Herpes zoster and other viral and postinfectious
of patients. The good response to steroids is one of the
inflammatory lesions
diagnostic clues.
Mixed connective tissue disease
An anterior cavernous sinus syndrome causes
Tolosa-Hunt-like syndrome, Melkersson Rosenthal
involvement of III, IV and VI cranial nerves along with
syndrome
involvement of ophthalmic division of Vth cranial nerve.
The III, IV, VI cranial nerve involvement with proptosis
Localizing the Site of Lesion suggest superior orbital fissure syndrome. Orbital apex
As the cavernous sinus lies within a dural envelope that syndrome involves optic nerve and III, IV, V and VIth
funnels the upper cranial nerves to the orbit, even a cranial nerves. Middle and posterior cavernous sinus
small lesion can produce multiple cranial neuropathy.3 syndromes are considered if V2 and V3 are involved
Common causes of cavernous sinus involvement can simultaneously. All three divisions of trigeminal nerve
be divided into vascular, neoplastic, inflammatory, and are likely to be affected in parasellar lesions. Involvement
miscellaneous disorders. Cavernous sinus thrombosis of VII and VIII along with or without VI suggests a
usually results from paranasal sinus infections, orbital cerebellopontine angle lesion. Unilateral caudal cranial
cellulitis, or a facial infection. Staphylococcus is the nerve involvement suggests a jugular foramen syndrome
most common causative organism. In diabetics, of the affected side and diseases of intracranial and
mucormycosis is of particular concern. The most extracranial structures of the base of the skull.
TABLE 1: Sites of lesion

Site CN involved Syndromes Causes
Sphenoidal fissure 3, 4, ophthalmic, 5, 6 Foix Invasive tumors of sphenoid bone, aneurysms
Lateral wall of cavernous sinus 3, 4, ophthalmic Tolosa-Hunt Aneurysms, granulomas, cavernous sinus thrombosis, tumors
of sinuses and sella turcica
Retrosphenoidal space fossa 2, 3, 4, 5, 6 Jaccoud Large tumors of middle cranial
Apex of petrous bone 5, 6 Gradenigo Petrositis, tumors of petrous bone
Pontocerebellar angle 5, 7, 8 and sometimes 9 CP angle lesion Acoustic neuromas, meningiomas
Jugular foramen 9, 10, 11 Vernet Tumors and aneurysms
Posterior laterocondylar space 9, 10, 11, 12 Collet-sicard Carotid artery dissection. Granulomatous lesions. Parotid
tumors, carotid body tumor
Posterior retroparotid space 9, 10, 11, 12 and Homer Villaret Tumors of parotid gland, carotid body; carotid artery
syndrome dissection. Granulomatous lesions
Posterior retroparotid space 10, 12 with or without 11 Tapia Neck injuries, parotid gland tumors
CHAPTER 60: Approach to Multiple Cranial Nerve Palsy 361
Other causes of multiple cranial nerve cranial nerve Cerebrospinal Fluid

involvement include Guillain-Barré syndrome, Miller- Cell count and differential
fisher syndrome2, GBS variant, diphtheria, HIV, Lyme Glucose and protein
disease, sarcoidosis, and certain chemotherapeutic Bacterial and fungal culture
agents. Idiopathic cranial polyneuropathy syndrome Cytology
starts with retroorbital, facial pain along with III, Flow cytometry
IV, VI and Vth cranial nerve palsie sand subsequent
involvement of the lower cranial nerves.3 PCR Studies
Lyme
Intermediate Syndrome Cmv
Neurotoxic effects of organophosphorus insecticide may Ebv
cause palatal, facial and extraocular muscle dysfunction Mycobacterium tuberculosis
and usually occur 12–96 hours after exposure.4,5
VDRL
Diagnosis Cryptococcal antigen
A careful evaluation for primary site of malignancy Histoplasma antigen
especially nasopharynx and any source of possible Angiotensin converting enzyme
intracranial infection leading to meningitis is required. Acid fast bacilli stain and culture
The first line tests include a complete blood count,
ESR, biochemistry and CSF examination. X-ray skull, Antibodies
cranial CT and MRI are adjunctive options. In patients Coccidiomycosis
with external ophthalmoplegia, neuro imaging should Blastomycosis
focus on the cavernous sinus, superior orbital fissure Aspergillosis
and orbital apex. Aneurysms are excluded by cerebral
Candida
angiography. Neurolymphomatosis is confirmed by
Other Studies
leptomeningeal biopsy.
MRI brain with contrast, MR angiography and
List of Investigations in Multiple CT angiography
CT head/sinuses/orbits
Cranial Palsy

Chest X-ray
Blood Imaging of chest, abdominal or pelvis
Complete blood count and differential Biopsy of lymph node or tissue
Biochemistry panel Meningeal biopsy
Erthrocyte sedimentation rate
C-reative protein CONCLUSION
Antinuclear antibody An accurate diagnosis of multiple cranial palsy
Extractable nuclear antibody poses a clinical challenge to the physician. Rare
Antineutrophilic cytoplasmic antibodies diagnoses such as leptomeningeal carcinomatosis
Rheumatoid factor and neurolymphomatosis must be considered in
Angiotensin converting enzyme undiagnosed cases. If nonspecific inflammation is
Lyme antibody suspected, a brief course of steroids may be effective.
FTA Other treatment is generally directed at the cause. Patient
HIV must be followed up with repeated neuroimaging if there
Cryptococcal antigen is no remission.
REFERENCES 4. Wadia RS, SadagopanC, Amin RB, Sardesai HV. Neurological

1. Davis L. Subacute and chronic meningitis. Continuum manifestations of organophosphorous insecticides
Lifelong Learning in Neurol. 2006;12(2):27-57. poisoning. J Neurol Neurosurg Psychiatry. 1974;34:841-7.
2. Barg RK, Karak B. Multiple cranial neuropathy: A common 5. Senayake N, Karalliedde L. Neurotoxic effects of organo
diagnostic problem. JAPI. 1999;47:10. phosphorous insecticides. An intermediate syndrome.
3. Juncos JL, Beal MF. Idiopathic cranial polyneuropathy: a N Engl J Med. 1987;316:761-3.
fifteen year experience. Brain. 1987;110:197-211.
CHAPTER
61
Nocturia: Evaluation and Management
Anish Kumar Gupta
INTRODUCTION CLINICAL PRESENTATION

Nocturia is defined simply as waking to void during sleep. Nocturia during a review of symptoms. Nocturia is
By definition even a single episode of awakening to urinate insidious in its onset. Patients may themselves report to
is nocturia, though clinically both epidemiological and the clinician or the history may be elicited during history
expert opinion is suggestive of a higher benefit is treating taking. The bother index must be assessed.
when awakening is more than two times in night.
PATHOPHYSIOLOGY
Although nocturia is common across varied
Nocturia can be attributed to any disorder or condition
age groups, the prevalence of nocturia increases
that causes one of the following as delineated in the Flow
proportionately with increasing age. Up to 60% of elderly
chart 1. The same Flow chart is also a guide to unravel
patients, defined by age >70 years, void 2 or more times
the causes in assessment and evaluation. Some of the
nightly.
aspects which need further focus are:
It is a source of significant bother for some patients.
The most distressing lower urinary tract symptom Increased Night Time Urinary Volume
has been found to be nocturia, it affects quality of life. Role of arginine vasopressin: Nocturnal polyuria may
Nocturia is associated with increased rates of higher be due to age related changes in the secretion and
rates of accidental falls and fractures, sleep disturbance, action of arginine vasopressin (AVP). The diurnal
depression, congestive heart failure, increased all-cause variation in AVP release is absent in many older
mortality. subjects.
Risk factors for nocturia include obesity, Solute diuresis: Dietary solutes (mainly urea, sodium,
hypertension, diuretic usage, snoring, restless leg and potassium) are excreted soon after a meal, also
syndrome, benign prostatic hyperplasia (BPH), prostate there is a decreased solute excretion in night, which
cancer, antidepressant usage, coronary artery disease, leads to healthy adult male having lower night time
congestive heart failure, and diabetes. awakening; disorders n this balance can lead to
Uncovering the etiology of nocturia and treating nocturnal polyuria.
it appropriately can be a diagnostic and a therapeutic Heart failure or other edematous states: (Nephrotic
challenge. syndrome and venous insufficiency) causes third
Flow chart. 1: Pathophysiology and assessment of nocturia
Nocturia
Bladder diary
Diminished bladder
Polyuria
capacity
Global polyuria
Nocturnal polyuria
(24 hr vol > 40 mL/kg)
Psychogenic polydipsia Glycosuria Diabetes insipidus
Cardiac dysfunction Edema status Glycosuria Sleep apnea Behavioral
spacing of fluids. Assumption of the supine position EVALUATION

permits mobilization of some of the edema fluid into Twenty-four hour fluid intake: Patients should be
the vascular space and leads to a solute diuresis. asked about the amount and types of fluid intake.
Autonomic dysfunction: Can increase urinary sodium Large fluid intakes (>40 mL/kg per day) is a common
excretion related to reduced sympathetic activity, cause responsible for nocturia. Questions should
resulting in a solute diuresis. Nocturnal polyuria is a be asked about the reason for the large fluid intake–
frequent symptom of Parkinson disease. psychogenic, history of renal stones, vigorous outdoor
exercise, general belief about fluid intake, attempt at
Low-volume Bladder Voids weight loss, diabetes insipidus; are important in
Low-volume voids may be due to either reduced bladder multidisciplinary management of the symptoms.
capacity or impaired bladder function. Overactive bladder Fluid intake at bedtime: Patients may drink large
and bladder outlet obstruction, often related to benign volumes immediately prior to bedtime. Treating
prostatic hypertrophy (BPH) are the most common causes physician should make a recommendation to reduce
for the same. night time fluid intake. Care should be taken not to
further restrict fluid intake in older patients who have
Sleep Disorders borderline or inadequate fluid intake to meet daily
Nocturia occurs in approximately 50% of patients with needs.
obstructive sleep apnea (OSA). Intake of diuretic fluids: Patients should be asked
about caffeine or alcohol intake prior to bedtime.
Obesity Both of these substances may predispose patients to
Abdominal adiposity is associated with a slight increased sleep disruption at night. Caffeine usage may result
risk of having two or more episodes of nocturia, odds in polyuria or detrusor overactivity and is a common
ratio [OR] 1.16. overlooked cause.
CHAPTER 61: Nocturia: Evaluation and Management 365
Medications: Prescription and over-the-counter —— Alpha-blocker agents (men only): Alpha-1

medica-tions, and their association with onset receptors are abundant in the prostate and
or worsening of symptoms of nocturia should be base of the bladder, and sparse in the body of
evaluated. Especially, patients who take twice-daily the bladder. Alpha-1-adrenergic antagonists
loop diuretics may be helped by switching the night target the dynamic component of bladder outlet
time dose to a mid-afternoon dose. obstruction and can cause a modest reduction in
—— Medicines which can affect bladder dynamics: several BPH symptoms, including nocturia.
Xanthines and beta blockers are associated No c t u r i a re s p o n s e t o a l p ha b l o c k e r s i s
with bladder storage problems. Cholinesterase significantly less than the response of other BPH-
inhibitors used for the treatment of dementia related symptoms.
may result in worsening of lower urinary tract —— 5-alpha reductase inhibitors: Decrease nocturia
symptoms. by reducing the size of the prostate gland.

Urinary tract symptoms: Questions should be asked Treatment for 4–6 months is generally needed
about other lower urinary tract symptoms, including before prostate size is sufficiently reduced to
obstructive symptoms (hesitancy, weak stream, improve symptoms.
incomplete emptying, or intermittency), irritative —— Bladder relaxant therapies: Bladder relaxant
symptoms (urinary frequency, urgency), and urinary medications allow for an increase in the bladder
incontinence. capacity and may reduce nocturia by both
Physical examination : Orthostatic vital signs, decreasing urge-associated voids and increasing
cardiovascular and pulmonary examination, rectal bladder capacity. Agents differ in efficacy, side
examination, focused neurourologic examination effects, costs, and impact on comorbid conditions
(anal wink, perineal sensations). that may improve or be exacerbated by the drug.
Anticholinergics with antimuscarinic effects are
TREATMENT frequently prescribed for nocturia.
Initial treatment includes adjustment of fluid intake, —— Antidiuretic therapies–Desmopressin : The
especially if fluid intake is excessive. pathogenesis of nocturnal polyuria, which is an

Optimizing treatment for underlying conditions, such important cause of nocturia, has been linked
as diabetes or congestive heart failure, is important but to either inadequate night time levels of AVP or
no direct benefit in decreasing nocturia has been noted. inadequate diurnal variation of AVP.
Treatment of peripheral edema by compression ddAVP, taken two hours prior to bedtime, reduces
stockings or afternoon elevation of the legs has been night time urine production via increase in urine
shown to be useful as part of management. osmolality and resultant decrease in urine volume.
Behavioral therapy, with emphasis on pelvic floor The persistent concern from data accumulated
muscle exercises (or Kegel exercises) has proven useful with ddAVP therapy has been the propensity of some
in women with nocturia and urge–predominant urinary individuals to excrete a concentrated, hyperosmolar
incontinence. The basic recommended regimen is three urine well into the day, inducing hyponatremia from
sets of 8–12 slow-velocity contractions sustained for 6–8 free-water intoxication. While mild hyponatremia is
seconds each, performed three or four times a week and often asymptomatic, severe hyponatremia, especially
continued for at least 15–20 weeks. with ongoing ddAVP therapy, may result in seizures or be
Pharmacologic therapy: Medications can be helpful life-threatening.
for the treatment of nocturia associated with The same is a promising modality of treatment, often
bladder overactivity, bladder outlet obstruction, and under used but needs to be followed up closely for side
nocturnal polyuria. effects when initiating treatment.
Other Treatment Strategies peripheral edema, obstructive sleep apnea [OSA]),

Surgical therap y f or prost atic enlarg ement : numerous treatments are potentially helpful.
Prostatectomy for benign prostatic hyperplasia Single-agent therapies available for nocturia are
(BPH) relieves many symptoms, but nocturia is the limited in their effectiveness, as they cannot address
symptom that persists most frequently following all of the relevant causes of nocturia. Conditions with
surgery. Some have suggested that BPH is often multiple causes can be most effectively addressed by
mistakenly implicated as the cause of nocturia in multidisciplinary intervention.
men.
Medication for associated sleep disorders: There BIBLIOGRAPHY
1. Dani H, Esdaille A, Weiss JP. Nocturia: aetiology and
are few studies that have focused on treatment of
treatment in adults. Nat Rev Urol. 2016;70(5):788-96.
nocturia with the use of medications for sleep. But it 2. Ebell MH, Radke T, Gardner J. A systematic review of the
is an area worthwhile working on. efficacy and safety of desmopressin for nocturia in adults. J
Physical activity: There is some evidence that increased Urol. 2014;192(3):829-35.
physical activity is associated with decreased lower 3. Kerrebroek PV, Abrams P, Chaikin D, Donoran J, Fonda
urinary tract symptoms, no randomized trials have D, Jackson S, et al. The standardisation of terminology
in nocturia: report from the standardisation subcomittee
shown reductions in nocturia.
of the International Continence Society. Neurology and
Urodynamics. 2002;21(t2):179-83.
MULTIDISCIPLINARY MANAGEMENT 4. Rao VN, Gopalakrishnan G, Saxena A, Pathak H, Dalela D,
International Consultation on Incontinence specifically Shah S, et al. Nocturia–Symptom or a Disease? J Assoc
recommended use of multicomponent interventions Physician India. 2016;64(11):56-63.
5. Weiss JP, Marshall SD. Nocturia. In: Wein AJ, Kavoussi
to treat lower urinary tract symptoms in older adults.
LR, Martin AW, Peters CA. Ed. Campbell–Walsh Urology.
As nocturia is a manifestation of various conditions Philadelphia: Elsevier, 2016.pp.1821-35.
(i.e. overactive bladder, benign prostatic hyperplasia, 6. Weiss JP. Nocturia: Focus on ethology and consequences.
congestive heart failure, poorly controlled diabetes, Rev Urol. 2012;14(314):48-55.
CHAPTER
62
Neuromyelitis Optica:
A Physician’s Perspective
INTRODUCTION blood have led to a newer term namely viz. neuromyelitis

Nervous system has a unique property of responding optica spectrum disorders (NMOSD).
to various insults in different forms with protean
ma n i f e s t at i o n s i n va r i ou s p a r t s o f n e u ro a x i s. EPIDEMIOLOGY
Inflammation, infection and demyelination affect the Most common age of presentation is 20–40 years.
system with varied pathogenesis giving rise to clinical, However, NMO may occur in children starting from
biochemical, neuroimaging characteristic features in the age of 2 years and adult in their 60s. Contrary to
each exciting event. So far as the demyelinating disease MS, NMO is more frequent in noncaucasian, especially
is concerned, we often talk in terms of multiple sclerosis Asians, although it has been described in all continents
(MS). However with our expanding knowledge along and races. NMO is more common in women than men
with available facilities of modern technological services, (ratio 9:1). Epidemiological, clinical and radiological
we can now distinguish other demyelinating disorders of data on NMO in India is not well documented. Larger
nervous system from MS. Once upon a time transverse studies are required regarding exact prevalence of NMO
myelitis along with near simultaneous involvement in India. In one study, it was estimated to be 2.6/100,000.2
of both optic nerves in the form of optic neuritis (ON)
(initially described by Devic in 18941) was considered to Clinical Presentation and Diagnosis of
be due to demyelination of inflammatory nature and was NMO and NMOSD (Limited Form)
termed as neuromyelitis optica (NMO), usually having Patient may present with visual problem in the form
a monophasic course. However, we can now make a of dimness or sudden loss of vision. On fundoscopy,
differentiation between NMO and MS by observing there is evidence of ON.
the natural course of the disease along with available Some patients present with paraplegia and sensory
investigations like laboratory markers and neuroimaging level usually in dorsal region, where MRI shows
studies. It is important to distinguish between these signal changes extending up to 3 or more spinal cord
two as the concept of monophasic disorder for NMO is segments.
probably no longer tenable because of relapsing nature ON and spinal cord involvement (long segment) can
of the disease in some instances. Similarly the extent occur simultaneously or in separate occasions.
of involvement of CNS and spinal cord, some areas of In some cases, there may be a time gap in between
brain along with some specific antibodies in CSF and these two clinical manifestations upto decades.3
Patient can present with nausea, vomiting, and the patients do not show positive aquaporin 4 antibody.
hiccup. They are considered to be seronegative NMOSD in
Narcolepsy can be important clinical features in some appropriate clinical background.
cases.
Aquaporin 4 antibody which is an autoantibody Pathogenesis
(NMO IgG) is an important marker of NMO and its AQP4-IgGs play an important role in pathogenesis.
spectrum. This can be demonstrated in blood and These IgGs bind to aquaporin 4. This binding results in
CSF in majority of cases. down-regulation of surface aquaporin-4 (AQP4) and
A section of people suffering for disease show CSF changes water homoeostasis in the CNS. It also activates
cells >50/µL (neutrophils) classical complement system leading to membrane
MRI brain is also important because it can show damage. There is increased BBB permeability and
signal changes in areas other than MS. infiltration of leukocytes, particularly eosinophils and
neutrophils that can be found in the CSF during acute
Diagnosis attacks. Interleukin 6 (IL-6) dependent plasmablasts
Because of the various clinical manifestations and may play a role in pathogenesis of NMO. It has been seen
course of the disease, there were constant change in that plasmablast population expands during relapse of
diagnostic criteria. However in 2006 Dean Wingerchuk, NMO. IL-6 also increases the survival of plasmablasts
had proposed certain criteria which have been well and their AQP4 antibody secretion. The combination
accepted by various authorities. In clinical practice, if of complement-mediated injury and leukocytosis
we find visual loss due to optic neuritis and features leads to the death of astrocytes, oligodendrocytes. The
suggestive of myelitis on clinical examination along with complement membrane attack complex causes changes
brain and spinal cord MRI findings (Figs 1 and 2) as in blood vessels, including their irregular thickening and
already described and a positive aquaporin 4 antibody hyalinization.
in CSF and blood, we can make presumptive diagnosis
of NMO. It is better to have two criteria from laboratory Treatment
backup namely MRI finding and positive aquaporin O nce the diagnosis of NMO/NMO SD is made,
4 antibody along with visual and spinal problem in management of acute exacerbation and prevention of
clinical background. It is also been noted that some of relapse is of paramount importance.
Fig. 1: Case 1: MRI brain and spinal cord in two of our cases
CHAPTER 62: Neuromyelitis Optica: A Physician’s Perspective 369
Fig. 2: Case 2: MRI brain and spinal cord in two of our cases
Acute Case ensures maximum efficacy. Recent study by Costanzi

Intravenous steroids: High dose methyl prednisolone and colleagues, demonstrated that a rise in MCV was
(1 gm) is given in acute cases for 5 days, unless there correlated with a reduction in annualized relapse rate in
is compelling contraindication. Decision regarding patients treated with azathioprine.5
continuation of steroid or addition of new treatment Mycophenolate mofetil: It is a immunosuppressant drug
modality depend on clinical course. It is common that blocks proliferation and clonal expansion of T and
practice to use steroid 1 mg/kg body weight for 30 days B lymphocytes. With a dose of 2 gm/day relapse rate
and then dose is gradually reduced over a period of 6–12 improves along with disability.6
months. Rituximab: Several case series support its benefit
Plasma exchange: It has been shown to be one in treating NMO refractory to other modalities of
of the modalities of treatment in patients having treatment.7.8 Dose schedule is based on use in rheumatoid
severe manifestation. It is usually considered when arthritis, i.e. 1 gm IV on day 1 and day 14 repeated 6
the treatment with steroids for 5 days does not show monthly or hematological malignancies, i.e. 375 mg/m/
significant improvement. Typically 5–7 exchanges done week for 4 weeks then 6 monthly. In case of NMO
over 2 weeks. duration of treatment is based on clinical response and it
Cyclophosphamaide: If patient is refractory to above is individualized.
management, intravenous cyclophosphamide can be Mitoxantrone: Two case series have reported its role in
given. refractory cases. 9,10 Major adverse effects are cardiac
dysfunction and treatment related acute leukemia.
Maintenance Therapy Management of associated comorbidities, depression,
Chances of recurrence are very high.4 So maintenance bowel and bladder care and regular physiotherapy
therapy should be given. Apart from steroids other should be done for proper rehabilitation.
drugs used are rituximab, azathioprine, mycophenolate
mofetil. Our Experience
Azathioprine: It is for long used for prevention of relapse During May 2015 to July 2017, we treated 12 patients
of NMO. It is also used as steroid sparing agent. The of NMO, 2 male and 10 female within the age range of
usual dose is 2.5-3 mg/kg/day. Rise of mean corpuscular 15–35 years in the indoor of medicine department of our
volume (MCV) of atleast five points from baseline institution (Table 1).
TABLE 1: Presenting features REFERENCES

Presenting feature No. of Presenting No. of 1. Devic E. Myèliteaigüecompliquée de névriteoptique. Bull
patient feature patient Med (Paris). 1894;8:1033-4.
2. Pandit L, Kundapur R. Prevalence and patterns of
Visual problem in 12 Paraplegia 11
terms of blurred vision Quadriplegia 01 demyelinating central nervous system disorders in urban
Mangalore, South India. MultScler. 2014;20:1651-3.
Visual loss (vision 6/60) 10 ( Male 2, Bladder 12 3. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker
Female 8) involvement
BG. The clinical course of neuromyelitisoptica (Devic’s
Loss of color vision 4 (Female 4) Nausea, 3 (Male 1, syndrome). Neurology. 1999;53:1107-14.
vomiting Female 2) 4. Wingerchuk DM. Diagnosis and treatment of neuromyelitis
hiccup optica. The neurologist. 2007;13(1):2-11.
5. Costanzi C, Matiello M, Lucchinetti CF, et al. Azathiprine:
MRI spine showed long segment myelitis in all 12 Tolerability, ef ficacy and predictors of benefit in
neuromyelitisoptica. Neurology. 2011;77:659-66.
patients whereas MRI brain was abnormal in 5 patients
6. Jacob A, Matiello M, Weinshenker BG, et al. Treatment
with involvement of areas not typical of MS. Aquaporin 4 of neuromyelitis optica with mycophenolate mofetil:
antibody was positive in all patients. retrospective analysis of 24 patients. Arch Neuro.
We treated the patients with conventional therapy, 2009;66:1128-33.
all of them responded. However, the visual problem 7. Jacob A, Weinshenker BG, Violich I, et al. Treatment of
neuromyelitis optica with rituximab: retrospective analysis
due to ON was less satisfactorily improved in 5 patients.
of 25 patients. Arch Neuro. 2008;65:1443-8.
Paraplegia partially improved 6 patients and require 8. Bedi GS, Brown AD, Delgado SR, et al. Impact of rituximab
substantial help till date. We gave rituximab 500 mg IV on relapse rate and disability in neuromyelitis optica. Multi
on day 1, day 14 and repeated 6 monthly for four cycles Scler. 2011;17:1225-30.
with instruction for regular follow up. None of the patient 9. Kim SH, Kim W, Park MS, et al. Efficacy and safety of
showed significant adverse effects till date. No history mitoxantrone in patients with highly relapsing neuromyelitis
optica. Arch Neurol. 2011;68:473-9.
of relapse in these patients. The patients have been
10. Weinstock-Guttman B, Ramanathan M, Lincoff N, et al.
instructed for regular follow up because they may require Study of mitoxantrone for the treatment of recurrent
need-based therapy if clinical symptomatology demands neuromyelitisoptica (Devic Disease). Arch Neurol.
in future. 2006;63:957-63.
CHAPTER
63
First Seizure: Should or Should
not be Treated?
PK Maheshwari, A Pandey, Akhilesh Kumar Singh
INTRODUCTION Preventing future seizures

About 10% of the population will have a seizure at Toxicities of antiepileptic drugs
some time in their lives but less than half of these
patients will have multiple seizures. So, it is important IMPORTANCE OF MULTIPLE SEIZURES
to assess the first seizure to evaluate the risk of seizure Occurrence of multiple seizures during analysis of first
recurrence (Table 1). International League Against seizure has to be looked for. Patient would not notice
Epilepsy, 2014 (ILAE) defines epilepsy as at least 2 events like myoclonic jerks after awakening, nocturnal
unprovoked seizures occurring more than 24 hours tongue biting or brief staring spells; instead they will seek
apart. Following which the risk of additional seizures is medical care after a generalized tonic-clonic seizure. A
high and antiepileptic drug therapy is required in such a careful analysis will help to determine multiple seizure
case. Unnecessary treatment of patients can be avoided events in a newly diagnosed seizure patient especially
by making an early proper assessment in those who are in case of complex partial seizures and children with
unlikely to have a second unprovoked seizure. Early absence seizures.
expert assessment by an experienced epileptologist will In case of multiple seizure episodes, the seizure
more appropriately guide the treatment. occurrence over time has to be determined. Multiple
Factors guiding treatment decisions: unprovoked seizures within a 24-hour period should
There is a chance of second seizure
be considered a single event and this by itself does not
Consequences following a second seizure
establish the diagnosis of epilepsy.
TABLE 1: Classification of first seizure

IS THERE ANY ROLE OF ANTIEPILEPTIC
Provoked seizure – Due to identifiable causes. e.g. seizure caused
DRUG PROPHYLAXIS?
zz
by toxin, medication, drug abuse or metabolic factors

zz Acute symptomatic seizure – Due to acute brain processes. e.g. The only evidence of supporting antiepileptic drug (AED)
seizures caused by stroke, traumatic brain injury, encephalitis, prophylaxis is in early post traumatic period of high risk
meningitis
head injury patients. No evidence exists for antiepileptic
zz Remote symptomatic seizure – Due to pre-existing brain injury
drug prophylaxis for the patients with brain tumors,
zz Seizure associated with epileptic syndrome, e.g. juvenile epilepsy central cavernous hemangiomas, cerebrovascular
zz Other unidentified – Cause is unknown even after evaluation accidents or craniotomy.
TABLE 2: Provoked vs. unprovoked seizures TABLE 3: Provoked seizure

Provoked seizures Unprovoked seizures zz Alcohol withdrawal
zz Generalized convulsive zz Focal seizures or focal with zz Barbiturate or Benzodiazepine withdrawal
events secondary generalization zz Metabolic (e.g. hyponatremia, hypocalcemia, hypoglycemia,
zz Usually do not require anti- zz Require antiepileptic drug hyperglycemia)
epileptic drug therapy therapy zz Drugs (e.g. cocaine, amphetamines, phencyclidine)
zz Requires elimination of
zz Medications (e.g. tramadol, imipenem, theophylline, bupropion)
provocating cause
secondary generalization and there is higher risk of

WHEN TO INITIATE ANTIEPILEPTIC
disabling seizure in an active adult. Febrile seizures do
DRUGS? not require antiepileptic drug treatment.
Following factors should be considered before starting
anti-epileptic drug treatment: Patient’s Age
In general, provoked seizures are generalized Elderly patients with unprovoked seizures do not have
convulsive events, not focal. Provoked seizures will idiopathic seizures. These seizures are due to undefined
recur if the patient is exposed again to the provocative etiology. In patients over the age of 60 with a new
agent. Seizures caused by alcohol intoxication or unprovoked seizure should be considered symptomatic
withdrawal will not be focal as intoxication/withdrawal and treated with antiepileptic drug. Unprovoked seizures
will lower the seizure threshold in a patient with focal in elderly should be considered focal, with or without
brain injury. So, a patient with focal seizures or focal secondary generalization, even if the presentation
seizures with secondary generalization should be is of only generalized convulsive seizure. Many first
considered as having an unprovoked seizure and unprovoked seizures within 24 hours in elderly can be
has to be treated accordingly. In reality, it is possible considered under remote symptomatic seizures. Living
to make only predictions of seizure recurrence. For and lifestyle situation of the patients has to be considered
example, young child with a single convulsion and with while treating the elderly patients. Cerebrovascular
all normal working parameters (clinical examination, disease is the most common cause of seizures in elderly.
electroencephalogram, neuroimaging) has a relatively
low risk of seizure recurrence (Tables 2 and 3). Acute vs. Remote Symptomatic Seizures
It is important to consider acute symptomatic seizures.
Types of Seizure The prognosis of first acute symptomatic seizure differs
Simple partial (focal) seizures with only sensory or focal from that of a first unprovoked seizure when the etiology is
motor symptoms without alterations of consciousness stroke, traumatic brain injury or encephalitis, meningitis.
are less disabling than complex partial seizures with Mortality is higher with acute symptomatic seizures
alteration of awareness. The decision to treat these simple during first month and lower risk for subsequent seizures
partial (focal) minor seizures should be individualized. when compared to remote symptomatic seizures.
7-year-old patient with focal seizure as facial twitch and
electroencephalogram (EEG) showing centrotemporal SEIZURE RECURRENCE
spikes can be left off medication unless generalized Status epilepticus, prior acute symptomatic seizures, or
tonic-clonic event occur or there is recurrence of similar a Todd paralysis increase the risk of seizure recurrence
focal seizures causing psychological distress. Similarly, in patients with remote symptomatic seizures. Low risk
a focal seizure in a 24-year-old patient with cavernous of seizure recurrence (<25%) is seen in patients with
hemangioma may warrant therapy as there is a risk of acute symptomatic seizures. But once the patient has
CHAPTER 63: First Seizure: Should or Should not be Treated? 373
TABLE 4: Patients at increased risk for seizure recurrence after TABLE 5: Differential diagnosis of a single seizure
first seizure
zz Syncope (including breath holding and pallid syncope)
Prior brain lesion or insult (most powerful predictor)
zz Transient ischemic attacks
Persistence of epileptiform EEG abnormality
zz Metabolic encephalopathy (including hypoglycemia or
Significant brain imaging abnormality electrolyte disturbance)
Nocturnal seizures zz Sleep walking
Positive family history/sibling with epilepsy zz Night terrors
History of acute symptomatic seizures zz Complex migraines
Note: The latter two risk factors increased the risk of seizure recurrence zz Cardiac arrhythmias
to 60% or more.
zz Pseudoseizures
subsequent unprovoked seizure, a positive history of zz Psychogenic nonepileptic events

acute symptomatic seizure increases the risk of seizure zz Cardiac and neurogenic syncope
recurrence (>60%) (Table 4).
zz Panic attacks
Seizures that begin in childhood are much more
likely to be idiopathic than in adults. The causes of zz Movement disorders
unprovoked seizures differs than those in adults. The
risk of injury due to seizure is less when compared to whether to begin antiseizure drug therapy, and direct
adults. First generation antiepileptic drugs have effects appropriate treatment to the underlying cause, if
on learning and cognitive profiles, and taking of daily known.
medication may be stigmatizing to the otherwise healthy Routine laborator y tests : Practice guidelines
young child in school which may cause poor drug recommend testing children based on individual
compliance and increase the risk of seizure recurrence. clinical circumstances and routinely measuring
Risk factors for seizure recurrence among children serum glucose and sodium levels in adults. Tests for
include remote symptomatic seizure, abnormal EEG uremia should be done in the patient suspected of
(Electroencephalogram), seizure occurrence during having renal disease.
sleep, history of prior febrile seizures, and a Todd Lumbar puncture and toxicological profile: New-
paralysis. An epileptiform EEG will predict seizure onset seizures may be the only symptom of central
recurrence than an abnormal nonspecific EEG (Table 5). nervous system infection in patients with human
immunodeficiency virus. Routine toxicological
APPROACH TO A CASE OF screening is not recommended.
FIRST SEIZURE Role of electroencephalography: Electroence-
The first seizure is more common than epilepsy: The phalogram (EEG) study is an essential component in
primary goal in evaluating a patient’s first seizure the diagnostic work up. Abnormal neurological status
is to identify whether the seizure resulted from a and abnormal EEG are the most significant predictors
treatable systemic process or intrinsic dysfunction of seizure recurrence. The value of EEG is to point
of the central nervous system and, if the latter, the to focal lesions (especially localized slow waves),
nature of the underlying brain pathology. This predict recurrence, and indicate a specific epilepsy
evaluation will determine the likelihood that a patient syndrome (spike pattern). When standard EEG is
will have additional seizures, assist in the decision negative, systematic case series have shown that
sleep deprived EEG will detect epileptiform (spike) seizures. The decision to provide anticonvulsant
discharges. Sleep deprived EEG may be carried out in treatment after first seizure should be individualized.
any routine EEG laboratory. Antiepileptic drug choice: The chosen antiepileptic
Ne u r o i m a g i n g : Ne u ro i ma g i n g s c a n s re v e a l drug should have high efficacy, long-term safety,

abnormalities in patients with a first seizure, good tolerability, and low interaction potential,
depending on patient demographics. MRI is the and the agent should allow a good quality of life,
preferred imaging method because it has greater especially because half of all patients never have
sensitivity for detecting abnormalities than CT. MRI another seizure without treatment. The accepted
is the best method for structural imaging. After a first principle is that one should begin with monotherapy.
seizure, abnormalities detected by MRI that lead All newer (second generation and third generation)
directly to intervention are more common in adults agents are acceptable choices and are likely just as effective
than children. as older agents. An American Academy of Neurology
(AAN) evidence-based guideline recommended
MANAGEMENT OF FIRST SEIZURE lamotrigine, oxcarbazepine, and gabapentin as
Any decision to start treatment is based on the risk of appropriate for initial monotherapy; however, this
seizure recurrence, the effectiveness of anticonvulsant guideline did not include newer antiepileptic drugs, such
treatment, and the adverse medical and socioeconomic as levetiracetam and pregabalin.
effects of chronic anticonvulsant treatment. Treatment
may be justified when the risk of recurrence is high. BIBLIOGRAPHY
Treatment strategy: In 2015, the American Academy of 1. Annegers JF, Hauser WA, Lee JR, Rocca WA. Incidence
Neurology (AAN) and the American Epilepsy Society of acute symptomatic seizures in Rochester, Minnesota,
1935-1984. Epilepsia. 1995;36:327.
(AES) released a new guideline on the prognosis and
2. Chang BS, Lowenstein DH. Quality standards Subcommitte
treatment of first unprovoked seizures. According to of the American Academy of Neurology. Practice parameter:
the guideline, immediate antiepileptic drug (AED) antiepileptic drug prophylaxis in severe traumatic brain
therapy, as compared with delay of treatment pending injury: report of the Quality Standards Subcommitte of the
a second seizure, is likely to reduce recurrence risk American Academy of Neurology. 2003;60(1):10-6.
within the first 2 years but may not improve quality 3. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official
report: a practical clinical definition of epilepsy. Epilepsia
of life.
2014;55(4):475-82. Doi:10.1111/epi.12550
Clinician’s recommendations whether to initiate 4. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy
immediate AED treatment after a first seizure should and unprovoked seizures in Rochester, Minnesota: 1935-
be based on individualized assessments that weigh 1984. Epilepsia. 1993;34:453.
the risk of recurrence against the adverse effects of 5. Hauser WA, Rich SS, Lee JR, et al. Risk of recurrent
AED therapy and that consider educated patient seizures after two unprovoked seizures. N Engl J Med.
1998;338(7):429-34.
preferences.
6. Hirtz D, Ashwal S, Berg A, et al. Practice parameter:
Antiepileptic drug therapy: Immediate anticonvulsant
evaluating a first nonfebrile seizure in children: report of the
treatment reduces the likelihood of a second seizure quality standards subcommittee of the American Academy
by half. However, immediate anticonvulsant therapy of Neurology, the Child Neurology Society, and the American
does not affect the long-term prognosis for achieving Epilepsy Society. Neurology. 2000;55(5):166.
1- or 2-year seizure-free remission and exposes many 7. Hirtz D, Berg A, Bettis D, et al. Practice parameter: treatment
of the child with a first unprovoked seizure : report of the
patients who would never have a recurrent seizure
Quality Standadrs Subcommitte of the American Academy
to anticonvulsant side effects. The consensus is of Neurology and the Practice Committee of the Child
that anticonvulsant treatment is needed after two Neurology Society. Neurology. 2003;60(2):166-75.
CHAPTER 63: First Seizure: Should or Should not be Treated? 375
8. Kho LK, Lawn ND, Dunne JW, Linto J. First seizure American Epilepsy Society. Neurology. 2007;69(21):1996-
presentation: do multiple seizures within 24 hours predict 2007.
recurrence? Neurology. 2006;67(6):1047-9. 10. Shinnar S, Berg AT, O’Dell C, et al. Predictors of multiple
9. Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: seizures in a chohort of children prospectively followed
evaluating an apparent unprovoked first seizure in adults from the time of their first unprovoked seizure. Ann Neurol.
(an evidence-based review): report of the Quality Standards 2000;48(2):140-7.
Subcommitte of the American Academy of Neurology and the
CHAPTER
64
An Overview and Practical Clinical Hints in
the Diagnosis of Temporal Lobe Epilepsy
DEFINITION residual pyramidal neurons abnormal distribution of

The general appearance of the CPS, is impairment of zinc, γ-aminobutyric acid-A receptor and glutamate
consciousness, which is a condition wherein the patient decarboxy-lase; and disorganization of the granule
is not able to respond to an external stimuli of any cell layer Increases in density of the corpora amylacea
type owing to unawareness of the patient contact with and peripheral type benzodiazepine receptor binding
environment and during the event when the seizure corresponded with glial proliferation. Histochemical
occurs. studies demonstrated the association of mossy fiber
sprouting with synaptic reorg-anization and changes
ETIOLOGY of several chemically defined inter-neuron systems
Most of the etiology in olden days are discovered with the in the dentate gyrus. Quantitative analysis using in
aid of temporal lobe resection, a type of surgery done for vitro autoradiography showed that neurotransmitter
CPS. But of late, imaging studies have cleared the issues receptor bindings related to neuronal excitation (AMPA
by detecting the possible etiology in the temporal lobe.1 and NMDA receptor) and inhibition (central type
They are mostly mesial temporal sclerosis, especially benzodiazepine receptor) were reduced differently as a
as neonatal asphyxial injuries, with loss of nerve cells function of neuronal loss in MTS. These cytochemical
in the hipocamplus, succeeded with fibrosis, sclerosis changes associated with neurotransmitters and their
and gliosis of the region, which form an irritable foci. receptors in the sclerotic hippocampus may constitute
In some cases, there were foci of abnormal tissues like the pathological background of epileptogenesis in TLE.2
hamartomas. Other miscellaneous lesions such as
tumors, post traumatic scars, infections, vascular lesion, PATHOPHYSIOLOGY
tuberous sclerosis and neuro cysticercosis. In a minority The discharges in the temporal limbic structures observed
of cases no histological observable findings is observed. to be responsible for CPS. Functional connections of
A genetic tendency is not established in cases of CPS. limbic system, creates the experiences and behavior
that occur during CPS. A wide network of association
PATHOLOGY pathways from the hippocampal formation causes, the
Kazumi Matsuda, Kazuichi Yagi, et al. reported neuronal spread of seizure activity from one foci to other foci. A
loss and astrogliosis in hippocampus, mesial temporal depth electrode recording technique of EEG in CPS,
region, amygdla, and entorhinal cortex. Aberrant seizure activity is observed in several limbic system
CHAPTER 64: An Overview and Practical Clinical Hints in the Diagnosis of Temporal Lobe Epilepsy 377
areas, Cingulate gyrus, amygdale, hippocampal gyrus experienced (Jamais-vu) if visual, (Jamais-Entandu).
and selected thalamic nuclei. An analysis of autonomic A condition called panoromic vision, which is a rapid
substrata of CPS offers an explanation, for the multiple recollection of episodes from the past experiences
clinical manifestation and electroclinical correlates of can occur.4 Affective symptoms composes features of
this disorder. fear, pleasure, displeasure, depression, rage, anger,
irritability, elation, and erotism. In some cases, there
CLINICAL FEATURES may severe autonomic symptoms such as papillary
The main features of CPS is impairment of consciousness, dilatation, pallor, flushing, piloerection, palpitation
which may or may not be preceded with symptoms. and systolic hypertension.5
(Motor, sensory, autonomic and psychic). There may Certain symptoms less commonly, occurs, with
be total absence of any other signs or symptoms during feeling of exhilaration, elation, serenity, satisfaction
the impaired conscious state, or automatisms may be and pleasure (Ecstatic seizures, Dostoyevesky
present. epilepsy).6,7
Such exhilaratory feelings may be sexual. This
INTERNATIONAL CLASSIFICATION OF sexual pleasure during an aura may consists of
THE CPS3 either sexual arousal or orgasm.8 Visual perceptions
CPS with simple partial onset with impairment of like polyoptic illusions, mono ocular diplopia,
consciousness only macropsia, micropsia, or distortion of distance.
CPS with simple partial onset followed by impaired Auditory perceptions distortions of sound like micro
consciousness and automatisms and macroacusia. Depersonalization, a feeling that
CPS with impairment of consciousness at the onset, the persons is outside the body may occur. Altered
and getting continued with motor seizures perception of size and weight of a limb is observed.
CPS with impairment of consciousness at the onset Structured hallucinations are perceptions without
with automatisms. corresponding external stimuli, affecting the
somatosensory, visual, auditory, olfactory and
SEIZURE PHENOMENA gustatory senses.2
Impairment of consciousness: The patient may look
vacant or frightened. Occasionally able to recall Automatism
vague sensations, and also do not realize anything Various type automatism which is a phenomenon
more has occurred. that includes, alimentar y-chewing movements,
Simple partial onset of seizures: May be with motor borborygmus, Mimetic—facial grimaces, fear expression,
signs with somato sensory or special sensory bewilderment, vacant tranquil look, laughing (Gelastic
symptoms, autonomic symptoms Automatisms seizures), or crying (Lacrimonic seizures), lip smacking,
alone. chewing, and kissing gestures.
Simple partial onset with psychic symptoms: Due to Gestural—purposeful or nonpurposeful hand
discharges occurring in focal areas of temporal limbic movements, sexual gestures such as masturbating
structures, they may be dysphasic symptoms, in the activity, pelvic thrust ing (Foci arising and reflecting in
form of ongoing speech arrest, vocalization, palilalia, the frontal area of the brain9
Dysmensic symptoms: Distortion of memory, temporal Ambulator y—Wandering or running (cursive
disorientation a state of dreamy state, a flash back, a seizures) are dangerous forms of seizures, as the patient
sensation of previously occurred experience, (Deja- has no awareness of what is happening, wherein the
vu phenomenon – visual, auditory (Deja-entendu). patient may unknowingly traverse a traffic, or fall in a
It can also a sensation which the patient has not well or ditch and injure himself.
A B
Figs 1A and B: Irregular fibrosis of hippocampus3
Verbal phenomenon—shrill cries, humming, short staring present, speech during the attack is absent.
phraces, explecities or swearing repeated in automatic Absent postictal confusion. Also characterized by the
fashion. classical EEG findings–3 Hz spike and wave, more
provoked by hyperventilation.
EEG PHENOMENON IN TLE OR CPS Migraine, syncope, onset usually adult, occurs in
Most of interictal EEG are normal. Scalp surface EEG, erect posture, flaccid muscle tone, pale skin, cold
positive in 10% of cases. Special procedures of EEG, like and clamy, EEG may not show seizure findings. May
sphenoidal EEG, hyperventilation EEG, sleep EEG, sleep be positive ECG changes. Clinically plantar is flexor,
deprivation EEG, enhances; the yield to positivity. The bladder incontinence is rare.
positivity of EEG shows spikes, and spike wave over the Hysterical (pseudo seizures): Motivationally
site of focus, and become some time generalized, when determined episodic behavior-tongue biting,
simple partial seizures becoming generalized. Focal incontinence may absent or rare. Self injury rare.
slowing and low voltage complexes are also observed. Often identifiable secondary gains. Normal ictal and
interictal EEG.
IMAGING STUDIES CT VS MRI TIA: Usually conscious patient, focal symptoms and
The hallmark of temporal lobe epilepsy could be signs. Focal deficit lasting and recovering with in
mesial temporal sclerosis on MR imaging is an atrophic 24 hours. Absent aura, and no significant abnormal
hippocampus associated with hyperintense signal EEG findings relevant to CPS. Mostly associated with
on long-repetition-time sequences confined to the cardiovascular findings. These features are absent in
hippocampus. Amidst CT and MRI, MRI would be CPS.
superior investigation. SPECT, PET, spectral analysis of Affective psychosis : Ideational disturbances,
MRI, may be contributory (Figs 1A and B).10,11 hallucina-tions, inappropriate affects which do occur
during CPS, which develop suddenly but do; not
DIFFERENTIAL DIAGNOSIS continue for ever, as they are in affective psychosis.
Absence seizures: Usually childhood, no aura, usually Other miscellaneous conditions do mimic CPS and
upto 10–15 seconds, alertness is out of contact, they are hypoglycemia, drugs in take, alcohol intake,
automatism—lip licking (Cf. lip smacking in TLE), may mimic, and they are appropriately ruled out.
CHAPTER 64: An Overview and Practical Clinical Hints in the Diagnosis of Temporal Lobe Epilepsy 379
MANAGEMENT disorders. An appropriate diagnosis, with most careful

Drug therapy: Usually, phenytoin, 5–7 mg per kg clinical history, obtained from the informers, relatives,
body weight (usual adult dose 100 mg twice or and assessment of various behavioral disorders, one
thrice daily), carbamazepine 10–20 mg per kg body should evaluate the necessity for further investigations
weight (usual adult dosage 250 mg twice daily) are like EEG. EEG also, should be carefully done, under
the usual management applied, modern drugs like senior consultant’s supervision to have the best yield.
Levecetratam 10–15 mg per kg body weight (upto 500 Not but not the least, the radiologists should be informed
mg tid), zonizamide 2 mg per kg weight (upto 100 before an MRI request about the suspicion of the
mg tid) either alone or in combination in resistant temporal foci, other wise adequate search will not be
cases are useful in managing CPS. Other AEDs, done by the radiologist, which may loose the diagnosis.
may not be appropriately controlling the seizures. The once difficult management schedules, with older
Phenobarbitone 1–2 mg per kg wt, as additional group of pharmacotherapy become very much treatable
therapy may be economical. Recent evidences shows schedule with the modern pharmacotherapy, and newer
the management with the noncompetitive antagonist generation of AEDs.
AMPA receptor, Parampanel (Fycompa) found to be
more effective, and it is available in strength of 2, to 8 REFERENCES
mg. In titrated dosages, it is found to be very effective 1. Falconer MA, Cavanaugh JB, et al. Clinico pathological
considerations of Temporal lobe epilepsy due to small focal
in resistant cases. It can be also used in nonresistant
lesions, a study of cases submitted to operation. Brain.
cases, as an adjuvant therapy. All precautions should 1959;82:483.
be taken, including the side effects of this drug before 2. Matsuda K, Yagi K, et al. Neuropathology 02/2002;
application. 19(2):217-28. DOI: 10.1046/j.1440-1789.1999.00234.x
Neurosurgical therapy: Considered only when 3. Dreifuss FE, et al. Proposal for revised clinical and
medical therapy in maximum doses has failed. electroencephalographic classification of epileptic seizures.
Epilepsia. 1981;22:489.
Not generally practiced now. May be indicated in
4. Lectures JH on the diagnosis of epilepsy. in J Taylor (Ed)
contemplated intractable and uncontrolled repeated
selected writings of John Hughlings Jacksons, Vol.1.
status TLE conditions. London: Hodder and Stoughten; 1931.
3. Behavioral methods of seizure control, learning 5. 7, 10 Daly, D. D. Ictal clinical manifestations of complex
theory, conditioning, psychodynamic processes or partial seizures. Adv Neurol. 1975;11:57.
various biofeedback techniques is used as an adjunct 6. Cirrgnotta F, et al. Temporal lobe epilepsy with ecstatic
to drug therapy. seizures. Epelepsia. 1980;21:705.
7. Williams D. The structure of emotions reflected in epileptic
experiences. Brain. 1956;79:29.
PROGNOSIS 8. Currier RD, et al. Sexual seizures. Arch of Neurol.
Usually compared to generalized seizures, CPS, has 1971;25:260.
guarded prognosis. But with the available modern 9. Spencer SS, et al. Sexual automatisms in CPS, Epilepsia. In
management with drug therapy, the prognosis is press, 1982.
enhanced to better side, till the toleration of the drugs. 10. Richard Bronen, Department of Diagnostic Radiology,
Yale University School of Medicine. American Society of
Neuroradiology.
CONCLUSION 11. Kuzniecky R, et al. A. Predictive value of magnetic
TLE is not an uncommon condition, and many of them resonance imaging in temporal lobe epilepsy surgery. Arch
are mistakenly diagnosed as psychiatric behavioral Neurol. 1993;50:65-9.
CHAPTER
65
Changing Scenario in Management
of Status Epilepticus
Rajesh Shankar Iyer
INTRODUCTION death, neuronal injury, and alteration of neuronal

networks, depending on the type and duration of
Status epilepticus (SE) has always remained a
seizures”.
challenge for the practicing physician. Despite various
From the operational point of view, this definition has
advances in diagnosis and management, the outcome
two dimensions. First reflects on the duration of seizure.
in many situations has been less than satisfactory.
After a period of time called t1, the seizure is considered
New disease entities are being recognized to cause
as “continuous seizure activity”. After a particular period
SE and new treatment strategies recommended. Of
of seizure activity, the risk of long-term consequences
particular interest is the most recent recognition of
arises. This is the second time point called t2. Based on
the entity of super-refractory SE and identification of
the currently available evidences, t1 and t2 have been set
hitherto unknown neuronal antibodies causing SE in
at 5 minutes and 30 minutes respectively in the scenario
autoimmune encephalitides. Here we focus on what
of convulsive SE. The time point t1 thus indicates the
is new in SE and discuss the recent thoughts on the
time of initiation of treatment and t2 determines how
definition and classification of SE and also elucidate the
aggressive and fast we should be in implementing the
new terminologies. We also give a short update on super-
treatment to prevent long term side effects.
refractory SE.
The proposed new diagnostic classification system
of SE has four axes: (1) semiology; (2) etiology; (3)
CHANGING DEFINITIONS electroencephalography (EEG) correlates; and (4) age.
AND CLASSIFICATION
The Task Force of the Commission on Classification and Axis 1: Semiology
Terminology and the Commission on Epidemiology of This deals with the clinical presentation of SE and
the International League Against Epilepsy (ILAE) has is based on two important clinical aspects: the motor
proposed a new definition of status epilepticus. It is symptoms and the level of impaired consciousness. The
as follows: “Status epilepticus is a condition resulting classification based on axis 1 is detailed in Table 1.
either from the failure of the mechanisms responsible for
seizure termination or from the initiation of mechanisms, Axis 2: Etiology
which lead to abnormally, prolonged seizures (after time Known or symptomatic
point t1). It is a condition, which can have long-term —— Acute (e.g. stroke, intoxication, encephalitis, etc.)
consequences (after time point t2), including neuronal —— Remote (e.g. posttraumatic, poststroke, etc.)
CHAPTER 65: Changing Scenario in Management of Status Epilepticus 381
TABLE 1: Classification of status epilepticus (SE) Time-related features : Prevalence, frequency,

With prominent motor Without prominent motor duration, daily pattern duration and index, onset
symptoms symptoms-nonconvulsive SE, (sudden vs. gradual), and dynamics (evolving,
NCSE
fluctuating, or static)
zz Convulsive SE (CSE) NCSE with coma Modulation: Stimulus-induced vs. spontaneous
—— Generalized convulsive
—— Focal onset evolving into

Effect of intervention (medication) on EEG
convulsive SE
—— Focal or generalized not
Axis 4: Age
known
Neonatal (0–30 days)
zz Myoclonic SE zz NCSE with coma
—— With coma —— Generalized
Infancy (1 month–2 years)
—— Without coma Typical absence status Childhood (> 2–12 years)
Atypical absence status
Adolescence and adulthood (>12–59 years)
Myoclonic absence
status
Elderly (≥60 years)
—— Focal
Without impairment of NEW TERMINOLOGIES

consciousness
Aphasic status Refractory Status Epilepticus
With impairment of
Refractory SE is defined as SE which is refractory to two
consciousness
—— Unknown whether focal or
intravenous AEDs, one of which is a benzodiazepine.
generalized
Autonomic SE
Super-refractory Status Epilepticus
zz Focal motor Super-refractory status epilepticus is defined as status
—— Repeated focal motor
seizures (Jacksonian)
epilepticus that continues or recurs 24 h or more after the
—— Epilepsia partialis continua onset of anesthetic therapy, including those cases where
(EPC) status epilepticus recurs on the reduction or withdrawal
—— Adversive status
—— Focal inhibitory SE
of anesthesia. This has high mortality and morbidity
rates. This term was first used in the London-Innsbruck
zz Tonic status
Colloquium on status epilepticus held in Oxford in 2011.
zz Hyperkinetic SE
New-Onset Refractory Status

——Progressive (e.g. brain tumor, progressive
myoclonus epilepsies, etc.)
Epilepticus (NORSE)
—— Status in various electroclinical syndromes
This indicates the occurrence of refractory seizures in
Unknown (i.e. cryptogenic). otherwise healthy individuals. Autoimmune encephalitis
is now emerging as the common cause of NORSE.
Axis 3: EEG Correlates
Name of the pattern: Periodic discharges, rhythmic Febrile-Infection Related
delta activity or spike-and-wave/sharp-and-wave Epilepsy Syndrome (FIRES)
plus subtypes This is a catastrophic form of epilepsy occurring in
Morpholog y: Sharpness, number of phases, school-going children between 4 and 9 years following
amplitude, polarity a febrile episode. The epilepsy is now understood to
Location: Generalized, lateralized, bilateral inde be immune-mediated and has generally got a poor
pendent, multifocal outcome.
SUPER-REFRACTORY STATUS inactivated 1 protein antibody (LGI1) and Contactin-

EPILEPTICUS associated protein 2 (CASPR2) antibodies. The other
prominent one to cause super-refractory SE is the
Pathophysiology of Super-refractoriness N-methyl-d-aspartate-antibody (NMDA). Alpha-amino-
Reduction in the number of functional gamma- 3-hydroxy-5-methyl-4- isoxazolepropionic acid receptor
aminobutyric acid (GABA) receptors in the cells (AMPA) antibody, Gamma-aminobutyric acid B receptor
affected in the seizure discharge-this loss of (GABA B) antibody, Metabotropic glutamate receptor
GABAergic receptor density explains the increasing 5 (mGluR5) antibody and the Dipeptidyl-Peptidase-
ineffectiveness of GABAergic drugs Like Protein-6 (DPPX) antibody can also mediate an
The number of glutaminergic receptors at the cell encephalitis presenting as super-refractory SE.
surface increases-this can trigger decrease in GABA
receptors TREATMENT OF SUPER-REFRACTORY
Changes in extracellular ionic environment-especially SE: AN UPDATE
the chloride concentration may render the inhibitory We have presented an algorithm for the management
GABA(A)-mediated currents excitatory of SE in Figure 1. We further discuss the current
Mitochondrial failure can result in failure of seizure understanding of the treatment of super-refractory SE.
termination and cellular damage
The blood–brain barrier may open in SE associated First Line Therapy
with inflammation leading to higher potassium levels General Anesthetics
and excitation-plays a role in seizure perpetuation They are very important in the treatment of super-
refractory SE. Thiopental, midazolam and propofol
Aims of Treatment are the first line drugs whereas ketamine may be
Limit excitotoxic damage considered a second line drug because of its potential
Neuroprotection: Block the processes triggered by neurotoxicity. These four drugs, their dosage, benefits
excitotoxicity and disadvantages are summarized in Table 2.
Avoid or treat the systemic complications of prolonged
unconsciousness and anesthesia. Antiepileptic Drugs
Two antiepileptic drugs at high doses.
Etiology of Super-refractory SE Avoid frequent changing of antiepileptic drugs.
They are usually caused by infections, drugs or toxins, Benzodiazepines and barbiturates with GABA-ergic
mitochondrial disorders, uncommon genetic diseases mechanisms of action may be avoided as they lose
and immunological disorders. Of great interest is the efficacy when the status is prolonged and also since
recent observation of cases where SE develops de novo the anesthetic drugs also have similar mechanism of
and no obvious cause is identified. It was a mistake action.
that many such cases were treated for presumed viral Antiepileptic drugs with predictable kinetics and low
encephalitis so far. With the identification of neuronal potential for drug interaction as well as no liver and
antibodies, it is becoming more and clear that most of kidney toxicity are preferred.
them were indeed nonviral immunologically mediated The possible options at the moment are levetiracetam,
disorders. lacosamide, pregabalin and topiramate.
Neuronal Antibody Mediated Second Line Therapy

Super-refractory SE Hypothermia
They include the voltage-gated potassium channel This should be done only at experienced centers.
(VGKC) antibodies namely Leucine-rich glioma Hypothermia is continued for 24–48 hours with target
Fig. 1: Algorithm for the management of status epilepticus
temperature between 32 and 35 °C. Endovascular cooling infection, thrombosis, disseminated intravascular
is the currently preferred method in adults. Hypothermia coagulation and cardiac arrhythmias.
benefits through reduction of brain metabolism and
ATP consumption and prevention of mitochondrial Magnesium and Pyridoxine Infusions
dysfunction and oxidative stress. It decreases the Both the drugs carry little risk and are easy to administer.
permeability of the blood-brain barrier and limits pro- Magnesium may be infused at 2–6 gm/hour to obtain
inflammatory reactions. The complications include acid– a serum level of 3.5 mmol/L. This may be continued
base and electrolyte disturbances, coagulation disorders, if effective and stopped if ineffective. In children,
TABLE 2: A comparison of the attributes of the four anesthetic agents

Drug Dose Benefits Disadvantages Recommendations
Thiopental/ Thiopental: Loading Strong antiepileptic Zero-order kinetics-tendency First-line therapy in severe
pentobarbital dose: 2–3 mg/kg action; long clinical to accumulate and long cases. Avoid in situations where
Maintenance dose: experience; lowers recovery time, hepatic pharmacokinetic interactions would
3–5 mg/kg/h core temperature; metabolism, autoinduction, be detrimental. Avoid in hepatic
Pentobarbital: neuroprotective effects drug-drug interactions; disease, myasthenia gravis, prophyia,
Loading dose: 5–15 hypotension, cardio- severe hemorrhage or burns,
mg/kg Maintenance respiratory depression; cardiovascular disease
dose: 0.5–3 mg/kg/h and pancreatic and hepatic
toxicity
Midazolam Loading dose: 0.1–0.2 Antiepileptic action only Less effectiove than other First-line therapy in most cases.
mg/kg Maintenance benzodiazepine suitable anesthetics; hypotension, Avoid in hepatic or renal disease,
dose: 0.1–0.4 mg/kg/h for prolonged infusion cardiorespiratory depression; myasthenia gravis, porphyria,
without accumulation risk of hepatic and renal adrenocortical insuffciency
impairment; and risk of
tolerance and break through
seizures
Propofol Loading dose: 3–5 Very rapid onset and Propofol infusion syndrome, First-line therapy in complex cases.
mg/kg recovery allowing ease especially in children; pain Use where other drugs cause
Maintenance dose: of control of anesthesia; at the injection site; and problematic hypotension.
5–10 mg/kg/h no drug interactions less drug-induced involuntary Avoid prolonged infusion (>48)
hypotension and cardio- movements especially at high doses and in
respiratory depression children.
Caution with concurrent steroid or
catecholamine therapy
Ketamine Loading dose: 1–3 No cardiodepressant or Limited published experience Second-line therapy especially where
mg/kg hypotensive action; anti- possible neurotoxicity hypotension or cardiorespiratory
Maintenance dose: up glutaminergic action depression is problematic
to 5 mg/kg/h
pyridoxine deficiency may be difficult to detect and Ketogenic Diet

disastrous if overlooked. Pyridoxine-responsive super- With the availability of readymade solutions, the
refractory SE has also been described. The dose of ketogenic diet is easy to administer in super-refractory
pyridoxine would be 180–300 mg/day. SE. It should not be used with prpofol anesthesia and
with steroids.
Immunological Therapy
A trial of immunotherapy is worthwhile in super-
Emergency Neurosurgery
refractory SE if there is no past history of epilepsy and
This may be tried if there is a clear-cut electrographic
no cause is identified. This is because of the increasing
focus or in the presence of a lesion. Lesionectomy,
roles of neuronal antibodies in SE and inflammation in
epileptogenesis. This would include high dose steroids multiple subpial transections, hemispherortomy and
and a course of intravenous immunoglobulins or plasma corpus callosotomy are the surgeries tried according to
exchange. Long term steroids and repeated courses of the situation.
immunoglobulins may be used if there is response. In
some resistant cases, second-line immunosuppressive Third Line Therapy
ag ents such as c yclophosphamide, r itux imab, There are only evidences from isolated case reports
cyclosporine A and tacrolimus need to be considered. regarding their efficacy and hence they may be tried in
very resistant cases where first and second line therapies 2. Dubey D, Kalita J, Misra UK. Status epilepticus: Refractory
fail. They include and super-refractory. Neurol India. 2017;65:S12-7.
Electroconvulsive therapy
3. Ferlisi M, Shorvon S. The outcome of therapies in refractory
and super‑refractory convulsive status epilepticus and
Cerebrospinal fluid drainage
recommendations for therapy. Brain. 2012;135(Pt 8):
Vagal nerve stimulation
2314‑28.
Deep brain stimulation 4. Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C,
Repetitive transcranial magnetic stimulation. Probasco JC, Jongeling AC, et al. New-onset refractory
status epilepticus: etiology, clinical features, and outcome.
Neurology. 2015;85:1604-13.
CONCLUSION
5. Khoujah D, Abraham MK. Status epilepticus: What’s New?
Status epilepticus is one of the most happening subjects Emerg Med Clin North Am. 2016;34(4):759-76.
in the field of neurology with rapidly changing concepts 6. Lionel KR, Hrishi AP. Seizures—just the tip of the iceberg:
in its diagnosis and treatment. The mystery is not Critical care management of super-refractory status
yet unraveled and more developments are expected epilepticus. Indian J Crit Care Med. 2016;20:587-92.
7. Rossetti AO, Lowenstein DH. Management of refractory
in the coming years. The most recent development
status epilepticus in adults: Still more questions than
has been the identification of super-refractory status
answers. Lancet Neurol. 2011;10:922‑30.
epilepticus. The neuronal antibody mediated disorders 8. Shorvon S, Ferlisi M. The treatment of super‑refractory
are increasingly recognized to present as super-refractory status epilepticus: A critical review of available therapies
SE. Immunotherapy is thus being recognized as a form of and a clinical treatment protocol. Brain. 2011;134(Pt
therapy in SE in addition to antiepileptic drugs and has to 10):2802‑18.
9. Trinka E, Cock H, Hesdorffer D, et al. A definition and
be initiated without delay especially in situations where
classification of status epilepticus—Report of the ILAE Task
the etiology remains uncertain despite all investigations. Force on Classification of Status Epilepticus. Epilepsia.
2015;56:1515-23.
BIBLIOGRAPHY 10. Zaccara G, Giannasi G, Oggioni R, Rosati E, Tramacere L,
1. Betjemann JP. Current trends in treatment of status Palumbo P. Convulsive status epilepticus study group of
epilepticus and refractory status epilepticus. Semin Neurol. the uslcentro Toscana, Italy. Challenges in the treatment of
2015;35(6):621-8. convulsive status epilepticus. Seizure. 2017;47:17-24.
CHAPTER
66
Present Status of Thrombolysis in Acute
Ischemic Stroke: Indian Scenario
V Shankar
INTRODUCTION hospital outside the time window. Factors associated

Thrombolysis for acute ischemic stroke with intravenous with early arrival were distance less than 15 kms from
tissue plasminogen activator (tPA) within 4.5 hours the hospital, history of coronary artery disease, higher
has been shown to improve functional outcome at educational status and presence of hemiplegia. In this
3–6 months in randomized controlled trials and is group of patients who present early and are eligible for
the mainstay of treatment. This review on the present thrombolysis according to current guidelines, nearly
status of thrombolysis in acute ischemic stroke–Indian one fourth were not thrombolyzed due to factors such as
scenario is based on a Pubmed search for the published nonaffordability, fear of bleeding complications, rapidly
articles on the subject and industry reports. A total of 68 improving symptoms, mild stroke, delays in referral to
articles were listed. They dealt with various aspects of the neurologist within the hospital and logistic reasons in
thrombolysis. The papers were classified accordingly and organizing endovascular treatment.
reviewed. Between 2011 and 2015 better organization of
stroke care in tertiary hospitals has shown significant
RATES OF THROMBOLYSIS improvement in door to CT time and door to needle time.
It was estimated in 2007 that 1.44–1.64 million cases of About 100 centers in India were using thrombolysis for
acute stroke occur in India every year and the numbers acute ischemic stroke in 2014 and the numbers must be
must be higher now in 2017. The number of cases growing. Increased stroke awareness among patients and
thrombolyzed across the country rose from 1648 in 2009 physicians, ambulance systems like 108, government
to 12286 in 2016. There are many reasons for this still funding for thrombolysis, and use of telestroke will
low rate of thrombolysis. Almost 75% of the patients increase the rates of thrombolysis.
and their relatives were not aware of the symptoms of
stroke and that thrombolysis is an effective treatment THROMBOLYSIS OUTCOMES
modality. About 75% of general practitioners were not T h e Sa f e I m p l e m e nt at i o n o f T h ro m b o l y s i s i n
clear about the beneficial effects of thrombolysis and Stroke–Non-European union World (SITS-NEW) trial in
80% were not aware of the need to administer it as early Asia including India showed 62.5% of treated patients
as possible within the 4.5 hours time window. As a with functional independence at 3 months (mRS 0–2),
result of poor awareness at the level of the patient and with 1.9% symptomatic intracerebral hemorrhage rate in
the primary care giver nearly 78% of patients reach the 591 patients in 48 centers using alteplase 0.9 mg/kg dose.
CHAPTER 66: Present Status of Thrombolysis in Acute Ischemic Stroke: Indian Scenario 387
This was comparable to the data in the European Safe affinity to PAI-1 and a 4-fold prolonged plasma half-life.
Implementation of Thrombolysis in Stroke-monitoring It is administered as a single bolus. It is less expensive
study and pooled results from randomized controlled than alteplase.
trials. An Indian trial in 92 patients with 0.2 mg/kg of
Age <60 years, admission glucose level <8 mmol/L, tenecteplase found an improvement =/>4 points on
NIHSS score of 10 +/– 6 were associated with major the NIHSS scale in 24 hours in 58% and =/>8 point
neurological improvement at 24 hours and this was an improvement in 22% of patients. The mRS score of 0–1
independent predictor of good outcome at 12 months. was seen in 70% of patients at 90 days. The intracerebral
Cardioembolic strokes and small vessel occlusions hemorrhage rate was 1.19% and the mortality at 90 days
benefit from thrombolysis. Advanced age and more was 5.49%.
severe strokes as assessed by NIHSS scores were
independent predictors of poor outcome. TELESTROKE
Telestroke is useful to reach out to patients in remote
THROMBOLYSIS DOSAGE locations. A telestroke management program has
The dose of tPA used in several Indian studies is the been developed in the state of Himachal Pradesh in
standard dose of 0.9 mg/kg. However, some centers have collaboration with AIIMS. The eighteen primary stroke
used dose ranges of 0.6–0.9 mg/kg, or a fixed dose of 50 centers have been set up in state hospitals with CT scan
mg in the 3–4.5 hour time window. The proportion of
facilities. One hundred and twenty doctors have been
patients with mRS 0–2 at 3 months was about 50% with
trained and patients have been managed successfully.
intracerebral hemorrhage rate of 0–1.7%.
This program can be replicated in other states. The
The need for a properly randomized dose optimization
Telemedicine network of ISRO links 78 remote health
study was highlighted in a study where 46 patients
centres to 22 speciality hospitals in major cities. A hub
received 0.6–0.7, 0.7–0.8, and 0.8–0.9 mg/kg. Clinical
and spoke model can work well wherein specialists at the
improvement was noted in 75%, 85.7% and 66.7% of
hub can interact with physicians in the spoke hospitals
patients in the three different groups.
and guide thrombolysis. Simpler alternatives like
smartphones, online data transfer, apps like whatsapp
SONOTHROMBOLYSIS
can also be used to guide thrombolysis.
Intravenous tPA was combined with transcranial low-
frequency ultrasound waves targeted on the occluded
arterial segment in 18 patients with large artery acute
COMPLICATIONS AND OTHER
ischemic stroke. Immediate dramatic improvement in OBSERVATIONS
NIHSS scores was seen in 30% and within next 24 hours Hemorrhage, anaphylaxis or arterial occlusions are
in 50%. At 6 months, 63% achieved mRS 0–2. 11% of known complications of IV tPA. Two cases of acute
the patients died. Symptomatic ich occurred in 5.5%. myocardial infarction following IV tPA have been
Authors concluded that sonothrombolysis was a safe way documented.
to augment effect of tPA and flow through the occluded Recurrent cardioembolic stroke in the initially
artery could be monitored in real time. unaffected side during thrombolysis for an acute
ischemic stroke has been reported.
TENECTEPLASE IV thrmbolysis has been used in stroke which was
Tenecteplase is a glycoprotein which has a similar later found to be due to right ventricular myxoma with
structure as alteplase with modification at three sites. PFO. It has also been used in a case of left atrial myxoma.
It has certain pharmacological advantages namely a 15 There is also a report of the use of IV thrombolysis
fold higher fibrin specificity, a 80-fold reduced binding beyond guidelines in a patient with a recurrent acute
ischemic stroke who had suffered a posterior circulation An Indian study of 45 patients who had
stroke 5 days earlier. contraindications to iv tpa or failed iv tPA and underwent
endovascular therapy found that 51% achieved a mRS of
INTRAARTERIAL tPA 0 and 64% a mRS of <2 at 3 months follow up. There was 1
Intraarterial tPA has been administered between 4.5 and procedural complication and mortality of 18%.
6.5 hours to acute ischemic stroke patients and mRS sores
</=2 at 90 days were achieved in 7 out of 10 patients. CONCLUSION
Since recanalization rates with IV tPA are low in Time is brain. We have to increase awareness of stroke
large artery occlusions, intraarterial tPA was used in symptoms and the need to reach hospital in time among
17 patients with MCA, carotid T and basilar occlusions the general public. Training programs for doctors,
presenting within 0.5–6 hours after onset. The eight development of national guidelines by the Indian Stroke
patients had a mRS score</= 2 at 3 months and there Association, development of primary and comprehensive
were 3 deaths in the series. stroke centres and the National Program on Prevention
Intraarterial tenecteplase has been used in a case of and Control of Cardiovascular Disease, Diabetes and
M1 MCA occlusion on the third postoperative day after Stroke can contribute to improving thrombolysis in
closed mitral commissurotomy with dramatic recovery. acute ischemic stroke to the required level in the overall
With the recent beneficial experience in using scheme of stroke management.
endovascular therapy with stent retrievers, the newer
American Stroke Association guidelines recommend BIBLIOGRAPHY
e n d ova s c u l a r m e c ha n i ca l t h ro mb e c t o my ove r 1. Bhatia R. A continuing journey. The fight against stroke in
intraarterial thrombolysis as first line therapy and India. World Neurology. 2014;29(6):1.
2. Boddu DB, Srinivasarao Bandaru VC, Reddy PG,
comment that initial intra arterial thrombolysis no
Madhusudan M, Rukmini MK, et al. Predictors of major
longer reflects current practice. neurological improvement after intravenous thrombolysis
in acute ischemic stroke: a hospital-based study from south
THROMBOLYSIS AND ENDOVASCULAR India. Neurol India. 2010;58(3):403-6.
THERAPY 3. Huded V, Nair RR, de Souza R, Vyas DD. Endovascular
treatment of acute ischemic stroke: an Indian experience
Thrombolysis for acute ischemic stroke is not an end in
from a tertiary care center. Neurol India. 2014;62(3):276-9.
itself. In a comprehensive stroke centre any patient who 4. Khurana D, Das B, Kumar A, Kumar SA, Khandelwal N, Lal V,
is eligible for tPA in the time window should receive tPA Prabhakar S. Temporal trends in intravenous thrombolysis
as early as possible. Noninvasive intracranial vascular in acute ischemic stroke: Experience from a tertiary care
imaging like CT angiography should then be obtained center in India. J Stroke Cerebrovasc Dis. 2017;26(6):1266-
as quickly as possible. If there is a proximal large vessel 73.
5. Pandian JD, Sudhan P. Stroke epidemiology and stroke care
occlusion, patients >18 years of age with prestroke mRS
services in India. Journal of Stroke. 2013;15(3):128-34.
0–1, ASPECTS score >/=6 and NIHSS score >/=6, should 6. Rha JH, Shrivastava VP, Wang Y, Lee KE, Ahmed N,
receive endovascular therapy with a stent retriever if Bluhmki E, Hermansson K, Wahlgren N. SITS investigators
groin puncture can be achieved <6 hours from onset. thrombolysis for acute ischaemic stroke with alteplase in an
Endovascular therapy should be considered in patients Asian population: results of the multicenter, multinational
with contraindications to IV tPA and those outside Safe Implementation of thrombolysis in stroke-Non-
European Union World (SITS-NEW). Int J Stroke. 2014;9
the IV tPA time window of 4.5 hours. Ideally patients
(Suppl A100):93-101.
treated with IV tPA in primary stroke centers should be 7. Sharma S, Padma MV, Bhardwaj A, Sharma A, Sawal N,
transported as early as possible to comprehensive stroke Thakur S. Telestroke in resource-poor developing country
centers for possible endovascular therapy if required. model. Neurol India. 2016;64(5):934-40.
CHAPTER
67
Immunomodulation in
Neurological Disorders
INTRODUCTION disease where immunomodulation has changed

Neurological disorders have long been considered the whole outlook of the neurologists (Fig. 1). The
untreatable and mainstay of neurological therapy initial relapsing remitting phase is considered to be
was rehabilitation. However, recognition of the role inflammatory, while the later progressive phase is
of autoimmunity in various neurological disorders degenerative leading to extensive neuroaxonal damage.
means that some of the conditions are now more As such much of the benefit of immunomodulation is in
treatable resulting in a significant decrease in morbidity the early phase and its use in progressive phase is limited.
and mortality. The neuroimmunologic disorders The pathophysiology of MS is complex and the exact
can be broadly divided into 4 groups: demyelinating immune mechanisms have not been fully elucidated.
disorders (MS and neuromyelitis optica), antibody
mediated neuromuscular disorders (such as MG, IMMUNOTHERAPY FOR MS RELAPSES
LEMS, neuromyotonia), inflammatory neuromuscular Relapses are defined as the development of new
disorders (such as Guillain-Barré syndrome and neurological symptoms lasting at least 24 hours, for
dermatomyositis), and autoimmune encephalopathies. which no other cause can be identified. Before starting
Immunomodulatory drugs that modify the response of treatment for a relapse, it is important to rule out a
the immune system by increasing (immunostimulators) pseudo relapse (Fig. 2). Secondly not all relapses
or decreasing (immunosuppressive) the production need to be treated and mild sensory symptoms that
of serum antibodies are increasingly being used in do not cause ataxia or useless hand and mild visual
neurological disorders. 1 Table 1 enumerates the symptoms can be best treated by rest and they may
major classes of immunomodulatory agents that are resolve completely with time. Steroids are the mainstay
being currently used in neurological disorders. In of treatment of MS relapses and the usual dose is 15
this chapter, we will briefly summarize the various mg/kg of methylprednisolone infused slowly, over
neurological conditions that are being treated with 90 minutes for 3–5 days with or without an oral taper
immunomodulation. depending on the perceived and documented severity
of the relapse. Oral steroids can be used in place of
CENTRAL NERVOUS SYSTEM
intravenous treatment and NICE guidelines recommend
DISORDERS 0.5 g oral methylprednisolone daily for 5 days. In
Multiple Sclerosis general relapses should be treated within 14 days of
MS is the most common inflammatory-demyelinating onset, but clinical benefit has been demonstrated upto
disease of the central nervous system (CNS) and one 8–12 weeks. Progression of symptoms for more than 3
TABLE 1: Immunomodulatory agents in neurological disorders
Class Mechanism of action Neurological uses
Glucocorticoids Inhibition of transcription of cytokines into T Acute relapses of MS, NMO

lymphocytes and macrophages ADEM
Demyelinating optic neuritis
Autoimmune encephalitis
Paraneoplastic encephalomyelitis
Chronic inflammatory demyelinating
Polyradiculoneuropathy
Inflammatory myopathies
Myasthenia gravis
Lambert-Eaton myasthenic syndrome
Vasculitic neuropathies
Temporal arteritis
Drugs that bind to Inhibition gene transcription of cytokines (e.g. IL-2) Multiple sclerosis
immunophilins in T lymphocytes (blocking their proliferation), Chronic inflammatory demyelinating
(Immunophillics) inhibition of cytokines of T lymphocytes Polyradiculoneuropathy
Cyclosporine A, Inflammatory myopathies
Tacrolimus Myasthenia gravis
Lambert-Eaton myasthenic syndrome
Cytostatics Inhibition of cell proliferation, inhibition of CIDP

Azathioprine, proliferation of T and B lymphocytes, inhibition of Idiopathic inflammatory myopathy
Cyclophosphamide, cell proliferation NMOSD
Mycophenolate and Myasthenia Gravis
Teriflunomide Autoimmune mediated encephelopathy
Mitoxantrone MS
Vasculitic neuropathies
Primary angiitis of CNS
Monoclonal antibodies Antibodies against key immunological receptors MS

Rituximab, Natalizumab, NMOSD
Alemtuzumab, Myasthenia Gravis
Daclizumab, Ocrelizumab Autoimmune mediated encephelopathy
IVIG Blocks Fc receptors on phagocytic cells GBS

Blocks Fab ligand mediated apoptosis CIDP
Neutralization of cytokines Myasthenia gravis—myasthenic crisis
Anti-idiotypic antibodies directed against idiotypes in NMOSD
circulating antibodies AME
Tumefactive demyelination
Plasma exchange Removal of pathologic antibodies, immune GBS

complexes, and cytokines CIDP
Myasthenic crisis
NMOSD
AME
Tumefactive demyelination
CHAPTER 67: Immunomodulation in Neurological Disorders 391
Fig. 1: T2W MRI showing white matter hyperintensities perpendicular to the lateral ventricles typical of MS
Fig. 2: Algorithm of management of acute relapse of MS
months indicates secondary progression and should the effectiveness of steroids. Overall 15% of patients may
not be treated with acute medication. Steroids hasten not have any effect and one–third of patients may report
recovery from relapse but do not have any effect on worsening of symptoms with steroids.2 ACTH in a dose
overall function. Beneficial effect starts between 7 days of 40 units of ACTH gel IM 2 times a day for 7 days, then
and 10 days after a 5-day course of steroids and it is 20 units 2 times a day for 4 days, and 20 units once a day
prudent to wait for at least 2 weeks before deciding on for 3 days is also approved for use in MS relapse. Being
more expensive and less readily available, it is used as a There are 2 approaches to using DMTs in MS:
second line agent in patients who had no or a suboptimal escalation and induction (Fig. 3). Escalation therapy
response to steroids, or had intolerable side effects to consists of an early start with first line DMDs (beta
steroids. Plasma exchange is also approved as 2nd line interferon, glatiramer acetate, teriflunomide, dimethyl
treatment for acute MS relapse and about 93% of patients fumarate) and if DMDs are ineffective or partially
showed marked improvement and 46% recovered to effective, switching to second line drugs (mitoxantrone,
baseline EDSS after a course of PE. The protocol is to give natalizumab, fingolimod, alemtuzumab).4-6 Induction
1.1 plasma volume units at each exchange every alternate therapy on the other hand consists of the early use
day. Initially 4 exchanges are given and any meaningful of highly active immunosuppressants followed by
improvement should occur by the fourth exchange, so long-term maintenance treatment, generally with
any noticeable improvement should prompt a full seven- immunomodulatory agents. Induction therapy is
session course. Tumefactive or fulminant MS relapses primarily meant for use in patients with aggressive MS i.e.
may be treated with PE, cyclophosphamide with steroids, 2 or more severe attacks with incomplete recovery that
Alemtuzumab and Natalizumab, although there are no affect more than 1 functional systems, MRI shows more
established protocols. 3 IV immunoglobulin (IVIG) is than 2 Gadolinium enhancing lesions or there are more
commonly used in neurologic practice, but its usefulness than 2 spinal cord lesions. Cladribine, cyclophosphamide
in MS is speculative with mixed results. and Stem cell transplant are 3rd line agents that are used
in aggressive MS patients with poor response to 1st or 2nd
DISEASE-MODIFYING line drugs. Medication can be stopped if patients develop
IMMUNOTHERAPY FOR MS secondary progression with EDSS >7 and do not suffer
From the first disease-modifying therapy (DMT), any relapses for at least 2 years.
interferon (IFN) b-1b (Betaseron) that was approved
in 1993, today we have more than 13 DMTs which Neuromyelitis Optica Spectrum
can be used by oral or parenteral route. DMTs can be Disorders
classified as Drugs of moderate efficacy (average relapse Neuromyelitis optica spectrum disorders (NMOSD) is
reduction in 30–50% range) that include the interferons an autoimmune disorder, mediated in most cases by
and oral agents and Drugs of high efficacy (average antibodies to the aquaporin-4 (AQP4) water channel.
relapse reduction substantially more than 50%) which Clinically, NMOSD is characterized by recurrent
include agents such as Alemtuzumab, Natalizumab optic neuritis (ON), relapsing longitudinally extensive
and Mitoxantrone (Table 2). In spite of such many transverse myelitis (LETM), area postrema syndrome,
drugs, there is a consensus that none of the currently acute brainstem syndrome, symptomatic narcolepsy or
available disease-modifying therapies significantly acute diencephalic clinical syndrome and symptomatic
modifies progressively increasing disability that is cerebral syndrome. NMSOD may be associated with
unrelated to relapses (progressive nonrelapsing MS). several other autoimmune disorders. In contrast to MS,
Currently all patients who are diagnosed to have RRMS ON in NMOSD is more often bilateral and severe with
by the MAGNIMS 2016 criteria should be offered DMTs. incomplete recovery, myelitis presents as a complete
Patients who had been diagnosed as RRMS but are not spinal cord syndrome with a lesion involving >3 vertebral
on any DMT and had not have relapses in 2 or more years segments and cerebral lesions may resemble ADEM.
and do not have new MRI lesion activity may be observed Intravenous methylprednisolone (IVMP) and plasma
by serial imaging and close follow-up. Patients with exchange comprise the standard treatments for acute
CIS should be offered consider interferon or glatiramer disease exacerbations in NMO. In contrast to MS, in NMO
acetate if there are more than 2 brain or spinal cord spectrum disorders IV methylprednisolone should be
lesions consistent with MS within 6 months of the event. followed by a prolonged prednisone taper, usually in the
TABLE 2: Disease modifying drugs used in MS

Agent Mechanism Dose Efficacy Adverse effects
(decrease
in relapse
rate)
IFN-β-la Promotes TH1 to TH2 shift 30 µg IM 18% Flu like symptoms, depression, thyroid
(Avonex) weekly dysfunction, liver enzyme abnormalities
IFN-β-1a Promotes TH1 to TH2 shift 22 µg or 44 µg 32% Skin site reactions, flu like symptoms,
(Rebif ) SC 3 times a week depression, thyroid dysfunction,
liver enzyme abnormalities
IFN-β-lb Decreases TH1 and 250 µg SC every 34% Skin site reactions, flu like symptoms,
(Betaseron) TH17 production, increases other day depression, thyroid dysfunction, liver enzyme
IL-10 production, decreases abnormalities
MHC II expression
Pegylated Promotes TH1 to TH2 shift 125 mcg SC, every 14 days 35% Flulike symptoms, depression, thyroid
interferon dysfunction, liver enzyme
(Plegridy) abnormalities
Glatiramer Promotes TH2 suppressor 20 mg SC 29% Skin site reactions, immediate
acetate cells, possibly promotes brain- once a day postinjection reaction, lipoatrophy
(Copaxone) derived neurotrophic factor
Dimethyl Down-regulates intracellular 120 mg twice daily for one 48% Mild depression, URI, thyroid dysfunction
fumarate adhesion molecules and week and 240 mg twice lymphocytopenia
VCAM expression daily thereafter PML (rare)
Fingolimod S1P receptor modulator, 0.5 mg orally once a day 51% First-degree AV block with first dose,
which leads to the bradycardia, macular edema, hypertension,
sequestration of lymphocytes Varicella Zoster, pelvic floor dysfunction in
within the lymph nodes selected patients, skin cancer, back pain
Teriflunomide Inhibits new pyrimidine 7 mg or 14 mg OD orally 33% Agranulocytosis, thrombocytopenia,
synthesis and rapid hepatotoxicity
proliferation of activated
lymphocytes
Mitoxantrone Topoisomerase-2 inhibitor 12 mg/m2 IV every 3 mo 66% Hair loss, cardiotoxicity, leukemia, infertility,
with a lifetime cumulative increased risk of infections, leukopenia, anemia,
dose of no more than 140 nausea, vomiting, thrombocytopenia
mg/m2
Natalizumab 300 mg IV every 28 d Blocks VLA-4 interaction 68% PML
(Tysabri) Consider stopping after 18 with VCAM1, Transient headache fatigue, recurrent
months if JCV Ab +ve thereby preventing UTIs, hypersensitivity reaction
leukocyte
extravasation across the
BBB
Alemtuzumab 24 mg/day or 12 mg/day for Anti CD52 humanized 75% Infusion reactions, infections (herpes, PCP),
5 days MAb and autoimmune disorders - thyroid disorders,
Repeat at 1 year thrombocytopenia, and glomerulonephritis
Daclizumab 150 mg SC once monthly Anti CD25 Humanized Mab 54% Elevation of hepatic transaminases, rash, eczema
Ocrelizumab 300 mg on days 1 and 15, Anti CD20 Antibody 80% Infusion reactions
repeat at 24 weeks Upper respiratory infections and nasopharyngitis
Also approved for PPMS
Azathioprine 2–3 mg/kg/day Purine analog interferes 18 – 23% Flu-like illness, hepatotoxicity, myelosuppression
with T and B cell
proliferation
Fig. 3: Algorithm for management of RRMS
range of 2–6 months because all patients with NMOSD receive prolonged immunosuppression because relapses
will require prolonged immunosuppression. The length in NMOSD can be seriously disabling. Azathioprine,
of taper will depend on the choice of immunosuppressive mycophenolate and Rituximab are the usual first line
agent, being longer in patients started on azathioprine agents used for attack prevention in NMOSD (Table 3).
and shorter in those initiated on Rituximab. If the It is important to note that Interferons, Natalizumab and
symptoms do not clearly improve with IVMP, plasma Fingolimod which are used in MS may be detrimental in
exchange is administered daily or every other day for up NMOSD.7
to five treatments. PLEX should be strongly considered in
situations where corticosteroids fail to stabilize worsening MYELIN OLIGODENDROCYTE
deficits, especially in cases of ascending cervical myelitis GLYCOPROTEIN (MOG) ASSOCIATED
because of the risk of neurogenic respiratory failure and DEMYELINATION
in patients who had previously been successfully treated MOG antibodies are predominately found in children
with PLEX. PLEX may prove to be beneficial in 50–60% with CNS demyelinating diseases, but have also been
of steroid refractory patients. In contrast to MS, PLEX described in adults with ADEM, in anti-AQP4 antibody–
should be used early in course of disease, with some negative NMOSD cases, optic neuritis, transverse
clinicians using combination of IVMP and PLEX. IVIG myelitis, recurrent optic neuritis and in patients with
and cyclophosphamide have also been used in acute antiNMDA receptor encephalitis with demyelination.
relapses of NMOSD. As mentioned earlier all patients MOG-IgG-associated myelitis has been reported
with NMOSD (AQP4 positive or AQP4 negative) should to be relapsing, although relapses appear to be less
TABLE 3: Prophylactic agents used in NMOSD as altered consciousness (lethargy, stupor, coma) and/
Agent Dose Mechanism or altered behavior (irritability or confusion) is one of
the major ADEM defining symptoms as proposed by
Prednisolone 2–20 mg daily Multiple
the international pediatric MS study group (IPMSSG).
Rituximab 1 g at day 1 and day AntiCD 20 antibody
14, repeat every 6
In the absence of encephalopathy, a diagnosis of CIS is
months (optional: entertained. Multiphasic ADEM (MDEM) is defined as
monitoring of CD19 two episodes consistent with ADEM separated by three
counts) months but not followed by any further events. The
Cyclophosphamide 7–25 mg/kg IV Inhibits mitosis term recurrent ADEM is now no longer used and third
monthly for 6 months
ADEM-like event is no longer consistent with MDEM,
Especially in cases
with concomitant but indicates a chronic relapsing demyelinating disorder,
SLE/SS often leading to a diagnosis of ADEM followed by optic
Azathioprine 2.5–3.0 mg/kg daily Blocks synthesis neuritis (ADEM-ON), NMOSD, MOG–IgG associated
of adenine and demyelinating disease or possibly MS. An initial episode
guanine of ADEM needs to be differentiated from ADEM because
Mycophenolate 750–3000 mg daily Inhibits inosine the long-term treatment is different (Table 4). Treatment
monophosphate of ADEM is high-dose intravenous methylprednisolone
dehydrogenase,
primarily the type II 10–30 mg/kg/day up to maximum dose of 1 g/day OD
isoform found in T for 3–5 days followed by oral taper for 4–6 weeks. An
cells and B cells increased risk of relapse has been reported with steroid
Mitoxantrone Initiation with 12 mg/ Intercalates DNA, taper of 3 weeks or less. IVIG and PLEX are 2 nd line
m2 monthly for 3–6 inhibits mitosis therapies but early use of these modalities alone or
months, maintenance
either one in combination with corticosteroids might
with 6–12 mg/m²
every 3 months; be beneficial in patients at risk of complications from
maximum cumulative cerebral edema and raised intracranial pressure.8
dose of 120 mg/m2
Methotrexate 7.5–25 mg once Folic acid antagonist Autoimmune Mediated Encephalopathy
weekly
Autoimmune mediated encephalopathy (AME)
represents a complex category of disease with diverse
frequent than with AQP4-IgG seropositive NMOSD. So, immunologic associations, clinical manifestations, and
treatment with prednisolone to prevent relapse might therapeutic outcomes that is caused by inflammation
be necessary for 6–12 months but the role of long term of the CNS that is initially incited by the interaction of
immunosuppressive treatment is still not clear though autoantibodies in the CSF or serum with specific neuronal
it might be justified in individual patients if there are antigens or sometimes non–neural specific antigens. A
further relapses. classification of AME is given in Figure 5. Neural specific
antigens can be either–intracellular proteins or neuronal
ACUTE DISSEMINATED cell surface or synaptic proteins (Table 5). Patients
ENCEPHALOMYELITIS with AME may present with limbic encephalitis (triad
Acute disseminated encephalomyelitis (ADEM) is a of anterograde amnesia, seizures, psychiatric illness),
postinfectious autoimmune demyelinating condition diencephalic encephalitis (somnolence, narcolepsy,
which produces inflammatory demyelination in the brain hyperthermia, hypothalamic-pituitary dysfunction,
and spinal cord (Fig. 4). ADEM has a polysymptomatic, weight gain or sexual dysfunction), brainstem
multifocal neurological presentation that rapidly progress encephalitis (cranial neuropathy, ophthalmoparesis,
to maximal deficit in 2–5 days. Encephalopathy, defined opsoclonus, parkinsonism, dysarthria or dysphagia) or
Fig. 4: T2 weighted hyperintensities in white matter of parieto-occipital lobe and thalamus in a 28-year-old male who developed polyfocal
neurological deficit following a febrile illness suggestive of ADEM
Fig. 5: Classification of autoimmune encephalitis
encephalomyelitis (additional myelopathy, spasms). those who cannot tolerate corticosteroids) and plasma
In addition, there may be peripheral nervous system exchange (generally reserved for critically ill patients).
involvement in the form of sensory neuronopathy In severe cases, combination of IVIG and IVMP has also
or peripheral nerve hyperexcitability. In general, been tried. The response to immunotherapy is variable
considering the high incidence of tumors, a thorough and significant predictors for improvement include:
screening for any neoplasm should be made and treated subacute onset, fluctuating course, shorter delay to
appropriately. All cases with a diagnosis of AME should treatment, presence of non-neural specific and cell
receive a trial of immunotherapy which also serves surface antibodies. Following the acute course–high
as a diagnostic test in seronegative cases. The acute dose oral steroids, or weekly IVMP or monthly IVIG
therapeutic phase consists of a trial of high dose pulse can be given for at least 6 weeks if there is a response
iv corticosteroids, IVIG (particularly in diabetics and to steroids. Steroids or IVIG can gradually be tapered
TABLE 4: ADEM vs MS
MS ADEM
Previous infection/ Absent Common: While a history of antecedent infection or vaccination is

vaccination indicative of ADEM, an increased frequency of antecedent events,
though to a lesser extent, has been reported in patients with a first
presentation of MS
Age of presentation Young adults - onset of MS has been Children: Children less than 10 years of age are more likely to have
reported at 1 year of age ADEM than MS at the time of an initial demyelinating event
Attacks Separated by >1 month Fluctuate over 3 months
Encephalopathy Rare Required
Margins of lesions Commonly well defined Usually ill defined
Lesion distribution Bilateral and not completely Bilateral and more symmetric than MS
symmetric
Periventricular white Typically, involved Usually spared

matter
Deep grey matter Uncommon Frequent (thalamus and basal ganglia)
Large MRI lesions Rare Frequent
‘Black holes’, hypointense Present Absent

lesions on T1-weighted
imaging
Enhancement Variable between lesions Frequently simultaneous in all lesions or none enhancement
Optic neuritis Present and usually unilateral Present and bilateral more frequently than in MS: Neuromyelitis optica
(NMO) is well recognized as a cause of a bilateral ON and may be an
alternative diagnosis in many cohorts, possibly limiting the usability of
bilateral ON as distinctive factor
Spinal cord lesions More common in the cervical spine Usually thoracic spinal cord
Short lesions Large lesions
Minimal cord selling and contrast Cord swelling is common and variable contrast enhancement
enhancement is also less common
T2 lesion is peripheral, ovoid and T2 lesion is multifocal, flame shaped and can be large (>1/2 of spinal
paracentral (< ½ of spinal cord) cord)
Dissemination in time Present Absent*

3
CSF Minimal pleocytosis (< 50 cells/mm ) Marked pleocytosis (>100/mm3) Increased protein
OCB No OCB
Increased IgG index IgG index negative (OCBs if present are transient)
CSF pleocytosis and elevated protein
can be seen in MS patients as well,
especially in pediatric MS
Pathology Confluent demyelination Perivenous sleeves of demyelination

TABLE 5: Intracellular vs synaptic antigens mediating AME IV) followed by maintenance therapy with methotrexate
Intracellular, onconeuronal Cell surface or synaptic receptor (MT X), azathioprine (AZ A), or less frequently,
antigen mycophenolate mofetil (MMF). It is recommended to
Affect older individuals Affects younger individuals and initiate high dose steroid therapy when the diagnosis is
children
suspected and if possible only start cyclophosphamide
Usually paraneoplastic May or may not be associated when there is diagnostic confirmation by angiography
with cancer
or histology. Cyclophosphamide can be given in daily
Damage is mediated by T-cell Appear to be antibody
mechanisms mediated oral dose or monthly pulses. Subsequently after 6
Examples: Hu, CRMP5, Ri, Yo, Examples: NMDAR, AMPAR,
months, consideration of a low-risk immunosuppressant
Ma2 GABA(B)R, LGI1, Caspr2, GlyR such as Azathioprine (1–2 mg/kg daily), methotrexate
Largely resistant to treatment Often responsive to (20–25 mg/week), or mycophenolate mofetil (1–2
(although stabilization or immunomodulatory therapies g daily) for maintenance of remission is advised.
improvement may occur)
Tumor necrosis factor α (TNFα) blockers such as
Infrequent relapses (usually Varies with antigen (10–25%
Infliximab can successfully treat patients with primary
monophasic and irreversible) may relapse)
CNS vasculitis that is resistant to glucocorticoids and
immunosuppressants.
after 4–6 months under cover of a steroid sparing agent
such as azathioprine, mycophenolate, methotrexate or
DISEASE AFFECTING THE PERIPHERAL
rituximab. In case, there is no response to 1st line therapy
NERVOUS SYSTEM
within 10 days second line therapy with Rituximab or
cyclophosphamide should be initiated in antibody Acute Inflammatory Demyelinating
positive cases (Fig. 6). In antibody negative cases, a brain Polyradiculoneuropathy
biopsy may be considered if the response is inadequate. Acute inflammatory demyelinating polyradiculo
Periodic attempts to withdraw immunosuppression neuropathy (AIDP) is an immunological disorder with
should be made every 2–3 years since some patients may an acute, often fulminant evolution characterized by
experience spontaneous remissions while others may a syndrome of rapidly progressive flaccid paralysis,
require lifelong therapy. Hashimoto Encephalopathy areflexia and albumin cytological dissociation in the
(now known as Steroid responsive autoimmune CSF (Fig. 7). Immunotherapy with PLEX or IVIG is
encephalitis with autoimmune thyroiditis) is managed considered as the mainstay of treatment and should be
in a similar way. started as soon as possible. The north American trial and
French Plasmapheresis Group trial have demonstrated
PRIMARY ANGIITIS OF CNS that PLEX halves the need for ventilation, hastens
CNS vasculitis can be secondary to systemic vasculitis or recovery and improves outcome at 1 year if administered
isolated to the CNS [Primary Angiitis of CNS (PACNS)]. within 4 weeks of onset. A Cochrane review confirmed
In contrast to common belief PACNS does not present as the value of plasma exchange over supportive therapy
recurrent strokes, instead the common presentations are: in hastening the recovery from GBS when started within
acute or subacute encephalopathy, relapsing remitting 30 days after disease onset. It is indicated in moderate-
neurologic deficits or symptoms suggestive of rapidly severe cases who are unable to walk without support
progressive space-occupying lesion with headache and >10M, with a significant decrease in VC or oropharyngeal
focal neurologic deficits. CSF is usually abnormal and paralysis (Table 6). The benefit is more when IVIG
angiography may reveal beading in small arteries, but is started within 2 weeks of onset and the strength of
meningeal biopsy is usually needed for confirmation. recommendation is weaker for use of IVIG beyond 4
PACNS is treated with a combination of corticosteroids weeks. In ambulatory patients, benefit of IVIG is not
(initially high dose IVMP) with cyclophosphamide (Class clear, but because there is no way to distinguish mild
Fig. 6: Suggested management protocol of AME
Fig. 7: Showing makedly prolonged distal latencies, reduced nerve conduction velocity and nonrecordable sensory nerve action potential
in right median nerve of acute onset with two weeks duration of proximal weekness in all four limbs suggestive of acute inflammatory
demyelinating polyneuropathy—Guillain Barré syndrome
cases from progressive cases, ambulatory patients are The mean time to improvement of one clinical
also treated with IVIG, particularly if neurological deficits grade in the various controlled, randomized PLEX and
are progressing. IVIG studies ranged from 6 days to 27 days. With both
TABLE 6: Plasma exchange and IVIG in AIDP four trials of oral corticosteroids oral corticosteroids may
Plasma exchange slow recovery, while IV steroids showed a nonsignificant
Indications trend towards more benefit as compared to placebo. The
zz Non-ambulatory patients: 4–5 PE (2–2.5L each time) within 4
combination of IVIG with methylprednisolone failed to
weeks of onset (Level A Class II evidence)
zz Ambulatory patients: 2 PE within 2 weeks of onset (Level B,
find significant long-term advantage over IVIG alone in
limited Class II) one trial.
zz Dose: 200–250 ML/KG (alternate day PE is better than daily PE)
Complications Chronic Inflammatory Demyelinating

Hemodynamic and cardiovascular
zz Hypotension
Polyradiculoneuropathy
Acute respiratory distress syndrome Chronic inflammatory demyelinating polyradiculo
Myocardial infarction neuropathy (CIDP) is characterized by multifocal
Arrhythmias
demyelination observed in spinal roots, proximal nerve
Complications due to vascular access
zz Septicemia
trunks, major nerve plexuses, and peripheral nerves
zz Thrombosis (Fig. 8). There are several variants of CIDP as enlisted
Complications associated with replacement fluids in Table 7, and the treatment in general is same except
zz Allergic reactions
for the DADS variant with IgM paraprotein which
zz HIV, Hepatitis
zz Bleeding
is more resistant to treatment (responds only to PE,
Depletion of plasma components minimally to IVIG). According to EFNS guidelines, a
zz Loss of clotting factors, globulins
trial of steroids should be considered in all patients
zz Loss of protein bound drugs
with CIDP and significant disability. Clinical experience
IVIG
suggests that steroids are more likely to induce remission
Indications
zz Non-ambulatory patients: 2 g/kg over 5 days within 2 weeks of as compared to other modalities, but the response is
onset (Level A, Class II) usually slower, with first signs of improvement usually
zz 2 g/kg over 5 days within 2–4 weeks of onset (Level B, Class II)
seen by 4 weeks, but occasionally it may take up to 5
zz Ambulatory patients: No indication but may be used in patients
who are progressing and present within 2 weeks of onset of months.12,13 Besides oral steroids, weekly doses of IVMP
illness and oral dexamethasone has also been used. Once a
Complications response is observed which usually takes 1–3 months,
zz Headache including aseptic meningitis
slow steroid tapering is started and most patients require
zz Deep venous thrombosis
zz Myocardial Infarction
low dose steroids for 1–2 years. In case of relapse or
zz Oligaemic renal failure unwanted adverse effects, immunotherapy with steroid
zz Anaphylaxis—especially in IgA deficiency
sparing agents may be added. The overall benefit with
IVIG is like that of steroids or PLEX, but the response
PLEX and IVIG, one or more episodes of deterioration is usually faster seen within 7–10 days, with maximum
following the initial improvement or stabilization after benefit in 2–3 weeks. The response is short lived and
treatment, described as “treatment-related fluctuations repeat courses are required after 4–6 weeks. Benefit
(TRIF)” may be encountered in as many as 6–16% of may not however be apparent after the first course of
patients. In patients who suffer such relapses or TRIFs, IVIG treatment, and some experts advocate repeating
additional courses of PE or IVIG are indicated.9-11 infusion of IVIG (1 g/kg) three weeks after the initial
There is, however, no evidence that PE beyond 250 treatment before determining efficacy. Subsequent
mL/kg or IVIG greater than 2 g/kg are of any added infusions are given at 3–8 week interval depending on
benefit in patients with AIDP, who have stable deficits clinical evaluation. Once maximum benefit is reached,
that are not improving as quickly as the patient and their same dose is continued for 6 months and then frequency
physician would like. The role of steroids is unclear as the of injections is gradually decreased. Notably in the
Fig. 8: Nerve conduction study of median nerve in a patient with CIDP shows increased distal latency and
conduction block with temporal dispersion
TABLE 7: Variants of CIDP
Classical CIDP: Symmetric proximal and distal motor predominant

CIDP
Multifocal acquired demyelinating sensory and motor neuropathy

(MADSAM)/Multifocal CIDP/Lewis Sumner syndrome (LSS)
Chronic sensory demyelinating neuropathy (Sensory CIDP)
Chronic immune sensory polyradiculopathy (CISP)
Pure motor CIDP
Distal acquired demyelinating symmetric neuropathy (DADS)
—— DADS with IgM paraprotein ± antimyelin associated

glycoprotein (anti-MAG) antibodies
—— DADS without an IGM monoclonal protein
Fig. 9: Showing asymmetric progressive weakness and wasting of

five years duration in a 40-year-male in the left thenar eminence.
ICE study, it was noted that a small portion of patients Nerve conduction studies revealed pure motor involvement with
(<20%) responded to one treatment and not require conduction block suggestive of MMN. The patient disease process
halted following IvIg therapy
further therapy. In younger patients in whom IVIG is well
tolerated it may be continued by extending the interval
between doses provided the patient does not relapse, Multifocal Motor Neuropathy
however older patients with comorbid disease, have a Multifocal motor neuropathy (MMN) is an immune-
high risk of thromboembolic events if IVIG is continued mediated demyelinating neuropathy characterized
for >5 years. In case of deterioration on tapering of IVIG clinically by asymmetrical weakness and atrophy,
or if requirement of IVIG remains high, steroids and/or typically in the distribution of individual peripheral
additional immunosuppressive agent should be added. nerves with a characteristic electrophysiological feature
Plasma exchange is as effective as prednisone and IVIG, of persistent conduction block in motor nerves in
but it is generally reserved for refractory cases.14 IVIG is segments not usually associated with compression
the treatment of choice of in pure motor CIDP. or entrapment (Fig. 9). Preferred treatment is IVIG,
reported to benefit 70% of patients in open uncontrolled should be on immunosuppressants. 17 In ocular MG

trials and four randomized, controlled, double-blind (OMG), use of steroids not only improves symptoms
trials. Improvement begins within 3 weeks of treatment more effectively than pyridostigmine alone, but also
but lasts only for weeks to months. Although about a third prevents generalization. So early steroid treatment
of patients may experience prolong remissions of longer should be discussed with all patients suffering from
than 12 months, the majority require repeated IVIG OMG and constitutes an effective treatment option in the
infusions or possibly additional immunosuppressive absence of contraindications. To avoid steroid induced
treatment. Rituximab has recently been used to treat worsening, steroids should be started in a low dose (5
immune mediated neuropathies including MMN. mg every alternate day) and dose gradually increased 5
mg every three days until symptoms improve or a target
Myasthenia Gravis dose of 0.75 mg/kg/alternate day for OMG or 1.5 mg/
Acquired MG is an autoimmune disorder of the kg/alternate day for generalized MG is reached. In this
neuromuscular junction. Rapid immunotherapies protocol, the onset of improvement will be significantly
(PLEX and IVIG) are used in newly diagnosed patient prolonged and often takes four to eight weeks. Remission
with substantial weakness requiring a quick therapeutic on corticosteroid therapy is defined as the absence of
effect, moderate – severe relapse i.e. deterioration in a symptoms and signs after pyridostigmine withdrawal
patient whose myasthenia was previously controlled and it may take several months to achieve full remission.
and myasthenic crisis (relapse requiring ventilatory Once remission is achieved slow tapering of steroids
assistance), preoperatively before thymectomy or other is attempted. One of the most common mistakes in
surgery and rarely to maintain remission in patients management of MG is failure to induce remission in a
with MG that is not well controlled despite the use of timely manner using corticosteroids. Since achievement
chronic immunomodulating drugs. Use of PLEX and of remission may take a long time, it is prudent to start
IVIG in MG is compared in Table 8. Historically, many azathioprine along with steroids to avoid adverse effects
neurologists have considered PLEX superior to IVIG but of steroids. The flaw with the escalation approach is
recent studies have shown that PLEX performed slightly that clinical benefit is often unpredictable and can be
better than IVIG, although both treatments were found significantly delayed and the risk of corticosteroid-
to be statistically equivalent relative to both the degree of related exacerbation is not eliminated. So, in patients
efficacy and the number of MG patients that benefitted with moderate–severe disease it is better to use the high
from their use.15,16 On the other hand, a Cochrane review dose regimen admitting the patient and with a cover
on this subject concluded that although efficacy is equal, of PE or IVIG. Besides azathioprine, mycophenolate,
side effects of IVIG may be fewer and less severe. cyclophosphamide, cyclosporine and tacrolimus are
In general, all patients with MG, whose symptoms also used as steroid sparing agents. Rituximab is of use in
are not adequately controlled on pyridostigmine alone patients with MuSK MG, who may be refractory to other
forms of treatment.
TABLE 8: PLEX vs IVIG in MG
IVIG PLEX CONCLUSION
Onset of action Late (5–10 days), Earlier (2–5 days) To conclude, neurotherapeutics has undergone
may be delayed a sea – change in the last 20 years and many new
upto 19 days immunotherapies are now available that have changed
Maximum effect 2 weeks 2 weeks the entire field of neurology. More and more conditions,
Duration of effect 4–8 weeks – lasts 3–4 weeks which were once thought to be untreatable are now
longer
potentially treatable and knowledge about these new
Complications Less More
immunomodulatory agents is essential in current
Cost More Less
neurological practice.
REFERENCES of the American Academy of Neurology. Neurology. 2012;

1. Villoslada P, Moreno B, Melero I, Pablos JL, Martino G, et 78(13):1009-15.
al. Immunotherapy for neurological diseases. Clin Immunol. 10. Meena AK, Khadilkar SV, Murthy JMK. Treatment guidelines
2008;128(3):294-305. for Guillain–Barré syndrome. Annals of Indian Academy of
2. Graves D, Vernino S. Immunotherapies in neurologic Neurology. 2011;14(Suppl1):S73-S81. doi:10.4103/0972-
disorders. Med Clin North Am. 2012;96(3):497-523, x. doi: 2327.83087.
10.1016/j.mcna.2012.05.001. 11. Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré
3. Frederick MC, Cameron MH. Tumefactive demyelinating syndrome. Lancet. 2016;388(10045):717-27.
lesions in multiple sclerosis and associated disorders. Curr 12. Oaklander AL, Lunn MP, Hughes RA, van Schaik IN,
Neurol Neurosci Rep. 2016;16(3):26. Frost C, Chalk CH. Treatments for chronic inflammatory
4. Rush CA, MacLean HJ, Freedman MS. Aggressive multiple demyelinating polyradiculoneuropathy (CIDP): an overview
sclerosis: proposed definition and treatment algorithm. Nat of systematic reviews. Cochrane Database Syst Rev.
Rev Neurol. 2015;11(7):379-89. 2017;1:CD010369.
5. Scolding N, Barnes D, Cader S, Chataway J, Chaudhuri A, 13. Hughes RA, Mehndiratta MM. Corticosteroids for chronic
et al. Association of British Neurologists: revised (2015) inflammatory demyelinating polyradiculoneuropathy.
guidelines for prescribing disease-modifying treatments in Cochrane Database Syst Rev. 2015;1:CD002062. doi:
multiple sclerosis. Pract Neurol. 2015;15(4):273-9. 10.1002/14651858.CD002062.pub3. Review. PMID:
6. Freedman MS, Selchen D, Arnold DL, Prat A, Banwell B, 25561247
Yeung M, Morgenthau D, Lapierre Y. Canadian Multiple 14. Mehndiratta MM, Hughes RA, Pritchard J. Plasma
Sclerosis Working Group. Treatment optimization in MS: exchange for chronic inflammator y demyelinating
Canadian MS Working Group updated recommendations. polyradiculoneuropathy. Cochrane Database Syst Rev.
Can J Neurol Sci. 2013;40(3):307-23. 2015;(8):CD003906. doi: 10.1002/14651858.CD003906.
7. Papadopoulos MC, Bennett JL, Verkman AS. Treatment 15. Dau PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler
of neuromyelitis optica: state-of-the-art and emerging LE. Plasmapheresis and immunosuppressive drug therapy
therapies. Nat Rev Neurol. 2014;10(9):493-506. in myasthenia gravis. N Engl J Med. 1977;297:1134-40.
8. A l ex a n d e r M , M u r t hy J M K . A c u te d i s s e m i n a te d 16. Bril V, Barnett-Tapia C, Barth D, Katzberg HD. IVIG and PLEX
encephalomyelitis: Treatment guidelines. Annals of Indian in the treatment of myasthenia gravis. Ann NY Acad Sci.
Academy of Neurology. 2011;14(Suppl1):S60-4. 2012;1275(1):1-6.
9. Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. 17. Sussman J, Farrugia ME, Maddison P, Hill M, Leite MI,
Evidence-based guideline: intravenous immunoglobulin in Hilton-Jones D. Myasthenia gravis: Association of British
the treatment of neuromuscular disorders: report of the Neurologists’ management guidelines. Pract Neurol.
Therapeutics and Technology Assessment Subcommittee 2015;15(3):199-206.
CHAPTER
68
Vertigo: Clinical Approach and Management
Lakshmi Narasimhan Ranganathan, Thamil Pavai N, Guhan R, Arun Shivaraman MM, Mugundhan Krishnan
INTRODUCTION Classification of Vestibular Disorders

Vertigo is commonly faced in neurologic consultation The vestibular disorders are classified into peripheral
constituting upto 13% patients. Vertigo, disequilibrium and central. Involvement of labyrinth and vestibular
and lightheadedness are commonly unified and nerve is categorized as peripheral disorders whereas
misdescribed by patients under the broader term involvement of vestibular nucleus and projections from
dizziness. Vertigo is characterised by rotatory illusion the nucleus to cerebellum, thalamus and cortical areas
of self or surrounding and may be accompanied by are categorized as central disorders.
autonomic and postural manifestations. Disequilibrium
is described as instability in posture without rotatory Differentiation of Peripheral and
nystagmus. Light headedness is character ised Central Vestibular Disorders
by misperception of spatial orientation and may be In a patient who presents with acute vestibular syndrome,
accompanied by autonomic symptoms. It may also be it is essential to differentiate central from peripheral
described as sense of tilting or swaying. causes. A three step approach, HINTS, which comprises
of Head impulse test (HIT), nystagmus and test for skew
Approach to Vertigo helps in detecting a central lesion with a sensitivity
Vertigo is a symptom and may result from pathological of 90%, that is higher than MRI brain with diffusion
dysfunction of the peripheral labyrinth, vestibular sequences. A normal head impulse, presence of gaze
neural structure and central brainstem structures. An evoked nystagmus and presence of skew deviation
appropriate focussed history and clinical examination is suggest central cause for vertigo. Nevertheless, head
required in deciphering and localizing the coordinates of impulse test may be positive in lesions (demyelination,
the lesions and the cause of it. The history is summarized lacunar infarct) involving the point of entry of the
in Table 1. Examination should be focussed on: vestibular nerve into the brainstem. The head impulse
General examination
test can be quantitatively measured using video HIT. It
Assessment of presence of vestibular dysfunction
quantitatively measures the VOR gain and the amplitude
Differentiation between central and peripheral
of the catch up saccade. The findings in vHIT are:
causes of vertigo. The general examination and tests Acute peripheral vestibulopathy—Ipsilateral reduction
of vestibular function are summarized in Table 2. in VOR gain

CHAPTER 68: Vertigo: Clinical Approach and Management 405
TABLE 1: History in a patient with vertigo

1. Description of symptoms
zz Symptom of sense of spinning favors the vertigo and central or peripheral vestibular dysfunction
zz Sense of near fainting favors cardiovascular etiology
zz It is difficult to ascribe mechanisms to other descriptions
2. Timing and duration of symptoms-vertigo lasting for the specified duration helps narrow the diagnosis
zz Seconds to minutes: Benign paroxysmal positional vertigo, vertebrobasilar transient ischemic attack, perilymphatic fistula
zz Hours: Menieres disease, migraine, perilymphatic fistula
zz Days: Vestibular neuritis, migraine, posterior circulation stroke
zz Continuous over several weeks: Central etiology, psychogenic
3. Trigger factors
zz Vertigo that occurs when the patient is rolling over in bed or following sudden turning of head suggests benign paroxysmal positional
vertigo
zz Dizziness that occurs following getting up and not in supine position favors hemodynamic mechanisms
zz Vertigo triggered by loud sound suggests tulip phenomenon seen in superior semicircular canal dehiscence
4. Associated symptoms
zz Associated symptoms of cranial nerve dysfunction favours central vertigo
zz Associated unilateral hearing loss suggests peripheral vertigo
5. Past history
zz History of migraine suggests migraine associated vestibulopathy
zz History of trauma may suggest post traumatic vertigo or may precede BPPV, vertebral artery dissection
zz History of diabetes mellitus, systemic hypertension and other vascular risk factors favor central cause of vertigo
zz History of drug intake that are known to produce dizziness may suggest drug induced etiology
zz Prior family history may suggest hereditary channelopathies
TABLE 2: General examination and tests of vestibular function Stroke in posterior inferior cerebellar artery—
General examination Bilateral symmetric reduction in VOR gain
zz Anemia Stroke in anterior inferior cerebellar involvement—
zz Nystagmus
Bilateral asymmetric reduction in VOR gain with
zz Otological examination
zz Blood pressure and pulse examination

more loss on the ipsilateral side.
zz Herpetic skin lesions A five step approach has a better sensitivity than
zz Cardiac auscultation
HINTS. It includes in addition to above steps the
Tests of vestibular function following: Look for presence of vestibular nystagmus
zz Vestibulo-ocular assessment
with the use of frenzel glasses to avoid fixation, look for
—— Head impulse test
—— Dynamic visual acuity saccadic and smooth pursuit eye movements in vertical
zz Vestibulospinal assessment and horizontal gaze. The characteristics of the nystagmus
—— Finger nose coordination for past pointing—Finger under
that helps differentiate central from peripheral disorders
shoots on the side of lesion and overshoot is evident on the
are summarized in Table 3.
contralateral side
—— Fukuda Unterberger test
—— Romberg test Triage-TiTrATE Approach

—— Tandem walking
Triage-Titrate approach to a patient presenting with
—— Star walking testfe
zz Assessment of nystagmus
vertigo includes:
zz Assessment of skew deviation Triage-Triaging a patient with red flag signs that
zz Other tests and maneuvers:

warrants early intervention
—— Dix hallpike manoeuvre
Timing-Timing denotes onset, duration and recurrent
—— Subjective visual vertical
—— Caloric test nature of the vertigo

TABLE 3: Difference between peripheral and central vertigo

Peripheral vertigo Central vertigo
Nystagmus Unidirectional nystagmus, horizontal and Direction changing gaze evoked nystagmus. Purely
torsional nystagmus horizontal or purely vertical or purely torsional
Latency, fatiguability of Latency present, fatiguable and decreases on No latency, not fatiguable and fixation does not
nystagmus and effect of fixation fixation affect the nystagmus
Head impulse test Abnormal on the ipsilesional side Normal
Skew deviation Absent Present
Associated symptoms Sensorineural hearing loss may be present Presence of cranial nerve involvement and long tract
signs
Fig. 1: TiTrATE approach to patients presenting with episodic and acute vestibular syndrome
Abbreviations: BPPV, benign paroxysmal positional vertigo; CPPV, central paroxysmal positional vertigo;
HINTS, head impulse test, nystagmus, test for skew
Trigger-Trigger denotes the activity and the circum Chronic persistent with obligate triggers
stances under which vertigo develops and targeted Chronic persistent without obligate triggers
examination to identify the possible etiology The targeted examination and the possible etiologies
Based on the above attributes the vertiginous patient of the acute presentation is depicted in Figure 1.
may fall into one of the following categories:
Episodic spontaneous
Peripheral Causes of Vertigo
Episodic triggered Benign Paroxysmal Positional Vertigo (BPPV)
Acute vestibular syndrome - spontaneous It is the leading cause of episodic vertigo characterized
Acute vestibular syndrome - triggered by vertigo that lasts from seconds to minutes provoked
by changes in head position and rolling in bed. It results TABLE 4: Disease specific treatment in vertigo
from dislodgement of calcium carbonate crystals from Etiology Treatment
the otoconia that then traverses the semicircular canal.
Benign paroxysmal zz Posterior canal: Epley maneuver,
These crystals inappropriately stimulate the cupola of
positional vertigo Semont maneuver
the semicircular canals. The posterior semicircular canal zz Horizontal canal: Log roll exercise,
(85%) is most commonly involved followed by horizontal Gufoni maneuver

zz Anterior canal: Yacovino maneuver
(10%) and anterior semicircular canal (5%). The typical
history would help in the diagnosis. Vestibular neuritis zz Corticosteroids: Prednisolone 60 mg /
Dix Hall-pike maneuver is helpful in identifying the day for 5 days followed by a rapid taper
in 5 days
canal involved based on the pattern of nystagmus. It is
essential to hold the patients in provocative position Meniere disease zz Diet modification: Avoid caffeine, salt,
for at least 30 seconds owing to the latency of the alcohol, nicotine
zz Medical therapy: Diuretic therapy when
nystagmus. In posterior semicircular canal involvement, diet modification does not provide
the nystagmus is upbeating with rotational component adequate control
zz Surgical treatment if medical therapy
(fast component towards the ground). In anterior,
fails to produce improvement: It
semicircular canal involvement the nystagmus is down
includes destructive and nondestructive
beating. In horizontal, semicircular canal involvement, procedures
the nystagmus is horizontal direction which changes in
Superior semicircular Surgical repair of anatomical deficit
direction with changing head direction. The involvement canal dehiscence
of horizontal semicircular canal is best elicited by
Multiple sclerosis Disease modifying therapy
Pagnini-McClure supine test in which the patient is
placed in supine position and the head is turned to the
right and then to the left while looking for the nystagmus. Vertebrobasilar Secondary prevention of stroke
It is essential to differentiate it from central positional ischemia
vertigo, characterized by the involvement of vermis of Vestibular migraine zz Mild cases: Dietary and lifestyle
the cerebellum. It causes vertigo incited by the changes modifications
zz Moderate to severe cases: Prophylaxis
in position accompanied by down beat nystagmus. The
with propranolol, amitriptyline,
nystagmus has onset without latency, not fatiguable and
topiramate, valproate sodium,
not accompanied by a rotational component all of which verapamil
are lacking in BPPV. Patients are treated using particle
Episodic ataxia type 2 Acetazoamide
repositioning maneuvers, the choice of which depends
on the canal involved (see Table 4). Vestibular zz In young individuals, large tumor
schwannoma size, significant hearing impairment
- surgical and radiation therpies are
Vestibular Neuritis decided based on patient specific
It occurs due to herpes simplex reactivation in the factors
zz In elderly individuals and small lesion
vestibular ganglion resulting in degeneration of the
size, observation is required to look
peripheral process and specialized sensory epithelium.
for rapid tutor growth. When the rate
Superior vestibular nerve carries special sensory of growth is >2.5 mm/year serves,
information from anterior and horizontal semicircular intervention is required
canal and utricle. It is more commonly involved due to Medulloblastoma Craniospinal radiotherapy, adjuvant
its slender course through temporal bone where it is combination chemotherapy
susceptible to entrapment and edema. Patient presents
Chiari malformation Suboccipital decompressive surgery
with vertigo associated with vomiting that has an acute
onset and last for few hours and may last upto days. In canal. When the intracranial pressure increases during
labyrinthitis, there is an accompanying hearing loss. sneezing, coughing and during valsalva maneuver, it
In herpes zoster oticus, patient may have ear pain in causes the pressure to be transmitted through the defect
association with vesicles in the external ear. resulting in episodes of vertigo associated with nausea
Examination reveals hypofunction of the involved and vomiting. Tulio phenomenon, vertigo induced by
vestibular apparatus evidenced by impaired head loud sounds occurs in patients with superior semicircular
impulse test and caloric test. Primary position nystagmus canal dehiscence. Vestibulo-ocular reflex evoked by click
may be evident with fast component opposite to in cervical vestibular evoked myogenic potential has
the side of lesion, does not change direction and it large amplitude with decreased threshold in patients
increases with an attempted gaze towards the side of with tulio phenomenon. HRCT of the temporal bone is
fast component (Alexander’s law). The intensity of the useful in detecting the defect.
nystagmus gradually decreases with time due to central
compensatory measures. Nevertheless, head impulse Central Causes of Vertigo
test is abnormal and can be used to demonstrate the It is essential to differentiate central causes of vertigo from
vestibular hypofunction. The nystagmus is absent when other benign causes. The symptoms are less disabling
the vestibular neuritis affects the inferior vestibular as compared to peripheral vestibular involvement.
nerve. Recurrence of vestibular neuritis is rare and hence However, the signs are more prominent and frequently
when present alternate diagnosis of episodic vertigo the patient is unable to walk unaided. Vertigo and
such as Meniere disease should be considered. Caloric imbalance may result due to involvement of central
testing may indicate the laterality of the vestibular vestibular pathway, ascending projections, thalamus
hypofunction. As it mimics acute stroke, neuroimaging is and cortex. The central vestibular pathway is depicted in
required in elderly patients with vascular risk factors and Figure 2. The central causes of vertigo may result from:
in those with atypical features. Disease is self limiting
and treatment required corticosteroids and vestibular Structural Causes
sedatives in the short term. Acylovir or valacyclovir Vertebrobasilar stroke/Transient ischemic attack
should be added in herpes zoster oticus. Demyelination
Tumor (Medulloblastoma, vestibular schwannoma)
Ménière’s Disease Craniovertebral junction lesions
It is characterized by endolymphatic hydrops owing to
vascular, genetic and immunologic factors. Patients are Nonstructural
usually affected in the ages between 40–60 years of age Vestibular migraine
with men and women affected equally. It is characterized Episodic ataxia syndromes
by episodes of vertigo, hearing loss and fullness of the Drugs and toxins
ear. Sudden falls without loss of consciousness may also
occur (Tumarkin otolithic crisis). Each episode of vertigo Structural Causes
may last from 20 minutes upto 12 hours. Audiometric and Vertebro basilar stroke/transient ischemic attack
vestibular assessment are nonspecific. Neuroimaging is (TIA): Stroke or TIA resulting from involvement of
required to rule out central causes of vertigo in patient the vertebrobasilar system that supplies the central
presenting with acute vestibular syndrome. vestibular connections causes imbalance. The symptoms
lasts for less than 24 hours in transient ischemic attack
Superior Semicircular Canal Dehiscence with a median duration of 8 minutes. The involvement
Superior semicircular canal dehiscence results from of the vestibular nucleus and cerebellum may result in
thinning of the superior wall of the superior semicircular sustained rotational vertigo. However, involvement of
Fig. 2: Vestibular symptoms resulting from disorders of central vestibular system
higher ascending projections, thalamus and cortex may favor the attribution of vertigo to multiple sclerosis as
result in transient rotational vertigo. The presence of they do not occur in peripheral etiology: gaze evoked
accompanying clinical findings such as diplopia, facial nystagmus, upbeat nystagmus, pendular nystagmus,
palsy, nystagmus, visual field defects may help delineate periodic alternating nystagmus, see-saw nystagmus,
the vascular territory. The brainstem involvement may parinaud syndrome and internuclear ophthalmoplegia.
result from vascular compromise of posterior inferior Malignancy: Medulloblastoma is the most common
cerebellar artery, anterior inferior cerebellar artery, infratentorial tumor in children. The involvement of
superior cerebellar artery, paramedian penetrating the cerebellum and vestibulocerebellar fibers causes
arteries and short circumflex arteries arising from unsteadiness along with features of raised intracranial
basilar artery and top of basilar artery. The wide spread pressure including headache and vomiting. Vermian
vascular etiology for the occurrence of vertigo suggest the involvement produces truncal and gait ataxia whereas
extensive and intricate vestibular and cerebellar network the hemispheric involvement produces incoordination
that pans across the brainstem. In the absence of vascular of limbs.
involvement in neuroimaging, the following needs to be Vestibular schwannoma is the most common
considered: cardiac and paradoxical thromboemboli, cerebellopontine angle tumor. It presents with
hypercoagulable and hyperviscosity syndromes, basilar unsteadiness, vertigo, hearing loss, facial palsy and
migraine and disorders of mitochondria. trigeminal sensory involvement. When the patient
Demyelination: Demyelination disorder exemplified by presents acutely, intratumoral hemorrhage should be
the multiple sclerosis may present with vertigo due to considered. Neuroimaging reveals T1 hypointense to
isotense lesion in the cerebellopotine angle with T2
demyelination involving the brainstem. However, vertigo
mixed hyperintensity and intense contrast enhancement.
in a multiple sclerosis patient is not always demyelination
and can be due to benign paroxysmal positional vertigo Craniovertebral junction lesions: It includes Chiari
or migraine. The presence of the following features may malformation, atlantoaxial subluxation and basilar
invagination. Vertigo occurs due to involvement streptomycin and tobramycin, the drugs and toxins
of the vestibular pathways in the medulla and that cause postural and gait instability by affecting the
vestibulocerebellum. cerebellar fibers include antiepileptic drugs (phenytoin,
The clinical manifestation of the imbalance and carbamazepine), chemotherapeutic drugs (cytarabine,
associated symptoms may depend on the site of 5 fluorouracil, vincristine) and toxins (alcohol, carbon
involvement by the structural lesion (Fig. 2). tetrachloride, toluene).
Nonstructural Etiology TREATMENT OF VERTIGO

Vestibular migraine: It is characterized by episodes of The treatment of vertigo depends on the correct diagnosis
vertigo and heightened sensitivity to motion. Diagnostic of the cause of vertigo. The three step approach to the
criteria requires the occurrence of a minimum of five treatment of vertigo include:
episodes of vertigo, increased motion sensitivity that Disease specific treatment
ranges in duration between 5 minutes and 72 hours Symptomatic treatment
that may be accompanied by headache, photophobia, Vestibular rehabilitation
phonophobia and visual aura. The duration of vertigo is

Disease specific treatment: Disease specific treatment is
widely varied between patients and between episodes in
summarized in Table 4.
the same patient. The exact mechanism is not known but
may result from increased sensitivity of brainstem nuclei Symptomatic treatment : Symptomatic treatment
causing photophobia, phonophobia, osmophobia. suppresses vestibular symptoms with the use of the drugs
Patient may also experience visual vertigo (optokinetic mentioned below. These are useful in the treatment of
motion sickness) characterized by vertiginous sensation symptoms that last from few minutes to hours and days.
on looking at moving scenes such as while traveling in However, long term use should be discouraged as it may
a train. Investigations including video-nystagmogram interfere with the compensatory mechanisms.
Histamine analogs
and neuroimaging are useful to rule out other etiologies
Antihistaminics
and have nonspecific findings in vestibular migraine. Its
Benzodiazepines
presence may significantly reduce the quality of life.
Antiemetics
Episodic ataxia syndromes: Episodic ataxia are a group Calcium channel blockers.
of seven autosomal dominant disorders characterized
Betahistine (H1 receptor partial agonist and H3
by episodic ataxia. Episodic ataxia (EA) 1 and 2 are more
receptor antagonist) acts through peripheral mecha
common compared to the rest. EA 1 is a potassium
nisms to decrease the asymmetric vestibular input.
channelopathy characterized by episodes of vertigo with
It acts through central mechanisms and increases
dysarthria that lasts for minutes. The interval between
histamine synthesis thereby augmenting central
episodes are characterized by myokymia. EA 2 is calcium
compensation. Dosage recommended is 4–16 mg thrice
channelopathy characterized by episodes of vertigo,
daily. Use is contraindicated in liver dysfunction and
ataxia and downbeat nystagmus with an episode lasting
pheochromocytoma. Cautious use should be exercised in
for minutes upto days. The downbeat nystagmus may
bronchial asthma. Antihistaminics (diphenhydramine,
be evident in supine position in between episodes that
dimenhydrinate, meclizine) are most commonly used.
helps to differentiate it from migraine. Neuroimaging
In pregnancy, meclizine is preferred. Benzodiazepines
may reveal vermian atrophy. It is essential to recognize
(diazepam, clonazepam) are useful when antihistaminic
the condition as it may respond to treatment with
are ineffective and the patient has accompanying
acetazolamide.
anxiety. Antiemetics (prochlorperazine, domperidone,
Drugs and toxins: Apart from the drugs that causes metaclopromide, promethazine) are useful when
vertigo by virtue of its vestibulotoxicity such gentamicin, the vertigo is accompanied by vomiting. The use of
metaclopromide may result in extrapyramidal side CONCLUSION

effects. Calcium channel blocker (Cinnarizine, A structured and systematic approach to vertigo is
Flunarizine) acts through calcium channel blockade required to elucidate the etiology, the lack of which may
through central and peripheral mechanisms. It also cause the investigator to be lost in the complex intricate
mediates through cholinergic receptor blockade and network of causation. A disease specific treatment should
histamine receptor blockade. It is useful in migrainous be pursued while the acute symptomatic treatment can
patients presenting with vertigo. produce short term relief.
Vestibular rehabilitation therapy: The clinical recovery BIBLIOGRAPHY

following a peripheral vestibular disorder predates 1. Brandt T, Dieterich M. The dizzy patient: don’t forget
the vestibular function recovery. This is due to the disorders of the central vestibular system. Nature Reviews
compensation by the central mechanisms. The Neurology. 2017;13(6):352-62.
2. Brandt T. Vertigo: its multisensory syndromes. Springer
rehabilitation accelerates the above process and utilizes
Science & Business Media; 2013 Jun 29.
the plasticity of the vestibular network in enhancing 3. Campbell WW, DeJong RN. DeJong’s the neurologic
the natural process of recovery. It has established examination. Lippincott Williams & Wilkins; 2005.
usefulness in peripheral vestibular disorders. However, 4. Choi KD, Lee H, Kim JS. Vertigo in brainstem and cerebellar
it may also be useful in central causes of vertigo. The strokes. Current opinion in neurology. 2013;26(1):90-5.
5. Fife TD. Dizziness in the outpatient care setting. CONTINUUM:
three mechanism include habituation, adaptation and
Lifelong learning in neurology. Selected Topics in Outpatient
substitution. In habituation, repeated stimuli decreases Neurology. 2017;23(2):359-95.
symptoms with subsequent stimuli. Substitution utilises 6. Newman-Toker DE, Edlow JA. TiTrATE: a novel approach to
visual cues and proprioceptive cues to compensate diagnosing acute dizziness and vertigo. Neurologic clinics.
vestibular dysfunction. Adaptation aims to improve 2015;33(3):577.
7. Ranganathan LN. Monograph on vertigo and syncope.
vestibulo-ocular reflex gain. Vestibular exercises should
Jaypee Publications, 2017. ISBN: 978-93-86261-30-4.
begin at the earliest after the symptom onset. The 8. Thompson TL, Amedee R. Vertigo: a review of common
rehabilitation is not useful in episodic vertigo that lasts peripheral and central vestibular disorders. The Ochsner
for seconds and in perilymphatic fistula. Journal. 2009;9(1):20-6.
SECTION
6
Gastroenterology/Hepatology
Acute Upper Gastrointestinal Bleeding Hepatorenal Syndrome: Clinical Considerations
Rajesh Upadhyay, Deepak Sharma Tanuja Pravin Manohar
Acute Pancreatitis Cirrhosis of Liver: Beyond Beta-blockers
G Loganathan, L Santhosh Vivekanadan and Diuretics
Anup K Das
The Gut Microbiota: A Forgotten Organ
Balvir Singh, Ram Prakash Pandey, Mridul Chaturvedi, Hepatitis B: Are We Moving Ahead Towards Cure?
TP Singh, Ashish Gautam Anil C Anand
Nonalcoholic Fatty Liver Disease: HIV/Hepatitis Coinfections
Is it Really Benign? PK Agrawal
AK Chauhan
Fecal Microbiota Transplantation:
Glucose Metabolism Disorders in Current Indications and Methods
Chronic Liver Disease L Ilavarasi, SS Lakshmanan
CHAPTER
69
Acute Upper Gastrointestinal Bleeding
Rajesh Upadhyay, Deepak Sharma
INTRODUCTION TABLE 1: Causes of upper gastrointestinal (UGI) bleeding
Acute upper gastrointestinal (UGI) bleeding is a common Causes of UGI bleed common Less common
medical emergency worldwide. It accounts for about Peptic ulcer (Duodenal/Gastric) Esophagitis
50–60% of all patients hospitalized for GI bleeding. The Variceal bleed (Esophageal/Gastric) Dieulafoy’s lesion
annual rate of hospitalization for UGI bleed has been Erosions Vascular ectasias
Mallory Weiss tear Portal congestive
estimated at 30–100 patients per 100,000 population.
gastropathy
It has a significant morbidity and mortality. Mortality
Gastric antral vascular ectasia
rates from UGI hemorrhage have remained fairly stable (GAVE)
at 3.5–7% over the past 20-30 years. The likely reason for UGI tumors
this is an increasing proportion of elderly patients with
comorbidities who have a higher mortality. Various causes of acute UGI bleed are shown in
Table 1.
ETIOLOGY
Peptic ulcer disease is the most common cause of acute RISK FACTORS
UGI bleed, accounting for about 50% of cases. Bleeding Independent risk factors for ulcer hemorrhage are
from duodenal ulcer is commoner than gastric ulcer (i) older age, (ii) use of aspirin or nonsteroidal anti-
bleed. Ulcer bleed stops spontaneously in 70-80% cases. inflammatory drugs (NSAIDs), and (iii) patients with
Mortality in such patients are negligible. In the group of history of previous peptic ulcer. In patients taking aspirin
patients, where bleeding recurs or persists the mortality is or NSAIDs the risk of bleeding is higher during initial
high at 25–30% especially in those with severe comorbid period of treatment and is dose dependant. COX 2
conditions. inhibitors have relatively lower risk compared to COX 1
Variceal bleed is another common cause of UGI inhibitors. Concomitant use of aspirin, NSAIDs, steroids,
bleed. In India, variceal bleed is common in some anticoagulants or dual antiplatelet therapy and advanced
regions whereas ulcer disease is commoner in other age may increase the risk of ulcer bleeding. H-Pylori
regions. Variceal bleed occurs in patients with liver infection is associated with recurrent peptic ulcer but is
cirrhosis and portal hypertension. Esophageal varices not an independent risk factor for ulcer bleed. However,
occurs in about 30–40% patients with cirrhosis and 60% H. Pylori eradication reduces the risk of ulcer bleed in
of patients with cirrhosis and ascites. aspirin users with a prior ulcer bleed.
416 SECTION 6: Gastroenterology/Hepatology
Upto 25% of cirrhosis patients with new varices will a brief history and physical examination should be done
experience bleeding within 2 years. The most important concurrently.
risk factors for variceal bleed include (i) pressure within An early decision must be made whether ICU or ward
the varix, (ii) variceal size, (iii) tension on the variceal care is indicated depending on severity of bleed and
wall and (iv) severity of the liver disease. The risk of hemodynamic stability. All patients with severe bleed
bleeding by 2 years is 7% patients in small varices as should be considered for ICU admission.
compared to 30% in those with large varices. Airway protection is critical during severe UGI
bleed, especially for those with altered sensorium or
CLINICAL PRESENTATION respiratory complications which have a significantly
Patients with UGI bleeding present with hematemesis, higher mortality. Endotracheal intubation should be
melena, or both. Hematochezia may be the only considered for prevention of aspiration in patients
presentation in 5–15% patients with UGI bleed. Painless with continuing hematemesis, altered mental status,
(silent) bleeding ulcers may often be the presenting altered respiratory status, or with severe neuromuscular
feature in elderly patients, inpatients or those on NSAIDs disorders. An adequate intravenous (IV) access, should
or aspirin. Patients with age >60 years, inpatient bleed be established with wide bore cannula and appropriate
and presence of comorbidities especially cardiovascular, fluid and blood products are infused. Blood–products
respiratory, hepatic, or malignant disease have a higher should be given with the aim of keeping hemoglobin
mortality. Several scoring systems are used to stratify above 7–8 g/dL, platelet count above 50,000/mm,
patients of ulcer bleed into high or low risk. Rockall and INR below 1.5. Fresh frozen plasma should be
and Glasgow Blatchford scoring (GBS) systems have given in cirrhotic patients, if fibrinogen level <1 g/L
been commonly used. Recently a modified GBS system or prothrombin time >1.5 times normal. Prothrombin
has been used as a better predictor of outcome in UGI complex concentrate should be considered in patients
bleed. In patients with variceal bleed the mortality is taking warfarin and actively bleeding.
best predicted by severity of liver disease score such Recent data suggests that a restrictive transfusion
as assessed by Child’s Pugh score or MELD score. strategy (packed red blood cells transfusion given
Patients with advanced liver disease (Childs-C or MELD only at hemoglobin level <7 g/dL, with a target of
>18), bleeding at time of endoscopy, severe anemia, 7–9 g/dL). However, this strategy needs to be modified
hypotension, failure to control bleeding, presence of in hypotensive patients with severe bleed or those with
renal dysfunction or requirement of >4 units of blood are associated cardiovascular disease. Over transfusion
some of the predictors of outcome from variceal bleed. should be avoided especially in patients with variceal
bleed since it may lead to rebound increase in portal
MANAGEMENT pressure.
The steps of management are: Nasogastric tube (NG) should be placed in patients
Resuscitation with severe bleed, hemodynamically unstable, altered
Assessment/stabilization sensorium or those where the site of bleed is unclear. NG
Medical therapy tube provides help in assessment of blood loss in patients
Definitive therapy (Endoscopy/Surgery/Inter with severe bleed and may also help to clear the stomach
ventional radiology) with gastric lavage prior to endoscopy. There is no value
Prevention of re-bleed of cold saline lavage and water may be used. Large
Initial management at first encounter with a patient volume lavage should be avoided since it may increase
with UGI bleed is resuscitation and stabilization with the risk of aspiration. The use of IV prokinetics such as
correction of fluid losses and restoring hemodynamic metoclopramide or erythromycin prior to endoscopy
stability. An evaluation of the severity of the bleed, and remains debatable.
CHAPTER 69: Acute Upper Gastrointestinal Bleeding 417
MEDICAL THERAPY should be considered for patients with shock and signs of
The aim of medical management is to reduce morbidity, ongoing bleed where hemodynamic stability is difficult
mortality, risk of re-bleeding, transfusion requirements, to achieve or when prior endoscopy has not localized the
duration of hospitalization, and need for endoscopic source. For all other patients, early endoscopy within 24
intervention or surgery. Gastric acidity adversely hours (preferably within 8–12 hours) should be the rule.
influences clot formation with maximal clot lysis at Endoscopy is diagnostic in almost 95% of patients
pH 2. Increasing intragastric pH to >6 improves the with severe UGI bleed and helps to stratify patients into
coagulation process and helps reduce bleeding. PPIs are high and low risk groups. Endoscopically demonstrated
most effective acid inhibitors and provide sustained high stigmata of recent hemorrhage (SRH) on ulcers identify
intragastric pH. Early institution of IV PPI reduces severity high risk ulcers from low risk of re-bleed. Endoscopic
of ulcer bleed, reduces the rate of re-bleeding, but does hemostasis for high risk ulcers reduces re-bleeding rates,
not decrease mortality. Re-bleeding is most common duration of hospitalization, need for the transfusion, and
during the first 72 hours, PPIs such as pantoprazole, need for surgery although its effects on mortality remains
esomeprazole should be given as a bolus of 80 mg IV, uncertain. At endoscopy, ulcers are graded as per Forrest
followed by an 8 mg/hr infusion for 3 days. There is no classification which grades the ulcer into those with high
clear benefit of one PPI over the other and in clinical versus low risk of rebleeding and mortality (Table 2).
practice any one may be used in the standard doses. Approximately 20–25% of patients with severe ulcer
In high-risk bleeding ulcer patients, endoscopic bleeding requiring ICU admission have a nonbleeding
therapy + PPI is superior to PPI infusion alone in visible vessel. Approximately 50% of these patients re-
preventing recurrent bleed. Patients with low-risk bleed during hospitalization when treated medically,
endoscopic findings (such as clean ulcer base or flat and 40% with severe bleed, not treated with endoscopic
spots) should be treated with oral PPI once daily. More hemostasis, require ulcer surgery. Only about 15% of
recent trials have suggested that: high-dose oral PPI is ulcer have active arterial type bleeding at endoscopy and
just as effective as an IV infusion after endoscopy therapy. is a challenge for endoscopic hemostasis with significant
In patients of variceal bleed, restrictive strategy of failure and recurrence of bleed.
transfusing PRBCs only when the Hb level is less than There are a number of endoscopic modalities for
7 g/dL has been shown to be associated with better treatment of ulcer bleed (Table 3). Combination of
survival in patients with cirrhosis. Antibiotics should two modalities has been found to be more effective in
be given to all patients to prevent bacteremia and achieving hemostasis compared to one modality. The
spontaneous bacterial peritonitis. Endoscopic therapy most common method used is injection of adrenaline
along with early pharmacologic therapy is better than
TABLE 2: Risk stratification of Forrest classification
pharmacologic treatment alone. Vasoactive agents are
associated with improved hemostasis and a shorter Forrest classification Rebleeding Mortality
rate rate
hospitalization period. Terlipressin, somatostatin and
Active bleed
octreotide are the options for pharmacologic therapy
Ia. Spurting bleed 55–100% 11%
but only terlipressin has survival benefit. Pharmacologic
Ib. Oozing bleed
treatment should be continued for 3–5 days to prevent
early re-bleeding. Recent bleed
IIa. Nonbleeding visible vessel (NBVV) 40–50% 11%
ENDOSCOPIC THERAPY IIb. Adherent clot 20–30% 7%
Endoscopy is the recommended modality for diagnosis Lesion without bleeding
and treatment of UGI bleed because of high diagnostic IIc. Flat spot 10% 3%
accuracy and low complications. Emergency endoscopy II1. Clean base 5% 2%
TABLE 3: Endoscopic modalities of treatment of ulcer bleed option and hemoclipping is likely to be more beneficial
zz Injection since it causes no significance tissue injury. Surgery in
—— Adrenaline such patients carries a higher morbidity and mortality.
—— Tissue glues
Variceal bleeding cannot be controlled in 10–15% of
—— Clotting factors
—— Nano powder
patients despite endoscopic therapy. When two attempts
zz Thermal at endoscopic treatment fail to control variceal bleed,
—— Heater probe alternative intervention such as transjugular intrahepatic
—— Bipolar probe
portosystemic shunt (TIPS) should be done. This group of
—— Nd: YAG laser
—— Argon plasma coagulation

patients have a higher mortality rate. Balloon tamponade
may be used to stabilize a patient until definitive
zz Mechanical
—— Hemoclips treatment can be carried out. Recently a covered SEMS
—— Banding (SX-Ella stent Danis) has become available, which is
retrieved within 7 days.
1:10000 at the edges of the ulcer and this should ideally
be combined with coagulation or mechanical clipping in SURGICAL TREATMENT
order to achieve the best results. Surgical treatment for ulcer bleed is indicated if there is
Bleeding from esophageal varices is diagnosed if failure to secure active bleeding by endoscopic means
there is active bleeding; signs of recent hemorrhage, or in patients with rapid exsanguination and inability to
(white fibrin plug or a red blood clot over a varix); identify a bleeding lesion.
varices with risk signs for bleeding, (cherry-red spot, Less than 5% of the patients require surgical
hematocystic spot, or red wale sign). Variceal bleed management. The choice of operation depends on
may also be considered in patients with hematemesis location of the ulcer, and overall condition of the patient.
when there is varices but no other lesions in UGI tract to Laparoscopic approach has become more appealing to a
account for the bleed. small subset of ulcer patients.
Endoscopic variceal ligation (EVL) is the modality of Emergency surgical treatment for uncontrolled
choice for variceal bleed. Initial ligation should be at or variceal bleed is extremely uncommon. Surgical
immediately below the site of bleeding on the varix. Other portosystemic shunts are effective in controlling variceal
large varices also should be banded at the same time. If bleed but have largely been abandoned because of high
active bleeding is not seen, ligation should be carried mortality rate.
out beginning at the gastroesophageal junction and
proceeding proximally at an intervals of 2 cm in a spiral ANGIOGRAPHIC THERAPY
fashion. If bleeding obscures the varices, then multiple Angiographic therapy for ulcer bleed is ideally suited for
bands are placed at the gastroesophageal junction endoscopic haemostasis failures who are poor surgical
circumferentially until bleeding is controlled, but the candidates. It is also suited for patients with severe
long-term risk of esophageal stricture is increased. bleeding where endoscopy has failed to reveal a bleeding
Bleeding can be controlled in upto 90% of patients site. Angiography can identify the site of bleeding if blood
with a combination of pharmacologic and endoscopic loss rate is 0.5 ml or more/min. Two different angiographic
treatment. therapeutic techniques can be used—vasoactive drug
Re-bleeding after endoscopy therapy occurs in infusion and embolization. Embolic materials, such
10–20% of patients with ulcer bleed and is a challenging as Gelfoam, tissue adhesives, coils, or other occlusion
problem. Endoscopic therapy is indicated for significant devices, can be selectively injected through a catheter
re-bleed. Evidence suggest that repeat endoscopic into the bleeding artery. Potential complications of
haemostasis using a different modality may be the best embolization therapy include ischemia and perforation.
CHAPTER 69: Acute Upper Gastrointestinal Bleeding 419
Flow chart 1: A practical algorithm for management of UGI bleed
Arterial embolization has been compared to surgery in gastrointestinal risks. In high risk cardiovascular patients
patients with failed endoscopic hemostasis and shown with recent coronary stenting, aspirin may be continued
to decrease the risk for subsequent surgery and reduce after endoscopic hemostasis.
complications without increasing the mortality rate. Re-bleeding after variceal bleed occurs in about 80%
cases within two years. Thus all variceal bleed patients
PREVENTION OF RE-BLEED should receive secondary prophylaxis with repeated
After endoscopic hemostasis of ulcer bleed, treatment sessions of EVL at 3–4 weeks interval till obliteration of
with PPIs is recommended for 6–8 weeks. Long term varices. Usually 2–4 endoscopic sessions are required.
acid reduction treatment is required for patients on Concomitant use of oral nonselective beta blockers such
continuing aspirin, NSAID or warfarin therapy. H. pylori as propranolol, nadolol or carvedilol is recommended to
positive patients should receive antibiotic therapy. reduce portal pressure.
The management of patients with ulcer bleed while An algorithm for management of UGI bleed has been
receiving antiplatelet therapy such as aspirin, clopidogrel shows in Flow chart 1.
or other anticoagulant is controversial. Although early
reintroduction of low dose aspirin after hemostasis BIBLIOGRAPHY
has a higher risk of recurrent bleed but this strategy 1. Bambha K, Kim WR, Pedersen R, et al. Predictors of early
decreases all-cause mortality rates due to reduction re-bleeding and mortality after acute variceal haemorrhage
in patients with cirrhosis. Gut. 2008;57:814-20.
in cardiovascular and cerebrovascular complications.
2. Barkun AN, Bardou M, et al. International Consensus.
Therefore, patients requiring secondary cardiovascular Recommendations on the management of patients with
prophylaxis should restart aspirin treatment within non-variceal gastrointestinal bleeding. Ann Intern Med.
7 days or as soon as cardiovascular risk outweigh 2010;152: 101-13.
3. de Francis R, Baveno VI faculty. Expanding consensus in Society of Gastrointestinal Endoscopy (ESGE) guideline;
portal hypertension: report of the Baveno VI consensus Endoscopy-2015.
workshop: Stratifying risk and individualising care for portal 7. Mehta D, Non-variceal upper gastrointestinal bleed, API
hypertension. J Hepatol. 2015;63:743-52. Medicine Update, 2013.
4. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal 8. Sachar H, Vaidya K, et al. Intermittent vs continuous proton
hypertensive bleeding in cirrhosis: Risk stratification, pump inhibitor therapy for high-risk bleeding ulcers: a
diagnosis and management: 2016 practice guidance by systematic review and meta-analysis, JAMA Intern Med.
the American Association for the study of liver disease. 2014; 174:1755-62.
Hepatology. 2017;65:310-35. 9. Singh SP, Panigrahi MK. Spectrum of upper gastrointestinal
5. Garcia-Tsao G, Bosch J. Varices and variceal hemorrhage in haemorrhage in coastal odisha, tropical gastroenterology,
cirrhosis: a new view of an old problem. Clin Gastroenterol 2013.
Hepatol. 2015;13:2109-17. 10. Villanueva C, Colomo A, et al. Transfusion strategies for
6. Gralnek lan M, et al. Diagnosis and management of nonacute upper gastrointestinal bleeding. N Engl J Med. 2013.
variceal upper gastrointestinal hemorrhage: European
CHAPTER
70
Acute Pancreatitis
G Loganathan, L Santhosh Vivekanadan
INTRODUCTION activation of proteolytic enzymes within pancreas

Acute pancreatitis is amongst the most common GI leading to cell damage and acute inflammatory response,
emergency requiring hospitalization in both medical which if unchecked, causes, acute pancreatitis.5 There
and surgical units. It results from acute inflammatory are a number of etiological factors which can cause
response of pancreas to a variety of inciting factors causing acute pancreatitis (Table 1 and Fig. 2). Gallstone and
a local and systemic inflammatory response syndrome. alcohol are common causes, while in 10–15% of cases
The incidence of acute pancreatitis ranges from 10 to the etiology remains unclear (idiopathic).4 Infections are
45 per 100,000 population.1,2 A rising incidence of acute uncommon causes but awareness is required, especially
pancreatitis is due to increased alcohol consumption and in Indian context.7,8
obesity which is a risk factor for gall stone formation.1,3 Why only a few with risk 7,8 factor for pancreas
The disease affects patients of all age groups; in India, develop acute pancreatitis needs further understanding.
the disease is more common in men than women, as Proposed mechanisms leading to activation of pancreatic
alcohol consumption (an important risk factor) is seen enzymes in acini include production of toxins like fatty
predominantly in men.4 20% of patients with pancreatitis
acid esters from alcohol, reflux of bile into pancreatic
develop severe manifestations with pancreatic and
duct due to obstruction of papilla by gallstone and
peripancreatic necrosis and multiple organ dysfunction.
inappropriate pancreatic enzyme activation due to
New evidence from randomized control trials considered
genetic mutations. 5 This is followed by damage to
as the reference standard universally had facilitated
pancreatic acinar cells, vascular injury, and acute
better understanding of the pathogenesis, the assessment
of disease severity. 5,6 Nutritional and fluid therapy, inflammatory response. 5 The cascade of events after
innovative interventional techniques with distinctive initial inflammation are almost similar irrespective of
role for endoscopic, radiological and surgical treatment the various causes of acute pancreatitis. In most patients,
strategies in managing patients with local complications the inflammation is controlled in few days leading to
have decreased morbidity and mortality (Fig. 1). recovery (mild pancreatitis) while in some, there is a
vigorous response leading to pancreatic necrosis and
ETIOPATHOGENESIS organ dysfunction (moderate-to-severe pancreatitis).9
Disruption or over whelming of protective mechanisms The cause of pancreatitis dictates the specific treatment
by pancreatic enzymes against autolysis cause premature to be offered and hence is important.
Fig. 1: The classification and mortality against the severity of acute pancreatitis
TABLE 1: Acute pancreatitis—causes

S. No. Cause Frequency % Diagnostic clues Comments
1 Gallstones 40 Direct sign: Demonstration of stone on imaging EUS can help diagnosis
Indirect sign: Hyperbilirubinemia, elevation of liver
enzymes and alkaline phosphatase
2 Alcohol 30 Acute flares on underlying chronic pancreatitis History, CAGE questionnaire
3 Hypertriglyceridemia 2–5 Fasting triglycerides >100 mg/dL
4 Genetic * Recurrent acute pancreatitis and chronic
pancreatitis
5 Drugs <5 Presence of allergy to drugs Idiosyncratic and usually mild
6 Autoimmune <1 Type 1: Obstructive jaundice. Elevated IgG4 and Type 1: Systemic disease involving
response to glucocorticoids pancreas, salivary gland and kidneys
Type 2: Possible presentation as acute pancreatitis, Type 2: Only pancreas
in young, IgG4 not elevated, response to
glucocorticoids
7 ERCP 5–10** Symptom reduction with rectal NSAID
or PD stent placement
8 Trauma <1 Blunt/penetrating trauma in the midbody where
it crosses the spine
9 Infections <1 Virus: CMV, Mumps, EBV most common,
Parasites: Ascariasis, Clonorchis
10 Surgical complication 5–10*** Due to pancreatic ischemia and could
be severe
11 Obstruction Rare Celiac, Crohn’s disease, pancreas divisum Rarely malignant pancreatic duct,
ampullary obstruction
12 Associated conditions Common Diabetes, Obesity and Smoking
*Not Known, **among patients undergoing ERCP, *** Among patients undergoing cardiopulmonary bypass
Abbreviations: EUS, Endoscopic ultrasound; CMV, Cytomegalovirus; EBV, Epstein-Barr virus
CHAPTER 70: Acute Pancreatitis 423
CLINICAL FEATURES, DIAGNOSIS and stays elevated longer. 8 Elevation of trypsinogen

AND SEVERITY PREDICTION activation peptide derived from trypsinogen has been
shown to have diagnostic and prognostic value.8
Diagnosis
The diagnosis of acute pancreatitis requires two of the Imaging
following three features according to Revised Atlanta Imaging findings include demonstration of altered texture
Classification 2012. in the region involved with edema, pancreatic necrosis,
1. Abdominal pain consistent with pancreatitis. pancreatic ductal disruption, pancreatic fluid collection
2. Elevation of serum amylase or lipase to more than (PFC), peripancreatic inflammation with edema, acute
three times upper limit of normal value. fluid collection with or without necrosis, inflammation
3. Findings consistent with acute pancreatitis on
of mesentery and omentum, free fluid (which may be
imaging (Ultrasound abdomen, Contrast Enhanced
inflammatory or pancreatic ascites), perinephric halo,
CT – CECT, MRI).
bilateral pleural effusion, left sided pleural effusion
often implying involvement of tail of the pancreas and
Clinical Features
pancreatic hydrothorax. Abdominal skiagram would
Patients with acute pancreatitis develop rapid onset,
show sentinel loop sign, colon cut off sign and features
acute severe upper abdominal pain more often in
of ileus. Imaging findings can help in identification of
epigastrium with radiation to back and lasts for many
the cause of pancreatitis like sausage shaped pancreas
hours to days. The pain worsens with food and gets
in auto-immune pancreatitis, demonstration of stone in
partially better in forward bending position. It is often
common bile duct indicative of acute biliary pancreatitis,
accompanied by nausea and vomiting and occasionally
pancreas divisum, traumatic pancreatitis (Figs 2A to
with abdominal distension. The pain settles in few days
D) periampullary malignancy/bile duct stricture with
in majority of cases with complete recovery. Features
of organ dysfunction like breathlessness, hypotension, dilated system leading to obstructive pancreatitis. USG
altered mental status, and reduced urinary output abdomen is the best screening test. Contrast enhanced
may develop. As a rule, fever in the first week is due to ultrasound which provides a dynamic view of the
inflammation and in the third week is due to infection “vascular pattern” is emerging as a reliable, noninvasive,
unless proved otherwise. Patients with alcohol-related imaging modality with sensitivity of 92% and specificity
acute pancreatitis may develop features of alcohol 84%. 10 CECT remains the ideal test for pancreatic
withdrawal. morphology and gives more detailed information
Abdominal examination may be normal or show on pancreatic necrosis. MRCP is good for imaging
minimal epigastric tenderness in mild acute pancreatitis. pancreatico-biliary ductal morphology.
In moderate-to-severe cases, there may be significant
epigastric tenderness, with or without guarding, Differential Diagnosis
abdominal distension due to ileus and/or ascites. Other The differential diagnosis of acute upper abdominal
findings which are less common include pleural effusion, pain includes perforated peptic ulcer (obliteration of
ecchymotic patches in flank (Grey Turner’s sign) or liver dullness and free air under diaphragm), mesenteric
periumbilical area (Cullen’s sign), and subcutaneous fat ischemia (symptom – sign discordance with evidence on
necrosis. CT and USG doppler with postprandial indices for arterial
ischemia) inferior wall myocardial infarction (ECG,
Enzymes ECHO, Trop T), aortic dissection (chest skiagram, USG,
Enzyme (amylase and lipase) elevation above three CT), acute cholecystitis (sonographic Murphy’s sign, gall
times the upper limit of normal is considered diagnostic bladder wall thickening >4 mm, and or pericholecystic
of acute pancreatitis. 7,8 Lipase has more specificity fluid collection), etc.9
A B
C D
Figs 2A to D: Specific etiology of acute pancreatitis. (A) MRCP image showing calculi in the CBD (white arrow). (B) MRCP image showing
pancreas divisum. Pancreatic duct is seen draining into the minor papilla (white arrow) while the CBD is seen draining into the major papilla
(white asterisk). (C) CECT image showing traumatic disruption of the pancreatic duct (white arrow) communicating with a small anteriror
peripancreatic collection (white asterisks). Dilated distal pancreatic duct in the tail. (D) CECT image showing diffusely enlarged, sausage-
shaped pancreas in a known patient of autoimmune pancreatitits
Disease Classification and and readily available, Bedside Index of Severity in Acute
Assessment of Severity Pancreatitis (BISAP) score,17 Harmless Acute Pancreatitis
The severity of acute pancreatitis is classified as mild Score18 (HAPS) with advantage of use within 30 minutes
(absence of local and systemic complications), moderate of admission with high specificity and predictability in
(presence of local or systemic complications or transient identifying patients who will not progress into severe
organ failure for < than 48 hours) and severe (persistent acute pancreatitis (Table 2) and organ failure based
organ failure for > 48 hours). Many scores are available scores like Goris multiple organ failure score,19 Bernard
but none is perfect. Ranson and Glasgow take 48 hours score, 20 sequential organ failure assessment (SOFA)
to complete,12-14 APACHE is a physiological score and is score,21 the logistic organ dysfunction score22 and the
cumbersome to use, systemic inflammatory response Marshal organ dysfunction score23 are used. This author
syndrome score (SIRS),15,16 is inexpensive, easy to use believes in use of CRP >150 at 48 hours24 and persistent
TABLE 2: Various scoring systems in severe acute pancreatitis

Systemic inflammatory response syndrome (SIRS) and interpretation
1 Temparature >38.3 °C or < 36.0°C
2 Heart rate 90 beats/minute
3 Respiratory Rate of >20 breaths/min or PaCO2 < 32 mm Hg
4 WBC count of >12000 c/mL, < 4000 c/mL or 10% immature (band) forms
SIRS is defined as 2 or more of the following variables:
SIRS Mortality rate42
No SIRS 0%
SIRS at admission but not persistent 8%
SIRS persistent from admission 25%
BISAP score—bedside index of severity in acute pancreatitis score

1 Blood urea nitrogen > 25 mg/dL
2 Abnormal mental status with Glasgow coma score < 15
3 Evidence of systemic inflammatory response syndrome
4 Patient age > 60 years
5 Imaging study reveals pleural effusion
Each variable has 1 point
Interpretation
1. 0–2 points: Lower mortality < 2%
2. 3–5 points: Higher mortality > 15%
Harmless acute pancreatitis score (HAPS)

1 Rebound guarding pesent
2 Creatinine < 2 mg/dL
3 Hematocrit <43% (male) and 39.6% (female)
Score of “0” is associated with absence of pancreatic necrosis, no need for dialysis or ventilator support and no fatal outcome with 97%
specificity and 98% positive predicitive value
American College of Gastroenterology (ACG) – ACG guidelines recommend the following clinical findings associated with a severe course for
initial risk assessment.33
Patient characteristics Laboratory findings
Age > 55 years Blood Urea Nitrogen (BUN >20 MG/dL
Obesity (Body Mass Index > 30 Kg/m2) Rising BUN
Altered mental status Hematocrit > 44%
Comorbid disease Rising hematocrit
Elevated creatinine
Systemic inflammatory response Radiological findings
syndrome
As given in 3.1 under SIRS Pleural effusion
Pulmonary infiltrate
Multiple or extensive extra pancreatic
collections
The presence of organ failure and/or pancreatic necrosis defines severe acute pancreatitis.
Contd...
Contd...
Modified CT severity index25

Prognostic indicator Points
Pancreatic zz Normal pancreas 0
inflammation zz Intrinsic pancreatic abnormalities with or without inflammatory changes in the peripancreatic fat 2
zz Pancreatic or peripancreatic fluid collection or peripancreatic fat necrosis 4
Pancreatic necrosis zz None 0
zz < 30% of parenchymal volume 2
zz >30% of parenchymal volume 4
zz Extra pancreatic complications (one or more of pleural effusion, ascites, vascular complications, 2
parenchymal complications, or gastrointestinal involvement)
Interpretation
CT Severity Index Severity
0–3 Mild acute pancreatitis
4–6 Moderate acute pancreatitis
7–10 Severe acute pancreatitis
organ failure for > 48 hours) as indicator of severe acute MANAGEMENT

pancreatitis. Systemic complications include failure of
organ system (cardiovascular, respiratory, renal) and
Acute Phase (Fig. 3)
exacerbation of pre-existing disorder (cardiac failure, Pain Alleviation
liver failure, chronic obstructive lung disorder), local Pain is the predominant symptom and leads to pain
complications comprise peripancreatic fluid collection, shock, hypovolemia and hypotension resulting in
pseudocyst, pancreatic/peripancreatic necrosis sterile decreased renal flow, renal perfusion and acute kidney
or infected). Prime determinant of poor outcome is the injury. Randomied controlled trials and meta-analysis on
persistence of organ failure for more than 48 hours. As analgesia with pain killers and opiods is inconclusive.5,6
against an overall mortality of 2%, it rises to 30% if organ
failure persists for >48 hours. Persistent organ failure Fluid Resuscitation
and infected pancreatic necrosis constitute “critical Pancreatic inflammation and SIRS leads to 3rd spacing
pancreatitis” associated with highest mortality.2 Other of fluid resulting in hypotension and hypoperfusion of
identified factors increasing the risk for complications/ organ leading to failure. Colloids are discouraged in all
death include age >60 years, numerous and severe critically ill patients while hydroxyethyl starch may even
coexisiting conditions, obesity with body mass index worsen mortality.11 Overzealous fluid administration
>30, long-term heavy alcohol use, irreversible azotemia, (10–15 mL/Kg/hour) has been shown to result in increase
hemoconcentration and persistent features of systemic in infection rate, abdominal compartment syndrome,
inflammatory response syndrome (SIRS) for >48 hours.3 need for mechanical ventilation and even mortality.27,28
Radiological scoring systems of severity have poor Too little as well as too much of fluids in acute phase can
clinical concordance.25 Early Warning Sign (EWS) is a be harmful.29 Administration of a crystalloid solution
simple clinical tool factoring six physiological parameter in the form of Ringer lactate at 200–500 mL/hour for
(heart rate, respiratory rate, temperature, systolic blood 6 hours if they come immeadiately and then to 150
pressure, level of consciousness and oxygen saturation) mL progressively or 5–10 mL/Kg/hour amounting to
and ensures timely recognition of all patients with 2500 mL–4000 mL/day is recommended.1,30 It is further
potential or established critical illness.26 recommended that fluid therapy be tailored to the degree
Fig. 3: Management of acute pancreatitis in early phase
of intra vascular volume depletion and cardiopulmonary In moderate-to-severe acute pancrreatitis, oral
reserve that is available to handle the fluid.31 feeding can be withheld for 2–3 days and started
Antibiotics as Prophylaxis and Treatment thereafter once the bowel movement is set in and free
Meta-analysis have shown no benefit of prophylactic from ileus. Simple tube feeding has replaced feeding
antibiotics and is not recommended for any type of acute through complex deeply placed intestinal tubes. Tube
pancreatitis unless infection is confirmed.32,33 feeding is required only if oral feed is not tolerated for 2
days beyond 72 hours.37,38 No significant advantage was
Nutrition
seen between nasojejunal and nasogastric tube feeding,
Mild acute pancreatitis in the absence of ileus can be
use of elemental, semielemental vs polymeric diet. Total
placed on oral nutrition from the day of admission
and should not evoke pain.34 A low fat diet soon after parenteral nutrition which is expensive, riskier and no
admission in the absence of severe pain, nausea, more effective than enteral nutrition should be reserved
vomiting and ileus can be started and is safe, associated only for those intolerant to enteral feeds or in unmet
with shorter hospital stay than clear liquids with slow nutritional goal status though in reality, it is more often
advancement to solid food.35,36 used.1,9,39,40
Endoscopic Retrograde Cholangio BEYOND THE EARLY PHASE (FIG. 4)

Pancreaticography (ERCP) The management of early phase of acute pancreatitis
Emergency ERC and endoscope sphincterotomy (ES) decides the course of illness beyond early phase. The
is the treatment of choice in patients with acute biliary revised Atlanta classification (2012) has identified
pancreatitis with concomitant cholangitis best done interstitial edematous pancreatitis into ‘acute pancreatic
within 24 hours.1,33 Conflicting advice is available on use fluid collection (<4 weeks)’ and ‘pseudocyst’ (>4 Weeks)
of early routine ERC and spihincterotomy from various and necrotizing pancreatitis (pancreatic gland necrosis
meta-analysis and guidelines. The result of APEC trial and peripancreatic fat necrosis) into ‘acute necrotic
and ISRCTN97372133, a multicentric randomized collection <4 weeks)’ and ‘walled-off necrotic tissue (>4
control trial study comparing early routine ERC plus weeks)’ (WON) (Table 3). Thus imaging more so CECT
ES with conservative management in 232 patients with (Figs 5 and 6), follow-up USG, EUS would help to identify
predicted severe acute biliary pancreatitis but without and monitor the behavior of these complications.
cholangitis is awaited.41 Acute pancreatic fluid collections (PFC) do not require
The use of endoscopic ultrasound (EUS) for detcction treatment and usually resolve. They form a wall and
of stones in common bile duct is emerging. An ERC evolve into pseudocyst with clear fluid over 4 weeks.
with EUS is most effective and EUS first strategy helps These pseudocysts need intervention, if they become
in establishing indication for ERC. EUS first startegy in symptomatic with infection, bleed within the cyst
a meta-nalysis was showed that it is promising and 71% or increase in size of the cyst resulting in pressure
ERC procedures can be avoided without a negative effect symptoms.
on the clinical course of acute pancreatitis. 42 Further, Acute necrotic collection (ANC) contains debris and is
EUS first startegy is less costly than ERC as observed by a mix of solid and semisolid tissue. Over 4 weeks with
decision tree analysis of cost-effectiveness.43 the formation of capsule, this becomes a walled-off
Fig. 4: Management of acute pancreatitis in late phase

TABLE 3: Revised Atlanta Classification of pancreatic and peripancreatic fluid collections

S. No. Type of collection Time in weeks Location Imaging appearance
1 Interstitial edematous pancreatitis
1A Acute Peeri-Pancreatic Fluid Collection < 4 weeks Adjacent to pancreas, extra Homogenous fluid attenuation, no
pancreatic only liquefaction, not encapsulated
1B Pseudocyst > 4 weeks Adjacent or distant to Homogenous fluid attenuation, no
pancreas liquefaction, Encapsulated
2 Necrotizing Pancreatitis
2A Acute Necrotic Collection < 4 weeks In parenchyma and/or extra Homogenous, nonliquefied material,
pancreatic variably loculated, not encapsulated
2B Walled-Off—Necrosis > 4 weeks In parenchyma and/or extra Homogenous, nonliquefied material,
pancreatic variably loculated, Encapsulated
A B
C D
Figs 5A to D: CECT images showing severity of acute pancreatitis. (A) Diffusely enlarged pancreas with peripancreatic oedema (asterisks)
and perirenal edema (white arrows). (B) Diffusely enlarged pancreas with peripancreatic fluid collection posterior to the distal body and tail.
(C) Small area of no parenchymal contrast enhancement in the tail suggestive of necrosis (<30% volume). (D) Large area of no parenchymal
contrast enhancement suggesting necrosis in the neck, body and tail (white arows) with associated splenic vein thrombosis (white asterisks)
A B
C D
Figs 6A to D: Severity of acute pancreatitis. CECT images showing complications of acute pancreatis. (A) Peripancreatic abscess with air
pockets (white asterisks). (B) Peripancreatic fluid collections, thrombosis of the retropancreatic splenic vein (white arrows) and the splenoportal
confluence (white asterisk). (C) Pancreatitis with ascites (white asterisks). (D) Pancreatic pseudocyst with capsule (arrows)
necrosis (WON). Symptomatic walled-off necrosis form of drainage (radiological/endoscopic/surgical).

need intervention. Suspected infection of the ANC or The infection is often monomicrobial and includes
WON calls for use of antibiotics that can penetrate the gram negative rods, enterobacter species, gram
wall and also concentrate in the pancreatic substance. positive organisms including Staphylococcus.31
Infection when suspected by clinical symptoms and Pancreatic ductal disruption (PDD) (Figs 7A to D)
signs (fever, leukocytosis, increasing abdominal pain, are divided into partial and complete leading to
air bubbles in the necrotic tissue, worsening organ internal or extrenal fistula. About 95% are associated
function), need microbiological confirmation by with chronic pancreatitis and is also seen in 38% of
Gram’s stain and culture of fluid obtained by USG/ severe acute necrotizing pancreatitis causing high
CT/EUS-guided Fine Needle Aspiration (FNA) for amylase pleural effusion and ascites called pancreatic
grams stain and culture and administration of culture hydrothorax, pancreatic ascites respectively and
directed antibiotics. 60% of noninfected ANC resolve refractory ascites. Internal pancreatic fistulas (IPF)
while the infected ANC/WON require appropriate include communicating pseudocyst, enteric or biliary
A B
C D
Figs 7A to D: Pancreatic ductal disruption, collection and bridging of disruption with stent. The USG (A) showing disruption in the course of
PD in the body region with collection and (B) showing upstream track of collection. ERCP (C) showing PD disruption in the tail region and (D)
showing a pancreatic stent across the PD disruption. A and B are from one patient and C and D are from another patient.
Abbreviations: USG, Ultrasound; PD, Pancreatic duct; ERCP, Endoscopic retrogarde cholangio pancreaticogram
fistulas. Pseudocyst is seen in 50% of patients with Management of PFC/Pseudocyst/ANC/WON/PDD:

pancreatic ascites.44 MPD disruption is associated The early surgical management has been superseded
with wore outcomes, increased hospital stay and by “step-up-approach” consisting of percutaneous
recurrent episodes of pancreatitis. Those with catheter drainage followed in case of lack of clinical
complete disruption have higher rates of failure of improvement by video-assisted retroperitoneal
endoscopic bridging leading to surgical intervention debridement (VARD). This was compared with
over those with partial disruption. ERCP and secretin necrosectomy via laparotomy in a multicenteric RCT
stimulated MRCP (80%) detect PD disruption. of 88 patients.45 The step up approach has resulted in
better outcomes with good results. PFC and ANC take baskets under direct vision and may require multiple
3–5 days to form and CECT done after 5–7 days would sessions in a few cases. The most common complications
identify these lesions. For pseudocyst and WON a are bleeding, perforation and infection. Use of carbon
repeat imaging using USG/CT/EUS will facilitate dioxide would minimize air embolism. Use of wide lumen
identification and guide in choice of the intervention. metal stents, fully covered self-expandable metal stents,
It is pertinent to postpone intervention till a wall lumen opposing metal stents that allow endoscope
is well formed usually within four weeks for better to pass into the cavity helps in better debriement and
drainage. has more success rate. Transpapillary drainage is done
Observations show that most of the acute PFC resolve in communicating small collections. Laparoscopic
while less than 15% form pseudocyst while more than necrosectomy using a retrogastric transmesocolic or
1/3rd of ANC evolved into WON and in that 55% required retroperitoneal approach to the lesser sac is the presently
intervention. used technique.46 Videoscopic–assisted retroperitoneal
debridement (VARD) is an alternate method.
Indications
Nageshwar Reddy et al.,47 Boumitri C et al,48 and Hon
A sterile ANC with presence of symptoms (abdominal
Chi Yep et al.49 have vividly described the interventions
pain or mechanical obstruction—gastric outlet
with images and results and recommend management
obstruction or biliary obstruction). Delay intervention
by multi-disciplinary team.
for 4 weeks or longer, if possible to 6 weeks.
The other complications observed are splenic artery
Infected pancreatic fluid collection needs endoscopic
aneurysm, splenic and portal venous thrombosis, gastric
drainage over percutaneous drain since a fistula can
stress ulceration, gastroparesis and ileus, obstructive
be avoided and over surgical drainage since it is more
symptoms due to compression of duodenum, bile duct
morbid and mortal.
by edematous and inflammed pancreas, abdominal
Asymptomatic WON or sterile ANC do not require
compartment syndrome, pancreaticopleural fistula.
intervention regardless of size since they resolve over
Symptom may enlarge to vomiting, vomiting blood,
time.
jaundice, breathlessness and needs cause directed
Procedure: Percutaneous/Endoscopic/Surgical approach.
Intervention is primarily drainage and can be done
radiologically, endoscopically and surgically. Drainage PREVENTION
of necrotic debris improves over all health, prevents The National Confidential Enquiry into Patient Outcome
organ failure. The requisites are presence of wall with and Death (NCEPOD) 26 observed that in 50% with
thickness of 4 mm, absence of demonstrable collaterals acute pancreatitis, the care needs to be improved,
in the planned region of entry and close approximation efforts to prevent recurrent episodes of pancreatitis
with neighboring organ for endoscopic cystogastro/ due to alcohol and gallstone need improvement by
cystoduodenostomy. Percutaneous drainage under 21%, better antibiotic use (unnecessary use in 20%),
USG/CT guidance avoiding hollow/solid viscous inadequate nutrition management in 15%, omission of
penetration. Endoscopic ultrasound-guided transmural use of early warning scores in 31%.26 Thus prevention
drainage (EUS-TD) is the preferred intervention in can be achieved in alcohol consumers by conjoint
nonbulging lesion within 1.5 cm from the gastric counseling, recurrence of acute biliary pancaretitis
wall and are more precise. The technique of Direct can be achieved by cholecystectomy in the same
Endoscopic Necrosectomy (DEN) involves dilatation of admission, hypertriglyceridemia induced pancreatitis by
the cystogastric tract with balloon, advancement of the optimal drugs, drug indueced pancreatitis by avoidance,
endoscope into the cavity of WON, normal saline lavage obstrucive causes by elimination or providing adequate
of the cavity, removal of necrotic debris using snares or drainage.
CONCLUSION 2. Dellinger EP, Forsmark CE, Layer P, et al. Determinants

based classification of acute pancreatitis severity: an
The incidence of acute pancreatitis due to gall stone
international multidisciplinary consultation. Ann Sug.
in the west and alcohol in this part of the globe is 2012;256:875-80.
increasing. The newer classification of complications, 3. Yadav D, Lowenfels AB. The epidemiology of pancreatitis
management at every day of disease, prevention of high and pancreatic cancer. Gastroenterology. 2013;144:1252-
morbid inciting events by early elimination and careful 61.
4. Gulen B, Dur A, Serinken M, et al. Pain treatment in patients
management all through the course of acute pancreatitis
with acute pancreatitis: a randomized controlled trial. Turk J
with focus on treating the underlying cause and in Gastroenterol. 2016;27:192-6.
alcoholics to manage withdrawal symptoms, early enteral 5. Meng W, Yuan J, Zhang C, et al. Parenteral analgesics
nutrition, timed intervention, use of pancreatic tissue for pain relief in acute pancreatitis: a systemic review.
penetrating antibiotics have led to increased recovery Pancreatology. 2013;13:201-6.
of patients. Recurrent episodes of pancreatitis can be 6. Ona B X, Rigau Comas D, Urrutia G. Opioids for acute
pancreatitis pain. Ona B X ed. Cochrane Database of
prevented, if the cause can be identified. Management of
Systemic Reviews. Chichester, UK: John Wiley & Sons Ltd.
acute pancreatitis in early phase is critical and aid better 2013.
late phase management. Interventions are essential in 7. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD,
patients with severe necrotizing pancreatitis and step up Sarr MG, et al. Classification of acute pancreatitis--2012:
approach after initial delay till four weeks at minimum will revision of the Atlanta classification and definitions by
help in reducing morbidity and mortality. Management international consensus. Gut. 2013;62(1):102-11.
8. Yadav D, Agarwal N, Pitchumoni CS. A critical evaluation of
of these patients with severe acute pancreatitis needs a
laboratory tests in acute pancreatitis. Am J Gastroenterol.
multidisciplinary team comprising of gastroenterologist, 2002;97(6):1309-18.
GI endoscopist, radiologist and surgeon and crticial care 9. Tenner S, Steinberg WM. Acute pancreatitis. In: Sleisenger
physician. and Fordtran’s Gastrointestinal and liver disease,
Pathophysiology/diagnosis/management, 10th Edition.
New York: Elsevier; 2015. pp. 969-93.
Acknowledgment
10. Yang Fei, Wei-Qin-Li. Effectiveness of contrast enhanced
I sincerely thank Dr Vijay Sadasivam MD, DNB, DMRD ultrasound for the diagnosis of acute pancreatitis: A
(Radiology), SKS Hospital, Salem, Dr M Venkatesan MD, systemic review and meta-analysis. Digestive Liver Disease.
DNB, DMRD (Radiology) and Dr R Subramanian MBBS, 2017;(49)623-9.
DMRD, Sreenivas Ultrasound Scan Center, Salem for 11. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid
providing images (2A,C & D,5 & 6, 7A &7B), (2A), and (7A resuscitation in critically ill patients. Cochrane Database
Syst Rev. 2013:CD000567.CD000567.doi.
& 7B) respectively.
12. Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs
I am deeply indebted with gratitude to Dr D Nagheswar and the role of operative management in acute pancreatitis.
Reddy, Asian Institute of Gastroenterology, Hyderabad Surg Gynecol Obstet. 1974;139:69.
for providing the images 7C & 7D. 13. Agarwal N, Pitchumoni CS. Simplified prognostic criteria in
Special thanks are to my wife Mrs L Jayalakshmi and acute pancreatitis. Pancreas. 1986;1:69.
14. Buter A, Imrie CW, Carter CR, et al. Dynamic nature of
our Grandson Rian Aadrick for sparing me the required
early organ dysfunction determines outcome in acute
time to complete this wonderous task.
pancreatitis. Br J Surg. 2002;89:298.
15. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet.
REFERENCES 2005;365:63.
1. Working Group IAP/APA acute pancreatitis guidelines. 16. Mofidi R, Duff MD, Wigmore SJ, et al. Association between
IAP/APA evidence based guidelines for the management early systemic inflammatory response, severity of multiorgan
of acute pancreatitis. Pancreatology. 2013;13:(Suppl 2): dysfunction and death in acute pancreatitis. Br J Surg.
e1-15. 2006; 93:738.
17. Wu BU, Johannes RS, Sun X, et al. The early prediction of saline in patients with acute pancreatitis. Clin Gastroenterol
mortality in acute pancreatitis: a large population-based Hepatol. 2011;9:710-7.
study. Gut. 2008;57(12):1698-703. 31. Campion W, Forsmark CE, Vege SS, and Wilcox C. Acute
18. Lankisch PG, Weber-Dany B, Hebel K, Maisonneuve P, pancreatitis. N Eng J Med. 2016;375:1972-81.
Lowenfels AB. The harmless acute pancreatitis score: a 32. Villataro E, Mulla M, Larvin M. Antibiotic therapy for
clinical algorithm for rapid initial stratification of nonsevere prophylaxis against infection of pancreatic necrosis
disease. Clin Gastroenterol Hepatol. 2009;7(6):702-5; quiz in acute pancreatitis. Cochrane Database Syst Reev.
607. PMID: 19245846. 2010;5:CD002941.
19. Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrère JS. Multiple- 33. Tenner S, Baillie J, Dewitt J, et al. American College
organ failure. Generalized autodestructive inflammation? of Gastroenterology Guideline: Management of acute
Arch Surg. 1985;120:1109. pancreatic. Am J Gastroenterol. 2013;108:1400-15.
20. Bernard GR, Doig G, Hudson L, et al. Quantification of organ 34. Eckerwall GE, Tingstedt BB, Bergenzaun PE, Andersson
failure for clinical trials and clinical practice. Am J Respir Crit RG. Immediate oral feeding in patients with mild acute
Care Med. 1995;151:A323. pancreatitis is safe and may accelerate recovery – a
21. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis- randomized clinical study. Clin Nutr. 2007;26:758-63.
related Organ Failure Assessment) score to describe 35. Jacobson BC, Vander Vliet MB, Hughes MD, et al. A
organ dysfunction/failure. On behalf of the Working Group prospective, randomized trial of clear liquids versus low fat
on Sepsis-Related Problems of the European Society of solid diet as the initial meal in mild acute pancreatitis. Clin
Intensive Care Medicine. Intensive Care Med. 1996;22:707.
Gastroenterol Hepatol. 2007;5:946-51.
22. Le Gall JR, Klar J, Lemeshow S, et al. The logistic organ
36. Teich N, Ashdassi A, Fischer J, et al. Optimal timing of
dysfunction system. A new way to assess organ dysfunction
oral refeeding in mild acute pancreatitis: results of open
in the intensive care unit. ICU Scoring Group. JAMA.
randomized multicentre trial. Pancreas. 2010;39:1088-92.
1996;276:802.
37. Bakker OJ, Van Brunschot S, Van Santvoort HC, et al.
23. Marshall JC, Cook DJ, Christou NV, et al. Multiple organ
Early versus on-demand nasoenteric feeding in acute
dysfunction score: a reliable descriptor of a complex clinical
pancreatitis. N Engl J Med. 2014;371:1983-93.
outcome. Crit Care Med. 1995;23:1638.
38. Stimac D, Poropat G, Hauser G, et al. Early nasojejunal
24. Corfield AP, Cooper MJ, Williamson RC, et al. Prediction of
tube feeding versus nil-by-mouth in acute pancreatitis: a
severity in acute pancreatitis: prospective comparison of
randomized clinical trial. Pancreatology. 2016;16:523-8.
three prognostic indices. Lancet. 1985;2:403.
39. Al-Omran M, Albalawi ZH, Tashkandi MF, Al-Ansary LA.
25. Mortele KJ, et al. A modified CT severity index for evaluating
Enteral versus parenteral nutrition for acute pancreatitis.
acute pancreatitis: Improved correlation with outcome. AJR.
Cochrane Database Syst Rev. 2010;1:CD0002837.
2004;183:1261-5.
26. O’Reilly D A, McPherson S.J, Sinclair M T, et al. Lessons 40. Yi F, Ge L, Zhao J, et al. Meta-analysis: total parenteral
from a national audit of acute pancreatitis: A summary of nutrition versus total enteral nutrition in predicted severe
the NCEPOD report ‘Treat the Cause’. Pancreatology. 2017. acute pancreatitis. Intern Med. 2012;51:523-30.
pp.329-33. 41. Schapers NJ, Bakker OJ, Besselink MG et al. Early biliary
27. Mao EQ, Tang YQ, Fei J, et al. Fluid therapy for severe acute decompression versus conservative treatment in acute
pancreatitis in acute response stage. Chin Med J. 2009; biliary pancreatitis (APEC Trial): study protocol for a
122:169-73. randaomized control trial. Trials. 2016;17:5.
28. Mao EQ, Tang YQ, Peng YB, et al. Rapid haemodilution is 42. Liu CL, Fan ST, Lo CM, et al. Comparison of early
associated with increased sepsis and mortality among endoscopic ultrasonography and endoscopic retrograde
patients with severe acute pancreatitis. Chin Med J. cholangiopancreaticography in the management of acute
2010;123:639-44. biliary pancreatitis: a prospective randomized study. Clin
29. Van Dijk SM, Hallensleben NDL, van Santvoort HC, Acute Gastroenterol Hepatol. 2005;3:1238-44.
pancreatitis: recent advances through randomised trials. 43. De Lisis S, Leandro G, Buscarini E, et al. Endoscopic
Gut. 2017 Aug 24. pii: gutjnl-2016-313595. doi: 10.1136/ ultrasonography versus endoscopic retrograde cholangio
gutjnl-2016-313595. [Epub ahead of print] Review. Dutch pancreaticography in acute biliary pancreatitis: a systemic
Pancreatitis Study Group. review. Eur J Gastroenterol Hepatol. 2011.
30. Wu Bu, Hwang JQ, Gardener TQ, et al. Lactated Ringer 44. Kozerak RA . Management of pancreatic ascites.
Solution reduces systemic inflammation compared with Gastroenterology and Hepatology. 2007;(3):362-4.
45. Van Santvoort HC, Besselink MG, Bakker QJ, et al. A step up 48. Boumitri C, Brown E, Kahlesh M. Necrotizing Pancreatitis:
approach or open necrosectomy for necrotizing pancreatitis. Current Management and Therapies. Clin Endosc.
N Engl J Med. 2010;362:1491-502. 2017;50:357-65.
46. Alsfasser G, Hrmeneit S, Rau BM, et al. Minimally invasive 49. Hon Chi Yep, Anthony Yuen Bun Teoh. Endoscopic
surgery for pancreatic disease–current status. Dig Surg. management of peri-panctreatic fluid collections. Gut and
2016; 33:276-83. Liver 2017;(11)604-11. Larvin M. Assessment of clinical
47. Nabi Z, Basha J, Reddy DN. Endoscopic management of severity and prognosis. In: The Pancreas, Beger HG,
pancreatic fluid collections – revisited. Worl J Gastroenterol. Warshaw AL, Buchler MW, et al (Eds), Blackwell Science,
2017;21:23(15):2660-72. Oxford 1998. p.489.
CHAPTER
71
The Gut Microbiota: A Forgotten Organ
Balvir Singh, Ram Prakash Pandey, Mridul Chaturvedi, TP Singh, Ashish Gautam
INTRODUCTION
Gut microbiota (gut flora) is the complex group of
microorganisms that lives in the human gastrointestinal
tract and health is usually due to intestinal microbiota.
Microbiota of one person can be different than others
in species and relative amount. Chiefly the gut flora are
strict anaerobes.
It is proved that alteration and diversification of gut
flora in intestine leads to various diseases such as allergies,
obesity and diabetes, dyslipidemia, cancer and intestinal
Fig. 1: Kinds of cells in the human body
inflammatory diseases and pseudomembranous colitis,
etc.1 More than 10 times the number of cells in our body
The gut microbiome is 150 times larger than the
COMPOSITION OF GUT MICROBIOTA human genome
On human body total human cells are approx one quarter Most heavily colonized organ: GIT
and rest are bacterial, fungal and protozoal (Fig. 1). Colon alone: > 70% microbes
Hu m a n g u t m i c ro b i o t a m a i n l y c o n s i s t s o f
phyla Firmicutes, Bacteroidetes, Proteobacteria, EMERGENCE OF MICROBIOTA
Verrucomicrobia, Actinobacteria, Cyanobacteria and After the delivery of baby gut seems to be sterile, but it
Synergistes. Out of these Firmicutes and Bacteroidetes has been observed that fetal colonization of microbiota
consists of 65% and 35% respectively.2 may occur in the newborn babies also. The microbial
strains present in upper gastrointestinal tract resembles
HUMANS AS MICROBIAL DEPOTS (FIG. 2) to mothers fecal microbiota.3
The microbial populations that reside in and on the The babies born by caesarean section are typically
host cells are commonly referred to as “microbiota”.2,4 having microflora like Staphylococcus, Corynebacterium
Gut microbiota is approx. 200 trillion cells and Propionibacterium species.5
More than thousand diverse specieces of gut micro All infants are initially colonised by large number of
biota Escherichia coli and Streptococci. During the first week
CHAPTER 71: The Gut Microbiota: A Forgotten Organ 437
Fig. 2: Microbiota diversity and its number increases as we procede downwards in GIT
of life, bacterial succession of strict anaerobic species mediators and helps ATP generation in liver), succinic
mainly Bifidobacterium, Bacteroides, Clostridium, and acid (anti-inflammatory).10
Ruminococcus.6 Breastfed babies become dominated by The gut microbiota also having favorable impact on
bifidobacterial (B.breve, B.bifidum, B.infantis), possibly lipid metabolism as well as in suppressing the inhibition
due to the contents of bifidobacterial growth factors of lipoprotein activity in adipocytes.13
in breast milk, 7 while formula-fed infants intestinal Anaerobic metabolism of peptides and proteins
microbiota is more diverse and have high numbers (putrefaction) by the microflora also produces short
of Enterobacteriaceae, Enterococci, Bifidobacterial, chain fatty acids but at the same time it generates a
Bacteroides and Clostridia (Fig. 3).8 series of potentially toxic substances also like ammonia,
amines, phenols, thiols and indols.11,12
GUT MICROBIOTA AS AN ORGAN Metabolically gut microbiota synthesizes the vitamin
There is a symbiotic relationship with the intestinal K and various components of B-complex.13 Bacteroides
mucosa and as an organ it imparts substantial metabolic, also synthesize conjugated linoleic acid (CLA), which
gut protective, immunological and trophic actions in is thought to be antidiabetic, antiatherogenic, anti
normal healthy individuals.9 obesogenic, hypolipidemic and immunomodulatory
properties.14 Gut microbiota have role in xenobiotic and
drug metabolism.15
Metabolic Functions
Undigested oligosaccharides and carbohydrates get
fermented to short chain fatty acids (SCFA), like acetic Prevention of Infection
acid (used by muscles), butyric acid (absorption of In vitro, bacteria compete for attachment sites in the
fluids and stimulation of proliferation in normal cells, brush border of intestinal epithelial cells, 16 bacteria
inhibits cell proliferation in neoplastic cell lines), compete for nutrient availability in ecological niches
propionic acid (decreases production of inflammatory and maintain their collective habitat by administering
Fig. 3: Human microbiome over time: response to environmental conditions and life stages
and consuming all resources. They have influence on In irritable bowel syndrome–ratio of Firmicutes
mucosal barrier by mucus production and by epithelial to Bacteroidetes increased along with increased
growth. Finally, bacteria can also inhibit the growth of Clostridium and decreased Bifidobacterium,
their competitors by producing antimicrobial substances Bacteroidetes.18
called bacteriocins.17 Inflammatory bowel disease-increased number of
Enterobacteriaceae, Escherichia coli and decreased
Gut Microbiota as an Immunomodulator Firmicutes, Bacteroidetes.19
The innate and adaptive immune systems also have been Colorectal cancer—increased Fusobacterium species,
modulated by gut microbiota. Gut associated lymphoid E.coli.20
tissues (GALT), effector and regulatory T cells, B cells Obesity—increased Firmicutes to Bacteroidetes
take keen role and participation in immunomodulation ratio, increased Actinobacteria and decreased
of immune system (Fig. 4).17 Bifidobacterium.21
Type 2 diabetes mellitus–increased opportunistic
LINK BETWEEN GUT FLORA pathogens (Clostridium spp., E. coli), Bacteroidetes
AND DISEASES spp. and decreased Butyrate producing organisms,
Microbial composition usually changes with age, Firmicutes.22
inflammation, use of antibiotics, use of probiotics and Parkinson disease—increased number of Entero
prebiotics, diet, weight loss, pregnancy, drugs (like bacteriaceae and decrease number of Provotellaceae.23
steroids, NSAID), stress, radiation, alcohol, pollution Hepatic encephalopathy—increased Entero
(Fig. 5). bacteriaceae, Streptococcaceae and decreased Lachno
Changes in gut microbiota is linked to various diseases spiraceae, Ruminococcus and Clostridium.24
like irritable bowel syndrome (IBS), inflammatory bowel
disease (IBD), Type 2 diabetes mellitus, obesity, hepatic FUTURE HOPES FOR VARIOUS DISEASES
encephalopathy, dyslipidemia, Parkinson disease, Probiotics are live microorganisms, sufficient amount
allergies and colonic cancer. of which reach the intestine in an active state, thus
Fig. 4: Role of the hidden organ
Fig. 5: Various factors influencing the density, diversity, and gut microbiota activity
positive health effects. They mostly include lactic 5. Maria DB, Martin B, Ruth L, Rob K. Development of
acid-producing bacteria and yeasts that reach the the human gastrointestinal microbiota and Insights
from high throughout sequencing. Gastroenterology.
gut unaltered, without providing damage to the host.
2010;140(6):1713-9.
Lactobacillus and Bifidobacterium produce harmful 6. Favier CF, Vaughan EE, De Vos WM, Akkermans ADL. Molecular
substances for Gram-positive and Gram-negative monitoring of succession of bacterial communities in
bacteria, and they compete with pathogens for cell human neonates. Applied and environmental microbiology.
adhesion. Probiotics has been observed for enhancing 2002; 68(1):219-26.
the immune system and favorable effect on lipid 7. Coppa Giovanni V, Bruni Stefano, Morelli Lorenzo, Soldi
Sara, Gabrielli Orazio.The first prebiotics in humans. Journal
profile, control of infections particularly decreases
of clinical gastroenterology. 2004;38(6 suppl):S80-3.
diarrheal incidences and act like antibiotics, suppress 8. Harmsen Hermie JM, Wildeboer-Veloo Alida CM, Raangs
tumors and prevent against various cancers like colon Gerwin C, Wagendorp Arjen A, Klijin Nicolette, Bindels
and bladder.25 Jacques G, Welling Gjalt W. Anaiysis of intestinal flora
Prebiotics are defined as “a selectively fermented development in breast-fed and formula-fed infants by using
ingredient that allows specific changes, both in the molecular identification and detection methods. Journal of
pediatric gastroenterology and nutrition. 2000;30(1):61-7.
composition and/or activity in the gastrointestinal
9. Sonneberg JL, XU J, Leip DD, Chen CH, Westover BP,
microflora that confers benefits upon host well-being Weatherford J, Buhler JD, Gordon JI. Glycan foraging in
and health”.26 vivo by an intestine-adapted bacterial symbiont. Science.
Fecal microbiota transplantation (FMT): Transfer 2005;307:1955-9.
of gut microbiota from a healthy volunteer donor to 10. Macfarlane S, Macfarlane GT. Regulation of short-chain
the recipient. Usually it is being done as retention fatty acid production. Proc Nutr Soc. 2003;62:67-72.
11. Macfarlane GT, Cummings JH, Allison C. Protein
enema, nasogastric tube, nasoduodenal tube or
degradation by human intestinal bacteria. J Gen Microbiol.
through colonoscope. Besides this capsules having 1986;132:1647-56.
freezed-dried material is also may be given orally 12. Smith EA, Macfarlane GT. Enumeration of human colonic
to re-establish the microbial population in the bacteria producing phenolic and indolic compounds:
gut of recipient. First documented in humans in effects of pH, carbohydrates availability and retention time
1958. Currently, it is very useful in the treatment of on dissimilatort aromatic amino acid metabolism. J App
Bacteriol. 1996;81:288-300.
pseudomembranous colitis caused by Clostridium
13. Baddini Feitoza A, Fernandes Pereira A, Ferreira da Costa N,
difficile infection. The future indications are ulcerative Goncalves Ribeiro B. Conjugated linoleic acid (CLA): effect
colitis, Crohn’s disease, Irritable bowel syndrome, modulation of body composition and lipid profile. Nutr Hosp.
Obesity, Diabetes mellitus, metabolic syndrome and 2009;24:422-8.
multiple sclerosis.27 14. Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK.
Pharmacometabolomic identification of a significant host-
microbiome metabolic interaction affecting human drug
REFERENCES
metabolism. Proc Natl Acad Sci USA. 2009;106:14728-33.
1. Sears, Cynthia L. A dynamic partnership: Celebrating our
15. Bernet MF, Brassart D, Neesar JR, Servin AL. Lactobacillus
gut flora. Anaerobe. 2005;11(5):247-51.
acidophilus LA 1 binds to cultured human intestinal cell
2. Simon GL, Gorbach SL. Intestinal flora in health and
lines and inhibits cell attachment and cell invasion by
disease. Gasteroenterology. 1984;86:174-93.
enterovirulent bacteria. Gut. 1994;35:483-9.
3. Collado M, Bauer lC, et al. Defining microbiota for
16. Brook I. Bacterial inter ference. Crit Rev Microbiol.
developing new probiotics. Microb E col Health Dis.
1999;25:155-72.
2012;23 PMCID:PMC 3747743.
17. Durkin HG, BAZIN H, Waksman BH. Origin and fate of IgE-
4. Gronlund MM, Lehtonen OP, Eerola E, Kero P. Fecal
bearing lymphocytes. I. Peyer’s patches as differentiation
microflora in healthy infants born by different methods
site of cells. Simultaneously bearing IgA and IgE. J Exp Med.
of delivery:permanent changes in intestinal flora after
1981;154:640-8.
caesarean delivery.
18. Ghoshal et al. [2012]; Jeffery et al. [2012b]; Rajilic- 24. Quigley EM, Stanton C, Murphy EF. The gut microbiota and
Stojanovic et al. [2011]; Saulnier et al. [2011] the liver. Pathophysiological and clinical implications. J
19. Frank et al. [2007]; Garrett et al. [2010]; Li et al. H e p a to l . 2 01 3 ; 5 8 : 10 2 0 - 7. d o i : 10 .1016 / j . j h e p .
[2012]; Manichanh et al. [2006]; Morgan et al. [2012] 2012.11.023.
20. Arthur et al. [2012]; Castellarin et al. [2012]; Kostic et al. 25. Scheinbach S. Probiotics: functionality and commercial
[2012]; McCoy et al. [2013] status, Biotechnol Adv. 1998;16:581-608.
21. Clarke et al. [2012]; Duncan et al. [2007]; Ley et 26. Roberfroid M. Prebiotics: the concept revisited. J Nutr.
al. [2005]; Schwiertz et al. [2009]; Turnbaugh et al. 2007; 137:830S-7S.
[2006, 2009a]; Zhang et al. [2009] 27. Eiseman B, Silen W, Bascom Gs, Kauvar Aj. Fecal enema
22. Qin et al. [2012]; Larsen et al. [2010] as an adjunct in the treatment of pseudomembranous
23. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, enterocolitis surgery. 1958;44(5):854-9.
Braak E. Staging of brain pathology related to sporadic
Parkinson’s disease. Neurobiol Aging. 2003;24:197-211.
CHAPTER
72
Nonalcoholic Fatty Liver Disease:
Is it Really Benign?
AK Chauhan
INTRODUCTION complications. It is now being increasingly reported that

Nonalcoholic fatty liver disease (NAFLD) is one of the NAFLD may be a multisystem disease, affecting several
most common presentations of chronic liver disease extra-hepatic organs including cardiovascular disease
across the world. The incidence of NAFLD has been (CVD), NAFLD-related chronic kidney disease (CKD),
reported to be approximately 20/10,000 personyears. sleep apnea, colorectal cancers, osteoporosis, psoriasis
The highest incidence is seen usually in the elderly and various endocrine disorders such as polycystic ovary
population, above 60 years of age. There is a gender syndrome.
difference in the incidence of NAFLD. Population based
studies suggest that more men are affected with the NAFLD IS A PROGRESSIVE CONDITION
condition, compared to men, with a reported incidence Table 1 lists the risk factors for disease progression. The
of 30–40% among men and15–20% among women. first step to NAFLD is accumulation of lipids in the liver
NAFLD appears most commonly in patients with type 2 cells (steatohepatitis), and is one of the important risk
diabetes (T2DM), with studies suggesting upto 70% with factors for disease progression.
copresentation of NAFLD. The presence of liver cell injury and inflammation
Indeed, several studies across the world, suggest a in addition to steatohepatitis is the next step in disease
clinical association between NAFLD and the metabolic progression, referred to as nonalcoholic steatohepatitis
syndrome (MetS) including dyslipidemia, hypertension, (NASH). While early NAFLD is relatively benign
T2DM and obesity. With a high prevalence of the progression to NASH significantly increases the risks
susceptible population of obesity and T2DM among of cirrhosis, liver failure, and hepatocellular carcinoma
Indians, it is no surprise that incidence of NAFLD in (HCC) (Fig. 1).
India is high (reported prevalence of 9–32%). The study On the other hand, statistics also suggest that only
of prevalence of NAFLD in type 2 diabetes patients in approximately 20% of NAFLD cases have progressive
India (SPRINT), published recently reiterates the rising liver disease leading to cirrhosis-which is a well-known
incidence in the older age group, with upto 60% of the risk factor for HCC.
61–70–year age group in India, having been diagnosed While the exact mechanisms of progression of
with this condition. NAFLD are not yet known, the major contributing
Newer studies across the world suggest that NAFLD is factors include liver inflammation, insulin resistance
also a contributor to the burden of extrahepatic chronic and metabolic stress. Newer data also suggests that
CHAPTER 72: Nonalcoholic Fatty Liver Disease: Is it Really Benign? 443
TABLE 1: Risk factors for development of NAFLD

Insulin resistance is central to the development of NAFLD, which represents the hepatic manifestation of metabolic syndrome
Metabolic syndrome Other risk factors
A waist circumference greater than 102 cm in men or greater than 88 Ethnicity: Hispanics and Asians are at higher risk than African
cm in women Americans
A triglyceride level greater than or equal to 150 mg/dL. Drug usage such as Tamoxifen, Corticosteroids, Amiodarone,
Methotrexate, Estrogens, Valproic acid, Antiretroviral medications
A high-density lipoprotein cholesterol level less than 40 mg/dL in Age: >50 years
men and less than 50 mg/dL in women
A systolic blood pressure greater than or equal to 130 mm Hg or a Increased ferritin levels and the patatin-like phospholipasedomain-
diastolic pressure greater than or equal to 85 mm Hg. containing 3 (PNPLA3) I148M polymorphism
A fasting plasma glucose level greater than or equal to 110 mg/dL.
Fig. 1: Progression of NAFLD to HCC
altered gut microbiota may play a role in promoting the greater risk of HCC compared with patients without
progression of NAFLD, thereby increasing the risk of diabetes.
HCC.
PATHOPHYSIOLOGIC LINK OF
ROLE OF METABOLIC RISK FACTORS METABOLIC RISK FACTORS WITH HCC
IN DISEASE PROGRESSION A chronic inflammatory condition is seen in patients
Central obesity and diabetes are by themselves risk with the metabolic syndrome such as those with obesity,
factors for hepatocellular carcinoma. Patients with diabetes. The same factors are believed to trigger
diabetes are known to be associated with a 2–4 fold progressive disease in those with NAFLD (Box 1).
BOX 1: Pathophysiologic mechanisms leading to progression TABLE 2: Single nucleotide polymorphisms associated with
increased hepatic fat content and elevated plasma liver enzyme
zz Insulin resistance and hyperinsulinemia
levels.
zz Oxidative stress
Single nucleotide polymorphism Attributed role
zz Hepatic stellate cells activation
PNPLA3 rs738409 C > G It is associated with the risk of
zz Cytokine/adipocytokine signaling pathways polymorphism progression to cirrhosis
zz Genetic and environmental factors
PNPLA3 I148M polymorphism Favors NAFLD progression and
liver fibrosis
BOX 2: Oxidative stress and its impact on hepatic cells Increased risk of HCC in severely
obese individuals
zz Apoptosis
zz Necrosis
NAFLD. Genome studies have shown single nucleotide
zz Inflammation
polymorphisms which are clearly associated with
zz Hepatic stellate cell activation
increased hepatic fat content and elevated plasma liver
zz Fibrogenesis
enzyme levels (Table 2).
zz Proinflammatory cytokine expression
zz Cell proliferation
EXTRAHEPATIC COMPLICATIONS
OF NAFLD
Insulin resistance: Insulin resistance and the compen NAFLD and CV Risk
satory hyperinsulinemia is believed to play a key role in Population based studies appear to indicate, that the
the pathogenesis of NAFLD-related HCC. The insulin- patient of NAFLD, is at a higher risk of CVD and related
like growth factor (IGF) axis, and the upregulation of morbidity and mortality with worse outcomes compared to
IGFs and IRS-1 production, have been shown to be that of progressive liver disease. NAFLD is an independent
contributing factors of HCC pathogenesis. contributor to the development of atherosclerosis and
Oxidative stress (and hepatic stellate activation): other cardiac alterations, leading to CVD. This is not
Oxidative stress and release of reactive oxygen species surprising, as both CVD and NAFLD appear to be linked
(ROS), at the hepatic mitochondrial, peroxisomal, and to with respect to the basic pathophysiology of insulin
microsomal levels can lead to significant hepatocellular resistance, oxidative stress, abnormal adipocytokine
injury which may trigger progression to HCC (Box 2). profile, endothelial dysfunction, lipid abnormalities, and
High concentrations of ROS at the damage site, can lead activation of inflammatory cascade. Based on strength of
to DNA alteration which in turn can result in genomic evidence, it has been suggested that the management of
instability and mutations in proto-oncogenes and tumor NAFLD and CVD must be integrated towards a common
suppressor genes, resulting in neoplastic transformation. approach of dealing with the underlying pathology.
Cytokine/adipocytokine signaling pathways: Proinfla

NAFLD and CKD
mmatory cytokines including tumor necrosis factor
Evidence linking NAFLD to the development and
(TNF)-a, interleukin (IL)-6, leptin, and resistin, and lower
progression of chronic kidney disease (CKD) is emerging
amounts of adiponectin are well known contributing
as a popular area of assessment. Data indicates infla
factors in NAFLD development and progression.
mmatory disorder as an underlying cause for both
Genetic and environmental factors: As with other disease conditions. Some other mechanisms include the
conditions, genetic and environmental factors, and role of obesity, the renin-angiotensin system, and
the interaction between them, can be attributed to an dysregulation of fructose metabolism and lipogenesis in
individual’s susceptibility and the clinical course of the development of both disorders.
CHAPTER 72: Nonalcoholic Fatty Liver Disease: Is it Really Benign? 445
NAFLD and Colorectal Cancers insulin resistance and hyperinsulinemia, oxidative stress,
NAFLD and colorectal cancer (CRC) have common hepatic stellate cell activation, cytokine/adipocytokine
risk factors which trigger disease progression. As with signaling pathways, and genetic and environmental
NAFLD, high levels of insulin and insulin-like growth factors. NAFLD in subjects with risk factors, also leads
factors may promote the development of CRC through to extra-hepatic complications with worsening or pre-
their proliferative and antiapoptotic effects. Decreased existing CVD and CKD. More recent data appears to link
levels of adiponectin lead to increased insulin levels it with colorectal cancer as well.
and insulin growth factor-1 (IGF-1) leading to cell
proliferation, apoptosis, and increased production of BIBLIOGRAPHY
vascular endothelial growth factor, all of which increased 1. Kalra S, Vithalani M, Gulati G, Kulkarni CM, Kadam Y,
Pallivathukkal J, et al. Study of prevalence of nonalcoholic
risk of NAFLD progression as much as raise the risk
fatty liver disease (NAFLD) in type 2 diabetes patients in
of CRC. A better understanding of the benefit of early
India (SPRINT). J Assoc Physicians India. 2013;61(7):448-
screening of CRC in NAFLD patients, may impact of 53.
treatment of NAFLD in the modulation of the risk of 2. LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG,
colorectal cancer. Goh KL, et al. World Gastroenterology organisation global
guidelines: Nonalcoholic fatty liver disease and nonalcoholic
CONCLUSION steatohepatitis. J Clin Gastroenterol. 2014;48(6):467-73.
3. Liu H, Lu HY. Nonalcoholic fatty liver disease and
Nonalcoholic liver disease may present as simple
c a rd i ov a s c u l a r d i s e a s e . Wo r l d J G a s t ro e n te ro l .
steatosis, or may occur as nonalcoholic steatohepatitis 2014;20(26):8407-15.
with or without cirrhosis development. NAFLD appears 4. Marcuccilli M, Chonchol M. NAFLD and chronic kidney
to be pathophysiologically linked to the metabolic disease. Int J Mol Sci. 2016;17(4):562.
syndrome—with obesity, T2DM and dyslipidemia 5. Muhidin SO, Magan AA, Osman KA, Syed S, Ahmed MH. The
raising the risk of development of NAFLD. Among relationship between nonalcoholic fatty liver disease and
colorectal cancer: the future challenges and outcomes of
the components of metabolic syndrome, obesity and
the metabolic syndrome. J Obes. 2012;2012:637538.
diabetes have been strongly linked to hepatocellular
6. Streba LA, Vere CC, Rogoveanu I, Streba CT. Nonalcoholic
carcinoma (HCC). Pathophysiologic mechanisms fatty liver disease, metabolic risk factors, and hepatocellular
that lead to NAFLD development and its progression carcinoma: an open question. World J Gastroenterol. 2015;
to nonalcoholic steatohepatitis and cirrhosis include 21(14):4103-10.
CHAPTER
73
Glucose Metabolism Disorders
in Chronic Liver Disease
INTRODUCTION MECHANISM OF IR AND GMD IN CLD

The association between glucose metabolism disorders Different mechanisms that have been proposed for
(GMD) and chronic liver disease (CLD) is being hyperinsulinemia and progression to IR and type 2 DM in
increasingly recognized the world over. It can be of 3 cirrhotic patients include (i) increased insulin secretion
types—diabetes occurring as a complication of CLD by pancreas due to increased β-cell sensitivity to glucose,
(hepatogenous diabetes), liver disease (LD) most (ii) decreased hepatic insulin removal and degradation
commonly nonalcoholic fatty liver disease (NAFLD) due to spontaneous portal-systemic shunting causing
occurring as a consequence of diabetes mellitus (DM) impaired delivery of insulin to the liver and decreased
and LD occurring coincidentally with DM. GMD refers rate of insulin degradation due to parenchymal liver
to a spectrum of abnormalities in glucose tolerance, damage, and (iii) receptor down regulation leading to
ranging from asymptomatic pre-diabetes which can be reduced insulin binding.
present either in the form of impaired fasting glucose Decreased insulin sensitivity in liver, muscles and
and/or impaired glucose tolerance as well as overt DM. adipose tissue, combined with decreased glucose
effectiveness and impaired feedback regulation of insulin
ROLE OF LIVER IN CARBOHYDRATE secretion compound the problem. In chronic hepatitis
METABOLISM C (CHC), HCV NS 5A protein has been implicated
The liver has an important role in carbohydrate additionally in increasing hepatic gluconeogenesis
metabolism; it normally maintains a tight control of (through FOX 01 pathway) and decreasing hepatic
nutrient supply to the tissues, glucose being taken up glucose uptake, hence accounting for a higher prevalence
during feeding for glycogen synthesis and being released of GMD in CHC. In NAFLD, additional factors implicated
during fasting by glycogenolysis or gluconeogenesis. are oxidative stress, hepatic steatosis and genetic factors
that decrease insulin sensitivity and increase serum
GLUCOSE METABOLISM IN triglycerides. Dysbiosis has recently been implicated in
DISEASED LIVER the genesis of type 2 DM in NAFLD. Pathogenesis of type 2
In the presence of hepatic disease, the metabolic DM in hereditary hemochromatosis is multifactorial: iron
homeostasis of glucose is impaired because of insulin overload, decreased insulin secretion, increased BMI,
resistance (IR) and impaired sensitivity of β-cells in the insulin resistance, cirrhosis and diabetes in first degree
pancreas. relatives appear to be responsible. In addition, a number
CHAPTER 73: Glucose Metabolism Disorders in Chronic Liver Disease 447
of disorders of liver are associated with pancreatic in 14% to 71%) by various researchers. Prevalence of IR
disease like hemochromatosis and alcoholic liver disease varies from 34% to 69%. Prevalence of NAFLD in type 2
(ALD) which may also contribute to hyperglycemia. diabetes was found to vary from 10% to 87%. The wide
variation in prevalence is because of the differences
MECHANISM OF LD IN DM in the demographic profile, the underlying LD of the
Mechanisms of diabetes contributing to liver damage patients studied (which varies from chronic hepatitis to
include (i) adipokine mediated increased oxidative end-stage liver disease enrolled for liver transplantation)
stress and aberrant inflammatory response in diabetes and LD of varied etiologies.
damaging the hepatoc ytes, (ii) insulin causing
overexpression of connective tissue growth factor [which CORRELATION OF GMD WITH
is known to induce several extracellular matrix (ECM) ETIOLOGY AND SEVERITY OF CLD
components especially in association with steatosis and AND RISK FACTORS OF DM
inflammation] in hepatic stellate cells (HSC) leading to GMD in CLD occurs independent of the established
fibrogenic response, and (iii) hyperglycemia causing risk factors for DM as most studies have refuted the role
activation of hepatic stellate cells through increased of traditional risk factors of DM like age more than 45
expression of the receptor for advanced glycation end- years, female gender, positive family history of DM and
product (RAGE) modulated by the transforming growth high BMI in causing GMD in CLD patients, though, few
factor β-1. Ligand activation of RAGE leads to formation have implicated older age as a risk factor. Obesity as a
of reactive oxygen species, which also contributes to the part of metabolic syndrome has been linked to NAFLD.
deposition of ECM in the liver. Likewise in studies trying to correlate the severity of
Progression from adipose tissue IR to NAFLD and liver disease with occurrence of GMD, majority showed
NASH has been explained as a four step process: (i) IR increased prevalence of IR, pre-diabetes and diabetes
provides a ‘lipotoxic environment’ that ensures a high with increasing severity of liver disease as per the CTP
free fatty acid flux and compensatory hyperinsulinemia score and also the liver fibrosis stage. IR and GMD have
which stimulates increased hepatic triglyceride synthesis, been found to be more prevalent in decompensated
(ii) development of hepatic steatosis and of a lipid pool cirrhosis as compared to compensated cirrhosis, which
from where lipid derived toxic metabolites may activate is higher than in patients with chronic hepatitis. Also,
inflammatory pathways, (iii) failure of liver to adapt to as per literature certain etiologies of liver cirrhosis like,
long-standing triglyceride accumulation brings about chronic hepatitis C, NAFLD, autoimmune liver disease,
chronic necrosis and inflammation, and (iv) chronic alcoholic liver disease and hemochromatosis may be
activation of HSC causing the final fibrosis. more commonly associated with GMD in most studies.
Hepatic steatosis is a feature of CHC, ALD and NAFLD Chronic hepatitis B on the other hand has not been
also and it further aggravates IR and type 2 DM, resulting found to have a higher prevalence of GMD.
in a vicious cycle.
As liver is a major storage organ for glycogen, in CLINICAL PRESENTATION
conditions where glycogen breakdown is impaired like OF GMD IN CLD
severe acute liver disease and advanced liver cirrhosis, Unlike the usual clinical presentation of type 2 DM, GMD
hypoglycemia can occur. in CLD are frequently asymptomatic. The classical triad
of weight loss, polydipsia and polyuria, other symptoms
BURDEN OF GMD AND due to recurrent styes, slow or non-healing ulcers,
IR IN CLD AND OF LD IN DM recurrent vaginitis, oral thrush and microangiopathic
Prevalence of GMD in patients with liver cirrhosis has target organ damage, i.e. nephropathy, retinopathy and
been found to be varying from 33% to 96% (overt DM neuropathy are rarely if at all seen. Macroangiopathy is
also less common except in patients with NAFLD and Medical Nutrition Therapy
chronic hepatitis C (CHC). It may be due to the protective and Lifestyle Modification
effects of low serum levels of lipids, Lp(a),decreased
These are the same as for diabetes in general except that
coagulation function and thrombocytopenia associated
sufficient daily intake of calories and proteins (not >20%
with cirrhosis.
of energy intake) is required as most CLD patients are
malnourished. Alcohol consumption must be stopped.
IMPLICATIONS OF GMD ON Active exercise is difficult in patients with active LD and
COMPLICATIONS OF CLD in patients with gross edema and ascites.
CLD with GMD are associated with increased morbidity
and mortality as compared to those with CLD alone. This
Pharmacotherapy
is a consequence of increase in complications related
Most oral antidiabetic (OAD) agents can be given in child
more to the underlying hepatic disease like bacterial
A CLD. Altered drug metabolism is primarily a concern
infections, spontaneous bacterial peritonitis, refractory
in patients with advanced LD. Also, CLD can sometimes
ascites, gastrointestinal bleed, hepatic encephalopathy
alter renal function, hence altering metabolism not
and hepatorenal syndrome and less so due to general
only of drugs metabolized in the liver but also those
or complications related to diabetes except for slightly
eliminated by the kidneys. Acarbose, incretin based
increased cardiovascular and cerebrovascular diseases
therapies and short-acting insulin analogues are the
in patients with NAFLD and CHC. Increased risk of
safest in Child B and C CLD.
hepatocellular carcinoma has been reported in patients
If blood sugars are not controlled with MNT and
of CLD with GMD. In patients with CHC, IR and GMD
LSM, start with OADs and rapidly advance to short acting
aggravate the course of hepatic inflammation with
prandial insulin if: blood sugar is still not controlled,
earlier and more severe fibrosis and a lower spontaneous
transaminases are >2 × ULN, or decompensation of
viral remission in response to antiviral therapy. GMD is
cirrhosis occurs. Watch for hypoglycemia.
associated with a longer hospital stay, shorter 30 days
A detailed description of management of DM in CLD
survival and increased 90 days rebleed and mortality
is not possible and only the special features of each class
following portal hypertensive variceal bleed.
of OADs are being mentioned here:
DIAGNOSIS AND MONITORING
The criteria for diagnosis of pre-DM and DM associated Metformin
with LD is the same as in the general population. However, Insulin sensitizing agent metformin is the oral agent
HbA1c may be falsely low in patients with cirrhosis, hence of choice except in patients with advanced LD, those
it is unreliable for diagnosis or monitoring. In patients with GFR <30 mL/min and in alcoholics because of the
with decompensated LD, monitoring must be done using risk of lactic acidosis. Additionally metformin has been
SMBG and fructosamine assay. If this is not available, found to decrease the risk of hepatic encephalopathy,
then for long term control we can use HbA1c but the target hepatocellular carcinoma and liver related deaths.
HbA1c should be 7.5–8.0% in CLD patients.
Sulfonylureas
TREATMENT OF GMD IN CLD Avoid insulin secretagogues – sulfonylureas in advanced
Optimization of blood glucose level is required not only LD because of increased risk of hypoglycemia and
to avoid late complications of DM but also for cirrhosis hepatotoxicity (reported with some). In mild CLD,
associated complications and outcomes following short-acting sulfonylurea can be used with a watch on
antiviral therapy. hypoglycemia.
CHAPTER 73: Glucose Metabolism Disorders in Chronic Liver Disease 449
Pioglitazone insulin requirement is high, however in decompensated

Pioglitazone may be used in patients with early NAFLD. cirrhosis—insulin requirement may vary and so dose
It should be avoided in patients with elevated serum needs to be adjusted frequently. It may be decreased due
transaminases (>2.5 × ULN), CTP class C patients and in to decreased capacity of liver for gluconeogenesis and
those with active LD. decreased hepatic break down of insulin, however it can
be increased due to IR. Short-acting insulin analogues
Meglitinides may offer equivalent or improved glycemic control
These should be used with caution. They may require compared to standard human insulin with decreased risk
an increase in dosing intervals and should be avoided in of hypoglycemia especially nocturnal and severe. Short-
advanced LD. acting insulins are preferred. Insulin however has been
reported to increase the risk of HCC.
Acarbose
It is safe and effective in cirrhotics as it is metabolized RESULTS OF OUR STUDY
exclusively in the gut. It can even be used in patients with A hospital-based observational study conducted on 100
mild encephalopathy as it additionally decreases gut in patients with liver cirrhosis by us in Lady Hardinge
ammonia levels. Medical College and Smt Sucheta Kriplani Hospital, New
Delhi, India from November 2015 to April 2017 found
GLP-1RA that GMD and IR are prevalent in about 40% of patients
These are safe. No dose adjustment is needed in hepatic with liver cirrhosis. Traditional risk factors of diabetes
injury and for dulaglutide and liraglutide, not even in mellitus like age > 45 years, high BMI, hypertension,
renal impaired patients. Liraglutide has been shown to
hypertriglyceridemia and a positive family history of DM
improve the liver histology in NASH patients.
increased the chances of GMD. Though the number of
patients with DM increased with increasing severity of
DPP-4 Inhibitors
cirrhosis (17%, 24% and 27% for CTP class A, B and C
They are effective and safe even in advanced CLD
respectively), it did not achieve statistical significance.
especially in patients with NASH and CHC. Sitagliptin
Presence of GMD with CLD was found to lengthen the
has been shown to improve NASH scores and reduce
duration of hospital stay, with no significant increase in
liver fibrosis.
mortality or complications of liver cirrhosis in our study.
SGLT-2 Inhibitors
Caution must be exercised while using in catabolic
BIBLIOGRAPHY
1. Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Targher
patients and in those with risk of hypovolemia, i.e. in older
G, Lonardo A. Type 2 Diabetes in Non-alcoholic fatty liver
patients, those on diuretics, those with cardiovascular disease and hepatitis C virus infection-liver: The “Musketeer”
diseases and cirrhotics with circulatory dysfunction. in the Spotlight. Int J Mol Sci. 2016;9:17(3):355.
They reduce transaminases in NASH but occasional 2. Elkrief L, Rautou PE, Sarin S, Valla D, Paradis V, Moreau
reports of diabetic ketoacidosis are there. They can cause R. Diabetes Mellitus in patients with cirrhosis: clinical
mild hepatotoxicity in patients with mild to moderate LD implications and management. Liver Int. 2016;36(7):936-
and are contraindicated in renal dysfunction. 48.
3. Greco AV, Mingrone G, Mari A, Capristo E, Manco M,
Gasbarrini G. Mechanisms of hyperinsulinaemia in Child’s
Insulin
disease grade B liver cirrhosis investigated in free living
It is probably the safest and most effective therapy in conditions. Gut. 2002; 51:870-75.
patients with liver dysfunction, though there is increased 4. Hamed AE, Abas B, Shaltout I, Esmt G, Gomez R, et
risk of hypoglycemia. In compensated cirrhosis— al. Managing diabetes and liver disease association,
Guidelines (Consensus) development. J Endocrinol Diabetes 8. Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N,
Obes. 2015;3(3):1073-81. Geerts A. Insulin resistance in hepatocytes and sinusoidal
5. Johnson DG, Alberti KG, Faber OK, Binder C. Hyperinsulinism liver cells: Mechanisms and consequences. J hepatol
o f h e p a t i c c i r rh o s i s : d i m i n i s h e d d e g r a d a t i o n o r 2007;41(1):142-56.
hypersecretion? Lancet. 1977;1(8001):10-3. 9. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait
6. Kawaguchi T, Taniguchi E, Itou M, Sakata M, Sumie S, Sata B, Vidaud M, et al. High glucose and hyperinsulinemia
M. Insulin resistance and chronic liver disease. World J stimulate connective tissue growth factor expression: a
Hepatol. 2011;3(5):99-107. potential mechanism involved in progression to fibrosis
7. Khan R, Foster GR, Chowdhury TA. Managing diabetes in non-alcoholic steatohepatitis. Hepatol. 2001;34(4 Pt
in patients with chronic liver disease. Postgrad Med. 1):738-44.
2012;124(4):130-37.
CHAPTER
74
Hepatorenal Syndrome:
Clinical Considerations
INTRODUCTION Type 1 HRS is an acute form of HRS. It is characterized

Hepatorenal syndrome (HRS) is an exclusive form of by rapidly progressing renal failure. It usually develops
functional renal failure which occurs in the setting of after one or more precipitating events. Patient with
advanced chronic liver disease, acute liver failure and type 1 HRS is usually critically ill and has multiorgan
alcoholic hepatitis. It is one of the dreaded complications dysfunction.
of cirrhosis wherein patient can survive only for few days Type 2 HRS usually occurs in cirrhotic patients with
or months in absence of any treatment. In cirrhosis, it relatively preserved hepatic function. It is characterized
occurs because of the interplay between vasodilators by moderate and slowly progressive renal failure often
and vasoconstrictors on renal vasculature. Once the preceded by diuretics resistant ascites.
patient develops HRS, a downhill course in the natural Type 3 HRS is acute renal failure occurring in cirrhotic
history of cirrhosis begins. Liver transplantation (LT) is patients with CKD, while HRS developing in acute liver
the only definitive modality available for curing HRS. failure is labeled as Type 4 HRS.
Because of huge expenses involved in LT and further
gross mismatch between demand and supply of this vital EPIDEMIOLOGY
organ, a majority of times this modality remains beyond HRS is a life-threatening complication, which occurs in
the reach of a common man. Hence, in developing about 10% of patients with decompensated cirrhosis.
country like India it is extremely important to give stress As per literature, 18% nonazotemic cirrhotic patients
on prevention of HRS in cirrhotic patient. develop HRS within one year and 39% within 5 years
after onset of the disease. Chances of development of
DEFINITION HRS increase whenever patient develops spontaneous
Hepatorenal syndrome (HRS) is defined as renal failure, bacterial peritonitis (SBP) or upper GI bleeding (UGIB).
which occurs in patients with the advanced liver disease HRS Type 1 patients have 80% mortality in 2 weeks if
without any detectable cause of renal failure. In this remained untreated while in Type 2 average lifespan is
unique form of renal failure only kidneys’ function gets about 4–6 months.
altered and is not associated with any structural changes
in kidneys. Depending upon the temporal course PATHOPHYSIOLOGY
of development and progression it is classified into Natural history of cirrhosis progresses from diuretic
following types. responsive ascites, dilutional hyponatremia, refractory
ascites and finally to HRS. HRS is on the extreme thereby augmenting renal vasoconstriction and causing
spectrum of hemodynamic changes which accompany decline in GFR. Loss of renal auto-regulation also
cirrhosis with portal hypertension. Systemic and contributes in causation of renal dysfunction. All these
splanchnic vasodilation together with severe renal factors contribute in developing renal dysfunction, i.e.
arterial vasoconstriction is the pathognomic feature of HRS.
HRS. Splanchnic vasodilation occurs because of actions
of various vasodilators like nitric acid produced by PRECIPITATING FACTORS
hepatocytes and stellate cells. Mesenteric angiogenesis (FLOW CHART 1)
driven by platelet-derived growth factor (PDGF) and Following factors are known to precipitate HRS:
vascular endothelial growth factor (VEGF) is also found to Gastrointestinal bleeding
have an important role in the causation of hyperdynamic Lactulose-induced diarrhea
circulation and splanchnic vasodilation. Splanchnic Aggressive diuretic use causing renal fluid losses
vasodilation produces a reduction in mean arterial Large volume paracentesis without volume expansion
pressure (MAP) as well as effective arterial blood volume Spontaneous bacterial peritonitis
which in turn initiates a sequence of compensatory Urinary tract infection
responses. These compensatory mechanisms include Use of nephrotoxic drugs such as NSAIDs or amino
stimulation of different vasoconstrictor systems. glycosides

Sympathetic nervous system (SNS): Stimulation of
cardiopulmonary volume receptors and arterial

Flow chart 1: Pathology of hepatorenal syndrome
baroreceptors causes SNS activation which in turn
leads to increased blood levels of noradrenaline. This
along with increased cardiac output tries to maintain
MAP.
Renin angiotensin aldosterone system (RAAS): Release
of aldosterone augments retention of sodium and

water by the kidneys and tries to restore blood volume
but ultimately leads to the development of ascites.
Nonosmotic release of antidiuretic hormone (AVP/
ADH): ADH enhances retention of solute free water

and responsible for causing hyponatremia.
These compensatory mechanisms however become
counterproductive. The splanchnic vascular bed becomes
refractory to the action of all these vasoconstrictors
but they act effectively on renal arteries causing renal
vasoconstriction. This leads to renal ischemia, which in
turn stimulates production of intrarenal vasoconstrictors
such as angiotensin II, adenosine, and endothelin,
further intensifying renal vasoconstriction. In the kidneys
to counteract the renal vasoconstriction there occur
increased production of vasodilators like prostaglandins,
nitric oxide and kallikrein. However, as cirrhosis
advances or any precipitating factor sets in, intrarenal Abbreviations: RAAS: Renin-angiotensin-aldosterone system;
vasodilators fail to counterbalance vasoconstrictors, SNS, Sympathetic nervous system, AVP: Arginine vasopressin
CHAPTER 74: Hepatorenal Syndrome: Clinical Considerations 453
DIAGNOSIS 1.5 g/kg on day 1 and 1 g/kg on day 3 along with

Diagnosis of HRS is confirmed only after exclusion of antibiotics. This was shown to reduce development
the factors such as hypovolemia or parenchymal renal of HRS.
disease, which can also cause renal dysfunction in Patients with history of SBP or having ascitic
cirrhosis. Hypovolemia is diagnosed when there occur fluid protein <1.5 g/dL should be given antibiotic
improvement in renal function following withdrawing prophylaxis in the form of Tab Norfloxacin 400 mg/
diuretics for at least 2 days and volume expansion day or Ciprofloxacin 750 mg/week. The patient who
with albumin at 1 g/kg/day (maximum 100 g/day). presents with UGIB should be given IV antibiotics to
Significant proteinuria (>500 mg/day), granular casts prevent SBP.
or RBCs in urine, or abnormal kidney size detected on In patients with tense ascites, IV albumin should be
USG abdomen suggest presence of parenchymal renal given 8 g/L of fluid removed while doing large volume
diseases. International Club of Ascites (ICA) developed paracentesis (LVP).
the criteria to diagnose HRS in 1996, and then based on Appropriate treatment should be given to prevent
exploration of knowledge in this field the criteria were and treat UGIB.
revised in 2007 and then in 2015. The recent revision was Nephrotoxic drugs such as aminoglycosides, NSAIDs,
based on the fact that serum creatinine overestimates radioactive–contrast media should be avoided in
GFR. ICA in recent revision has considered the definition cirrhotic patients.
of AKI, which was developed primarily for defining In patients with advanced cirrhosis (CTP Class C)
AKI in critically ill patients. Dynamic change in serum with refractory ascites beta-blockers should be
creatinine compared to baseline value (instead of an gradually tapered and then discontinued.
absolute value of 1.5 mg/dL) is the key criterion for
diagnosis of cirrhosis-related AKI. Rest of the criteria BIOMARKERS IN HRS
remain same. A serum creatinine value obtained in the Cystatin C (Cys-C): Cys-C is one of the serum
previous 3 months or most recent one is considered as biomarkers for GFR. It moves freely across the
baseline value. In patients without a previous value, the g l o m e r u l a r m e m b ra n e a n d i s m e t a b o l i z e d
serum creatinine on admission should be considered as completely in the renal proximal tubular cells.
the baseline value. Cys-C is a reflection of early changes and is an ideal
endogenous marker of GFR. A growing number of
DIAGNOSTIC CRITERIA FOR reports have demonstrated that Cys-C can be used as
HEPATORENAL SYNDROME a marker for AKI assessment in cirrhosis.
Cirrhosis of liver with ascites Neutrophil Gelatinase Associated Lipocalin (NGAL):
Acute kidney injury defined by increase in serum Urinary NGAL has shown promising results in HRS.
creatinine > 0.3 mg/dL from baseline within 48 hours NGAL is secreted in high levels by the damaged
or > 50% above baseline within 7 days tubules for inducing re-epithelialization. It is
No features suggestive of shock detectable in the blood and urine within a couple of
No evidence of hypovolemia hours of injury. Urinary NGAL levels are significantly
No recent/current history of receiving nephrotoxic high in acute tubular necrosis (ATN) as compared to
drugs other causes of AKI including HRS.
No features suggestive of parenchymal renal disease.
TREATMENT
PREVENTIVE MEASURES If a cirrhotic patient presents with renal dysfunction, the
Early recognition and appropriate treatment of SBP other causes mentioned in the diagnostic criteria should
can prevent HRS. It is advisable to give IV albumin be ruled out. Central line insertion and monitoring of
fluid balance is critical in managing patients of renal free liver dialysis or albumin dialysis. It helps to remove
dysfunction in cirrhotic patients. The treatment of HRS albumin-bound substances accumulating in liver failure.
aims at plasma volume expansion and increase in renal
perfusion pressure. vasopressor therapy with albumin is Liver Transplant
mainstay of treatment in HRS. Liver transplant (LT) is the only definitive treatment for
Type 1 and 2 HRS as in majority of times HRS is either
Albumin with Vasoconstrictors recurrent or irreversible. Rest of the treatments act only
Terlipressin with albumin: Terlipressin with albumin as a bridge till LT is done. In order to improve graft
is the therapeutic combination of choice for type survival after LT, it is very important to reverse HRS with
1 HRS. Patient is given albumin infusion 20-40 g/
pharmacological treatment or RRT. If renal functions
day. Terlipressin is started with 0.5 mg 6 hourly as
remain deranged >4 weeks prior to LT, consideration
IV boluses. Serum creatinine is measured after 3
should be given to simultaneous liver and kidney
days. If reduction in serum creatinine is < 25% from
transplant.
baseline, the dose of terlipressin is doubled. Dose
can be titrated up to 12 mg/day. This treatment
is continued for 14 days. Almost 50% of patients
SUMMARY
show reversal of HRS type 1. As per recent research, Hepatorenal syndrome (RS) is a dreaded complication of
continuous infusion of terlipressin 2 mg/day is liver cirrhosis with significant morbidity and mortality.
equally effective and have comparatively less side With revised diagnostic criteria, HRS can be diagnosed
effects. Terlipressin is contraindicated in patients at an early stage and associated with early institution
having ischemic heart disease, peripheral vascular of pharmacotherapy. Emphasis should always be given
disease and cerebrovascular disease. This therapy to prevent and treat precipitating factors aggressively.
can be beneficial in 60–70% of patients with type 2 Pharmacotherapy has only a limited role in the
HRS. management of HRS as it usually recurs even when
Midodrine with octreotide (with albumin): Midodrine reverted with the medical management. Liver transplant
is given orally 5–10 mg, three times/day and titrated is the only definitive modality of treatment. If renal
up to 12.5 mg three times/day. Octreotide is started dysfunction remains >4 weeks prior to LT combined
with 100 μg thrice a day subcutaneously and can be liver-kidney transplant may be considered for better
increased up to 200 μg thrice a day. results.
Noradrenaline with albumin: Noradrenaline infusion
0.5–3 mg/hour as continuous IV infusion along with BIBLIOGRAPHY
albumin can also be used effectively especially in 1. Acevedo JG, Cramp ME. Hepatorenal syndrome: Update on
critically ill patients. diagnosis and therapy. World J Hepatol. 2017;9(6):293-9.
2. Bucsics T, Krones E. Renal dysfunction in cirrhosis: acute
Renal Replacement Therapy kidney injury and the hepatorenal syndrome. Gastro
Patients who fail to respond to medical line of treatment enterology Report. 2017;5(2):127-37.
should be started on renal replacement therapy 3. European Association for the Study of the Liver. EASL
clinical practice guidelines on the management of ascites,
(RRT). RRT is usually kept reserved for patients awaiting
spontaneous bacterial peritonitis, and hepatorenal
liver transplantation.
syndrome in cirrhosis. J Hepatol. 2010;53:397-417.
4. Fukazawa K, Lee HT. Updates on Hepato-renal syndrome.
Liver Replacement Therapy J Anesth Clin Res. 2013;4:352.
Molecular adsorbent recirculating system (MARS) is the 5. Ge PS, Runyon BA. The changing role of beta-blocker therapy
modality used with mixed results. It represents a cell- in patients with cirrhosis. J Hepatol. 2014;60(3):643-53.
CHAPTER 74: Hepatorenal Syndrome: Clinical Considerations 455
6. Lei L, Li L, Zhang H. Advances in the Diagnosis and 9. Mattos AZD, Mattos AAD, Mendez-Sannchez N. Hepatorenal
Treatment of Acute Kidney Injury in Cirrhosis Patients. syndrome: Current concepts related to diagnosis and
Biomed Res Int. 2017;2017:8523649. management. Annals of Hepatology. 2016;15(4):474-81.
7. Low G, Alexander GJM, Lomas DJ. Hepatorenal syndrome: 10. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis,
Aetiology, diagnosis, and treatment. Gastroenterol Res prevention and treatment of hepatorenal syndrome in
Pract. 2015;2015:207012. cirrhosis. Gut. 2007;56:1310-8.
8. Mathur P, Nabi BN. Hepatorenal syndrome-current concepts
in pathophysiology. Gastroenterol Hepatol Open Access.
2017;7(1): 00225.
CHAPTER
75
Cirrhosis of Liver: Beyond
Beta-blockers and Diuretics
Anup K Das
INTRODUCTION and determining the appropriateness and optimal

Cirrhosis of liver represents a late stage of progressive timing for liver transplantation. Only important areas
hepatic fibrosis due to multiple etiologies characterized in these issues frequently encountered in our day-to-
by distortion of the hepatic architecture and the formation day practice will be discussed, many of which are often
of regenerative nodules ultimately leading to portal overlooked or missed.
hypertension. This can result in the formation of venous
collaterals (varices) and associated circulatory, vascular, VARICEAL HEMORRHAGE
functional, and biochemical abnormalities leading to Variceal hemorrhage is associated with high mortality
ascites and other complications (decompensation). rates. Non-selective beta-blockers (NSSB, Propranolol,
Here from the prognosis becomes poor with liver Nadolol) are very useful in preventing first variceal
transplantation becoming the best therapeutic option. bleeding and re-bleeding by reducing portal pressure
The median survival is ≤6 months in decompensated (blocking beta1 receptors reduces cardiac output,
cirrhosis and a Child-Pugh score ≥12 or a Model for and blocking beta2-receptors produces splanchnic
end-stage liver disease (MELD) score ≥21. The median vasoconstriction and reduces portal flow). In primary
survival of patients with compensated cirrhosis is >12 prophylaxis, beta-blockers reduces the bleeding risk
years. In presence of an acute complication (e.g. variceal from 30 to 15%; while in secondary prophylaxis, this
hemorrhage or spontaneous bacterial peritonitis) the risk decreases from 60 to 42% by first year. Carvedilol, a
median survival is ≤6 months, if the Child-Pugh score is newer NSBB with additional anti-α1-adrenergic activity,
≥12 or the MELD score is ≥18. Varices that have not bled are is superior to propranolol in reducing portal pressure.
considered to have compensated cirrhosis, even though Ascites is treated with a combination of diuretics and
the prognosis is poorer than compensated cirrhosis sodium restriction. The 15–20% of patients with cirrhotic
without varices (3.4 versus 1% one-year mortality). The ascites who show no response to one week’s treatment
general management for cirrhosis include—managing with potent diuretics (spironolactone 160 mg/day with
symptoms and laboratory abnormalities, preventing, furosemide 80 mg/day) are considered to have refractory
identifying, and treating the complications of cirrhosis, ascites. At present, effective treatments for refractory
Preventing superimposed insults to the liver, Slowing ascites include Tolvaptan, large-volume paracentesis
or reversing the progression of liver disease, pdentifying (LVP—4000-6000 mL/day) combined with albumin
medications that require dose adjustments/avoidance, (5 g/L), ascites ultrafiltration/ reinfusion, transjugular
CHAPTER 75: Cirrhosis of Liver: Beyond Beta-blockers and Diuretics 457
intrahepatic portosystemic shunt (TIPS), and ultimately HEPATORENAL SYNDROME (HRS)

liver transplantation. Hopefully, with the development Type I and Type II occurs in the setting of SBP and
of vasoactive drugs, rifaximin, ascites drainage pump, refractory ascites respectively. Prerenal causes account
and other new therapies, the treatment of refractory for majority of cases, followed by ATN. Acute kidney
ascites may be more effective to reduce the need for liver injury (AKI) occurs in 20–49% of hospitalized cirrhotic
transplantation. patients and has to be excluded from HRS. AKI is defined
A successful treatment of ascites (minimization as an increase in SCr from baseline by 26.5 μmol/L
of the fluid without intravascular volume depletion) within 48 hours of hospitalization or an increase of ≥
results in improved quality of life, reduced infections but 1.5 times baseline during the index hospitalization.
treatment modalities vary with the severity of ascites. But SCr is an unreliable estimate of kidney function in
Low volume ascites only needs conservative measures cirrhosis and single readings may be even less reliable
such as sodium restriction (2 g/day), avoiding alcohol/ in the setting of AKI. Due to reduced creatine synthesis
NSAIDs without fluid restriction. Moderate volume by the liver, lowered creatinine production because of
cases need low volume diuretics (Spironolactone and/ muscle wasting, and an increased volume of distribution,
or furosemide at 100:40 ratio). Large volume ascites SCr may overestimate kidney function by upto 100%.
interferes significantly with daily activities of patients Moreover, its use for estimating GFR have not been
necessitating LVP. Refractory ascites recurs quickly validated in populations with cirrhosis. Therefore, using
after paracentesis, and has a poor prognosis and needs a combination of absolute and relative changes in SCr
(as recommended in recent international guidelines
frequent paracentesis or a TIPS. Surgical shunts have no
defining AKI) allows early detection of AKI in cirrhosis
benefit over these. Patients having dyselectrolytemias,
without delaying therapeutic interventions. There is a
renal insufficiency and hepatic encephalopathy usually
graded increases in mortality associated with increasing
have refractory ascites.
severity of AKI, especially stage I. Present data suggest
About 30–45% of cirrhotics will have overt hepatic
that even transient changes in renal function predict poor
encephalopathy with 70% of all showing subtle changes.
prognosis. This is relevant in cirrhosis since the response
It is the most common preventable complication
to vasoconstrictor therapy decreases with higher SCr
for re-hospitalization in cirrhosis. The grading of
levels at treatment initiation. Neutrophil-gelatinase-
encephalopathy includes the underlying etiology, associated lipocalin (NGAL) and urine interleukin-18 are
time course, clinical severity and precipitating factors. novel biomarkers for diagnosing, predicting the severity
Alcohol intoxication/withdrawal, hypoglycemia, and clinical outcomes of AKI.
dyselectrolytemias, neuroinfections, neurosedatives,
psychiatric conditions and organ failures should be SPONTANEOUS BACTERIAL
excluded. Apart from standard treatment, a daily diet PERITONITIS (SBP)
consisting of 30–40 KCl/kg (1.2–1.5 g/kg protein, complex Spontaneous bacterial peritonitis (SBP) is ascitic fluid
carbohydrates and fat, BCAA supplementation, 25–45 infection without an evident intra-abdominal surgically
g/day fibre,) spread over small meals and a late night treatable source. Bacterial translocation, overgrowth
snack should be encouraged. Worsening of sensorium and hypochlorhydria may be responsible. Low serum
needs a CT brain to rule out hemorrhage/infarct/ protein and prolonged prothrombin time entails the
hypoperfusion and cerebral edema, and if present, needs greatest risks. Empiric antibiotic therapy is indicated
aggressive treatment. Two new oral preparations aimed with temperature > 37.8°C (100°F), abdominal pain
at reducing ammonia generation/excretion are glyceryl and/or tenderness, altered mentation and ascitic fluid
phenylbutyrate and ornithine phenylacetate and are polymorphonuclear leukocyte ≥250 cells/mm3. Ascitic
undergoing RCT and phase II trials (Table 1). fluid lactoferirn is a marker for SBP. In SBP, beta blocker
458
TABLE 1: Commonly encountered complications in decompensated cirrhosis with salient principles of treatemt and their survival
Complications Prevention Treatment Survival
Variceal bleed NSSB, Variceal band Resuscitation, restrictive blood/platelet/FFP 80–85% at 1 month
Ligation in: transfusion, vasopressors, sclerotherapy, band Rebleeding in 60% by 2 years
zz Small varices with alcohol intake, high C-P grade and ligation, TIPSS, surgical shunts with 67% survival
Red Wale Mark
zz Large varices
Ascites Low Sodium Diet Low Na+ diet, diuretics, large volume paracentesis, 50% at 2 years 75% at 1 year (in
TIPPS, surgical shunts Refractory ascites)
Hepatic encephalopathy Treating precipitants (Infection, bleeding, electrolyte 42% at 1 year 23% at 3 years
imbalance, sedatives, high proteins) lactulose, (After hospitalization)
rifaximin, metronidazole
SECTION 6: Gastroenterology/Hepatology
Heptorenal syndrome Avoiding precipitants Exclude AKI Median survival

(HRS)
MAP <80 mm Hg dilutional hyponatremia low urinary Na Terlipressin, octreotide, or midodrine or Type I–2 weeks Type II - 3-6
(5 mEq/L) hyperlkalemia, alcohol, LVP, SBP, malnutrition, noradrenaline months
Infections (viral and bacterial), avoiding NSAIDs SBP—use Dialysis liver support device OLT
of volume expanders such as albumin
Spontaneous bacterial By Norfloxacin 400 mg/day 5 days therapy with 3rd generation cephalosporin In hospital mortality 10-30%
peritonitis (usually
monomicrobial and Gm-
ve but Gm+ve infections
increasingly being
reported)
Ciprofloxacin 500 mg/day Fluoroquinolones not to be used in those already
on fluoroquinolone prophylaxis.
Primary prophylaxis
GI bleed, Low ascites
protein<1g/dL, Low ascitic protein<1.5 g/dL with a) Avoid beta-blockers Diuretics and restricted Fungal and viral infection need
CP score≥9 and serum bilirubin ≥ 3 mg/dL or b) s/ use of PPI Antibiotic resistance is increasing and to be excluded, if no response to
creatinine≥1.2 mg/dL or BUN ≥25 mg/dl or s/Na antibiotic use in previous 30 days is a risk factor, prevent mortality
≤ 130 mEq/L secondary prophylaxis indefinitely then combination antibiotics (Amoxy-clav +
Survivor of SBP Cephalosporin) or (Betalactam+Betalactamase
inhibitor + glycopeptides) given.
TABLE 2: Some important situations that need to be considered for a comprehensive management including prevention in cirrhosis
Associated issues Learning points Remarks
Bacterial infections Nosocomial infections in 15-35% of cirrhotics – SBP, UTI, RTI, spontaneous Difficult to recognize as signs of infection lacking.
bacteremia, Cellulitis/Soft tissue infection/Lymphangitis. 30–50% are culture negative. Can precipitate HRS,
Prophyllactic antibiotic in GI bleed, Low serum and ascitic protein, SBP device HE, hemodynamic instability. Associated coagulation
Associated Infections (ventilator, Central line or urinary catheter) in ICU anomalies predisposes to DIC. Overall, mortality rate
setting need prompt care Infections lead to unexplained deterioration and increased by 50%
relative adrenal insufficiency common.
(ACLF) Acute-on-chronic Systemic translocation of gut bacteria, immune failure and systemic Treatment and prevention of sepsis is important for
liver failure inflammatory signs present. Circulatory and cardiac dysfunction occurs, survival (90 day mortality is 50%). G-CSF may be tried.
Multiple organ failure is end result. Most common features are jaundice, Survival depends on number of organ failures.
encephalopathy ascites and varices. CLIF-C ACLF score is a better
prognostication model than others e.g. MELD or CTP scores.
Immunization agains HAV, HBV, All cirrhotics should be tested for anti-HAV Ig and HBsAg and vaccinate, To prevent ACLF
pneumococcal and influenza if non-immune
Hematological anomalies (PVT) Superficial cutaneous or subcutaneous beeds suggest thrombo Coagulation tests are of little value. Goal of therapy is to
thrombocytopenia, coagulopathy, cytopenia while deep-seated bleeds suggest coagulation disorders. achieve hemostasis, not correction of laboratory values.
anemia, portal vein thrombosis PVT is possibly due to stimulation of hepatic prothrombotic factor Vit K, FFP, Platelet transfusion, cryoprecipitate, aprotinin,
low WBC count, neutrophilic chemotaxis, stimulation. May lead to fibrosis and HRS. rF VII. Prophylactic use is ineffective. PT>4 sec is unlikely
complement levels Anemia is multifactorial—acute/chronic bleed, hypersplenism, hemolytic to respond to FFP. Thrombopoietin and interleukin-11
cryoglobulinemia and increased risk of anemias, ethanol-induced bone marrow suppression, folate/vit B 12 and under trial for thrombocytopenia.
lymphoma (Hep B) G-6-PD deficiency, aplastic, Zieve’s syndrome, post-antiviral therapy.
Platelet count<50000/µL needs platelet transfusion in active bleeding.
Desmopressin is ineffective. No clear data on use of anticoagulation in PVT
and myeloproliferative diseases are present in 30% of PVT.
Contd...
CHAPTER 75: Cirrhosis of Liver: Beyond Beta-blockers and Diuretics
459
460
Contd...
Associated issues Learning points Remarks
Nutritional Multifactorial—decreased or unbalanced food intake, malabsorption, Early dietician review needed. BMI and skin-fold thickness
Sarcopenia is predominant—due metabolic, inappropriate fasting/restricted diet and intestinal bacterial inaccurate for nutritional assesment. Subjective global
to reduced energy intake, reduced overgrowth. Exocrine pancreatic deficiency common. Multidisciplinary assessment is helpful. Hand grip test predicts outcome
substrate for muscle production, BCCA intervention — Energy 30-35 kcal/kg/day ( Protein 1-1.5 g/kg/day, Glucose (correlates with MELD). DEXA scan of abdominal muscles
oxidation, myostatin expression and 5-6 g/kg/day, 25-30% of total calories as medium chain triglycerides.). Enteral gold standard.
pro-inflammatory cytokines. Predictive of feeding preferred> Continuous/cyclical naso-gastric/jejunal feeds in sick Low serum retinol may predispose to HCC in alcoholic
survival. patients> Parenteral feeds where enteral feeding is impossible (end stage cirrhosis. But Vit A supplementation above 100,000 units/
Micronutrient deficiency is common and liver disease). Gastrostomy contraindicated in gastric varices. day must be avoided.
SECTION 6: Gastroenterology/Hepatology
should be corrected. Overfeeding with glucose & fats not recommended.

Dose adjustments of other medications Careful drug history is essential to look for NSAIDs, ATT, antibiotics or Nephrotoxic drugs to be avoided in decompensated
including unknown herbal medications unknown village medication. In those receiving steroids, Vit D and calcium state, For analgesia only paracetamol or tramadol is
All medications must be screened supplements should be given. indicated. Vit K should be used with caution.
for hepatotoxicity. Idiosyncratic drug
reaction is unpredictable.
End-of-Life care Teminal illness where Terminal decompensation and ACLF common presentations. Earlier Integrated palliative and supportive care needed
no cure is possible. Clear guidelines identification of cases surviving in near future difficult but Supportive and with symptom contro, improving quality of lifel plus
unavailable. It is important to identify the Palliative Care Indicators Tool (SPICT) may be useful psychological, social, spiritual and practical symptom.
needs of the patient and family.
Preventive aspect a) P
rimary prevention: To prevent cirrhosis, b) Secondary prevention: To detect To screen high-risk populations HBV/HCV +ves,
Epidemiologically, 10% of general cirrhosis at earliest stage, c) Tertiary prevention: To anticipate and detect Alcohol/iv drug abusers, unsafe sex, obesity, NAFLD,
population is expected to develop complications, d) Primordial prevention: Eliminating risk factors of cirrhosis Diabetes mellitus, Family members of Wilson, disease,
cirrhosis and 67% of cirrhosis are detected to develop, i.e. alcohol-related/NASH: related cirrhosis hemochromatosis, AIH, HBV and treat the underlying
accidentally. disease. Educating adolescent children about lifestyle,
sanitation. Non-availability of alcohol is a primordial
prevention
CHAPTER 75: Cirrhosis of Liver: Beyond Beta-blockers and Diuretics 461
use is associated with worse outcomes compared In a cirrhotic liver, vascular distortion can not be
with those not receiving beta blockers. In those with reversed unlike the fibrosis part. Hepatic fibrosis is a
bacterascites (bacteria present in the ascitic fluid, but dynamic process where hepatic stellate cells (HSC),
PMN <250 cells/mm3) antibiotics are given. Renal failure, Kupffer cells and recruited mononuclear cells are the
a major cause of death, develops in 30–40%. The risk key players. In early, compensated stages, it may regress.
decreases with IV albumin (1.5 g/kg body weight within Oxidative stress (ROS) accelerates the process and may
six hours of diagnosis and 1.0 g/kg body weight on day be induced by rennin angiotensin pathway of HSC,
three). along with other mediators such as TGF-β, nitric oxide
Acute-on-chronic liver failure (ACLF) is a syndrome and inflammatory cytokines (Table 2). Vasoconstrictor
in cirrhosis characterized by acute decompensation, angitensin II is produced leading to inflammation, tissue
organ failure, (s), and high short-term mortality. It may repair and fibrosis. Degree of fibrosis varies according to
develop at any phase during the clinical course of the the duration, composition, spatial distribution and scar
disease. According to the number of organ failures, cellularity. Increased septal thickness and micronodules,
ACLF is graded into three stages: ACLF-1 = renal failure which are proportional to ECM crosslinking, predicts
or single nonrenal organ failure if associated with renal poor outcomes. In addition to targeting the etiology
dysfunction and/or cerebral dysfunction; ACLF-2 = two of cirrhosis, anti-fibrotic agents are being developed
organ failures; and ACLF-3 = three to six organ failures, to downregulate HSC activation, angiotensin receptor
with increasing 28-day mortality rate (from 23 to 74%). antagonists and other mediators of fibrogenesis in the
ACLF patients show marked systemic inflammation future.
(ie, increased plasma cytokines levels) and immune
dysfunction. Alcohol, sepsis and HBV are common CONCLUSION
triggers for ACLF, but in 20%–45% of cases, the trigger There are many treatment related, multisystem,
remains unknown. Liver transplant is the definitive complex issues particularly in decompensated cirrhosis.
treatment. Prevention at different levels is important as is anticipating
In adults liver injury stimulates bone-marrow the complications and their fall out. Importantly, the fact
derived stem cells for hepatocyte regeneration. Stem cell that liver transplant is the only curative, but expensive
transfusion is being tried in cirrhosis and hepatocellular treatment option, will add to the burden of end-of-life
failure. Granulocyte Colony Stimulating factors [(G-CSF terminal care in our setting.
(5 mg/kg daily SC for 6–12 days)] have been tried in ACLF.
It may promote hepatocyte repair by facilitating migration BIBLIOGRAPHY
of bone marrow-derived progenitor cells and stem cells, 1. Gourdas Choudhury (Ed) Cirrhosis. 1st edn. Reed Elsevier
especially CD34+ cells. Increased hepatocyte growth India Ltd. 2015:51-55.
factor, induction of hepatic progenitor cell proliferation 2. Greenslade L. End-of-Life-Care for Patient with Liver
Disease. In: Tim Cross (Ed). Liver Disease in Clinical Practice
and improvement of hepatic microenvironment are
Switzerland: Springer International Publishing. 2017;355-
other reported effects of G-CSF. Improved neutrophil 67.
count and neutrophil function may contribute to some 3. Jung YK, Yim HJ. Reversal of liver cirrhosis: current evidence
reversal of immune dysfunction commonly observed in and expectations. Korean J Intern Med. 2017;32: 213-28.
ACLF. Upto 44% reduction in short term (60–90 days) 4. Kathleen Yan, Sc.B, Guadalupe Garcia-Tsao, Novel
mortality, improvement in liver function, increased Prevention Strategies for Bacterial Infections in Cirrhosis.
Expert Opin Pharmacother. 2016;17(5):689-701.
WBC count and CD34+ count (peripheral and hepatic)
5. King A, Barton D, Beard H A, Than N, Moore J, et al. REpeated
have been reported in Asian ACLF patients. It may be an AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC):
alternative in ACLF when liver transplant is unavailable a multicentre, phase II, open-label, randomised controlled
or contraindicated, but needs further studies. trial of repeated autologous infusions of granulocyte
colony-stimulating factor (GCSF) mobilised CD133+ bone 8. Tandon P, Jame s MT, Abraldes JG, Karvellas CJ, et al
marrow stem cells in patients with cirrhosis. A study Relevance of New Definitions to Incidence and Prognosis of
protocol for a randomised controlled trial. BMJ Open. Acute Kidney Injury in Hospitalized Patients with Cirrhosis:
2015;5(3):e007700. A retrospective population-based cohort study PLoS One.
6. Kirnake V, Arora A, Gupta V, Sharma P, Singla V, et al 2016;11(8):0160394.
Hemodynamic response to carvedilol is maintained for long 9. Tripath D, Peter C. Hayes Beta-blockers in portal hyper
periods and leads to better clinical outcome in cirrhosis: A tension: new developments and controversies Liver Inter
prospective study. J clin Exp hepatol. 2016;6:175-85. national. 2014;4;655-66.
7. Shah SC, Shah PS, Shah KP (Eds). Preventive Measures 10. Wang SZ, Ding HG. New therapeutic paradigm and concepts
for Cirrhosis of Liver and its Progression. 1st edn Jaypee for patients with cirrhotic refractory ascites. Sugg Zhonghua
Brothers Medical Publishers. 2016. pp. 1-23. Gan Zang Bing Za Zhi. 2017;25:249-53.
CHAPTER
76
Hepatitis B: Are We Moving
Ahead Towards Cure?
Anil C Anand
INTRODUCTION endemicity, however, huge population of the region

The World Health Organization (WHO) has estimated accounts for a large chunk of the entire pool of HBV
that ‘approximately one-third of the world population carriers of the world.2
is infected with hepatitis B virus (HBV), with serological
evidence of past or present infection’. Chronic HBV EPIDEMIOLOGY OF HBV IN INDIA
infection afflicts more than 350 million (5–7% of the Epidemiology of hepatitis B in India has been
world’s population) and approximates 2 billion people summarized recently. 3 more than 40 million HBV
have been infected worldwide. Approximately 15–40% carriers live in India and we contribute over 10–15% of
of patients who have been infected with HBV will go on burden of HBV infection worldwide. One in 25 infants
to develop its life-threatening complications (including born in India, are estimated to develop chronic HBV
cirrhosis, liver failure, and hepatocellular carcinoma) infection, and this will contribute nearly one million new
and it may be responsible for up to 1.2 million deaths per infected infant every year to the pool. Nearly 100,000
year due to this disease. deaths in India are attributed to complications related
Prevalence of HBV infection varies in different to HBV infection every year. Several published reports
countries and they can be categorized on basis of indicate that between 2–4.7% of Indian population is
prevalence of hepatitis B surface antigen (HBsAg) in positive for HBsAg. Recently a meta-analysis was carried
general population. High prevalence countries have ≥ 8% out with studies showing prevalence of HBV in India
of the population as HBsAg positive, while intermediate and it estimated that the point-prevalence of hepatitis B
or low prevalence countries have 2–7% and <2% of among non-tribal and tribal populations was 3.07% [95%
population that is HBsAg positive respectively. South- CI: 2.5–3.64] and 11.85% (CI 10.76–12.93) respectively.
East Asia, China, most of Africa, most of the Pacific Overall point-prevalence was estimated to be 3.70% (CI:
islands, the Amazon Basin and parts of the Middle East 3.17–4.24).4
are categorized as areas of high endemicity. South Asia, HBV infection has high prevalence among many
Eastern and Southern Europe, Russia, Central and South tribal populations. It could be due to inbreeding, poor
America have been classified as areas of intermediate hygienic conditions, close person-to-person contact and
endemicity (2–7%). United States, Western Europe and certain socio-cultural practices which are conducive to
Australia are areas with low endemicity (< 2%).1 India has transmission of HBV.5 Studies carried out among tribes of
been classified under the countries with intermediate Andaman and Nicobar Islands have also shown very high
prevalence of HBsAg positivity. (Nicobarese tribe—23.3%, IMMUNOPATHOGENESIS

Shompen tribe–37.8%, Jarawa tribe–65%). 13,14 Even in Virus induces a series of innate 13 and adaptive 14
Arunachal Pradesh there are hotspots of HBV infection. immune responses. HBV is said to display immense
For example, HBsAg prevalence in the Idu Mishmi tribe ‘stealth and cunning’15 and all viral proteins have the
has been found to be 21.2%. 6 Another group where capability to interfere in many of immune responses. In
prevalence of HBV is higher than in general population immunocompetent adult viral proteins induce robust
is that of patients with human immunodeficiency virus adaptive CD8 T-cell response. This includes induction
(HIV) infection as in intravenous drug users in North of both a cytolytic dependent and independent antiviral
East India.7 HBsAg prevalence among pregnant women effect via the expression of antiviral cytokines. B cells
has been found to be 0.9–6.3%. Earlier it was thought are also induced similarly to produce neutralizing
that most pregnant patients are mostly non-replicative antibodies such as anti-HBs and anti-HBe, which help
carriers, but recent studies suggest that more than half in blocking the spread of the virus. cccDNA can only
of such patients (56.8%) may be HBeAg positive. The be cleared by death of infected hepatocytes. HBV viral
common Indian genotypes are genotype A followed by proteins down regulate pattern recognition by cells,
D. Some reports suggest that Gentotype C can be seen in bring about changes in NK cell receptors and lead to CD4
Eastern India and there are rare reports of genotype E, F and CD8 T-cell exhaustion.16
and G in India. 8 Impairment in HBV specific T-cell function leads
to chronic HBV infection. Recent data suggests that
THE VIRUS children and young adults can also mount robust innate
HBV is a hepatotropic DNA viruses with an extremely and adaptive responses, unlike old patients and therefore
compact genomic organization.9 HBV genome is small the concept of ‘immune tolerance’ is being revised.16
(3.2 kb) and partially double-stranded, so called relaxed- HBV persistence in body is the result of overcoming of
circular (rc) DNA. It contains four overlapping open innate and adaptive responses, and it includes virus-
reading frames which encode a total of seven proteins, specific as well as global T-cell exhaustion/dysfunction.
i.e. PreS1/PreS2/HBsAg (large, medium, and small This a complex process mediated by multiple regulatory
surface envelope glycoproteins), HBeAg (HBVe antigen), mechanisms promoted by viral proteins in individuals
HBcAg (HBV core antigen), HBV Pol/RT (polymerase, with genetic susceptibility.
reverse transcriptase activity), and finally HBx (HBVx
antigen, which is a regulator of transcription required
NATURAL HISTORY OF HBV INFECTION
Chronic HBV infection is an eventful and active
for the initiation of infection 10 Once the virus enters
interaction between the virus and the host immune
hepatocytes, the nucleocapsid is transported to the
response. Natural history of viral infected may pass
nucleus and releases the rcDNA genome. It is here that
through five phases though not necessarily all in same
rcDNA is converted to a covalently closed circular DNA
patient.17
(cccDNA). cccDNA gathers host’s histone and forms an
episomal chromosome like structure which serves as a Phase 1: HBeAg-positive chronic HBV infection: (High
transcription template for different viral proteins.11 Host HBeAg, HBV-DNA and normal ALT; minimal or no
cell is forced to manufacture complete infectious virions liver necro-inflammation in liver) usually seen in
(diameter of 42 nm), and also an enormous amount of perinatal infection and may last for years. This phase is
non-infectious sub-viral particles of HBsAg which do characterized by patients that are highly infectious and
not contain genome. HBV DNA can get integrated in rarely if ever show spontaneous HBeAg loss.
the host genome randomly and make the patient more Phase 2: HBeAg-positive chronic hepatitis B: (High
susceptible to develop hepatocellular carcinoma.12 HBeAg, HBV-DNA and elevated ALT; moderate to severe
CHAPTER 76: Hepatitis B: Are We Moving Ahead Towards Cure? 465
liver necroinflammation in liver +/- fibrosis) many one can achieve higher rates of HBeAg seroconversion
patients may lose HBeAg and develop anti-HBe (i.e. and HBsAg loss. However, the efficacy of interferons is
seroconversion) and is followed by significant HBV-DNA only modest, and treatment has several adverse effects.
inhibition. After this phase patients may enter phase 3. Adverse effects and the fact that it involves prolonged
Phase 3: HBeAg-negative chronic HBV infection : injections limit its tolerability and acceptability.
(Antibodies to HBeAg appear, HBV-DNA levels are low Nucleoside analogues are given orally, have minimal
or undetectable and ALT is normal; there is minimal liver adverse effects and are required to be given for an
necro-inflammation and fibrosis in liver), these patients indefinite duration. They effective suppress the viral
may loose HBsAg spontaneously in 1to 3% of cases per replication but do not cure the patient.
year folllowed by appearance of anti-HBs. Serum HBsAg
levels in this phase are typically low (<1,000 IU/mL). What is Cure in HBV Infection?
Initially HBeAg seroconversion was considered as a
Phase 4: HBeAg-negative chronic hepatitis B: (Detectable
desirable endpoint of treatment, however, subsequently
antibodies to HBeAg, moderately high HBV-DNA and
discovery of latent HBV infection and cccDNA changed
elevated ALT; as well as necroinflammation biopsy
that. Today we are satisfied with loss of HBsAg as
present in liver) a majority these patients have HBV
acceptable endpoint, but if it will signify cure and
mutations in the precore and/or the core promoter
elimination of cccDNA is not clear. The available
regions and will rarely develop spontaneous disease
antivirals can suppress HBV replication as long as they
remission.
are given but are unable clear HBsAg consistently, hence
Phase 5: HBsAg-negative phase: (Patients are HBsAg need to be given indefinitely. Available drugs are not very
negative, antibodies to HBcAg positive, HBV-DNA effective against cccDNA, the ‘seemingly indestructible
undetectable or very low and normal ALT; minimal or no “mini-chromosome” of the hepatitis B virus in nuclear
liver necroinflammation in liver), this is apparent cure and episomal location’. This mini-chromosome continues
but occult infection (cccDNA) is persisting in the liver. to produce virus progeny in infected host liver cells, even
Such patients will remain at risk of developing HCC. If in people being treated. If cure is desired, we would
these patients are immunosuppressed for some reason, have to find ways to destroy or silence cccDNA and also
HBV reactivation can occur in these patients. provide long-term immunity. It is possible that any single
drug may not be able to achieve that end. Scientists are
MANAGEMENT OF CHRONIC HBV hopeful that another big leap in the search for a cure of
INFECTION AND INNOVATIVE HBV is possible if new complementary drugs against
APPROACHES fresh targets are identified. 18
Available Treatments
The currently available treatments include immunomo-
NEWER DRUGS AND INNOVATIVE
dulatory therapies (including conventional IFN-α, Peg- APPROACHES
IFN-α and thymosin α), and nucleoside/nucleotide Once it is understood as to how HBV interacts with host
analogues (NA). The latter include nucleoside analogues liver cells, we can evolve methods to interfere at various
(lamivudine (L AM), entecavir, telbivudine and stages of life cycle of HBV. Several new drugs are being
emtricitabine) and nucleotide analogues (adefovir, developed with exactly same thought to attempt a cure of
tenofovir). Tenofovir and Entecavir are the preferred NA HBV. A summary of these drugs is given below.19-21
because they have highest barrier to drug resistance.
These two drugs are currently the first-line treatment. Drugs Targeting Viral Replication Cycle
Advantage of pegylated interferon is that it has a finite Entry inhibitors: This group of drugs block the entry of
duration of treatment, there is no drug resistance and hepatitis B into liver cells. It is achieved through binding
to a specific viral protein called ‘pre-1’ and/or a specific RO 7020322 (RG7834) is currently in phase I clinical
liver cell protein working as receptor for HBV. An example trials
is myrcludex B (undergoing phase II clinical trials) which
Antisense molecules: These drugs bind to the viral mRNA.
targets sodium taurocholate cotransporting polypeptide
This action interferes with its transcription to viral
to inhibit entry of HBV into hepatocyte.
protein.
siRNA: SiRNA or “silencing” RNA, are nucleotide drugs IONIS-HBVRx (GSK 3228836), is currently in phase I
that block or destroy the viral RNA. Example of these development.

drugs include IONIS-HBVLRx (GSK 33389404) is currently in phase
ARB-1467 and ARC-520 are currently in phase II

I development.
clinical trials
ALN-HBV is currently in preclinical trials
HBV cccDNA inhibitors: These are based on exciting
Hepbarna (BB-HB-331) is currently in preclinical concept and are still preclinical studies. They include
trials Zinc finger proteins CCC- 0975/CCC-0346MC2791/
ARB-1740 is currently in preclinical trials MC3119CRISPR/Cas They work by blocking transcription
Lunar-HBV is currently in preclinical trials of cccDNA and thereby halt cccDNA production, leading
to stoppage of cccDNA transcriptional activity as well as
Capsid inhibitors: These drugs act by meddling with
gene editing to allow mutation of cccDNA.
viral capsid formation. Capsid is the protein shield
that protects and covers the viral DNA. Interference
Indirect-acting Hepatitis B
with capsid formation leads to its destabilization and
disruption and blockage of viral reproduction. Examples
Drugs in Development
of these drugs include: Therapeutic vaccines: Several therapeutic vaccines are
Morphothiadin (GLS4) is currently in phase II clinical under development using different antigens to stimulate
trials immunity as a potential therapy.
NVR 3-778 is currently in phase II clinical trials NASVAC HBsAg/HBcAg based vaccine is undergoing
AIC 649 is currently in phase I clinical trials phase 3 clinical trials

JNJ-56136379, Bay-41-4109 are currently in phase I HBsAg-HBIG based vaccine is also undergoing phase
clinical trials 3 clinical trials

HBV CpAM, AB-423, GLP-26 are still in preclinical GS 4774 and ABX 203 are currently in phase II
trials. development
INO-1800 is currently in phase I development
HBV-DNA polymerase inhibitors: Like existing drugs,
HB-110, DV-601, TG1050 and Hep-T-cell are currently
they inhibit DNA polymerase. Tenofovir alafenamide
(already marketed), besifovir and other modified in phase I development
TomegaVax HBV is in preclinical trials
tenofovir pro-drugs. Its advantage is that it can penetrate
into liver cells more easily. CMX 157 is currently in phase Innate and adaptive immune defense pathways: As has
II clinical trials. been outlines above, innate immune system plays a
HBsAg inhibitors: These drugs interfere with the crucial role in elimination of several viruses. Several
transcription of hepatitis B surface antigen (HBsAg). This new approaches are being explored to stimulate innate
protein is essential for virus to enter the liver cell and also immune system so as to overcome the stealth and
exit the liver cell. Examples of these drugs are: cunning of HBV.
Rep 2139 is currently in phase II clinical trials GS 9620 is a TLR-7 agonist currently undergoing
Rep 2165 is currently in phase II clinical trials phase II clinical trials

CHAPTER 76: Hepatitis B: Are We Moving Ahead Towards Cure? 467
Pegylated interferon lambda stimulates cell mediated appears highly probable that a combination with drugs
immune responses and is undergoing Phase II that enhance immune responses against HBV will do the
clinical trials trick and achieve ultimate goal of a ‘definitive cure’ from
STING agonists produce type-1 Interferon dominant chronic HBV infection.
cytokine responses and are undergoing preclinical
studies REFERENCES
RO6864018 (RG7795, ANA773) is currently in phase II 1. Te HS, Jensen DM. Epidemiology of hepatitis B and C
development viruses: A Global overview. Clin Liver Dis. 2010;14:1-21.
2. Puri P, Srivastava S. Lower chronic hepatitis B in South
SB9200 is currently in phase II development
Asia despite all odds: Bucking the trend of other infectious
PD-1/PD-L1 inhibitors have been developed with
diseases. Trop Gastroenterol. 2012;33(2):89-94.
view to restore T-cell function in HBV infection and is 3. Acharya SK, Madan K, Duttagupta S, Panda SK. Viral
still undergoing preclinical studies. hepatitis in India. Natl Med J India. 2006;19(4):203-14.
4. Batham A, Gupta MA, Rastogi P, Garg S, Sreenivas
Host-acting p athway: Compounds that induce
V, Puliyel JM. Calculatingprevalence of hepatitis B in
programmed cell death in infected hepatocytes to India: using population weights to look for publication
eliminate the cccDBA of HBV bias in conventional meta-analysis. Indian J Pediatr.
EYP001 is currently in phase 1 development 2009;76:1247-57.
CRV 431 (CPI 431-32) is currently in preclinical trials. 5. Murhekar MV, Murhekar KM, Sehgal SC. Epidemiology of
hepatitis B virus infection among the tribes of Andaman
and Nicobar Islands, India. Trans R Soc Trop Med Hyg.
CONCLUSION
2008;102: 729-34.
Current treatment falls short of our expectations of 6. Biswas D, Borkakoty BJ, Mahanta J, Jampa L, Deouri LC.
causing cure of HBV infection. Oral nucleotides/ Hyperendemic Foci of Hepatitis B Infection in Arunachal
nucleosides such as entecavir or tenofovir act by Pradesh, India. J Assoc Physicians India. 2007;55:701-4.
causing suppression HBV replication. HBV can become 7. Saha MK, Chakrabarti S, Panda S, et al. Prevalence of HCV
reactivated, once these drugs are drug discontinued. and HBV infection amongst HIV seropositive intravenous
drug users and their non-injecting wives in Manipur, India.
Episomal cccDNA and integrated HBV-DNA in host
Indian J Med Res. 2000;111:37-9.
genome are responsible for persistent latent HBV
8. Kumar GT, Kazim SN, Kumar M, et al. Hepatitis B virus
infection which allows reactivation. Understanding of genotypes and hepatitis B surface antigen mutations in
viral kinetics have led to development of new drugs family contacts of hepatitis B virus infected patients with
which have capability of attacking different stages of the occult hepatitis B virus infection. J Gastroenterol Hepatol.
HBV life cycle. Such drugs include, inhibitors of viral 2009;24(4):588-98.
entry, novel polymerase inhibitors, capsid and assembly 9. European Association for the Study of the Liver. EASL 2017
Clinical Practice Guidelines on the management of hepatitis
inhibitors, virus release blockers, and disruptors of
B virus infection. J Hepatol. 2017;67:370-98.
cccDNA formation and transcription. In addition, we 10. Tong S, Revill P. Overview of hepatitis B viral replication and
also have in pipeline newer drugs that enhance immune genetic variability. J Hepatol. 2016;64:S4-S16.
responses specific targeting HBV inhibition. Such 11. Lucifora J, Protzer U. Attacking hepatitis B virus cccDNA-The
drugs include TLR agonists, checkpoint inhibitors and holy grail to hepatitis B cure. J Hepatol. 2016;64:S41-S48.
therapeutic vaccines. With a large spectrum of drug 12. Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced
hepatocellular carcinoma. J Hepatol. 2016;64:S84-S101.
likely to become available in near future, it appears
13. Maini MK, Gehring AJ. The role of innate immunity in
plausible that we will be able to eliminate cccDNA of
the immunopathology and treatment of HBV infection.
HBV leading to cure from this infection. If a single drug J Hepatol. 2016; 64: S60-S70.
does not appear effective in eliminating latent HBV 14. Bertoletti A, Ferrari C. Adaptive immunity in HBV infection.
reservoirs such as cccDNA and integrated HBV-DNA, it J Hepatol. 2016;64: S71-S83.
15. Wieland SF, Chisari FV. Stealth and Cunning: Hepatitis B and 19. Chen G, Wang C, Lau G. Treatment of chronic hepatitis B
Hepatitis C Viruses J Virol. 2005;79(15):9369-80. infection-2017. Liver International 2017;37(suppl-1):59-66.
16. Faure-Dupuy S, Lucifora J, Durantel D. Interplay between 20 S o r i a n o V, B a r r e i ro P, B e n i te z L , P e ñ a J M , d e
the hepatitis B virus and innate immunity: from an Mendoza C. New antivirals for the treatment of chronic
understanding to the development of therapeutic concepts. hepatitis B. Expert Opin Investig Drugs. 2017;26(7):843-51.
Viruses. 2017;9(5): 95; doi:10.3390/v9050095. doi: 10.1080/13543784.2017.1333105. Epub 2017;26.
17. European Association for the Study of the Liver. EASL 2017 21. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B
Clinical Practice Guidelines on the management of hepatitis cure: From discovery to regulatory approval. Journal of
B virus infection. J Hepatol. 2017;67:370-98. hepatology. 2017;67:847-61.
18. Loggi E, Vitale G, Conti F, Bernardi M, Andreone P. Chronic
hepatitis B: Are we close to a cure? Digestive and Liver
Disease. 2015;47:836-
CHAPTER
77
HIV/Hepatitis Coinfections
PK Agrawal
INTRODUCTION The estimated number of people suffering from

chronic hepatitis B infection were 257 million and with
The management of HIV/AIDS has undergone a
chronic hepatitis C infection were 71 million globally in
revolution in recent years. Following the introduction of
2015. In the same year the death caused by viral hepatitis
highly active antiretroviral therapies (HAARTs) in 1996,
(1.34 million) was more than the death caused by
there was a rapid and dramatic decrease in mortality
tuberculosis and HIV. It has also been observed that the
associated with opportunistic infection that complicate
death caused by viral hepatitis is increasing while death
advanced HIV infection. Hepatitis viral infections remain
caused by tuberculosis and HIV is decreasing.
important causes of morbidity and mortality worldwide
Liver diseases are one of the most important cause of
and may exist as isolated infections or as co-infections
death in HIV. Persons living with HIV and coinfected with
either with HIV or with each other. Chronic viral hepatitis
viral hepatitis should provide treatment both for HIV and
B (HBV), hepatitis C (HCV) and/or delta hepatitis (HDV)
HBV/HCV.
comprise the most common liver disease in HIV infected
individuals worldwide. Liver disease due to chronic
PATHOGENESIS
HBV and HCV is the most frequent cause of non-AIDS
Hepatitis B is an immune mediated infection. Liver
related death among persons with HIV in Europe, the
inflammation is minimal in uncontrolled HIV. But after
United States and Australia. Factors influencing the rate
initiation of HAART there is immune reconstitution
of co-infection include the natural history of disease,
leading to more liver damage. There is higher HBV-DNA
the primary mode of transmission and the geographic
levels, lower serum ALT, advanced liver fibrosis and
distribution.
more risk of end stage liver disease in a patient with
HIV coinfected with HBV than those with HBV alone.
EPIDEMIOLOGY Although healthy adults who are infected with HBV have
In 2016 an estimated 36.7 million people were living with less than 10% chance to develop into chronic hepatitis B,
HIV globally (Among these 2.7 million had HBV infection when a HIV positive adult is infected, this risk jumps to
and 2.3 million had HCV infection). The number was 5.1 almost 25%. Overall liver related mortality is increased
million in Asia and the Pacific and 2.1 million in India in in HIV-HBV coinfected patients. CD4 restoration is less
the same year. than satisfactory in response to HAART in these patients.
The majority (85%) living with HIV who become advertently with change in HIV therapy for virologic
infected with HCV have chronic hepatitis C an infection failure, hence consider maintaining HIV therapy with
that will stay with them for life unless they are successfully activity against HBV when changing ART.
treated. Hepatitis C can cause mild to moderate liver
scarring (fibrosis) or serious liver scarring (cirrhosis). HIV HIV-HCV Coinfection
increases the risk for and can speed up the development HCV–RNA persistence impairs response to ART and
of liver damage from hepatitis C. People with fewer than enhances renal, bone and CNS comorbidities in HIV.
200 CD4 cells are more likely to have liver damage from HIV accelerates progression of HCV disease. Sustained
hepatitis C. viral response (SVR) is associated with a decrease in liver
Effect of HCV coinfection on HIV progression is related, AIDS related and nonliver related and non-AIDS
unknown. There could be accelerated clinical progression related mortality in HIV/HCV.
of HIV-1. There may be impaired CD4 cell recovery ART should be initiated for most HIV/HCV coinfected
and faster HIV disease progression in HCV coinfected patients regardless of CD4 cell count. In HIV treatment
patients despite ART therapy. There could be no impact patients with CD4 >500 cells/mm3, ART may be deferred
on CD4 count, viral load, HIV progression or survival. until HCV treatment is completed. In patients with CD4
<200 cells/mm3, ART should be initiated immediately,
TREATMENT HCV therapy delayed until HIV treatment is stable.
HIV-HBV Coinfection Decision when to initiate HCV treatment is case by
For the treatment of HIV –HBV coinfection, agents case. Initiating HIV treatment first can increase CD4
selected should be active against both viruses if either counts, may improve response to HCV therapy. Initiating
HIV or both HIV/HBV infections meet the criteria for HCV treatment first (in those with high CD4 counts and
therapy. low viral load) can simplify treatment and improve ART
First goal of the clinician is to select the patient tolerability.
whether to treat for HIV alone, for HBV alone or for both PEG-IFN treatment should be deferred in HIV/HCV
the viruses. For patients having HIV or HIV with HBV the co-infected patients with liver decompensation. These
treatment endpoints remains the same although loss of patients could be considered for liver transplantation.
HBeAg or HBsAg as well seroconversion to anti-HBeAg PEG-IFN plus Ribavarin therapy can be considered in
and anti-HBs is not common. The treatment must patients with compensated cirrhosis (Child-Pugh class
include agents active against both viruses in HIV-HBV A). The treatment in coinfected patients should be
coinfection. Not doing so will lead to emergence of HIV continued for 48 weeks regardless of HCV genotype.
strains that are resistance to NRTI (nucleoside reverse Avoid didanosine, stavudine and zidovudine in
transcriptase inhibitor). The recommendations from combination with ribavarin therapy. Antiretroviral
the recent USA and Europe guidelines advocate the use agents may cause drug induced liver injury (nevirapine),
of two anti-HBV drugs as part of HAART in HBV - HIV caution should be taken.
coinfection. The aim of this combination therapy is to Various newer directly acting anti HCV drugs
decrease the development of resistance even though very are available like sofosbuvir, simeprevir, daclatasvir,
little data exists on either mono or coinfected patients ledipasvir, velpatasvir, they are efficacious but caution
with such therapy. should be taken considering these drugs because of
The preferred treatment for dual HBV/HIV co- various interaction with antiretroviral drugs. Combination
infection is the combination of tenefovir and lamivudine of daclatasvir with sofosbuvir is recommended for HCV
(emtricitabine). Rebound hepatitis may be associated genotype 2 and 3 And combination of ledipasvir with
with removal of hepatitis B therapy it could occur in sofosbuvir is recommended for HCV genotype 4, 5 or 6.
CHAPTER 77: HIV/Hepatitis Coinfections 471
VACCINATION CONCLUSION
Vaccination against hepatitis A and B should be given The liver is frequently affected in patients with HIV. HIV/
to all HIV patients who are not immune. Response viral hepatitis shows more rapid liver fibrosis progression.
to vaccination is poor in HIV patients especially in With improved control of HIV disease with HAART, liver
those with lower CD4 counts. These individuals poorly disease has emerged as one of the leading causes of
maintain the antibody titres after vaccination. May death in patients with HIV. The complexities of HBV/
consider increase dose (double the dose ) of HBV vaccine HCV-HIV coinfection highlight the importance of close
for adequate response. Patient with higher CD4 counts working relationships between hepatologists, infectious
and undetectable plasma HIV-RNA may give improved disesase specialists and primary care providers in order
response on doubling the HBV vaccine dose. to optimize patient outcomes.
CHAPTER
78
Fecal Microbiota Transplantation:
Current Indications and Methods
L Ilavarasi, SS Lakshmanan
INTRODUCTION of Clostridium difficle infection in the year 1983 in the

form of fecal enemas.5 Currently, we have datas which
Human Gut Microbiota
are emerging on the potential clinical applicability
Human intestine provides a nutrient-rich environment
of FMT beyond clostridium difficile infection in both
to numerous microbes. Our gut has nearly 1014 microbes,
gastrointestinal and nongastrointestinal conditions,
of which most of them reside in the large intestine. These
which includes inflammatory bowel disease (IBD),
microbes are mostly anaerobes. There is a progressive
irritable bowel syndrome (IBS), diabetes mellitus,
distal increase in bacteria from 101 cells per mL in the
obesity, multiple sclerosis (MS), Autism, Parkinsonism
stomach, 103 cells per mL in the duodenum, 104 cells per
and depression (Fig. 1).
mL in the jejunum,107 cells per mL in the the ileum to 1012
cells per mL in the colon.1 These numerous microbes are
FECAL MICROBIOTA
known to produce antimicrobial proteins like defensins,
cathelicidins, and C-type lectins.2,3 TRANSPLANTATION TECHNIQUES
Therefore considering these significant roles of Appropriate donor selection is of utmost importance, as
microbiota in the homeostasis of numerous physiologic it can cause serious infections if the donor is not properly
processes and also taking into account the imbalance of identified (Fig. 2).
microbiota in many disease states, such as antibiotic-
associated diarrhea and Clostridium difficile infection DONOR SELECTION
(CDI), fecal microbiota transplantation (FMT) has been Usually majority of the donors are patient identified like
an innovative attempt to restore the disturbed microbiota spouse relative, or close friend.6 In order to decrease
by infusion of fecal suspension from a healthy individual. the practical concerns associated with FMT, universal
FMT was first reported by Ge Hong in the fourth century stool donors were identified and screened. Fresh or
in China. He initially had described its use in treating frozen fecal material was used for FMT in patients with
food poisoning or severe diarrhea.4 In modern medicine, recurrent CDI, and the FMT results were compared
FMT was first described by Eiseman and colleagues with patient identified donors (Table 1). No significant
for the treatment of pseudomembranous colitis in differences in outcomes were seen between patient-
1958. Schwan and colleagues used FMT for treatment identified donor FMT and universal donors.7
CHAPTER 78: Fecal Microbiota Transplantation: Current Indications and Methods 473
Fig. 1: Diseases associated with alterations in gut microbiota
Fig. 2: FMT technique

TABLE 1: Minimum general steps to follow for the preparation of fresh and frozen fecal material
Fresh fecal material
zz Fresh stool should be used within 6 hours after defecation
zz To protect anaerobic bacteria, the storage and preparation should be as brief as possible
zz Until further processing, the stool sample can be stored at ambient temperature (20–30°)
zz Anaerobic stroage and processing should be applied, if possible
zz A minimum amount of 30 g of feces should be used
zz Fecal material should be suspended in saline using a blender or manual effort and sieved in order to avoid the clogging of infusion
syringes and tubes

zz A dedicated space, disinfeted using measures that are effetive against sporulating bacteria, should be used
zz Protective gloves and facial masks should be used during preparation
Frozen fecal material

zz At least 30 g of donor feces and 150 mL of saline solution should be used
zz Before freezing, glycerol should be added up to a final concentration of 10%
zz The final suspension should be clearly labelled and traceable, and stored at –80°C
zz On the day of fecal infusion, fecal suspension should be thawed in a warm (37°C) water bath and infused within 6 hours from thawing
zz After thawing, saline solution can be added to obtain a desired suspension volume
zz Repetitive thawing and freezing should be avoided
HISTORY TO BE OBTAINED FROM DONOR STOOL PREPARATION:

THE DONOR EUROPEAN CONSENSUS 2017
Medical history See Table 1.
Received antibiotics
A tattoo, or body piercing within the past 3 months ROUTES OF ADMINISTRATION OF FMT
High-risk sexual behavior
Fecal Enemas

History of IBD, IBS, constipation, chronic diarrhea,

They are inexpensive; easy to administer; can be given at
colonic polyps
home; but reaches only till splenic flexure and requires
Colorectal cancer
repeated administration.
Immunocompromised state
Metabolic syndrome, morbid obesity
Chronic fatigue syndrome
COLONOSCOPY GUIDED
Has more benefits and more effective; can even reach
STOOL EVALUVATION terminal ileum, currently used this method but in cases
Clostridium difficile toxin or toxin genes by poly of acute colonic distention , very severe active colitis
merase chain reaction assay cannot be done.
Stool culture for standard enteric pathogens
Standard ova and parasite UPPER GI ENDOSCOPY GUIDANCE
Giardia species antigen Directly or through nasogastric/nasojejunal tube
Cryptosporidium antigen Theoretical risks of small intestinal bacterial
Isospora species (acid-fast stain) overgrowth can be there but no cases reported so far
Helicobacter pylori stool antigen when given through this route.
DONOR BLOOD SCREENING Clostridium difficle INFECTIONS

Serologic testing for hepatitis A, B, and C, Considering the high recurrence rate in clostridium
HIV-1 and -2 difficile infection in patients treated with antibiotics,
Syphilis FMT has been increasingly employed as an alternative
treatment for CDI, with promising results. In 2014, a IRRITABLE BOWEL SYNDROME
meta-analysis of clinical studies showed that FMT was Overall, subjects with IBS-D had significantly higher
effective in 87% of diarrhea cases (a total of 536 patients) levels of Enterobacteriaceae and significantly lower
caused by Clostridium difficile, with primary resistance levels of Faecalibacterium prausnitzii compared with
to prior therapy with metronidazole and vancomycin. the healthy control subjects, suggesting an imbalance
Long-term follow-up study of 77 patients who had of protective and potentially harmful bacteria. Chassard
undergone FMT for recurrent CDI (follow-up period of and colleagues noted that in individuals with IBS-C,
17 months) reported a primary cure rate of 91%, with the number of Enterobacteriaceae was increased 10-
all late recurrences of CDI (in 15 of 77 patients, 19%) fold compared with healthy control subjects.11 Long-
occurring in the setting of antimicrobial therapy for an term follow-up study of 45 patients with IBS-C were
infection unrelated to C difficile.8 administered a liquid culture containing 20 species of
nonpathogenic enteric aerobes and anaerobes through
INFLAMMATORY BOWEL DISEASE colonoscopy. Thirty of the patients were followed during
a period of 9–19 months. Improvements, including
Dysbiosis more frequent defecation and an absence of bloating
It is a shift in the composition of the microbiota, with and abdominal pain, were reported in 60% of patients.
reduced diversity of luminal microbiota which happens Evidence for FMT in IBS is limited. Need more studies.
in patients with IBD. There is a decrease in Firmicutes
and Bacteroidetes and a concomitant increase in FMT IN OBESITY/INSULIN RESISTANCE
mucosal-adherent bacteria such as Proteobacteria.9 AND DIABETES
Firmicutes are major producers of short-chain fatty Studies in mice and humans have shown a relative
acids such as butyrate, a substrate with immunoregulatory abundance of Firmicutes with a corresponding decrease
properties. of Bacteroidetes in obese subjects. In 2004, investigators
Fecal microbiota transplantation [FMT] has been found that the alteration of microbiota in mice leads to
investigated as a potential treatment for inflammatory increased body fat in the recipient mice.13 More studies in
bowel disease [IBD]. Many trials conducted. A systematic humans are needed, results suggest that alterations of the
review found 9 articles, representing 26 patients (18 microbiota have potential for treating insulin resistance
ulcerative colitis, 6 Crohn’s disease, and 2 indeterminate)
FMT IN NEUROLOGICAL DISEASES (FIG. 3)
who had received FMT for management of IBD. Out of
The close association between the digestive system
26, 17 completed study. Following FMT, 13 of 17 patients
and the brain has been recognized for many centuries.
(76%) were able to discontinue all IBD medications
Disruption in the this axis has been implicated in
within 6 weeks, and at 4 months, all had symptom
altered stress response and overall behavior, and the
reduction or resolution.10
significant role of microbiota in homeostasis of this
A systematic review was conducted until January neural network has been an active area of research.12
2017. It was concluded that FMT appears effective in UC This may contribute role of FMT in many neurological
remission induction, but long-term durability and safety diseases like parkinsons, depression, anxiety and
remain unclear. Additional well-designed controlled demyelination disorders.
studies of FMT in IBD are needed, especially in CD and
pouchitis. Less response seen in Crohns Disease. Not CURRENT AND FUTURE DIRECTIONS
all studies of FMT for the treatment of IBD, have had This consensus indicates that the only clinical
positive outcomes. indication with sufficient evidence of benefit from
Fig. 3: Pre- and post-FMT changes
the implementation of FMT in clinical practice is 3. Salzman NH, Underwood MA, Bevins CL. Paneth cells,
CDI. The consensus panel strongly recommends the defensins, and the commensal microbiota: a hypothesis on
intimate interplay at the intestinal mucosa. Semin Immunol.
implementation of FMT centers for the treatment of CDI
2007;19(2):70-83.
in adults.14 Moreover, there is no strong evidence-based 4. Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize
recommendation for the use of FMT in other clinical the 1,700-year-old fecal microbiota transplantation? Am J
conditions, although interesting findings come from the Gastroenterol. 2012;107(11):1755.
application of FMT for the treatment of UC, MS, IBS and 5. Schwan A, Sjolin S, Trottestam U, Aronsson B. Relapsing
more recently, graft-versus-host disease. Indeed, future Clostridium difficile enterocolitis cured by rectal infusion of
homologous faeces. Lancet. 1983;2(8354):845
therapy may include artificial FMT capsules with defined
6. Kelly CR, de Leon L, Jasutkar N, et al. Fecal microbiota
bacterial payloads that target a specific disease state. transplantation for relapsing Clostridium difficile infection in
26 patients: methodology and results. J Clin Gastroenterol.
REFERENCES 2012;46(2):145-9.
1. Brandt LJ. American Journal of Gastroenterology Lecture: 7. Hamilton MJ, Weingarden AR, Sadowsky MJ, et al.
Intestinal microbiota and the role of fecal microbiota Standardized frozen preparation for transplantation of
transplant (FMT) in treatment of C. difficile infection. Am J fecal microbiota for recurrent Clostridium difficile infection.
Gastroenterol. 2013;108(2):177-85. Gastroenterology. 2010;142:490-6.
2. Hooper LV. Do symbiotic bacteria subvert host immunity? 8. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term
Nat Rev Microbiol. 2009;7(5):367-74. follow-up of colonoscopic fecal microbiota transplant for
recurrent Clostridium difficile infection. Am J Gastroenterol. 12. Mayer EA. Gut feelings: the emerging biology of gut-brain
2012;107(7):1079-87. communication. Nat Rev Neurosci. 2011;12(8):453-66.
9. Sartor RB. Microbial influences in inflammatory bowel 13. Backhed F, Ding H, Wang T, et al. The gut microbiota as an
diseases. Gastroenterology. 2008;134(2):577-94. environmental factor that regulates fat storage. Proc Natl
10. Allegretti JR, Hamilton MJ. Restoring the gut microbiome Acad Sci USA. 2004;101(44):15718-23.
for the treatment of inflammatory bowel diseases. World J 14. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota
Gastroenterol. 2014;20(13):3468-74. transplantation for Clostridium difficile infection: a
11. Chassard C, Dapoigny M, Scott KP, et al. Functional systematic review. Ann Intern Med. 2015;162:630-8.
dysbiosis within the gut microbiota of patients with
constipated-irritable bowel syndrome. Aliment Pharmacol
Ther. 2012;35(7):828-38.
SECTION
7
Respiratory System
Clinical Approach to a Patient of Dyspnea ARDS: Recognition and Management
Alok Gupta, Rajat Gupta Niteen D Karnik, Priya Bhate
Syndrome Z Clinical Approach to Solitary Pulmonary Nodule
Devendra Prasad Singh BNBM Prasad
Asthma COPD Overlap Syndrome Challenges in the Management of CAP
Kashinath Padhiary Prashant Prakash, Akhilesh Kumar Singh
Global Warming and its Health Impact Air Pollution and its Health Impact
PS Shankar Vishal Chopra, Prabhleen Kaur, Siddharth Chopra
CHAPTER
79
Clinical Approach to a Patient of Dyspnea
Alok Gupta, Rajat Gupta
INTRODUCTION respiratory infections, tuberculosis, diabetes, chronic

Dyspnea is defined as “ a subjective experience of kidney disease are the diseases which are associated with
breathing discomfort that consists of qualitatively dyspnea in their disease course. Therefore, as a clinical
distinct sensations that vary in intensity [and] vary in their feature, dyspnea is an important concern and should be
unpleasantness and in their emotional and behavioral looked for.
significance”. Dyspnea is a subjective experience that
includes three characteristic and specific sensations MECHANISM
such as effortful respiration which is manifested by Mechanism of dyspnea is not fully understood, however
increased work of breathing in ventilatory muscles, a afferent receptors, pathways and responses to various
sense of asphyxiation due to bronchoconstriction and humoral and internal milieu changes include lung
stimulation of airway receptors and air hunger due to receptors, carotid receptors, cortex, hypothalamus and
afferent and efferent mismatch. medullary center (Fig. 1). Various sensory receptors
Dyspnea can be a result from interaction between just like chemoreceptors (aortic and carotid bodies),
physiological, psychological, environmental and social stretch receptors, metaboreceptors, vagal receptors
factors which is considered pathologic when it is more (vagal C fibers) pain receptors, etc. are involved in
than expected for a given level of exertion. It is stated in pathophysiology of afferent pathway of sensation of
literature that when there is reduction of tidal volume dyspnea. Afferent information is processed at the level
occurs by 30%, sense of dyspnea arises. of motor and sensory cortex and in respiratory center in
According to WHO (2015), among the top 10 causes brainstem and then the appropriate motor command,
of death globally, following 7 causes e.g. ischemic which is called as corollary discharge, is given to muscles
heart disease, stroke, lower respiratory infections, involved in respiration. When there is a mismatch occurs
chronic obstructive pulmonary disease, lung cancer between the afferent information and motor command,
along with trachea and bronchus cancers, diabetes it may result in dyspnea.
mellitus, tuberculosis are associated with different Air hunger: Stimulated by hypercapnia and hypoxia-
aspect of dyspnea. According to data from Institute for sensed by central and peripheral chemoreceptors
Health Metrics and Evaluation (IHME), India (2015), respectively.
among the 10 top causes of mortality in India, ischemic Work effort : Stimulated by respiratory motor
heart disease, COPD, cerebrovascular disease, lower command-sensed by chest wall receptors, muscle
482 SECTION 7: Respiratory System
of causes. Depend on this, dyspnea may be classified as

following (Table 1).
Diseases Related to the Left Heart

Myocardium of left ventricle plays an important role to
maintain stroke volume, cardiac output and ejection
fraction which is responsible to maintain perfusion
of end-organs. Diseases affecting myocardium like
ischemic cardiomyopathy resulting from coronary
artery disease and nonischemic cardiomyopathies e.g.
hypertensive heart diseases, valvular heart diseases,
cause a significant decline in cardiac output which
ultimately leads to increase in left ventricular end systolic
and diastolic volume and pressures followed by elevation
in pulmonary capillary pressures responsible for
development of interstitial edema. As it progresses, later
Fig.1: Important pathways responsible for dyspnea
on due to stimulation of pulmonary stretch receptors
Abbreviations: AMYG, amygdala; ACC, anterior cingulate cortex; CB,
cerebellum; MO, medulla oblongata; M1, primary motor cortex; MDT, and hypoxia because of V/Q mismatch, a sense of
medial dorsal thalamus; PAG, periaqueductal grey; PFC, prefrontal breathlessness is appreciated. Dyspnea of cardiovascular
cortex; PCC, posterior cingulate cortex; S1, primary somatosensory
cortex; S2, secondary somatosensory cortex; SMA, supplementary
origin has a characteristic feature of orthopnea and
motor cortex; VPT, ventroposterior thalamus paroxysmal nocturnal dyspnea. Diastolic dysfunction,
usually associated with some valvular heart diseases
Spindles, joint and tendon receptors and metabo like mitral regurgitation and some infiltrative diseases,
receptors and depends upon central corollary is characterized by a markedly reduced compliance of
discharge. left ventricle, may lead to severe dyspnea even with mild
Chest tightness Stimulated by bronchoconstriction-
degrees of exertion.
which is transmitted through receptors such as Heart failure is distinguished as three specific entities:
rapidly adapting stretch receptors (RARs) and C-fiber 1. (HFrEF) Heart failure with reduced ejection fraction
receptors. (LVEF < 40%)
Dyspnea relief Stimulated by lung inflation-sensed by 2. (HFpEF) Heart failure with preserved ejection
slowly receptors (SARs). fraction (Elevated cardiac filling pressure)
Dyspnea is influenced by sensor y as well as 3. (HFmrEF) Heart failure with mid-range ejection
nonsensory factors such as emotion and attention. Both fraction (signs of diastolic dysfunction are combined
plays an important role in sensory perception of difficult with an LVEF between 40% and 49%).
breathing in adult and pediatric patients. As a rationale In all types of congestive heart failure, association
for effective and satisfactory therapy of dyspnea, an with dyspnea is seen irrespective of systolic and diastolic
integrated approach towards pathophysiology and dysfunction.
neurophysiology understanding must be considered.
Diseases Related to the Pericardium
CAUSES OF DYSPNEA Constrictive pericarditis and cardiac tamponade are the
Dyspnea is one of the most common yet difficult to define conditions associated with diastolic type of heart failure
subjective and complex experience as well as objective demonstrated by diastolic equalization of pressure
reaction, which is a result of wide variety and long list between right and left chambers of heart with normal
CHAPTER 79: Clinical Approach to a Patient of Dyspnea 483
TABLE1: Important conditions related to dyspnea

Cardiac Pulmonary Others
Ischemic coronary artery disease Airway Asthma Anemia/Hemoglobinopathy
Chronic bronchitis
Bronchiolitis obliterans Deconditioning/Obesity
Airway mass lesion
Arrhythmia e.g. atrial fibrillation Laryngeal disease Thyroid diseases (Hyper and Hypo)
Tracheal stenosis/ Tracheomalacia
Left ventricular heart failure Parenchymal Acute alveolitis Metabolic acidosis (Diabetic ketoacidosis,
(reduced or preserved EF) Emphysema lactic acidosis, sepsis, renal failure, liver
Pneumonitis failure, etc.)
Pulmonary fibrosis
Pulmonary edema
Metastatic disease
Lymphangitic carcinomatosis
Valvular heart disease Pleural or Effusion Neuromuscular causes like
chest wall Pneumothorax central nervous system disorders,
Pleural mass myopathy and neuropathy, phrenic nerve
Fibrothorax and diaphragmatic disorders, spinal
Kyphoscoliosis cord disorders, systemic neuromuscular
Chest wall injury disorders
Intracardiac shunt (PDA, ASD, VSD) Abdominal distention Drug-induced conditions e.g. penicillin,
quinidine, sulfonamides, dapsone,
amiodarone, methotrexate, nitrofurantoin,
aspirin, progesterone, ticagrelor
Pericardial disease (Constrictive Vascular Pulmonary hypertension Gastroesophageal reflux
pericarditis, Cardiac tamponade) Thromboembolic disease
Pulmonary vasculitides
Veno-occlusive disease
Myxoma Psychogenic
Intense pain
EF and lower normal stroke volume. Later on due to and pulmonary thromboembolic disease. These
progressive limitation of cardiac output, lactic acidosis conditions cause increase in pulmonary artery pressure
develops and further stimulation of metaboreceptors and which leads to pulmonary receptor stimulation, resulting
chemoreceptors contribute in development of dyspnea. dyspnea manifests as hyperventilation, tachypnea,
Various etiological factors include: tuberculosis, trauma, tachycardia and hypoxemia. Various predisposing risk
malignancy, radiation, connective tissue disorders, etc. factors associated with pulmonary embolism are deep
(Fig. 2). venous thrombosis (DVT) of lower limbs, recent surgery,
obesity, prolonged immobilization, genetic factors, etc.
Diseases of the Pulmonary Vasculature According to WHO, pulmonary hypertension is divided
Ventilation as well as perfusion of pulmonary system both into five categories: PAH, PH due to left heart disease, PH
are important aspects in maintaining the integrated circuit due to chronic lung disease, PH associated with chronic
of breathing. When there is a deficit in the given standards, thromboembolic disease, and a group of various diseases
shown by V/Q mismatch, it leads to the subjective as well that only rarely cause PH, e.g. sarcoidosis, sickle cell
as objective experience of dyspnea. Certain pathologic disease, schistosomiasis, etc. PAH itself is an important
conditions related to pulmonary vasculature are like entity in causation of dyspnea irrespective of varied
primary pulmonary hypertension, pulmonary vasculitis etiology.
Fig. 2: Algorithm of differential diagnosis of dyspnea related to cardiovascular system

Abbreviations: ECG; electrocardiogram; CPK-MB, creatine kinase-MB; CAG, coronary angiography; CHF, congestive heart failure; LV, left
ventricular; RV, right ventricular; PA, pulmonary artery
Diseases Related to the Airways the alveolar-capillary gas exchange interface which may
Airway patency and dynamic conduit are essential lead to hypoxemia. During investigative analysis, PFT of
requirements to complete a respiratory cycle constituting these group of patients reveal reduction in vital capacity
active inspiration followed by passive expiration. There (VC) and total lung capacity (TLC), a high normal
are multiple conditions characterized by expiratory Tiffeneau index, and decreased CO diffusion. In patients
airflow obstruction due to chronic inflammation, called over age 65 years, dyspnea is one of the main symptoms
as obstructive lung diseases (Asthma and COPD), of pneumonia suggestive of infective pathology. Among
associated with dynamic hyperinflation of lungs and immunocompromised patients, however, especially
the chest wall with altered dynamic airway functions those who are HIV-positive, increasing shortness of
and reduced tidal volume. Asthma and COPD, both are breath is often the sole presenting symptom of pulmonary
the conditions of ventilation perfusion (V/Q) mismatch infection. Diffuse pulmonary fibrosis from any cause
(initially hypoxia followed by hypercapnia) which usually presents with the gradual onset of dyspnea. Other
worsens later and progress into Type II respiratory signs of diseases causing pulmonary fibrosis, such as
failure. sarcoidosis, scleroderma, and asbestosis, may be present
Diseases of the upper airways involves ears, nose, or it may be idiopathic (Fig. 3).
and throat can also cause dyspnea. In disturbances of
the upper airways, the main symptom associated with Other Diseases
dyspnea is stridor, a high pitched breath sound resulting Mild to moderate anemia is associated with exertional
from turbulence in airflow manifest as inspiratory dyspnea, however there is not any sharp cut-off value of Hb
stridor in supraglottic airway compromise, expiratory in below which anemic patients show symptoms of dyspnea
bronchopulmonary airway compromise, and biphasic and it varies with every other individual. The mechanism
stridor in airway compromise at or just below the glottis. of obesity related breathlessnss is probably due to high
cardiac output condition and reduced compliance of
Diseases Related to the Chest Wall the chest wall causing impairment of ventilatory pump
As we all know respiration is a synchronous effort of function. Cardiovascular deconditioning (poor fitness)
active and passive process. Chest wall abnormality is an is recognized by the early development of anaerobic
important issue regarding the case of dyspnea. There are metabolism followed by generation of lactic acidosis in
some conditions causing stiffening of chest wall such as muscles and stimulation of chemo- and metaboreceptors
kyphoscoliosis and some causing weakness of ventilatory with a very low threshold of exertion.
muscles such as myasthenia gravis or the Guillain-Barré Neuromuscular diseases that can cause dyspnea by
syndrome are associated with increased respiratory ventilatory muscle weakness and resultant increased
efforts. Large pleural effusion when associated with efforts include muscle diseases such as myasthenia,
atelectasis causes dyspnea by stimulation of pulmonary muscular dystrophies, motor neuron diseases such as
receptors and increased work of breathing. amyotrophic lateral sclerosis, and neuropathies such as
Guillain-Barré syndrome.
Diseases Related to the Lung Parenchyma Various psychological and social factors also play an
Interstitial lung diseases are a group of diseases related important role in perception of breathlessness which
to lung parenchyma, originating from infections, chronic causes a large proportion of patients presenting with
inflammatory conditions, occupational exposures, or dyspnea in the hospital settings. There are various groups
autoimmune disorders characterized by decreased of mental illnesses like anxiety disorders, somatization
compliance of lung parenchyma due to increased stiffness disorders, panic disorders or “functional complaints”
and increased work of breathing. In addition, there is which are included in the assessment of dyspnea, it
V/Q mismatch and the thickening and/or destruction of should be kept as diagnosis of exclusion before that
Figure 3 contd...
Figure 3 contd...
Fig. 3: Algorithm of differential diagnosis of dyspnea related to respiratory system

Abbreviations: ECG; electrocardiogram; COPD, chronic obstructive pulmonary disease; PFT, pulmonary function testing; ABG, arterial blood gas;
6MWT, 6-minute walk test; ILD, interstitial lung disease; PCWP, pulmonary capillary wedge pressure; DLco, diffusion capacity of lulng for carbon
monoxide; BAL, broncho-alveolar lavage; ANCA, antineutrophil cytoplasmic antibody; DAH, diffuse alveolar hemorrhage
Note: Some other causes related to pulmonary involvement are due to varying etiology e.g. ARDS, septicemia, toxemia, poisoning, etc.
an extensive somatic work-up to rule out any other That’s why assessment and measurement of severity of
pathological disease has to be performed. Improvement dyspnea in a well planned approach remains a crucial
of dyspnea with distraction or physical exercise may be a part in evaluation and management of the symptom as
clue towards this type of causes (Fig. 4). it is well established that qualitative aspect of difficult
breathing varies with a very wide range among patients.
ASSESSMENT OF DYSPNEA Following questionnaires in conjunction with clinical
Dyspnea is a complex and synthetic sensation that arises methods provide baseline information in assessment of
from multiple sources of signalling of various receptors individuals’ status regarding their illness perception and
rather than from a single neural receptor or mechanism. also set a benchmark to assess course of disease, whether
Fig. 4: Algorithm of differential diagnosis of dyspnea which are related neither of respiratory nor to cardiovascular system
Abbreviations: PFT, pulmonary fuction testing; ERV, expiratory reserve volume; FRC, fuctional residual capacity; MTx, methotrexate
the condition is improving or deteriorating, so helpful in —— associated with emotional stress, anxiety, panic
timely intervention in form of management of diseases. condition
Modifie d Me dical Res earch Council (MRC ) Pathogenesis
breathlessness scale —— diseases involving respiratory system
Modified Borg dyspnea scale —— diseases involving cardiovascular system
Visual analogue dyspnea scale (VADS) —— diseases involving mixed cardiac and pulmonary
Baseline dyspnea index (BDI) system

P u l m o n a r y f u n c t i o n a l s t a t u s a n d d y s p n e a —— other causes
questionnaire (PFSDQ) —— hysterical causes
Oxygen cost diagram (OCD) In elderly and multimorbid patients, due to

Likert scale simultaneous presence of multiple underlying diseases,
Modified Medical Research Council (MMRC) scale the diagnosis and management of dyspnea are sometimes
categorizes dyspnea into 5 categories; 0 being no become difficult, that’s why a multidimensional approach
dyspnea even with strenuous activities depending upon has to be applied for.
age and past performance of an individual whereas
dyspnea grade 4 comprises shortness of breath even in PHYSICAL EXAMINATION
minimal activities such as putting on clothes. Dyspnoea An observant clinician should look for the signs of dyspnea
grade 1–3 comprise of dyspnea on exertion on uphill during interview of the dyspneic patients. Tachypnea,
task, dyspnea on walking at level and dyspnea on walking inability of the patient to speak in full sentences before
few steps in increasing order. stopping to get a deep breath, use of accessory muscles of
respiration, supraclavicular retractions, tripod position
HISTORY TAKING of sitting suggests a condition of respiratory distress,
History taking is an integral part in initial assessment and indicative of increased airway resistance or stiffness of
evaluation of dyspnea, therefore a careful and precise lung and chest wall. When measuring the vital signs,
history taking should be sought for. A comprehensive the physician should carefully look for the respiratory
history includes documentation of exposures (workplace, rate and character, pulse rate, rhythm and character and
animals and birds, hobbies), medication history (drug- blood pressure. In a condition having pulsus paradoxus
induced pulmonary conditions), and description of (fall of systolic pressure by >10 mm Hg) , the possibility
past medical diseases, trauma, and surgical procedures. of COPD or asthma acute exacerbation , or pericardial
The patient history should address all the features of disease should be considered.
symptom dyspnea the onset, duration, severity, character, During the general examination, signs of anemia
periodicity, progression of symptoms, aggravating and (pale conjunctivae), cyanosis (central or peripheral or
ameliorating factors, which are helpful in determining both), bilateral edema feet (in right heart failure; CHF
the differential diagnosis. or cor pulmonale), any anatomical ribcage deformity
Temporal e.g. kyphoscoliosis, central obesity (obstructive sleep
—— acute (<4 weeks) vs. chronic (>4 weeks), apnea), pursed lip breathing (in severe obstructive
—— intermittent or episodic vs. permanent or lung disease), or extreme cachexia (suggestive of
continuous malignancy, chronic inflammatory diseases) should be
Situational sought. Chest examination should focus on shape and
—— depending on level of exertion symmetry of chest wall and movements and trachea
—— depending on postural variation position; percussion (dullness is indicative of fibrosis,
—— depending on exposure(s) of substances or pleural effusion, consolidation; hyper-resonance is a
environment factors sign of pneumothorax, emphysema); and auscultation
(wheezes, rhonchi, prolonged expiratory phase, and erythrocyte sedimentation rate, basic metabolic panel,
diminished breath sounds are clues to disorders of the electrocardiography, chest radiography and spirometry.
airways; decreased breath sounds in pleural effusion, If still the diagnosis remains in doubt after these tests,
pneumothorax, etc.; rales suggest interstitial edema or further advanced investigations and other causes like
fibrosis, end inspiratory coarse squeaks in interstitial anxiety related hyperventilation, neuromuscular disease
lung diseases; pleural rub often indicates a pleural or deconditioning should be considered.
effusion; whispering pectoriloquy in lung parenchyma
consolidation, succussion splash in hydropneumothprax, Chest Radiography
etc.). Evidence of conditions related to stasis of blood Chest radiography is important tool in evaluating
flow e.g. deep venous thrombosis may indicate the patients presenting with complain of dyspnea of
presence of pulmonary thromboembolism. suspected pulmonary origin irrespective of other
The cardiac examination include careful inspection physical examination findings. However, it must be kept
and palpation of precordium, apical impulse and beat, in mind that negative chest radiography does not rule
any thrill/heave, signs of elevated right heart pressures out infiltrative lung disease. Chest radiography is also
(jugular venous distention, edema, tender congestive helpful in diagnosing the patients of heart failure in acute
hepatomegaly, accentuated pulmonic component to (prominence of bronchovascular markings) as well as in
the second heart sound); pulmonary hyperexpansion chronic setting (cardiomegaly) and evidence of specific
e.g. emphysema, obesity, or cardiac tamponade are chamber enlargement in valvular heart disease.
the conditions of decreased heart sounds. An S3 or S4 Some findings in chest radiograph may be deceptive,
heart sound may indicate decreased left ventricular specially in pulmonary embolism, which are helpful in
compliance, while murmurs may suggestive of valvular recognition of disease. Skiagram signs in pulmonary
pathology or any septal defect. embolism are following:
On abdominal examination of patient, the paradoxical Fleischner sign: Enlarged pulmonary artery
movement of the abdomen should be noted: inward Hampton hump: Peripheral wedge of airspace
motion in inspiration is a sign of diaphragmatic weakness opacity and implies lung infarction
while pulmonary edema is suspected when there is Westermark sign: Regional oligemia (highest positive
rounding of the abdomen occurs during exhalation. predictive value)

Clubbing of the digits is an important finding helpful Knuckle sign: Abrupt tapering/cut-off of pulmonary
in evaluation of dyspnea which may arise suspicion artery

towards an etiology of lung cancer, bronchiectasis, Palla sign: Enlarged right descending pulmonary
interstitial pulmonary fibrosis, etc. Collagen-vascular artery

diseases, which has a frequent association with Chang sign: Dilated right descending pulmonary
pulmonary diseases is suggested by findings of joint artery with sudden cut-off

swelling and deformity features of raynaud’s disease. Steeple sign (wine bottle sign) refers to the frontal
Patients complaining of exertional dyspnea should be chest radiograph finding in which tapering of the upper
asked to perform exertion under observation in order trachea looks like reminiscent of a church steeple, seen in
to manifest the symptoms and reading of fall in oxygen condition called, croup. The Thumb sign in epiglottitis is
saturation. a manifestation of an edematous and enlarged epiglottis,
seen on lateral soft-tissue radiograph of neck.
LABORATORY STUDIES
Following the initial assessment by history and physical Electrocardiography
examination, management part includes various lines Electrocardiography may confirm rate and rhythm
of laboratory investigations which should be carried abnormality, and should be ordered if dyspnea due to
out carefully e.g. pulse oximetry, complete blood count, cardiac origin is suspected. During ECG interpretation,
underlying heart disease, electrolyte abnormalities, measurement of lung volumes must be done to confirm
or various systemic disease all possibilities should the diagnosis. To differentiate between intra- or extra-
be considered. A history and ECG suggestive of atrial thoracic obstruction, and fixed or variable obstructive
fibrillation increases the likely diagnosis of congestive disorders, flow-volume loop curves studies must be
heart failure. Prior infarction may be found in patients considered.
with ischemic cardiomyopathy. Other conditions like
obesity, hypothyroidism, COPD, pericardial effusion, Blood and Serum Tests
infiltrative heart disease, etc. show features of low In a patient complaining of shortness of breath, initial
precordial QRS voltages in ECG. Cor pulmonale is defined laboratory testing include a complete blood count,
as an alteration in the structure and function of the right ESR and basic metabolic panel. Anemia may cause
ventricle of the heart caused by a primary disorder of the dyspnoea which is typically aggravated on exertion and
lung, pulmonary vasculature and thoracic cage. It can associated with generalized fatigue, while polycythemia
be suspected by peaked P waves (p-pulmonale >0.25 may indicate chronic hypoxia as seen in COPD patients.
mV) in electrocardiograph, which is helpful for early Abnormalities in white blood cell differentials like
intervention. leukocytosis or neutropenia, may suggest underlying
immune processes or infectious pathology.
Pulse Oximetry and ABG Analysis Brain natriuretic peptide (BNP) is a cardiac
Pulse oximetry is a rapid and effective screening tool neurohormone secreted by myocardium of ventricular
in emergency department for patients presenting with wall in response to tension. In assessment of dyspnea,
unpleasant breathing efforts to detect hypoxia, with plasma N-terminal proBNP concentrations are increased
the advantage of lower cost, easy to use technique, in left ventricular hypertrophy, dilatation, systolic as
non-invasiveness, immediate results and continuous well as diastolic dysfunction, although it has no role in
assessment as compared with ABG sampling. Pulse pulmonary dysfunction. Because of its correlation with
oximetry has become an important tool in the hands of NYHA class, it is a valuable tool in the early diagnosis and
physician. Low SpO2 in a febrile patient may indicate strategic management of patients with heart failure thus
an early ventilatory therapy specially in the settings of reducing mortality. A BNP level more than 100 pg/mL is
conditions like viral pneumonia. taken as the cut-off value as significant for heart failure.
An arterial blood gas (ABG) analysis is a very specific If the clinical analysis suggestive of an acute coronary
and descriptive tool helpful in the initial assessment by syndrome as the cause of dyspnea, serial determination
defining the cause of dyspnea respiratory or metabolic, of cardiac biomarkers viz. troponin (troponin I or
pH of blood acidosis or alkalosis, types of respiratory troponin T) can be used with a high degree of certainty to
failure hypoxic or hypercarbic, etc. In a chronic smoker rule out acute myocardial ischemia (positive predictive
patient with acute dyspnea it is used to detect elevated value 75–80%).
carboxyhemoglobin levels. D-dimer, a marker of fibrin degradation, persist for
about 7–12 days and indicative of recent or ongoing
Spirometry fibrinolysis, has an important role in assessing severity
In evaluation of dyspnea, spirometry should be included of pulmonary embolism and also helpful in defining the
as an early investigation which is performed to diagnose risk of recurrence of thromboembolic disease. However,
airflow obstruction. Obstructive airway disease, such a negative test can help in excluding pulmonary embolus
as COPD, asthma, or chronic bronchitis is indicated condition.
by reading of reduced forced expiratory volume in one
second (FEV1) or FEV1/forced vital capacity (FVC) ratio; ADVANCED STUDIES
while reduced FVC and normal or increased FEV 1/ Additional advanced testing depends on the suspected
FVC ratio is suggestive of restrictive lung disease, but cause of dyspnea includes pulmonary function tests,
echocardiography, imaging studies like computed appropriate and widely used imaging study is high-
tomography (CT), MRI, ventilation/perfusion scanning, resolution chest CT. HRCT chest generates extremely high
stress testing, direct visualization by bronchoscopy and definition images at multiple section levels of airways,
right or left cardiac catheterization, depending upon lung alveoli, interstitium and pulmonary vasculature
indication. which aids a milestone in diagnostic approach of
dyspnea.
Comprehensive Pulmonary Function Tests CT contrast angiography is an investigation of
In addition to spirometry, pulmonary function tests choice for the diagnosis of pulmonary embolism either
include a wide group of measurements like blood gas acute or chronic. Also it is very helpful in diagnosing
evaluation, lung volume measurement (i.e. RV, FRC various inflammatory disorders or malignancies,
and TLC) and carbon monoxide diffusion in the lung mediastinal disease, interstitial lung disease, or occult
(DLCO). Total lung capacity, which is the max amount emphysema. Cardiac CT is helpful in differentiation of
of air that can fill in the lungs is reduced in patients transmural and subendocardial infarction. Coronary
with restrictive parenchymal disease, but is normal or calcium (Agatston score minimal 0–10, mild 10–100,
increased in air trapping conditions e.g. obstructive lung moderate 100–400 or severe >400) can be determined
disorders like COPD with air trapping. In patients with with the help of cardiac CT scan which is an important
normal spirometry and lung volumes measurement tool to detect coronary artery calcification.
but a reduced DLCO, the possibilities include anemia, Cardiac MRI using gadolinium based contrast agent
early interstitial lung disease, and pulmonary vascular is an important noninvasive tool for the assessment of
disease for which further evaluation should be done. cardiac function and morphology. It is the best current
Neuromuscular causes of dyspnea have a characteristic method to detect size and assess the transmural extent
finding of reduction in maximal inspiratory and of myocardial scar and determine myocardial viability.
expiratory pressures. It is helpful to separate ischemic from nonischemic
cardiomyopathy, diagnosis and follow-up of patients
Echocardiography with congenital heart disease and valvular disease,
Echocardiography is an important and convenient pericardial disease and cardiac tumors.
diagnostic test in assessment of cardiovascular status of Technitium scan, positron emission tomography
patients. With the help of this diagnostic modality, we (PET), single photon emission computed tomography
can identify impaired systolic and/or diastolic function, (SPECT) are the various radionuclide perfusion imaging
ejection fraction, right ventricular and pulmonary studies which rely on sarcolemmal integrity and
artery pressures, wall thickness and compliance, and intact energy production via effective mitochondrial
valvular anomalies. Transthoracic echocardiography function. It is useful to differentiate hibernating viable
is routinely done in established centers in patients myocardium, stunned viable myocardium and scar.
whenever dyspnoea of cardiac origin is suspected. Radiopharmaceuticals used in SPECT study are
Transesophageal echocardiography has higher sensitivity technitium-99m sestamibi, tetrofosmin, thallium 201,
and specificity as compared to previous and used in iodine 123 metaiodobenzylguanidine (MIBG). In PET
special circumstances e.g. aortic dissection, acute study, perfusion tracers used are ammonia (N 13 ),
endocarditis, thromboembolic conditions, valvular heart rubidium (Rb 82 ), etc., while metabolic tracers are
disease, etc. fluorodeoxy-glucose18 (physical half- life 110 min), C11
acetate, C11 palmitate.
Computed Tomography/
Magnetic Resonance Imaging Ventilation/Perfusion Scanning
In dyspnea of uncertain diagnosis and if there is suspicion A ventilation/perfusion (V/Q) scan is a nuclear medicine
of diffuse or localized pulmonary disease, the most scan that uses radioactive material to examine airflow
(ventilation) and blood flow (perfusion) in the lungs. of ischemic coronary artery disease inspite of medical
Ventilation/perfusion scanning, because of its high therapy. Gallium scanning may be used to identify
sensitivity, should be done to exclude thromboembolic inflammatory, infectious or neoplastic processes.
cause of pulmonary hypertension. A rare patient in whom exact cause of dyspnea remain
Initial ventilation phase of the test, inhalation of unidentified, specialized procedures such as a lung
gaseous radionuclide ( aerosol xenon or technetium biopsy, myocardial biopsy, genetic evaluation may be
DTPA) is followed by the perfusion phase of the test required.
(injection of radioactive isotope technetium macro
aggregated albumin (Tc99m-MAA) intravenously), later MANAGEMENT
on involves consecutive image capturing by gamma The first and most important goal in management
camera. A localized area of decreased uptake, indicative of dyspnea is to correct or lessen the intensity of the
of decreased perfusion with normal ventilation images underlying disease which is, responsible for the symptom
(mismatched defect) suggests a pulmonary embolus or that may help to improve the patients’ quality of life.
blood clot in the lungs. The V/Q scan may be used in some Supplemental O2 should be administered if the patient’s
circumstances as in renal failure, where radiocontrast saturation falls to the significant and worrisome levels
would be inappropriate. It is also an important lung at any stage of physical activity. Various therapeutic
performance quantification tool pre- and post-lung interventions are used to treat dyspnea depending
lobectomy surgery. upon their pathophysiologic mechanisms e.g. exercise
training, O2 supplementation, pharmacologic therapy,
Stress Testing nutrition, inspiratory muscle training, positioning, cold
Cardiovascular stress testing with the virtue of its air application on the face, chest wall vibration, ventilator
capability to determine ventilatory gas exchange and support, continuous positive pressure support, surgical
metabolic oxygen demands like Treadmill testing, stress volume reduction, desensitization, education, cognitive
echocardiography (exercise or dobutamine induced), behavioral approach, etc. Specific management in
dobutamine stress MRI, stress perfusion imaging a dyspneic patient depends upon rapid work-up for
(Technitium scan, Thallium scintigraphy, SPECT, PET cardiopulmonary and other causes, so that definitive
scan) may identify the likelihood of coronary ischemia. It therapy may be instituted early. Yoga and graded exercise
is also a very important tool to assess myocardial viability can now be included as an adjunct to conventional
in pre as well as post-PTCA and post-CABG patients therapy for pulmonary rehabilitation programs for
because of its noninvasiveness. COPD patients as recent studies suggest that it helps by
reducing dyspnea, fatigue and pulse rate, and improving
Invasive Testing functional performance and peripheral capillary SpO2.
Bronchoscopy, together with bronchio-alveolar lavage
or biopsy, is now a routinely available tool to identify CONCLUSION
malignancy, interstitial lung diseases, sarcoidosis, Dyspnea is the highly unpleasant experience of
to confirm typical or atypical infectious processes breathlessness experienced by patients due to varied
like fungal infections, etc. Diagnosis of pulmonary pathologies, such as respiratory, cardiovascular, both
arterial hypertension is established with the help of cardiorespiratory, metabolic and neuromuscular
right heart catheterization, which is a definitive tool diseases, mechanical causes, and panic disorder.
to test the vasoreactivity of the pulmonary circulation Because of the highly subjective nature of complaint,
and assess the hemodynamic impairment severity. the clinician confronts the main difficulty, whose
Coronary angiography may be needed for diagnostic task is to determine the diagnosis by ruling out other
and therapeutic intervention in symptomatic patients possible differentials, judge the severity of the underlying
condition and start an appropriate and rational treatment 5. Fedullo A, Sinburne A, McGuire-Dunn C. Complaints of
for the benefit of patients’ life as soon as possible. breathlessness in the emergency department. NY State J
Med. 1986;86:4-6.
Treatment of the primary cause of dyspnea is essential,
6. Gillespie D, Staats B. Unexplained dyspnea. Mayo Clinic
but despite optimum treatment, patients often continue Proceedings. 1994;69(7):657-63.
to suffer from dyspnea and the associated decrease in 7. L i g h e z a n , D a n i e l F, et a l . Ac u te d y s p n e a : Fro m
quality of life. To improve and optimally target, the best pathophysiology, evaluation to diagnosis. TMJ. 2006;56:n.
possible approach of managing a patient of dyspnea and 8. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J,
better understanding of the underlying mechanisms is Loscalzo J. eds. Harrison’s Principles of Internal Medicine,
19th Edition. New York, NY: McGraw-Hill; 2016.
necessary because “one size does not fit all”.
9. Michelson E, Hollrah S. Evaluation of the patient with
shortness of breath: an evidence based approach. Emerg
BIBLIOGRAPHY Med Clin North Am. 1999;17:221-37.
1. Boyars MC, Karnath BM, Mercado AC. Acute dyspnea: A sign 10. Nishino T. “Dyspnoea: Underlying mechanisms and
of underlying disease. Hosp Phys. 2004;7:23-7. treatment”. BJA. 2011;106(4):463-74.
2. Burki N, Lee LY. Mechanisms of dyspnea. Chest. 2010;138: 11. Parshall MB, Schwartzstein RM, Adams L, et al. An official
1196-201. American Thoracic Society statement: update on the
3. Cinarka, Halit. An evaluation of chronic dyspnea in a mechanisms, assessment, and management of dyspnea.
chest disease clinic. Journal of Pulmonary & Respiratory Am J Respir Crit Care Med. 2012;185:435-52.
Medicine. 2014;4(2):n. 12. Wahls Steven A. Causes and evaluation of chronic
4. Dyspnea. Mechanisms, assessment, and management: dyspnea. Am Fam Physician. 2012;86(2):n.
a consensus statement. American Thoracic Society. Am J
Respir Crit Care Med. 1999;159(1):321-40.
CHAPTER
80
Syndrome Z
Devendra Prasad Singh
DEFINITION hypertension. Wisconsin Sleep Cohort Study clearly

Obstructive sleep apnea (OSA) is defined as intermittent shows dose dependent relationship between severity of
cessation of the breathing during sleep which is OSA and hypertension.
associated with acute derangement in blood gases,
increased sympathetic surge and other metabolic OBESITY
changes. The body mass increases with incidence of OSA,
OSA has been closely and independently linked to conversely 50% of the morbidly obese patients have OSA.
the incidence of the quartet of metabolic syndrome The obesity in OSA holds the key because of its links
which includes hypertension, obesity, dyslipidemia and with insulin resistance and micro- and macro-vascular
impaired glucose tolerance. These four are clustered diseases.
together to be called as metabolic syndrome X. When
OSA occurs in conjugation with metabolic syndrome X, it INSULIN RESISTANCE
has been termed as Syndrome Z. As engaged by the central obesity, insulin resistance and
The obstructive sleep apnea is quite a common type II diabetes mellitus are common occurrence with
occurrence affecting 10% of middle aged males and OSA sharing same risk factors like male sex, advancing
5% of females. Systemic hypertension is commonly age and central obesity (Wisconsin Sleep Cohort Study).
reported in patients with OSA, the patients are typically
overweight having a central distribution of body fat. PATHOPHYSIOLOGY OF SYNDROME Z
They have typically impaired fasting glucose tolerance OSA is characterized by recurrent episodes of airway
too. Although dyslipidemia has not yet been extensively narrowing caused by collapse of pharyngeal muscles
studied in OSA but pertaining to its association with during sleep leading to apnea-awakening cycle.
insulin resistance, which causes lipoprotein lipase Incomplete obstruction of airways causes turbulent
resistance, lipid abnormality is an obvious sequel. airflow resulting in snoring. 40% of males and 20%
females snore during sleep. The cycle of apnea and
OSA AND HYPERTENSION awakening may repeat many times in nights leading to
40% of people with OSA have high blood pressure and periodical arousal from sleep.
40-80% of people with noncontrolled hypertension Apnea-waking cycles cause cyclic sympathetic
have OSA. Sleep apnea is very commonly coupled with activation and inhibition of vagal tone leading to
Flow chart 1: Sleep apnea-awakening cycle leading to hypoxia-hypercapnia
Fig. 1: Pathogenesis of Syndrome Z
tachycardia and systemic hypertension. Persistent Endothelin, a potent vasoconstrictor is an important

sleep-wake cycles result in sustained systemic factor in pathogenesis of hypertension. Increased
hypertension in wakefulness. level of adhesion molecules and vascular smooth
Vascular effects of OSA: Intermittent hypoxia increases muscle proliferation are also additional predisposing
O 2 free radicals which activates inflammatory factors in the causes of hypertension in OSA (Flow
pathways and impairs vascular endothelial function. chart 1 and Fig. 1).
CHAPTER 80: Syndrome Z 497
OSA correlates with an increased burden of systemic Diagnosis: The gold standard—overnight polysomno
inflammation and higher concentration of hsCRP, IL- gram.
1, IL-8, IL-6, TNF-alfa and ICAM. Sleep apnea severity index is apnea hypopnea index
(AHI).
Cardiovascular Diseases are Associated AHI is the number of apnea and hypopnea per hour
with Higher Incidence of OSA of sleep. Mild OSA–AHI of 5–14 events/h moderate
Epidemiological studies show that OSA is found in OSA–AHI of 5–29 events/h and severe OSA: AHI of
7–10% of general population while 30–83% patients of ≥30 events/h.
hypertension, 30–58% of coronary artery disease and Cardiovascular consequences of Syndrome Z
43–91% of cases of strokes are associated with obstructive
sleep apnea. Therefore OSA should be screened in such OSAs AND HYPERTENSION
patients by sleep studies. Patients of OSA are more prone to develop hypertension.
Wisconsin Sleep Cohort study, the sleep heart health study
DIAGNOSIS OF SYNDROME Z and the nurses health study confirm dose dependent
There are five components of Syndrome Z: OSA, central relationship between severity of sleep apnea and risk of
obesity, hypertension, dyslipidemia and Type-2 diabetes hypertension. OSA occupies the top position in the list
mellitus. of secondary causes of hypertension in JNC-VII. OSA
1. OSA: Diagnosis by characteristic clinical features and is also a very common cause of resistant hypertension.
sleep study. If a patient requires 3 or more antihypertensive drugs
2. Central obesity: Defined by waste circumference with screening for OSA is mandatory. ABPM rules out
ethnic specific values i.e. for south Asians or Indians: diagnosis of spurious hypertension like white-coat and
≥90 cm for males and ≥80 cm for females. also is a method of choice for detecting true resistant
3. Hy p e r t e n s i o n : B e s t m e t h o d i s a m b u l a t o r y hypertension.
BP monitoring (ABPM) which displays not only
“nondipping” pattern but also detects true resistant OSA and Cardiovascular Disease
hypertension. There are robust bodies of evidence to confirm that there
4. Dyslipidemia: By laboratory diagnosis—Serum are more incidences of fatal and nonfatal MI in patients
triglyceride >150 mg/dL and HDL <40 mg/dL in male of OSA. OSA is also associated with higher mortality
and <50 mg/dL in female. and cardiovascular events and it is well correlated with
5. T2DM: By fasting blood sugar >100 mg/dL. severity of OSA i.e. AHI. Prognosis of congestive heart
failure also increases when associated with OSA. There
OSA: CLINICAL FEATURES is more incidence of stroke in severe OSA. Therefore
Nocturnal symptoms: Snoring is the most frequent association of OSA with metabolic syndrome makes
symptom of OSA, witnessed apnea. Syndrome Z more deadly and more fatal.
Daytime symptoms : During daytime patients
Treatment of OSA: The main objectives of treatment
complain of fatigue, morning headache, decreased
of OSA is to reduce the cardiovascular morbidity and
vigilance, excessive daytime sleepiness (EDS) and
mortality and correct the metabolic abnormalities.
forgetfulness. EDS is assessed by Epworth Sleepiness
OSA is treated by life style modification, continuous
Scale (ESS).
positive airway pressure (CPAP), oral appliances and
Physical examination : Reveals obesity, neck
surgery.
circumference >17 cm in male and >15 cm in
female, retrognathia or micrognathia and class III/IV Continuous Positive airway pressure (CPAP): CPAP is the
Mallampati score. standard and effective therapy of OSA. The device uses
airflow pressure to prevent pauses in breathing (Apnea). Blood Pressure

It prevents the pharyngeal wall collapse during sleep and Beta blockers seem to be the ideal choice for control of
thereby does not allow hypoxia-hypercapnia to develop. hypertension in OSA as sympathetic over activity is one
Inflammatory markers which are the causative factors of the important pathogenetic factor but data suggest
of cardiovascular diseases are also decreased by CPAP that angiotensin-converting enzyme (ACE) inhibitors
therapy. or an angiotensin II receptor blockers (ARBs) are the
As CPAP therapy prevents apnea cycles it also
best choices in the treatment of hypertension with OSA.
decreases the surge of sympathetic activity caused by
As OSA is associated with secondary aldosteronism
arousal. There is significant effect of CPAP therapy on
addition of aldosterone antagonists offers clinical
hypertension. The therapeutic effect is more pronounced
benefits by reducing edema of upper airways.
when higher is the level of hypertension.
CPAP therapy: Also improves mortality and morbidity of Insulin Resistance
ischemic heart diseases. Treated OSA patients exhibits Insulin resistance is the primary pathophysiologic
less coronary events and improved survival. mechanism for metabolic syndrome. Several drug
CPAP therapy prevents cardiac arrhythmia associated classes like biguanides and thiazolidinediones (TZDs)
with OSA. It also shows beneficial effects on morbidity increase insulin sensitivity. CPAP therapy is also shown
and mortality in patient of stroke. to improve insulin sensitivity.
Drug Therapy of OSA Antiplatelets and Statins Therapy

CPAP does not relieve excessive daytime sleepiness in As Syndrome Z is a constellation of OSA, hypertension,
all OSA patients. Modafinil 200–400 mg/day increases T2DM and dyslipidemia all promoting increased
alertness in these patients. atherosclerosis, use of aspirin and statins is strongly
recommended.
OSA and Type 2 Diabetes Mellitus
OSA is associated with increased prevalence of metabolic CONCLUSION
syndrome. It is not confirmed whether treatment of OSA Patients with OSA should be checked for modifiable
with CPAP would modify these outcomes. cardiovascular risk factors like obesity, hypertension,
dyslipidemia and T2DM; at the same time patients with
LIFESTYLE MODIFICATIONS metabolic syndrome may be hiding OSA which must be
Behavioral Methods searched by sleep study and treated by CPAP therapy.
A variety of behavioral interventions are available to This will significantly reduce cardiovascular morbidity
modify sleep apnea. 10–15% reduction in weight can and mortality.
lead to an approximately 50% reduction in sleep apnea
severity in moderately obese male patients. Patients BIBLIOGRAPHY
of OSA must not take alcohol and sedatives as they 1. Danger LF, Borolotto LA, Maki-Nunes C, Trombetta IC, Alves
promote pharyngeal wall collapse during sleep. Sleep MJ, et al. The incremental role of obstructive sleep apnea
deprivation also leads to upper airway instability during on markers of athrosclerosis in patinets with metabolic
syndrome. Atherosclerosis. 2010;208:490-5.
sleep, increasing the likelihood of collapse. Avoiding
2. Drager LF, Lopes HF, et al. The impact of obstructive
supine position may modify the severity of the apnea in sleep apnea on metabolic and inflammatory markers in
patients. Finally, smoking cessation should be strongly consecutive patients with metabolic syndrome erratum
encouraged since it is a risk factor for cardiovascular in Chest. 2009;135:950-6. Erratum in: Chest. 2009;135:
diseases as well as OSA. 1406.
CHAPTER 80: Syndrome Z 499
3. Foster GD, Sankers MH, Miliman R, Zammit G, Borradaile 6. Reid PT, Innes JA. The sleep-disordered breathing.
KF, et al. Obstructive sleep apnea among obese patients Davidson’s Principles & Practice of Medicine, 22nd Edition,
with type 2 diabetes. Diabetes Care. 2009;32:1017-9. Churchill Livingstone, Elsever. 2014. pp. 725-7.
4. Macy Mei-sze Lui, Jamie Chung-mei MM Lam, et al. 7. Wellman A, Redline S. Harrison’s Principles of Internal
C-reactive protein is associated with obstructive sleep apnea Medicine. 19th Edition, McGraw Hill Education. 2015;1723-7.
independent of visceral obesity. Chest. 2009;135:950-6. 8. Wilkos I, McNamara SG, Collins, Fl. et al. “Syndrome Z”: the
5. Paul E. Peppard, is obstructive sleep apnea a risk factor for interaction of sleep apnea, vascular risk factor and heart
hypertension—Differences between the Wisconsin sleep disease. Thorax. 1998;53(Suppl):525-8.
cohort and the sleep heart health study. J Clin Sleep Med. 9. Young T, Finn L, Preppard PE, Szklo-Coxe, M, Austin D, et al.
2009;5(5):404-5. Sleep disordered breathing and morality; eighteen-year follow-
up the Wisconsin sleep cohort, Sleep. 2008;31:1071-8.
CHAPTER
81
Asthma COPD Overlap Syndrome
Kashinath Padhiary
INTRODUCTION Patients having diagnosis of asthma and COPD

Asthma chronic obstructive plumonary disease (COPD) together belong to ACOS ( Asthma being diagnosed
overlap syndrome (ACOS) remained as a speculative on GINA guidelines and COPD diagnosed on GOLD
entity for a long time. Though the American thoracic guidelines).
society mentioned asthmatic bronchitis as an entity as It has been simplified by some authors that if in the
early as 1962, its features were not described in detail. same patient asthma and COPD have been diagnosed
The main reason of non-recognition as an independent at different times or by two different physicians it can be
entity was most of the studies were conducted on COPD taken up as cases of ACOS. But the definition given by the
excluded asthma and studies conducted on Asthma scientific committee consisting of GINA (Global Initiative
excluded COPD. The American Thoracic Society, 1995 for Asthma) and GOLD (Global Initiative for Chronic
classified 11 distinct syndromes where there were overlap Obstructive Lung Disease) is the most acceptable
in six. A Spanish COPD guideline proposes 4 COPD one. ACOS is defined as a syndrome characterised by
phenotypes one of them being ACOS. Majority of the persistent airflow limitation with several features usually
workers believe that it is a separate phenotype. After associated with asthma and COPD.2
2014, many publications have come up with different
aspects of this disease. Many meta-analyses have also INCIDENCE
been done so that the details of the illness are coming to There are wide variations in different studies. The
the front. It is required to know the entity as its treatment prevalence of ACOS varies according to the age of
guidelines are little bit different from both asthma and the population. It is almost nonexistent in extreme
COPD, and its natural course is also different. of populations. But it increases from 40+ years to 70+
years population. In an Italian study,3 its incidence was
DEFINITION reported to be 1.65, 2.1%, and 4.5% in the age groups
Many authors have defined it differently. Zeki et al. 1 of 20–44, 45–64 and 65–84 years respectively. In the
defined ACOS in two different ways: (i) Asthma with diagnosed cases of asthma the incidence of ACOS was
partially reversible airway obstruction with or without noted to be 16%, 30% and 60% in age groups of 20–44,
reduced CO diffusion capacity. (DLco) to <80% predicted. 45–64 and 65–84 years age range respectively. Whereas
(ii) COPD accompanied by reversible/partially reversible the frequency of ACOS in diagnosed cases of COPD is
airway obstruction with or without environmental 33%, 27% and 25% respectively. The frequency of ACOS
allergy or reduced DLco. increases with advancing age, <10% in below 50 years age
CHAPTER 81: Asthma COPD Overlap Syndrome 501
and >50% in patients over 80 years. ACOS accounts for CLINICAL FEATURES
15–25% of cases of COPD.5 Pooled prevalence of ACOS in Often it starts as breathlessness and wheezing and later
COPD population has been found out to be 27% and 28% on they develop cough and sputum production. Chest
in population and hospital-based studies respectively.4 tightness at late night or early morning is also complained
by some. Like bronchial asthma or chronic bronchitis
PATHOGENESIS episodic increase in symptoms are observed. The
Eosinophilic inflammation is mainly seen in asthma. frequency of acute exacerbations is more in ACOS than
Asthmatics who becomes smokers develop neutrophilic in COPD patients. Very quickly their respiratory function
inflammation of the small airways, such inflammation gets compromised forcing them for hospitalisation.
are resistant to bronchodilator inhalation. Long-standing Examination shows lengthening of expiratory time,
nonsmoker asthmatics also develop remodeling of the diffuse ronchi (wheezing), diffuse crackles. Evidence
small airways causing partial response to bronchodilator, of temporary air trapping can also be observed during
a feature of ACOS. About 16% of asthmatics develop acute exacerbations. Peripheral eosinophilia and
overlap syndrome after 20 years of follow-up. sputum eosinophilia can be detected as evidence of
bronchial hyper-responsiveness.
CONTRIBUTING FACTORS Like asthma or COPD, there will be no much changes in
Age: Very rare below 40 years of age and above 85 X-ray chest. However, alteration of pulmonary functions
years of age. In certain studies, it is found that the can be noticed. FEV1, FEV1/FVC and PEFR are reduced.
incidence of ACOS is about 1.6% in the age group of In acute conditions, oxygen saturation may be reduced
20–44 years of age, 4.5% in the age group of 60–85 (clinical evidence is cyanosis). Some reversibility of the
years of age. airway obstruction can be demonstrated. Reversibility
Sex: Women are at a greater risk of suffering from is not as complete as in asthma. 68% had exertional
ACOS. dyspnea (COPD feature), 63% about had paroxysmal
Smoking status: Smokers and ex-smokers are at dyspnea with wheezing (asthma feature), 72% had
greater risk. Both active and passive smoking increase chronic productive cough (COPD feature).
the chances of developing ACOS. However, vehicular
smoke is not associated with higher risk of developing DIAGNOSIS
ACOS, though it contributes to develop COPD. Symptoms of airway obstruction and non-reversible
Pre-existing respiratory illness: It is not yet certain that airway inflammation in middle-aged individuals are the
in ACOS the two entities just exist together or itself hallmark of ACOS. Though objective evidence of both
is an independent entity. But it is postulated that in can be established but it is not feasible to use them in
some cases it starts as asthma and the COPD part gets daily practice. Different biomarkers have been utilised
added to it later on, particularly if these people start to detect ACOS.6 These are-Surfactant protein-A (SP-A),
smoking. Long duration of asthma also predisposes soluble receptor for advanced glycation end products
to develop ACOS. (sRAGE), myeloperoxidase (MPO) and neutrophil
Higher frequency of ACOS was observed in patients gelatinase-associated lipocalin (NGAL). Out of them, the
having history of pulmonary tuberculosis and first two are derived from pneumocyte and the latter two
bronchiectasis. from neutrophil. Only NGAL assessment has been useful
Many comorbid factors have been tried to be co- to detect ACOS. Researchers have tried to find objective
related to ACOS. Only hypertension, obesity, diabetes evidence for ACOS by measuring fractional exhaled nitric
and metabolic syndrome had some correlation. oxide (FENO) and blood level of IgE. FENO is considered
Features of allergic rhinitis were more common in as a biomarker of asthma like airway inflammation, and
asthma than ACOS (59% vs 53%). elevated IgE indicates presence of atopic factors. Usually,
the cut off value of FENO is taken as >35 ppb. And that of acute exacerbations and hospitalizations. They have
IgE is 173 IU/mL. Presence of these factors also indicates a worse quality of life in comparison to either asthma
that these patients will be benefited by ICS. Taking 35 or COPD alone. 9 Acute exacerbations are 2–3 times
ppb as the cut-off value the incidence of ACOS in COPD more frequent than COPD cases. Exacerbations
patients is 16.3%. GINA and GOLD both have approved increase the morbidity, mortality and hospital stay
use of these two biomarkers to detect ACOS patients. and compromises the quality of life. However, 6 MWD
Different researchers have given different guidelines (6 minutes walking distance) was not significantly
for diagnosis. A Spanish study 7 gave two major and different in any of the three group. Frequency of hospital
two minor criteria. The major criteria are positive admission, ICU admission, and attendance of emergency
bronchodilator test and sputum eosinophilia. Minor ward were higher than COPD cases.10 ACOS patients
criteria are high IgE level in serum and moderately required higher costs (5 times more) of treatment in
positive bronchodilator test (FEV1 >12% and FEV1 >200 comparison to asthma. Health-related quality of life was
mL increase after inhalation of bronchodilator). These lower than both COPD and asthma.
criteria have not been accepted widely.
Some important factors for diagnosis are: TREATMENT
—— Major: Age >40, raised IgE, smoking history, Inhalational corticosteroids (ICS) are essential for the
post-bronchodilator FEV1<80%, FEV1/FVC<70% treatment of these cases. In addition to that LABA are
—— Minor: > or = 15% rise or . >or = 12% and or = 200 useful. Long-acting muscarinic antagonists (LAMA)
mL increase following bronchodilator inhalation. such as tiotropium bromide are also useful. Leukotreine
Increase in peak expiratory flow rate by 20% or more. receptor antagonist, oral corticosteroids and SABA
Presence of bronchial hyper-responsiveness can be are also beneficial in some cases. Even theophylline
delineated. As challenges to different agents can lead derivatives can also be used. Briefly, it can be told that
to very severe attacks of bronchospasm, these are rarely treatment is combination of COPD and asthma.
practiced. However histamine, mannitol, hypertonic
saline, adenosine and methacholine can be used to REFERENCES
detect bronchial hyper-responsiveness (BHR). 1. Zeki AA, Schivo M, Chan A, et al. The asthma-COPD overlap
syndrome: A common clinical problem in elderly. J Allergy
BODE index (Body mass index, airflow obstruction,
(Cairo). 2011;2011:861-926.
dyspnoea, exercise capacity) has also been utilized to 2. Asthma, COPD and Asthma: COPD Overlap syndrome
diagnose these ailments. BODE index was higher in (ACOS) Global initiative for Asthma (GINA) 2014. http://
ACOS group than COPD group. www.ginasthma.org/.
Spirometry, eosinophil count and total IgE have 3. de Marco R, Pesce G, Marcon A, et al. The coexistence
of asthma and chronic obstructive pulmonary disease:
been utilized to help the diagnosis. ACOS group had
Prevalance and risk factors in young, middle-aged and
less eosinophil count and higher IgE value compared to
elderly people from the general population. PLos One
asthma group. 2013;8:e62985 (PubMed).
High-resolution CT can be utilized to find out the 4. Alshabanat A, Zafari Z, Albanyan O, et al. Asthma and
ACOS patients from COPD patients.8 COPD overlap syndrome (ACOS): A systematic review and
meta-analysis. https://doi.org/journal.pone.0136065
5. Skold CM. Remodelling in asthma and COPD—differences
PROGNOSIS
and similarities. Clin Respir J. 2010;(Suppl 1):20-7.
People above 85 years of age rarely show ACOS though 6. Iwamoto H, Gao J, Koskela J, et al. Differences in plasma
COPD is common. This means the overall outcome and sputum biomarkers between COPD and COPD-asthma
of ACOS is worse than COPD. They get more frequent overlap. Eur Respi J. 2014;43:421-9. (Pubmed)
CHAPTER 81: Asthma COPD Overlap Syndrome 503
7. Soler–Cataluna JJ, Cosio B, Izquierdo JL, et al. Consensus 9. Kauppi P, Kupiainen H, Lindqvist A, et al. Overlap syndrome
document on the overlap phenotype COPD-asthma in COPD. of asthma and COPD predicts low quality of life. J Asthma.
Arch Bronchopnemol. 2012;48:331-7. 2011;48(3):279-85.
8. Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, 10. Menezes AM, Montes de Oca M, Perez-padilla R, et al.
Make BJ, et al. The clinical features of the overlap between Increased risk of exacerbation and hospitalisation in
COPD and asthma. Respir Res. 2011;12:127. subjects with an overlap phenotype: COPD Asthma. Chest.
2014;145(2):297-304.
CHAPTER
82
Global Warming and its Health Impact
PS Shankar
Combustion of fossil fuels, including coal, petroleum ailment and injuries. It is associated with an increased
products and natural gas has resulted in global warming financial loss.4
at an alarmingly increasing speed. There is emission of
green house gases, airborne particulate matter, nitrogen SURFACE TEMPERATURE
oxide, and sulphur dioxide into the atmosphere. During the past hundred years from 1906 to 2005, average
surface temperature of the globe has risen by 0.75 degree
HEALTH IMPACT Celsius. During the corresponding period the global sea
Global warming has posed a public health challenge level has risen on an average by approximately 2 mm
due to its impact on health of the people. 1 Montreal per year. The green house effect is predominantly due to
Protocol of 1987 gave new directions in safeguarding the high concentration of carbon dioxide (CO2). The level of
planet by phasing out chlorofluorocarbons (CFCs) and CO2 has risen from 280 to 360 parts per million (ppm).
related compounds which were causing depletion of the This is evident since the industrial revolution, and it
ultraviolet (UV) rays-absorbing ozone.2 has occurred predominantly due to the burning of fossil
There is deforestation and burning of fossil fuels due to fuels. The climate is changing at a faster rate in the recent
human activities. They are bringing about a change in the years than in any period during the last millennium.5
concentration of atmospheric constituents or properties The United Nations Inter-governmental Panel
of the earth’s surface that facilitate absorption or scatter on Climate Change (IPCC) of the United Nations
of radiant energy. 3 The result is markedly increased Environmental Program (UNEP) and the World
production of anthropogenic green house gases such as Meteorological Organization (WMO) visualized that if
carbon dioxide, methane and nitrous oxide. In addition current trends continue, sea level will rise between 18
there is emission of noxious particles and pollutant gases and 59 cm and global temperature between 1.8°C and
such as sulphur dioxide, carbon monoxide and nitrous 4.0°C by the end of this century. The concentration of
oxide. Warm air and raised atmospheric temperatures carbon dioxide is likely to increase from 540 ppm to
cause rapid water evaporation of surface water, increased 970 ppm by 2100 if there is an unhindered use of fossil
humidity and greater amount of precipitation, resulting fuel. Decreasing snow cover, melting of polar icecaps,
in heat waves, hurricanes, floods and droughts and their receding glaciers, and raising temperature of sea water
attendant physical effects.3 They affect the health of the have already caused detectable rise in the sea level. All
people and there is an increase in the number of patients these events have serious consequences on the health
getting admitted to the hospital for treatment of their of people living in coastal regions. It brings the areas of
CHAPTER 82: Global Warming and its Health Impact 505
towns and cities under water, makes the sewage systems affect food production. Its consequences are mostly
inoperable, salinates the rice fields, and affects hygiene indirect leading to poor nutritional status, starvation
and health in the region. and undernourishment. Water is scarce and very little
Any small alteration in global temperatures can is left over for washing. The hygiene is poor. There is an
bring about relatively large changes in the frequency of increased incidence of diarrheal diseases, micronutrient
extreme temperatures. High temperatures are associated deficiencies, scabies, conjunctivitis and trachoma,
with increased deaths of elderly and persons with pre- undernourishment, and increased susceptibility to
existing diseases. Heat waves causing higher average infection. Fungal growth is facilitated by an increase in
ambient air temperatures not only increase mortality soil temperature. Dry conditions are associated with wild
from cardiovascular, cerebrovascular and respiratory fires and smoke. Rising sea levels inundate low-lying
diseases, but also cause air pollution. areas leading to environmental exodus and salinate the
Extremes of temperature cause physical injury. There land.
is poor nutritional status and an increased incidence of
respiratory and diarrheal diseases due to overcrowding, OZONE
disruption of water supplies and choked sewage system. There is an increase in ground level ozone formed
There is an increased chance of occurrence of floods chemically from temperature dependent precursor
due to an increased evaporation of ocean water. It leads pollutants (nitrogen oxide, volatile organic compounds
to occurrence of floods, which is associated with an from power plant emission and automobile exhaust,
increased number of injuries and drowning. This is felt in presence of light and higher temperature. Ozone
immediately in the community. As days pass, there is decreases pulmonary function, irritates conjunctiva
an acute shortage of clean drinking water. There is an and mucosa of the upper respiratory passages, induces
increased chance of contamination of water leading to asthma and pulmonary edema.7 Rise in the local air
spread of diseases such as cholera and hepatitis A and pollution and warm weather conditions act as risk
hepatitis E. Ultimately the increased salination leads factors for an increased incidence of chronic obstructive
to the destruction of the crop lands leading to marked pulmonary disease (COPD).
reduction in the output of agricultural products. It causes Experimental studies have shown that a higher
under-nutrition and malnutrition in the community. concentration or carbon dioxide leads to an increased
production of pollens and ragweed (Ambrosia
EL NINO artemisifolia).
The El Nino event causes shift of warm equatorial water When the level of CO2 doubles from 300 to 600 ppm,
from the Western to Eastern Pacific ocean. This occurs there is likelihood of a four-fold increase in the level of
periodically every 3–7 years leading to extremely dry this highly allergic pollen.8 Global warming increases
conditions, droughts and devastating fires in many the concentration of radon in the lower layers of the
regions of the World and torrential rains and flooding atmosphere.9 Being a source of alpha radiation radon
in other regions.6 There is an increased incidence of is likely to increase the development of bronchogenic
communicable diseases such as cholera and hepatitis carcinoma.
A due to drinking of contaminated water, leptospirosis
due to contact with contaminated water from excreta DISEASES
of rodents, respiratory infections from overcrowding of The ecology of many arthropod vectors responsible
flood survivors or from overgrowth of molds in flooded for transmission of diseases to human beings has
houses.3 changed due to global warming. There is emergence
Global climate change brings about changes in or resurgence of different types of infectious diseases.
hydrologic cycle (floods and droughts). Droughts Among them diseases that are indirectly transmitted
stand distinctly apart. They require either a vehicle for Heavy rainfall can increase risk of water-borne disease
transfer from host-to-host (e.g. water- and food-borne outbreaks. Fecal contamination of drinking water leads
diseases) or an intermediate host or vector as part of to cholera epidemics. There is contamination of drinking
their life cycle. Arthropod vectors such as mosquitoes, water due to discharge of the excess waste water directly
flies, ticks or fleas play an important role in spread of into surface water bodies. It results in infections with
many diseases. The insects being cold-blooded, any Escherichia coli and Campylobacter jejuni.11 There can
slight change in temperature can bring about significant be occurrence of contamination of drinking water by a
biologic effect on transmission of diseases. Warmer protozoan, Cryptosporidium parvum, and it may lead to
climate is associated with overproduction of mosquito, an increased morbidity and mortality.12 This is especially
sandfly and tick vectors, their biting and transmission noted in developed countries. There is an increased risk
of diseases such as malaria, dengue, leishmaniasis, Rift of cholera outbreaks in the land in the vicinity of the
Valley fever causing hemorrhagic fever syndrome and great lakes of Africa.13 N meningitides, the pathogen of
tick-borne Lyme disease.10 Hot summer months facilitate Meningococcal meningitis is carried by dust particles,
the spread of West Nile virus through bites of mosquitoes and it occurs during dry seasons. There is lengthening
across Western hemisphere. Unsafe domestic water of dry periods due to El Nino effect. It is associated
storage practices in unusually warm and dry conditions with a wider spread of pathogens in African countries.
facilitate viral infection such as chikungunya in the Aedes
Their epidemics are striking once in 5–10 years.14 Winter
mosquitoes.
temperatures in Lima, Peru are increased due to El Nino
Anopheles mosquitoes do not have any control over
event. The temperatures are increased by more than 5 °C
their temperature regulation system. A rise in humidity
above normal. It is noted that there is increased number
or ambient temperature is associated with a sustained
of admissions in the hospital for childhood diarrhea by
influence on their activity, dispersal and spread. Malaria
8% for every degree centigrade rise in air temperatures
which has a great potential to spread in the tropical
above normal.15
zones, will increase its area of activity to larger areas due
to climate change. Among tropical diseases, Malaria is
FUTURE
an extremely climate-sensitive disease. Dengue fever
Human population is threatened with health hazards in
is spread by the bites of mosquito, Aedes aegypti. The
the coming years due to climate change. This is due to
mosquito has widened its geographical boundaries in
tropical regions. Aedes is strongly influenced by climate disruption of water and food supplies. In addition, there is
changes that include variability in temperature, moisture an increased spread of vector-borne diseases. There is an
and solar radiation. Any small rise in temperature urgent need for reduction of greenhouse gas emissions.
facilitates viral introduction into a susceptible community, It is only possible by reducing combustion of fossil fuels,
in turn causing an increased chance of an epidemic. and development of renewal energy technology. There is
The ambient temperature influences the spread and need to establish stations equipped with remote sensing
activities of the sandflies, vectors of leishmaniasis. Heavy (RS) and geographic information systems (GIS) to
rainfall is associated with an explosion of the mouse monitor sea-level rise and extreme weather conditions.
population which may increase the chances of outbreak In addition public health education programs are to
of Hantavirus pulmonary syndrome (HPS). Extreme be held regularly. Ongoing preventive measures, and
flooding with an increased population of rodents can control measures for vector borne diseases have to be
lead to outbreak of leptospirosis. continued. Every attempt has to be made to improve the
Successful stabilization of carbon dioxide emissions, nutritional status of the population.4
vector-control program, relocation of human population Changes in climate and ecology affect health status of
and vaccination are to be undertaken to control such the population. Instead of concentrating the fight against
diseases. a single agent of the disease, the preventive measures
CHAPTER 82: Global Warming and its Health Impact 507
should be of broad range affecting the environment from production of common ragweed as a test case. World
different angles.16 Resource Review. 2000;12:449-57.
9. Cuculeanu V, Iorgulescu D. Climate change impact on
the radon activity in the atmosphere. Romanian Jour
REFERENCES Metereology. 1994;1:55-8.
1. Patz JA, Eingelberg D, Last J. The effects of changing weather 10. Yoganathan D, Ram WN. Medical aspects of global warming.
on public health. Ann Rev Public Health. 2000;21:271-397. Am J Ind Med. 2001;40:199-210.
2. Staropoli JE. The public health implication of global 11. Hrideu SE, Payment P, Huck PM, et al. A fatal water-borne
warming. JAMA. 2002;287:2282. disease epidemic in Walkerton, Ontario, comparison with
3. Patz JA, Kaliq M. Global climate change and health in other water-borne outbreaks in the developed world. Water
challenges for future practitioners. JAMA. 2002;287: Sci Technol. 2003;47:7-14.
2283-4. 12. MacKenzie WR, Hoxie NU, Proctor ME, et al. A massive
4. Gross J. The severe impact of climate change on developing outbreak in Milwaukee of Cryptosporidium infection
countries. Med Glob Surviv. 2002;7:96-100. transmitted through the public water supply. N Engl J Med.
5. IPCC, Climate change 2007, impacts, adaptation and 1994;33:161-7.
vulnerability: contribution of working group II to the fourth 13. WHO Cholera in 1997. Weekly Epidemiological Record.
assessment report of the IPCC. Cambridge (UK), Cambridge 1998;73:201-8.
University Press, 2007. 14. Hart CA, Cuesvas LE. Meningococcal disease in Africa Ann
6. Patz J. Public risk assessment linked to climatic and Trop Med Parasitol. 1997;91:777-85.
ecological change. Human and Ecological assessment. 15. Checkley W, Epstein LD, Gilman RH, et al. Effect of El
2001;7:1317-27. Nino and ambient temperature on hospital admissions
7. McConnell R, Bechane K, Gilliand F, et al. Asthma in for diarrheal diseases in Peruvian children. Lancet.
exercising children exposure to ozone: a cohort study. 2000;355:442-50.
Lancet. 2002;359:386-91. 16. Patz JA, Uejio CK, Gibbs HK. Disease emergence from
8. Ziska LH, Caulfield FA. The potential influence of rising global climate and land use change. Med Clin N Am.
atmospheric carbon dioxide (CO2) on public health: pollen 2008;92:1473-91.
CHAPTER
83
ARDS: Recognition and Management
Niteen D Karnik, Priya Bhate
INTRODUCTION of 200 and 300. SpO2 is not always concordant with PaO2
Acute respiratory distress syndrome (ARDS) was first (e.g. having SpO2 of 100% on FiO2 of 1.0 would be severe
recognized in 1967. Mortality increases with severity and ARDS using S/F ratio regardless of PaO2). Extravascular
ranges from 26% to 58%. Prompt diagnosis and optimal lung water (EVLW) measured using transpulmonary
treatment of ARDS is life-saving. Diagnosis is made thermodilution techniques may help to diagnose ARDS.
when all four criteria of the Berlin definition (Table 1) Increased EVLW is associated with higher mortality in
are met. The 2012 Berlin definition is compared to the ARDS. However EVLW is expensive, invasive and not
1994 American-European consensus criteria (AECC) easily available.
definition in Table 1. Conditions that mimic ARDS (Table 3) should be
excluded.
RECOGNITION CPE is the chief differential for ARDS (Table 4).
ARDS should be suspected in a patient with new onset However, cardiac dysfunction and ARDS may coexist.
respiratory distress or within one week of a known
clinical insult (Table 2). Recognizing high risk patients MANAGEMENT
and intervening with a conservative fluid strategy or The management of ARDS involves the following aspects:
Treatment of underlying medical and surgical
lung-protective ventilation may decrease risk of ARDS.
Lung Injury Prediction Score (LIPS), biomarkers (Plasma disorders (e.g. tropical infections, sepsis, aspiration,
angiopoietin-2, IL-6, TNF α) or genetic markers (e.g. ACE trauma, etc.)
gene polymorphism) may aid recognition. Supportive treatment of the critically ill patient (e.g.
adequate nutrition, prophylaxis against venous

DIAGNOSIS thromboembolism)
Berlin definition is used to diagnose ARDS. Chest X-ray Specific measures for ARDS
and arterial blood gas analysis (ABG) are mandatory Numerous interventions (Table 5) have been studied
investigations. Echocardiography is needed to exclude but only some are recommended (Table 6) in ARDS.
hydrostatic edema.
When ABG is unavailable/difficult, the ratio of Low Tidal Volume Ventilation
oxyhemoglobin saturation using pulse-oximetry (SpO2) Conventional MV leads to cyclic overdistension causing
to FiO2 (S/F ratio) may be used instead of PaO2/FiO2 (P/F ventilator induced lung injury (VILI). Inflammatory
ratio). S/F ratios of 235 and 315 correlate with P/F ratios mediators released due to VILI can extend the
CHAPTER 83: ARDS: Recognition and Management 509
TABLE 1: The Berlin definition versus the AECC definition

Characteristic Berlin definition 2012 AECC definition 1994
Timing Within 1 week of a known clinical insult or new or worsening respiratory symptoms Acute (without any specification)
Chest Bilateral opacities on chest X-ray or CT scan that are not fully explained by effusions, Chest X-ray with bilateral infiltrates
imaging lobar/lung collapse, or nodules
Origin of Respiratory failure not fully explained by cardiac failure or fluid overload PAWP ≤18 mm Hg when measured
edema Need objective assessment (e.g. echocardiography) to exclude hydrostatic edema if or no clinical evidence of left atrial
no risk factor present hypertension
Oxygenationa Mild 200 mm Hg < PaO2/FIO2 ≤300 mm Hg with PEEP or CPAP ≥5 cm H2Ob Based on PaO2/FiO2 regardless of
Moderate 100 mm Hg <PaO2/FIO2 ≤200 mm Hg with PEEP ≥5 cm H2O PEEP
Acute lung injury (ALI): ≤300
Severe PaO2/FIO2 < 100 mm Hg with PEEP ≥5 cm H2O ARDS: ≤200
Abbreviations: CPAP, Continuous positive airway pressure; FiO2, Fraction of inspired oxygen; PaO2, Partial pressure of arterial oxygen; PEEP, Positive
end-expiratory pressure; PAWP, Pulmonary artery wedge pressure.
a
If altitude is higher than 1000 m, the correction factor should be calculated as follows: [PaO2/FiO2 x (barometric pressure/760)].
b
Noninvasive ventilation may be used to deliver CPAP in mild ARDS.
TABLE 2: Risk factors associated with ARDS TABLE 3: ARDS mimics

Direct injury Indirect injury zz Cardiogenic pulmonary edema (CPE)
Aspiration Sepsis zz Acute exacerbation of interstitial lung disease
Infection (viral, bacterial, etc.)* Severe nonthoracic trauma zz Diffuse alveolar hemorrhage e.g. Goodpasture’s disease
Near drowning Cardiopulmonary bypass zz Cryptogenic organizing pneumonia
Toxic inhalation Pancreatitis zz Acute interstitial pneumonia
Lung contusion Burns zz Acute eosinophilic pneumonia
Military tuberculosis Multiple blood transfusions zz Malignant infiltration of the lungs e.g. leukemia
Drug overdose/drug reactions
*In tropical countries including India, acute febrile illnesses like
malaria, leptospirosis, dengue and H1N1 influenza are common
causes of ARDS with seasonal peaks.
TABLE 4: Differences between ARDS and CPE

ARDS CPE
Examination zz Cardiac examination - normal zz S3 or S4 gallop
zz Raised JVP
zz New or changed murmur
Chest X-ray zz Uniform bilateral opacities zz Cephalization of pulmonary vasculature

zz Kerley B lines, pleural effusion, cardiomegaly-absent zz Kerley B lines
zz Opacities do not resolve with diuretics zz Pleural effusion
zz Cardiomegaly
zz Opacities resolve with diuretics
ECHO zz Usually normal zz Valvular, diastolic or systolic dysfunction may be

apparent
Chest USG zz Dyshomogeneous alveolar interstitial syndromea (AIS) with spared zz Homogenous AIS with normal pleural line and no
areas, pleural line abnormalities and lung consolidations lung consolidation
b
zz Absent or reduced sliding sign zz Normal sliding sign
zz Lung pulse present zz Lung pulse absent
BNPc levels zz Normal zz Elevated

a
more than 3 “ultrasound lung comets” or “white lung” appearance for each examined area
b
absence of lung sliding with the perception of heart activity at the pleural line
c
Brain natriuretic peptide
TABLE 5:Therapeutic interventions for ARDS

Therapeutic intervention Comment
Ventilatory management
Low tidal volume ventilation (LTVV) zz ARDSnet ARMA trial compared LTVV (6 mL/kg predicted body weight [PBW]) with conventional
mechanical ventilation [MV] (12 mL/kg PBW): found mortality benefit (31% vs 40%). (2000)
High PEEP or ‘open lung’ zz Assessment of low tidal volume and elevated end-expiratory volume to obviate lung injury (ALVEOLI)
trial compared high vs low PEEP: no improvement in outcomes. (2004)
zz Lung open ventilation study (LOV) compared conventional PEEP and plateau pressures (Pplat) <
30 cm H2O vs recruitment maneuvers (RM), higher PEEP and Pplat< 40 cm H2O: found improved
oxygenation, decreased need for rescue therapy, no mortality benefit. (2008)
zz Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress
syndrome (EXPRESS) trial compared lower PEEP vs higher PEEP-found more ventilator free days (VFD)
and more organ failure-free days with higher PEEP, no difference in mortality. (2008)
zz Meta-analysis by Briel et al compiled data from the above 3 trials (2299 patients): improved survival
with higher PEEP in ARDS. (2010)

Recruitment maneuvers (RM) zz Transient improvements in oxygenation but no mortality benefit (LOV study)
High-frequency oscillation zz High frequency oscillation for acute respiratory distress syndrome (OSCAR) study compared HFOV
ventilation (HFOV) vs usual care: no mortality benefit. (2013)
zz Oscillation for acute respiratory distress syndrome treated early (OSCILLATE) trial: stopped early due
to increased mortality in ARDS patients treated with HFOV. (2013)

Partial liquid ventilation (PLV) zz A review (401 patients) of 2 studies of PLV in ARDS: more adverse events and no mortality benefit.
Nonventilator management
Fluid management zz Fluids and catheters treatment trial (FACTT) compared conservative vs liberal fluid strategy in ARDS.
Conservative group had improved respiratory function, more VFD, fewer ICU days but no mortality
benefit at 60 days. (2006)
Extracorporeal membrane zz Conventional ventilation or ECMO for severe adult respiratory failure (CESAR) trial: decreased
oxygenation (ECMO) mortality in ARDS patients referred to an ECMO center compared to usual care. (2009)
zz Australia and New Zealand extracorporeal membrane oxygenation (ANZ ECMO) influenza
investigators: improved survival of 71% with ECMO for influenza A (H1N1) ARDS. (2009)
Prone positioning zz Meta-analysis by Gattinoni et al: prone positioning reduced mortality in severe ARDS by ~10% but
can cause complications. (2010)
zz Prone positioning in severe acute respiratory distress syndrome (PROSEVA) study: early prone-
positioning decreased mortality in severe ARDS. (2013)

Hemodynamic monitoring zz Pulmonary-artery catheter did not improve survival and caused more complications than central
venous catheter. (2006)
Pharmacotherapy
Corticosteroids (early) zz Methylprednisolone (MPS) infusion in early severe ARDS study: improved organ dysfunction and
decreased ICU length of stay. (2007)
Corticosteroids (late) zz Efficacy and safety of corticosteroids for persistent ARDS study: increased mortality with starting
MPS > two weeks after ARDS onset. (2006)
Neuromuscular blockers zz Improved survival in severe ARDS
Recombinant angiotensin- zz No mortality benefit
converting enzyme 2
Azole therapy zz No mortality benefit
Phosphodiesterase inhibitors zz No mortality benefit
Inactivated recombinant factor VIIa zz No mortality benefit
Aerosolized B-2 agonist therapy zz No mortality benefit
Statins zz No mortality benefit
Inhaled nitric oxide zz No mortality benefit but improved oxygenation
Surfactant zz No mortality benefit
TABLE 6: Recommendations for therapy in ARDS

Therapy ATS/ESICM/SCCM Recommendations (2017) KSCCM/KATRD Recommendationsa (2016)
Low tidal volume ventilation Strong in favor Recommended (1A)
Prone positioning Strong in favor Recommended if not contraindicated (1B)
Higher PEEP Conditional in favor Recommended (2B)
Recruitment maneuvers Conditional in favor May reduce mortality (2B)
High-frequency oscillation ventilation Strong against Not recommended (1B)
ECMO in severe ARDS Unclear-more evidence needed Recommended as rescue therapy (2C)
Inhaled nitric oxide — Not recommended (1A)
Neuromuscular blockers for 48 hours after — Recommended (2B)
starting mechanical ventilation (MV)
Systemic steroids — Cannot reduce mortality (2B)
Abbreviations: ATS, American Thoracic Society; ESICM, European Society of Intensive Care Medicine; SCCM, Society of Critical Care Medicine;
KSCCM, Korean Society of Critical Care Medicine; KATRD, Korean Academy of Tuberculosis and Lung Diseases
a
Strong (1) and Weak (2) recommendations based on high (A), moderate (B) and low (C) quality of evidence.
inflammatory response of ARDS. Low tidal volume —— Plateau pressures (Pplat): ≤ 30 cm H2O
ventilation (LTVV) can reduce VILI. Procedure for If Pplat> 30 cm H O: decrease VT by 1 mL/kg
2
administering LTVV (based on ARDS net protocol): (minimum = 4 mL/kg).
Calculate PBW (predicted body weight) If Pplat< 25 cm H O and VT< 6 mL/kg, increase
2
Males = 50 + 2.3 [height (inches)-60] VT by 1 mL/kg until Pplat> 25 cm H2O or VT
Females = 45.5 + 2.3 [height (inches)-60] = 6 mL/kg.
Set initial tidal volume (VT) = 8 mL/kg PBW, initial
If Pplat< 30 and breath stacking occurs: may
respiratory rate <35 bpm to approximate minute increase VT by 1 mL/kg to 7 or 8 mL/kg if

ventilation Pplat remains < 30
Reduce VT by 1 mL/kg at intervals ≤ 2 hours until VT
—— I: E RATIO < 1
= 6 mL/kg PBW.
—— Oxygenation: PaO2 55–80 mm Hg/SpO2 88–95%.
Use minimum PEEP of 5 cm H O and incremental
2
FiO2/PEEP combinations to achieve goal.
Adjust VT and RR to achieve goal:
Prone Positioning
Prone positioning improves oxygenation in patients with
GOALS:
—— pH: 7.30–7.45
ALI/ARDS. Proposed mechanisms include an increase
Acidosis management: (pH < 7.30)
in end expiratory lung volume, improved ventilation-
If pH 7.15–7.30: Increase RR until pH > 7.30 or
perfusion matching, uniform distribution of lung stress
PaCO2 < 25 (Maximum set RR = 35). with tidal cycling, and regional improvement in lung
If pH < 7.15: Increase RR to 35. If pH remains mechanics. Potential risks include endotracheal tube
< 7.15, VT may be increased by 1 mL/kg steps and CVP lines obstruction/dislodgement, pressure
until pH > 7.15, may give NaHCO3 ulcers, increased sedation and limited mobilization.
Alkalosis management: (pH > 7.45) Decrease Adult patients with severe ARDS should receive prone
RR if possible. positioning for >12 hours/day unless contraindicated.
TABLE 7: Higher PEEP/lower FiO2

FiO2 0.3 0.3 0.3 0.3 0.3 0.4 0.4 0.5 0.5 0.5–0.8 0.8 0.9 1.0 1.0
PEEP 5 8 10 12 14 14 16 16 18 20 22 22 22 24
Higher PEEP CO 2 at lower blood flow rates than that required for
Higher PEEP improves recruitment, reduces lung stress, oxygenation, enabling ultra-lung protective ventilation
and prevents atelectrauma. Potential risks include (VT=4 mL/kg). The possible benefit of this strategy needs
injury like pneumothorax and pneumomediastinum evaluation.
from end-inspiratory alveolar overdistention, increased
intrapulmonary shunt, increased dead space, and higher CONCLUSION
pulmonary vascular resistance. Higher PEEP can be The last decade has seen emergence and recognition
administered using various strategies. In EXPRESS study, of ARDS as a major cause of morbidity and mortality
PEEP was kept as high as possible so that Pplat remained in ICUs worldwide. Innovate strategies have evolved
28–30 cm H2O. In ALVEOLI study, it was based on the to improve the survival of ARDS patients and decrease
Table 7. their length of stay on ventilator and in ICUs. The use
of ECMO to improve the survival of tropical infections
Recruitment Maneuvers related ARDS in the developing world could be a major
future challenge.
Recruitment maneuvers (RMs) are transient elevations
in applied airway pressures to open/recruit collapsed
BIBLIOGRAPHY
alveoli. RMs cause short-term physiological benefits
1. Aokage T, Palmér K, Ichiba S, Takeda S. Extracorporeal
(reduced intrapulmonar y shunt and increased membrane oxygenation for acute respiratory distress
pulmonary compliance). Complications include syndrome. J Intensive Care. 2015;3:17.
hemodynamic compromise and barotrauma. 2. Boyle AJ, Mac Sweeney R, McAuley DF. Pharmacological
treatments in ARDS; a state-of-the-art update. BMC Med.
Extracorporeal Membrane Oxygenation 2013;11:166.
3. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter
Extracorporeal membrane oxygenation (ECMO) is SD, et al. Higher vs lower positive end-expiratory pressure
indicated in severe ARDS for refractory hypoxemia or in patients with acute lung injury and acute respiratory
severe respiratory acidosis despite optimal conventional distress syndrome: systematic review and meta-analysis.
measures. ECMO oxygenates blood and removes carbon JAMA. 2010;303:865-73.
dioxide (CO 2 ) using an extracorporeal membrane 4. Cho YJ, Moon JY, Shin ES, Kim JH, Jung H, Park SY, et al.
Clinical practice guideline of acute respiratory distress
oxygenator that consists of a blood chamber and a gas
syndrome. Korean J Crit Care Med. 2016;31:76-100.
chamber separated by a semipermeable membrane. Gas 5. Davies A, Jones D, Bailey M, et al. Extracorporeal membrane
exchange occurs as venous blood and sweep gas pass oxygenation for 2009 influenza A(H1N1) acute respiratory
along either side of the membrane. Oxygenated blood distress syndrome. JAMA. 2009;302:1888-95.
is returned to a vein (veno-venous ECMO) or an artery 6. Fan E, Del Sorbo L, Goligher EC, et al. An official American
Thoracic Society/European Society of Intensive Care
(veno-arterial ECMO).
Medicine/Society of Critical Care Medicine Clinical Practice
Lower VT and airway pressures than current standard- Guideline: Mechanical ventilation in adult patients with
of-care may reduce VILI. Reduction of VT is limited acute respiratory distress syndrome. Am J Respir Crit Care
by hypercapneic respiratory acidosis. ECMO removes Med. 2017;195:1253-63.
7. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency 10. Koh Y. Update in acute respiratory distress syndrome. J
oscillation in early acute respiratory distress syndrome. N Intensive Care. 2014,2:2.
Engl J Med. 2013;368:795-805. 11. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory
8. Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, distress syndrome. The Journal of Clinical Investigation.
Beale R, et al. The Berlin definition of ARDS: an expanded 2012;122(8):2731-40.
rationale, justification, and supplementary material. 12. The ARDS Definition Task Force Acute respiratory distress
Intensive Care Med. 2012;38:1573-82. syndrome: the Berlin definition. JAMA. 2012;307(23):2526-
9. Guérin C, Reignier J, Richard JC, et al. PROSEVA Study 33.
Group. Prone positioning in severe acute respiratory 13. Thompson BT, Chambers RC, Liu KD. Acute respiratory
distress syndrome. N Engl J Med. 2013;368:2159-68. distress syndrome. N Engl J Med. 2017;377:562-72.
CHAPTER
84
Clinical Approach to Solitary
Pulmonary Nodule
BNBM Prasad
INTRODUCTION lesion must be completely surrounded by well aerated

It is not uncommon to encounter an isolated chest lung and not associated with atelectasis, lung infiltrates,
radiological opacity in clinical practice during routine mediastinal lymphadenopathy and pleural effusion.5, 6
evaluation of an otherwise asymptomatic individual. HRCT imaging of the chest has greatly enhanced nodular
Such a finding often poses a strong diagnostic and detection, localization and characterization. It is to be
therapeutic challenge to a clinician who has to quickly noted that many such lesions that were termed SPN
decide whether the opacity is benign or malignant since previously by the chest X-ray may display many small
its presence may be a sinister indication of underlying nodules when evaluated by CT scan, necessitating a need
malignancy that warrants urgent measures to achieve for CT evaluation to strictly qualify such lesions as SPNs.
the best possible outcome. Reported incidence of Based on density of the lesion it is possible to precisely
solitary pulmonary nodule (SPN) has increased in recent classify a SPN as solid, partly solid or ground glass for
times, due to routine use of high resolution computed enabling early cancer detection by estimating probability
tomography (HRCT) imaging of the chest for screening of malignancy. Thanks to CT imaging, now there is
purposes.1-4 Even very small nodules including those greater awareness about the existence of subcentimetric
that are less than a centimeter (that are otherwise missed SPNs having a diameter of ≤8 mm that are otherwise
by chest X-ray) can be detected by HRCT. For optimal missed by conventional chest X-ray. 4 The term ‘coin
management of a SPN, a systematic approach with lesion’ is no longer used to describe a SPN since it
proper history taking, clinical examination and imaging denotes a flat two dimensional structure like that of a
studies is an essential requisite before embarking upon coin while SPN is more of a spherical structure. When the
risky invasive procedures for establishing diagnosis and diameter of the nodule is more than 3 cm, then the term
treatment since many SPNs are benign in nature often ‘lung mass’ is used to describe such a lesion since risk of
requiring careful observation and follow-up. malignancy is very high warranting prompt diagnosis
and surgical resection.1
DEFNITION
The term solitary pulmonary nodule (SPN), earlier CAUSES
known as coin lesion is used to describe a radiological There are many causes of SPN and their incidence
opacity in the lung that is single, discrete, spherical, depends on age, geographic location and smoking habits
well circumscribed and 3 cm or less in diameter. Such a of the patient. Etiology of SPN can be broadly grouped
CHAPTER 84: Clinical Approach to Solitary Pulmonary Nodule 515
TABLE 1: Causes of SPN etiology differs in various studies depending upon the
zz Developmental type of population studied. High incidences have been
—— Bronchial cyst
reported among patients who underwent low dose
—— Bronchial atresia with mucoid impaction
—— Sequestration
CT scan for cancer screening with prevalence of SPN
zz Vascular
ranging from 12% to 51%. 8, 9 Similarly surgical studies
—— AV malformation have observed high incidences of malignancy because
—— Hematoma
surgical approach was mandated by high clinical
—— Pulmonary infarction
—— Pulmonary artery aneurysm

suspicion of cancer.10 In endemic areas for granulomatous
zz Lymphatic diseases such as tuberculosis, histoplasmosis and
—— Intrapulmonary lymph node coccidioidomycosis, 75% of SPNs detected on chest X-ray
—— Lymphoma
were due to granulomas.11
zz Granuloma (Infection/Infestation)
—— Fungal granuloma-histoplasmosis, coccidioidomycosis,
cryptococcosis, aspergillosis APPROACH TO DIAGNOSIS

—— Mycobacterial granuloma Clinical evaluation: Detailed history and clinical
—— Septic emboli
—— Round pneumonia
examination are initial steps that offer significant clues to
—— Dicrofilariasis a diagnosis. Most of the SPN discovered during routine
—— Echinococcal cyst
chest radiography remain asymptomatic at the time of
Inflammatory (noninfection) detection. Young individuals under the age of 30 years,
—— Rheumatoid nodule
—— Paraffinoma
otherwise asymptomatic and nonsmokers are unlikely
—— Sarcoidosis to have malignancy. Most of the benign SPNs upto
—— Wegener’s granulomatosis
90%, are granulomatous in origin and may manifest
Tumor with constitutional or systemic symptoms. History
Malignant
—— Metastasis-breast, colon, kidney, head and neck, etc. of travel to endemic areas, low grade fever, human
—— Primary lung cancer immunodeficiency virus (HIV) infection, hemoptysis,
—— Carcinoid
—— Pulmonary lymphoma
and chest pain may be present. Tuberculosis is common
—— Pulmonary sarcoma in many parts of the world including India and forms
—— Plasmocytoma
an important differential diagnosis. Every effort should
Benign
—— Hamartoma
be made to rule out tuberculosis before labeling SPN
—— Chondroma as malignant. Rarely tuberculosis and malignancy
—— Teratoma
may coexist especially in high risk groups. History of
—— Lipoma
—— Adenoma exposures to TB, positive skin test, younger age group

—— Endometriosis and systemic symptoms of low grade fever, anorexia
zz Miscellaneous and weight loss are some of the features that offer
—— Rounded atelectasis
clues to a clinical diagnosis of tuberculosis. Fungal
—— Amyloidosis
infection such as histoplasmosis and coccidioidomycosis
should be considered in endemic areas such as South
under categories of developmental and acquired
America and these conditions exhibit features similar
conditions including infections, inflammations and
to that of tuberculosis. Developmental anomalies like
neoplasms. Various causes of SPN are enumerated in the bronchial cyst may be symptomatic in about 40% of cases
Table 1. manifesting with cough, chest pain or breathlessness.
Malignancy is an important differential diagnosis
PREVALENCE of SPN and should be suspected in individuals who are
On routine chest radiography 1–2 cases of SPN are smokers and over the age of 35. Rarely malignancy is seen
detected per 1000 chest X-rays.7 Reported incidence of under the age of 35. Incidence of malignancy increases
with the age and majority of cases detected are between the borders of the nodule and study the relationship
4 th and 6 th decades of life. Bronchogenic carcinoma of the nodule with adjacent structures such as vessels
is the most common cause of malignant SPN. Other and the pleura. 12 While studying the SPN in various
malignant conditions though rare include carcinoid CT sections, attention should be given to size, shape,
tumor, sarcoma, solitary metastasis and lymphoma. location and margins of the lesion. Careful examinations
Recent or past history of malignancy of head and neck of CT sections for the presence or absence of associated
should be obtained since it helps to differentiate whether findings such as calcification, ground glass attenuation,
the SPN is secondary to metastasis or due to primary satellite lesions, focal pleural thickening, feeding blood
lung cancer. History of smoking, exposures to radiation vessels, parenchymal infiltrates, and lymphadenopathy
and mineral dusts such as silica, asbestos, arsenic, (that are otherwise missed in the chest X-ray) are
cadmium and chromium are associated with increased essential for determining the nature of the lesion. CT
risks of lung cancer. scan is highly useful in making specific diagnosis in
Thorough general physical and systemic examinations, several conditions such as rounded atelectasis, a mucous
specifically looking for evidence of developmental plug, AV malformation or bronchial cyst.13,14 By careful
anomalies, systemic infections, inflammations and analysis of following features it is possible to differentiate
malignancy are to be carried out in every case. Clinical whether the SPN is benign or malignant.
evaluation should also specifically look for SPN mimics
such as a skin nodule, nipple shadow and monitor leads. Size: Small lesions, lymphadenopathy, chest infiltrates
Inflammatory conditions such as collagen vascular and focal pleural thickening can be detected easily by
disease, Wegener’s granulomatosis and sarcoidosis high resolution mutidetector-row CT scanners that use
are extremely rare to present as SPN but should always 16–128 detector channels to obtain thin sections ranging
be kept in mind. Presence of systemic findings such from 0.6 mm to 2 mm. Benign SPNs are generally smaller
as subcutaneous nodule, eye and musculoskeletal in size, often subcentrimetric. Malignant SPNs are
involvements aid diagnosis in such conditions. usually larger in size with high probability of malignancy
when the size is more than 2.3 cm in diameter.
Chest radiology: Chest X-ray generally is able to identify
nodules when they are about 0.8–1 cm in diameter. 7 Margin: Benign lesions have smooth margins and
Some nodules may be missed in PA view and therefore are round in shape. Lobulated margin is a feature
lateral view is always recommended while screening of hamartoma but can be seen in carcinoids and
for pulmonary nodules. Careful evaluation of apex, adenocarcinoma.15 Rarely malignant lesion can have a
diaphragmatic area, behind the heart and behind ribs smooth margin especially in those solitary metastasis
should be done since small nodules in these locations from breast, colorectal region and kidney. Malignant
may be missed. Efforts should be made to locate the nodules have irregular spiculated margins otherwise
nodule (pulmonary or outside lung) and ascertain that known as ‘corona radiata’ (Fig. 1).12
detected opacity fulfills all criteria’s of SPN. Normal Distribution: Benign SPNs can be present in any part
anatomic structures such as nipple shadows should of the lung either right or left. Bronchial cyst that is
be distinguished from SPN by using nipple markers. easily detected by CT scan are close to tracheobronchial
Previous X-ray if available should be obtained and tree often abutting these structures, with CT scan
reviewed along with the current one for assessing the density as that of water. Presence of air-fluid level
stability of the nodule.
heralds communication with the airway and secondary
CT scan of the chest: CT scan is the corner stone for infection. SPN due to sequestration of the lung is more
diagnosis as it helps to define and characterize a common in posterior basal segment of the left lung.
pulmonary nodule.7 By employing thin-section high- Malignant lesions have a predilection for distribution in
resolution CT imaging it is possible to clearly define upper lobe of right lung since most of the carcinogens
Density: CT scan helps to characterize density of the

lesion as solid, partly solid and ground glass opacity
(GGO). Dense lesions are generally benign. Small
nodules less than 1 cm that is solid is unlikely to be
malignant while in those that are ground glass or partly
solid in appearance, the possibility of malignancy should
be kept in mind. 18,19 Ground-glass opacity is a focal
pulmonary opacity with a sub-solid density and preserved
morphology of the lung beneath the opacity. SPN with
ground glass opacification is seen in bronchoalveolar
carcinoma, adenocarcinoma and atypical adenomatous
hyperplasia. Solid or partly solid nodule is observed in
adenocarcinoma, squamous cell carcinoma and small
Fig. 1: CT chest showing SPN with spiculated margins suggestive of cell carcinoma of the lung. It may be noted that the
malignancy
lesion, to begin with having ground glass density, later
becoming solid is highly suspicious of adenocarcinoma.20
have tendency to deposit in the right upper lobe region.
Halo sign characterized by the presence of thin rim of
Upper lobe predilection is also seen in granulomas due
ground glass opacification around SPN is a feature of
to tuberculosis, fungal infection and silicosis.
invasive aspergillosis and bronchoalveolar carcinoma.
Associated findings : Presence of satellite lesions In conditions due to cryptogenic organizing pneumonia
surrounding a central SPN suggests granulomatous and paracoccidioidomycosis, focal round ground–glass
conditions such as pulmonar y tuberculosis. CT opacification surrounded by a rim of consolidation can
appearances suggestive of malignancy include a lesion be seen. This feature is termed as reverse halo sign.
more than 2 cm, spiculated or irregular contour, presence
Calcification: Identifying calcification and its pattern in
of air bronchogram within the nodule, bubbly air the SPN gives important clues to the etiology. Plain CXR
collections (“pseudocavitation”) or cavities and vascular may miss calcification in 50% of cases. CT scan has high
convergence.13,14,16,17 Vascular convergence is suggestive degree of sensitivity and also helps to know the pattern
of vascular and/or lymphatic invasion by the tumor.16 of calcification. Presence of calcification in the lesion is
It may be noted that ‘bronchus sign’ or presence of air detected by measuring attenuation value of the nodule
in the bronchus leading to in the nodule/bronchus and a nodule that is well defined with smooth margins
contained in the nodule makes possibility of the lesion and CT attenuation values of 200 hounsfield units (HU)
being malignant less likely. However, rare tumors of the or more is more likely to be benign in nature (Fig. 2).
lung such as primary lymphoma of the lung can have However, minimal and eccentric calcification
air bronchus sign. In AV malformation both draining can be seen in malignant lesions. Various patterns of
and feeding vessels extending from the hilum can calcification have been described. Eccentric calcification
seen by contrast CT. ‘Feeding vessel sign’ suggested by can be observed when a granuloma is engulfed by the
the presence of vessel leading directly to a nodule is tumor. Laminar or concentric, diffuse, central, strippled
often associated with septic emboli but also is seen in and pop corn patterns of calcification are suggestive of
malignancy and arteriovenous fistula. SPN lying adjacent benign nature of the nodule. Granulomatous conditions
to pleural thickening and due to rounded atelectasis are characterized by the presence of central, concentric
has characteristic ‘comet tail sign’ indicating a bundle of or laminar and strippled patterns of calcification in the
curvilinear bronchi and vessels extending to hilar aspect nodule. Popcorn calcification, a feature of hamartoma
of the lesion. is present in 50% of cases. Hamartoma has elements of
Fig. 2: CT images of a well-circumscribed SPN in left upper lobe having a spec of calcification
suggestive of benign nature of the lesion
Contrast enhancement: Dynamic CT imaging of the

nodule (by using rapid infusion of IV contrast for
enhancement of the nodule) helps to distinguish a benign
nodule from that of malignant one since malignant
lesions show greater contrast enhancement than benign
lesions with few exceptions such as hamartomas and
tuberculoma.23 Thresh hold value of 15 H is used as a
cutoff value to differentiate a malignant SPN from a
benign SPN since contrast enhancement of less than 15
H almost always suggests a benign lesion. Because of
false positive results in some benign conditions, this test
lacks specificity with limited clinical utility.6
Growth pattern: Growth pattern of SPN is measured
Fig. 3: CT image showing well-defined SPN having calcification and
areas of low attenuation (fat deposits) typical of hamartoma by calculating it’s doubling time. Doubling time (dt) is
defined as the time required in days for two fold increase
cartilage, fibromyxoid stroma and adipose tissue. It is a in the volume of the tumor and is calculated by using
slow growing tumor that can attain large size of about 6 mathematical expression 4πr 3/3 (assuming that SPN
cm.21,22 CT scan typically shows calcification intermixed is a spherical structure) and by the formula (t×log2/
with areas of low attenuation representing fat deposits {3×[log(d2/d1)]}.24
within the lesion (Fig. 3). Note: r = radius of the SPN;
Cavitation: Both benign and malignant SPNs can t = time in days between chest radiographs;
cavitate. Benign conditions associated with cavitations d1= diameter of the SPN in the previous radiograph
include tuberculosis, fungal infections, abscess and and
cysts. SPN due squamous cell carcinoma is associated d2 = diameter of SPN in the present radiograph.
with cavitation. Eccentic caviatation with wall thickness The ability to detect nodule growth is a function
more than 15 mm suggests malignancy while cavity wall of image resolution and by using high resolution
thickness of less than 15 mm favors benign nature of SPN. multidetector CT scans of chest it is possible to accurately
assess the growth pattern by three dimensional volume TABLE 2: Schedule of follow-up CT imaging in solid SPN
analysis of the tumor. Three dimensional volume Size No risk factor for cancer Risk factor cancer
analysis is time consuming and labor intensive.6 Serial ≤4 mm No follow-up CT after 12 months, no
CT scans are required to be done over a period of time further imaging if nodule
for assessing the growth pattern of the SPN. Studies shows no change
have shown that volumetric CT scan of the nodule >4–6 mm CT in 12 months CT at 6–12 months
No change then no Repeat CT at 18–24
repeated after 30 says or even earlier after the initial additional follow-up months if nodule shows no
study can detect any change in the volume of a 5 mm change
nodule.2,25-27 It may be noted that in the natural evolution >6–8 mm CT 6–12 months CT 3–6 months
of the cancer, a single cancer cell to begin with multiplies Repeat at 18–24 months Repeat CT at 9–12 months
if there is no change and 24 months if
relentlessly to become about 1 billion cells after 30
nodule shows no change
doublings when the tumor attains 1 cm diameter. Further,
>8 mm CT 3–6 months CT at 3 months
it takes another 10 doublings for the tumor to attain a Repeat CT at 9–12 Repeat CT at 6, 12 and 24
diameter of 10 cm, when patient has usually died.29 For months and 18–24 months if nodule shows no
the tumor to double its volume there is an increase in the months if nodule shows change
no change
diameter of the nodule by 26%. Most of malignant SPNs
have a doubling time ranging from 20 days to 300 days.5,6
Among lung tumors doubling time varies depending on TABLE 3: Schedule of follow-up CT imaging in nonsolid SPN
histology. It has been observed that squamous and large Pure ground-glass nodule Part-solid, part ground-glass
cell tumors have an average doubling time of 60–80 days nodule
while adenocarcinomas have a doubling time of about Nodule size ≤5 mm; no follow- Nodule ≤8 mm: CT imaging at 3,
up needed 12 and 24 months with annual
120 days. Small cell carcinoma of the lung has a faster
CT for 1–3 years thereafter
growth rate with a doubling time that is even less than
Nodule size >5 mm: CT at 3 Nodule >8 mm: CT imaging at
30 days in some cases.28 Benign nodules have a doubling months and if no change then 3 months followed by PET and/
time that is generally either below 20 days or more than follow-up annually for 3–5 years or biopsy if nodule persists
400 days. SPN due to acute infection or inflammation
exhibits rapid growth with a doubling time of less than years is recommended for the evidence of malignancy
20 days. Slow growth is observed in chronic granulomas when the lesion is partly solid or ground glass in
and hamartoma. It has been observed that SPNs which appearance.6, 30, 31 Based on expert consensus guidelines,
remain stationary for about 2 years are mostly benign.5, 6 the schedule for conducting follow-up CT imaging in
Follow-up imaging: There is always a debate how long solid and nonsolid nodules are shown in Tables 2 and 3
respectively.6
and how frequently SPN has to be followed up by serial
chest CT imaging. It is recommended to follow up SPN by Positron emission tomography (PET): PET imaging
serial low dose HRCT with thin sections.6 If facility exists of SPN is used for precise localization of SPN and
much more sensitive volumetric CT is recommended for determining whether the nodule is benign or
for facilitating growth detection. Frequency of follow malignant by measuring uptake of positron-emitting
up by CT imaging depends on the size and density of radioisotope-18 fluorodeoxy-D-glucose (FDG). The
the nodule and probability for lung cancer. Generally uptake of FDG depends on metabolic activity of SPN.
small nodules less than 4 mm with no lung cancer Majority of malignant tumors are FDG avid denoting
risks do not require follow up. Solid lesions that remain their high metabolic activity with FDG uptake of 2.5 SUV
stable on CT scan without any significant increase (standard uptake value) or more. Though a threshold
in size for two years is benign warranting no further level of 2.5 SUV is used to differentiate a benign lesion
follow up. However longer follow up for another 1–3 from malignancy, it is the degree of FDG uptake by the
nodule that determines malignant nature of the nodule. stains or molecular analyses, especially in malignant
It has been observed that greater FDG uptake by the nodules where it may be impossible for pathologists
tumor (compared to mediastinal blood pool) is more to distinguish primary from metastatic carcinoma of
strongly associated with malignancy. 6,32,33 However, nonpulmonary origin such as colon, breast, etc. by
lower FDG uptake can be seen in lesions that are less conventional histological methods.
than 8 mm in size and in certain malignancies such as
Transthoracic needle aspiration/CT guided needle biopsy:
lepidic predominant adenocarcinoma (bronchoalveolar
CT guided transthoracic needle aspiration (CT FNA) is a
cell carcinoma), minimally invasive adenocarcinoma/ useful technique even when the lesion is small and less
c a rc i n o m a i n s i t u , c a rc i n o i d s a n d m u c i n o u s than 2 cm in diameter. High diagnostic yield is expected
adenocarcinomas.34, 35 On the contrary higher SUV for when SPN is peripheral in location (outer third of the
FDG are seen in various granulomatous conditions lung). CT FNA has very high sensitivity of 90%, when
like tuberculosis, mycoses, sarcoidosis, rheumatoid employed for sampling peripherally located nodule with
arthritis and atypical mycobacterial infections, besides a diameter of 1.5 cm or more.5, 39 Major complications of
uncontrolled hyperglycemia.36-38 transthoracic FNA include pneumothorax, air embolism
Tissue diagnosis: Various diagnostic options including and hemorrahage. Risk of pneumothorax can be high
fiberoptic bronchoscopy, percutaneous CT-guided up to 35% with 10–15% requiring tube thoracostomy
biopsy, and surgical resection are available. These or catheter drainage. 40 Presence of emphysema and
procedures are limited by complications and difficulty bullous disease makes this procedure highly risky. It is to
in obtaining adequate tissue when the lesion is small. be avoided in those who have poor respiratory reserve,
Choosing a particular option of diagnosis depends on bleeding diathesis and severe pulmonary hypertension.
the location and size of SPN as well as availability of Bronchoscopy: Specimens for cytological and histological
resources and cost, benefits and risks associated with studies can be obtained by fiberoptic bronchoscopic
such a procedure. They should be employed in patients techniques-bronchial lavage, bronchial brushing,
with a high risk for malignancy. While deciding whether bronchial biopsy and transbronchial lung biopsy.
to biopsy the lesion or not, it is extremely important Bronchoscopy enables multiple sampling from the
to decide whether the result of the biopsy is going to suspicious area without an appreciable increase in the
drastically change the management. For example, risk for pneumothorax or major bleeding. Diagnostic
when SPN is detected in a known case of malignancy, yield by bronchial lavage, brushing and biopsy is variable
likelihood of metastasis is very high and decision to depending upon the location and size of the nodule.41
biopsy is to be taken only when primary lung tumor is Diagnostic yield is high when there are bronchial
strongly suspected or some other alternative diagnosis mucosal abnormalities or a bronchoscopically visible
other than metastasis like tuberculosis is a strong nodule. Proximal/centrally located SPN of more than 2
possibility. CT findings strongly favoring malignancy cm in diameter and a CT finding of positive bronchus sign
such as irregular margins, eccentric cavitation, solid (a bronchus visible on CT that is leading to or contained
indeterminate nodule, and nodule having varied density within the nodule) are associated with diagnostic yields
(part solid and part ground glass density) with evidence ranging from 60% to 90%. 42 In peripherally located
of growth on serial imaging, obviously warrant an SPN, bronchoscopic yield proportionately decreases
early tissue diagnosis so also in patients having high as the distance between the nodule and main stem
risks for malignancy such as heavy smoking, history bronchi increases. Diagnostic yield by combining
of occupational exposures and older age. Whatever bronchoscopic techniques of brushing, lavage and
option the clinician may chose, it is imperative to obtain transbronchial biopsy is 34% and 63% in lesions that
sufficient tissue that is required for gross and microscopic are less than 2 cm in diameter and more than 2 cm in
examination as well as for special immunochemical diameter respectively.39,43 Ultrathin bronchoscopes can
be used to sample distal lesions. Further, diagnostic consequences of therapy–surgical or nonsurgical on the
yield can be enhanced by fluoroscopy, electromagnetic outcome. If the probability for cancer is close to 0, then
navigation (using three-dimensional CT reconstruction observation with serial CT scan is good enough. On the
combined with electromagnetic navigation of an other hand, if the probability of cancer is close to 1, going
extended working channel) and radial endobronchial for surgical excision after staging work up is the best
ultrasound (EBUS). In systematic review of results of option in an otherwise surgically fit candidate. Those
these advanced techniques, the reported diagnostic yield SPN that comes under intermediate probability of cancer
varied from 67% to 73%-electromagnetic navigation 67%, risk require careful evaluation by various nonsurgical
radial EBUS 71%, ultrathin bronchoscopy 70%, guide methods before considering surgery as a diagnostic or
sheath techniques 73%, and virtual bronchoscopy 72%.41 a therapeutic measure. Risk assessment is an important
These sophisticated techniques requiring high degree step for appropriate management of a SPN.5, 6 SPN with
of expertise are costly, time consuming and limited to high risks of malignancy includes a diameter of 2.3 cm
few select centers. However, they enable sampling of or more with spiculated margin or corona radiata (on
even a small nodule (as small as 7 mm) with a very high imaging) in current smokers (>20 cigarettes per day)
diagnostic yield of 80% or more. who are more than 60 years old with previous history
Surgical biospsy: Surgical biopsy employs conventional of cancer. Low probability of malignant SPN includes a
thoracotomy or Video-Assisted Thoracic Surgery (VATS) smooth well defined nodule with a diameter less than 1.5
for obtaining tissue for diagnosis and for carrying out cm in individuals who are under 45 years of age and are
surgical resection. VATS is preferred over conventional nonsmokers. Moderately increased risk for malignancy
thoracotomy as it has low morbidity and mortality with is observed in SPNs that are between 1.5 cm and 2.2 cm
a short hospital stay.44 Surgical resection remains the in diameter with scalloped edge (on imaging) in smokers
“gold standard” since this procedure offers adequate (up to 20 cigarettes per day/former smokers within last 7
tissue and definitive therapy for patients with malignant years) who are aged between 45 years and 59 years.
SPN including solitary metastasis from solid tumors.45 Specific therapy is to be instituted once diagnosis is
Diagnostic yield is much higher compared to other established. Surgery can be considered in malignant SPN
methods with sensitivity close to 100%. Lesions can either primary or due to metastasis after assessing the
be missed if they are tiny and difficult to palpate. risk benefit ratio and lobectomy with systematic lymph
Surgical biopsy enables adequate tissue sampling for node sampling remains the procedure of choice.46 Role of
various studies including frozen section examination wedge or segmental resections in the management of lung
before proceeding for lobectomy or wedge resection. cancer remains controversial. Thermal ablation using
Complications of surgery occur due to both general radiofrequency energy is a minimally invasive procedure
anesthesia and lung resection. Common complications that can be usefully employed to treat a malignant SPN
associated with pulmonary resection are persistent due to primary or metastasis in cases where surgery is
air leak and infection. Risk factors for surgery include contraindicated.47 Surgery is also warranted in certain
severe underlying co-morbidities such as uncontrolled complicated and symptomatic benign conditions such as
hypertension, severe heart disease, bleeding diathesis cyst, sequestration and hamartoma.
and poor lung reserve with projected post operative Finally the decision for definitive surgery either
FEV1<40% and VO 2 max <15 Ml/kg/min. Surgical VATS or conventional thoracotomy depends on many
mortality and morbidity and for pulmonary resection is factors including cost, risks, availability of expertise,
around 2% and 10% respectively. patient preferences and absence or presence of severe
comorbidities.48 Systematic approach to management of
MANAGEMENT a SPN taking into consideration cancer risks (probability
Management strategy of SPN revolves on the probability of cancer), consequences of surgery-benefit and harm
of the lesion of being malignant or nonmalignant and and existing comorbidities is outlined below:
If SPN has benign calcification pattern or 2 years in such cases. No further follow up is recommended
of radiographic stability, then no further testing is when the nodule is small and remains static for 2 years.
recommended except in stable GGO where further In those cases with imaging evidence of malignancy
1–3 years follow up is recommended. including significant changes in growth pattern, surgical
If SPN is unstable and negative for benign pattern of resection is the best option, provided surgical risk is low.
calcification, then assess probability of cancer and In remaining cases with high probability of cancer and
surgical risks (lobectomy). If probability of cancer is high surgical risk, alternative therapeutic options such as
high and lobectomy risk is minimal, then surgery is limited resection, radiofrequency ablation, stereotactic
the best option. If lobectomy risk is high but is feasible, surgery and active observation are considered.
then lobectomy is recommended. If the probability of
cancer is intermediate and lobectomy risk is high, REFERENCES
then one has to perform PET and if PET is positive for 1. Almeida FA, Uzbeck M, Ost D. Initial evaluation of the
nonsmall cell lung cancer patient: diagnosis and staging.
malignancy, then surgery is recommended. If PET is
Curr Opin Pulm Med. 2010;16(4):307-14.
negative for malignancy, then CT FNA is to be done 2. van Klaveren RJ, Oudkerk M, Prokop M, et al. Management
and if it is nondiagnostic then active surveillance is of lung nodules detected by volume CT scanning. N Engl J
recommended. Med. 2009;361(23):2221-9.
If risk of lobectomy is too high with high probability 3. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer
of cancer, observe those with severe comorbidities; mortality with low-dose computed tomographic screening. N
Engl J Med. 2011;365(5):395-409.
in some consider CT FNA and if CT FNA is
4. Xu DM, van der Zaag-Loonen HJ, Oudkerk M, et al. Smooth
nondiagnostic observe such cases. If CT FNA is or attached solid indeterminate nodules detected at
positive for malignancy consider alternate therapies baseline CT screening in the NELSON study: cancer risk
such as segmentectomy, external beam radiation and during 1 year of follow-up. Radiology. 2009;250(1):264-72.
sterotactic surgery. 5. Ost DE, Gould MK. Decision making in patients with
pulmonar y nodules. Am J Respir Crit Care Med.
2012;185(4):363-72.
CONCLUSION 6. Gould MK, Donington J, Lynch WR, et al. Evaluation
Detection of SPN is not uncommon in clinical practice of individuals with pulmonary nodules: when is it lung
during routine screening. Often diagnosis is challenging cancer? Diagnosis and management of lung cancer, 3rd
due small nature of the lesion and difficulty in obtaining edn: American College of Chest Physicians evidence-
the tissue. Prompt action is mandatory when SPN is based clinical practice guidelines. Chest. 2013;143(5
Suppl):e93S-120S.
discovered. Immediate challenge to the clinician is
7. Lillington GA. Management of solitary pulmonary nodules.
in making the decision-whether the nodule is benign Dis Mon. 1991;37(5):271-318.
or malignant? A comprehensive approach by proper 8. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early lung
history taking, clinical examination and study of existing cancer action project: overall design and findings from
images including previous and present radiographs and baseline screening. Lancet. 1999;354(9173):99–105.
9. Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer
high resolution CT is vital before deciding the need for
screening with CT: Mayo Clinic experience. Radiology.
nonsurgical or surgical procedures. An astute clinician
2003;226(3):756-61.
should be able to decide about the best course of action 10. Rubins JB, Rubins HB. Temporal trends in the prevalence of
for the patient. Clues in the history, physical examination malignancy in resected solitary pulmonary lesions. Chest.
and images regarding surgical and cancer risks can 1996;109(1):100-3.
be used effectively to guide further diagnostic and 11. Trunk G, Gracey DR, Byrd RB. The management and
evaluation of the solitary pulmonary nodule. Chest.
therapeutic decisions. Wait and watch is the best policy
1974;66(3):236-9.
for benign cases of SPN who are otherwise asymptomatic. 12. Zwirewich CV, Vedal S, Miller RR, Muller NL. Solitary
Careful observation for 2 years including surveillance pulmonary nodule: high-resolution CT and radiologic-
CT to assess for the stability of the nodule is preferred pathologic correlation. Radiology. 1991;179(2):469-76.
13. Winer-Muram HT. The solitary pulmonary nodule. Radiology. 28. Casey JJ, Stempel BG, Scanlon EF, Fry WA. The solitary
2006;239:34-49. pulmonary nodule in the patient with breast cancer.
14. Trotman-Dickenson B, Baumert B. Multidetector-row CT Surgery. 1984;96(4):801-5.
of the solitary pulmonary nodule. Semin Roentgenol. 29. Geddes DM. The natural histor y of lung cancer: a
2003;38:158-67. review based on rates of tumour growth. Br J Dis Chest.
15. Harders SW, Madsen HH, Rasmussen TR, Hager H, 1979;73(1):1–17.
Rasmussen F. High resolution spiral CT for determining the 30. Godoy MC, Naidich DP. Overview and strategic management
malignant potential of solitary pulmonary nodules: refining of subsolid pulmonar y nodules. J Thorac Imaging.
and testing the test. Acta Radiol. 2011;52(4):401-9. 2012;27(4):240-8.
16. Kishi K, Homma S, Kurosaki A, et al. Small lung tumors with 31. MacMahon H, Austin JH, Gamsu G, et al. Guidelines for
the size of 1 cm or less in diameter: clinical, radiological management of small pulmonary nodules detected on CT
and histopathological characteristics. Lung Cancer. scans: a statement from the Fleischner Society. Radiology.
2004;44:43-51. 2005;237(2):395-400.
17. Seemann MD, Seemann O, Luboldt W, et al. Differentiation 32. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods
of malignant from benign solitary pulmonary lesions using for staging non-small cell lung cancer: Diagnosis and
chest radiography, spiral CT and HRCT. Lung Cancer. management of lung cancer, 3rd edn: American College
2000;29:105-24. of Chest Physicians evidence-based clinical practice
18. Takashima S, Sone S, Li F, et al. Small solitary pulmonary guidelines. Chest. 2013;143(5 Suppl):e211S-e50S.
nodules (< or =1 cm) detected at population-based CT 33. Fletcher JW, Kymes SM, Gould M, et al. A comparison of
screening for lung cancer: reliable high-resolution CT features
the diagnostic accuracy of 18 F-FDG PET and CT in the
of benign lesions. Am J Roentgenol. 2003;180(4):955-64.
characterization of solitary pulmonary nodules. J Nucl Med.
19. Li F, Sone S, Abe H, Macmahon H, Doi K. Malignant versus
2008;49(2):179-85.
benign nodules at CT screening for lung cancer: comparison
34. Herder GJ, Golding RP, Hoekstra OS, et al. The performance
of thin-section CT findings. Radiology. 2004;233(3):793-8.
of (18)F-fluorodeoxyglucose positron emission tomography
20. Takashima S, Maruyama Y, Hasegawa M, et al. CT findings
in small solitary pulmonary nodules. Eur J Nucl Med Mol
and progression of small peripheral lung neoplasms
Imaging. 2004;31(9):1231-6.
having a replacement growth pattern. Am J Roentgenol.
35. Lindell RM, Hartman TE, Swensen SJ, et al. Lung cancer
2003;180(3):817-26.
screening experience: a retrospective review of PET in 22
21. Gjevre JA, Myers JL, Prakash UB. Pulmonary hamartomas.
non-small cell lung carcinomas detected on screening
Mayo Clin Proc. 1996;71(1):14-20.
chest CT in a highrisk population. Am J Roentgenol.
22. Siegelman SS, Khouri NF, Scott WW Jr, et al. Pulmonary
2005;185(1):126-31.
hamartoma: CT findings. Radiology. 1986;160(2):313-7.
23. Yamashita K, Matsunobe S, Tsuda T, et al. Solitary 36. Lowe VJ, Fletcher JW, Gobar L, et al. Prospective investigation
pulmonary nodule: preliminary study of evaluation with of positron emission tomography in lung nodules. J Clin
incremental dynamic CT. Radiology. 1995;194(2):399-405. Oncol. 1998;16(3):1075-84.
24. Good CA, Wilson TW. The solitary circumscribed pulmonary 36. Dewan NA, Gupta NC, Redepenning LS, Phalen JJ, Frick
nodule; study of seven hundred five cases encountered MP. Diagnostic efficacy of PET-FDG imaging in solitary
roentgenologically in a period of three and one-half years. J pulmonary nodules. Potential role in evaluation and
Am Med Assoc. 1958;166(3):210-5. management. Chest. 1993;104(4):997-1002.
25. Tsubamoto M, Johkoh T, Kozuka T, et al. Coronal multiplanar 37. Fletcher JW. PET scanning and the solitary pulmonary
reconstruction view from whole lung thin-section CT by nodule. Semin Thorac Cardiovasc Surg. 2002;14(3):268-
multidetector-row CT: determination of malignant or benign 74.
lesions and differential diagnosis in 68 cases of solitary 38. Langen KJ, Braun U, Rota Kops E, et al. The influence of
pulmonary nodule. Radiat Med. 2003;21(6):267-71. plasma glucose levels on fluorine-18-fluorodeoxyglucose
26. Kostis WJ, Reeves AP, Yankelevitz DF, Henschke CI. Three- uptake in bronchial carcinomas. J Nucl Med. 1993;34(3):
dimensional segmentation and growth-rate estimation of 355-9.
small pulmonary nodules in helical CT images. IEEE Trans 39. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis
MedImaging. 2003;22(10):1259-74. of lung cancer: diagnosis and management of lung cancer,
27. Xu DM, Gietema H, de Koning H, et al. Nodule management 3rd edn: American College of Chest Physicians evidence-
protocol of the NELSON randomised lung cancer screening based clinical practice guidelines. Chest. 2013;143(5
trial. Lung Cancer. 2006;54(2):177-84. Suppl):e142S-e65S.
40. Westcott JL. Percutaneous transthoracic needle biopsy. 45. Gould MK, Fletcher J, Iannettoni MD, et al. Evaluation of
Radiology. 1988;169(3):593–601. patients with pulmonary nodules: when is it lung cancer?:
41. Wang Memoli JS, Nietert PJ, Silvestri GA. Meta-analysis of ACCP evidence-based clinical practice guidelines, 2nd edn.
guided bronchoscopy for the evaluation of the pulmonary Chest. 2007;132(3 Suppl):108S-30S.
nodule. Chest. 2012;142(2):385-93. 46. Howington JA, Blum MG, Chang AC, Balekian AA, Murthy
42. Gaeta M, Pandolfo I, Volta S, et al. Bronchus sign on CT SC. Treatment of stage I and II non small cell lung
in peripheral carcinoma of the lung: value in predicting cancer: diagnosis and management of lung cancer, 3rd
results of transbronchial biopsy. Am J Roentgenol. edn: American College of Chest Physicians evidence-
1991;157(6):1181-5. based clinical practice guidelines. Chest. 2013;143(5
43. Schreiber G, McCrory DC. Performance characteristics Suppl):e278S-e313S.
of dif ferent modalities for diagnosis of suspected 47. Thanos L, Mylona S, Pomoni M, et al. Percutaneous
lung cancer: summary of published evidence. Chest. radiofrequency thermal ablation of primary and metastatic
2003;123(1 Suppl):115S-28S. lung tumors. Eur J Cardiothorac Surg. 2006;30:797-800,
44. Cardillo G, Regal M, Sera F, et al. Videothoracoscopic 48. Ost D, Fein A. Management strategies for the solitary
management of the solitar y pulmonar y nodule: a pulmonary nodule. Curr Opin Pulm Med. 2004;10(4):272-8.
single-institution study on 429 cases. Ann Thorac Surg.
2003;75(5):1607-11.
CHAPTER
85
Challenges in the Management of CAP
Prashant Prakash, Akhilesh Kumar Singh
INTRODUCTION > 37.7°C, chills, and rigors, and/or severe malaise); and
A number of international guidelines for community (c) new focal chest signs on examination (bronchial
acquired pneuomonia (CAP) are available which include breath sounds and/or crackles); with (d) no other
the Infectious Disease Society of America (IDSA), explanation for the illness.2
American Thoracic Society (ATS), British Thoracic When a chest radiograph is available, CAP is defined
Society (BTS), and European Respiratory Society (ERS) as: symptoms and signs as above with new radiographic
guidelines. In this context a need for Indian Guidelines shadowing for which there is no other explanation (not
on Management of Pneumonia seem to be the need of due to pulmonary edema or infarction).2 Radiographic
the hour. shadowing may be seen in the form of a lobar or patchy
The process of Indian/National pneumonia consolidation, loss of a normal diaphragmatic, cardiac or
guidelines development was undertaken as a joint mediastinal silhouette, interstitial infiltrates, or bilateral
exercise by the Department of Pulmonary Medicine, perihilar opacities, with no other obvious cause.
Postgraduate Institute of Medical Education and
Research, Chandigarh, with sponsorship from two
EPIDEMIOLOGY AND ETIOLOGY
National Pulmonary Associations (Indian Chest Society Epidemiology of CAP in India
and National College of Chest Physicians) and this was Around 20% of the mortality due to infectious diseases in
published in 2012.1 In this chapter, we will be reviewing India is caused by lower respiratory tract infections. The
the challenges in the management of CAP with emphasis mortality in India has been variably reported between
on International Guidelines and with special reference to 3.3% and 11% in other studies.1
Indian/National guidelines.
Etiology of CAP Worldwide
DEFINITION OF CAP A microbiological diagn osis could be made in only
CAP can be defined both on clinical and radiographic 40–71% of cases of CAP. 1 A list of etiological agents
findings. In the absence of chest radiograph, CAP is responsible for CAP has been outlined in Table 1.3
defined as: (a) symptoms of an acute lower respiratory
tract illness (cough with or without expectoration, DIAGNOSIS OF CAP
shortness of breath, pleuritic chest pain) for less than 1 The algorithmic approach to diagnosis and management
week; and (b) at least one systemic feature (temperature of CAP is outlined in Figure 1.1
TABLE 1: Pathogens associated with community-acquired radiographic resolution at 4 weeks. Radiographic

pneumonia3 resolution may be delayed in the elderly. Patients with
Relative frequency (%) radiologic deterioration would almost always have
Streptococcus pneumoniae 35–80% one or the other clinical feature suggestive of clinical
Haemophilus influenzae 5–6% failure (persistent fever, abnormal auscultatory findings,
Atypical pathogens or persistent tachypnea). In the presence of such
- Legionella spp* 2–15% clinical indicators, it becomes essential to obtain a chest
- Mycoplasma pneumoniae 2–14% radiograph. Lack of partial radiographic resolution by
- Chlamydophila spp.ŧ 4–15% 6 weeks, even in asymptomatic patients, would require
ǂ
Staphylococcus aureus 3–14%
consideration of alternative causes (e.g. endobronchial
Enteric Gram-negative bacilli** 6–12%
obstruction or noninfectious causes like pulmonary
Pseudomonas aeruginosa# 4–9%
vasculitis, organizing pneumonia, and others).1
Coxiella burnetii 2–4%
Moraxella catarrhalis <1% Role of Computed Tomography in the
Influenza A virus 10–15%
Diagnosis of CAP
Other viruses@ 5–10%
High-resolution CT (HRCT) findings of CAP include
Mycobacterium tuberculosis! Less than 1–5%
air space consolidation, ground-glass attenuation, and
Unknown 15–40%
thickening of the bronchovascular bundle. Centrilobular
* Vary in importance between countries; more than 95% are L.
nodules favored nonbacterial pneumonia, while airspace
pneumophila serogroup 1; outbreaks are common.
ŧ
More than 99% due to Chlamydophila pneumoniae in adults. nodules were more common with bacterial pneumonia
ǂ
Increasing in areas with high prevalence of community-acquired (specificities of 89% and 94%, respectively) when located
methicillin-resistant S. aureus. in the outer lung areas. 4 When centrilobular nodules
** Main species associated with CAP are Escherichia coli and Klebsiella
pneumoniae.
were the principal finding, they were specific but lacked
#
Risk factors include chronic steroid therapy, structural lung disease, sensitivity for nonbacterial pneumonia (specificity 98%
previous hospitalization. and sensitivity 23%). CT chest may, however, be useful
@
lncluding respiratory syncytial virus, adenovirus, parainfluenza virus,
in the diagnosis of complications of pneumonia like lung
metapneumovirus, varicella-zoster virus, measles and hanta virus.
!
Relative frequency varies considerably in different parts of the world. abscess and empyema. CT of the thorax should not be
performed routinely in patients with CAP as per National
Pneumonia Guidelines.1
Clinical Features of CAP
Common symptoms of CAP include fever, cough, ROLE OF MICROBIOLOGICAL
sputum production, dyspnea, and pleuritic chest pain. INVESTIGATIONS IN CAP
Physical examination may reveal focal areas of bronchial
breathing and crackles. Respiratory and nonrespiratory
Blood Cultures
symptoms associated with a pneumonic illness are less Blood cultures have a low sensitivity but high specificity
commonly reported by older patients with pneumonia.1 in identifying the microbial etiology.
Recommendations (as per National Pneumonia
Role of Chest Radiography in Guidelines)1
Diagnosis of CAP Blood cultures should be obtained in all hospitalized
A chest radiograph is the cornerstone for the diagnosis patients with CAP.
of CAP. 1 Importantly, resolution of chest radiograph
findings may lag behind clinical cure during follow- Sputum Gram Stain and Cultures
up, and upto 50% of patients may not show complete The yield of sputum cultures varies from 34% to 86%.
CHAPTER 85: Challenges in the Management of CAP 527
Fig. 1: Algorithmic approach to diagnosis and management of CAP1

Abbreviations: ARDS, acute respiratory distress syndrome; CXR, chest radiograph;
ICU, intensive care unit; LFTs, liver function tests; SaO2, arterial saturation
Recommendations (as per National Pneumonia Pneumococcal Antigen and PCR Detection
Guidelines)1 Pneumococcal antigen can be detected in the urine using
An initial sputum Gram stain and culture (or an
proprietary rapid immunochromatographic membrane
invasive respiratory sample as appropriate) should be tests. Pneumococcal PCR has a poor sensitivity.
obtained in all hospitalized patients with CAP.
Sputum quality should be ensured for interpreting Recommendations (as per National Pneumonia
Gram stain results. Guidelines)1
Sputum for acid-fast bacilli (AFB) should be obtained Pneumococcal antigen detection test is not required
as per RNTCP guidelines for nonresponders. routinely for the management of CAP.
Pneumococcal PCR is not recommended as a routine Role of Biomarkers in CAP

diagnostic test in patients with CAP. CAP can occasionally be confused with pulmonary
edema or pulmonary embolism. Also, it is difficult
Legionella Antigen Detection to differentiate CAP of viral etiology from that of
Legionella is an important causative agent of CAP in bacterial etiology. Biomarkers like procalcitonin (PCT)
India. As the sensitivity is relatively low, a negative test and C-reactive protein (CRP) may be of some value
does not rule out the possibility of Legionella pneumonia. in resolving these issues. PCT levels rise in many
A positive test is highly specific and potentially changes inflammatory conditions and more so in bacterial
the duration of antibiotic therapy.
infections.1 As PCT is not a marker of early infection
Recommendations (as per National Pneumonia (increases after 6 h), a single value may be falsely low and
Guidelines)1 serial values should be obtained to guide antibiotic use
Legionella urinary antigen test is desirable in patients in the course of a suspected infective illness.
with severe CAP.
Guidelines)1
Other Atypical Pathogens
Procalcitonin (PCT) and C-reactive protein (CRP)
Mycoplasma, Chlamydia, and respiratory viruses
measurement need not be performed as routine
are important etiological agents of pneumonia. If
investigations for the diagnosis of CAP.
Legionella, M. pneumoniae, and C. pneumoniae are
considered, only Legionella spp. are associated with
Risk Stratification in CAP
significant mortality. Due to empiric coverage and a
There are various scores for assessing the risk in a patient
widely favorable outcome for atypical agents, testing
with CAP: pneumonia severity index (PSI), CURB-65,
for Mycoplasma and Chlamydia in patients with mild
to moderate CAP might not be required. Besides, there CRB-65, SMART-COP, SMRT-CO, A-DROP, and others.
are no well-validated rapid tests for Mycoplasma and Some of these scoring systems are outlined in Table 2.1
Chlamydia. Although serological and PCR-based tests Among these severity assessment scales, the CRB 65 is
are available for respiratory viruses, they seldom have the only tool that can be applied to outpatients as well.5
any bearing on the management of the patient from CURB-65 was, however, found to be less useful in the age
influenza. Reverse transcriptase PCR (RT-PCR) is a rapid group >65 years compared those below 65 years.
and accurate method for the detection of influenza virus In the Indian context, Shah et al., found that both
infection, but is not routinely required except in the PSI and CURB 65 had equal sensitivity in predicting the
setting of an outbreak.1 risk of death from CAP. The PSI was more sensitive in
predicting ICU admission than CURB 65, although the
latter had better overall specificity.6 The CURB-65 and
Guidelines)1
CRB-65 scores are not as extensively validated as the PSI;
Investigations for atypical pathogens like Mycoplasma,
however, they are recommended by most societies for
Chlamydia, and viruses need not be routinely done.
the initial assessment and risk stratification of CAP.2,7
ATS-IDSA criteria are helpful in deciding the level
GENERAL INVESTIGATIONS AND
of care (ward vs. ICU) once the admission decision has
RISK STRATIFICATION REQUIRED IN
been made. There are two major and nine minor criteria,
PATIENTS WITH CAP and the presence of any of the major criteria or at least
General Investigations in CAP three of the minor criteria qualifies for an ICU admission
These are outlined in Figure 1.1 (Table 2).7
TABLE 2: Summary of commonly used criteria for risk stratification in CAP1

CURB-65 CRB-65 SMART-COP SMRT-CO ATS-IDSA criteria
Confusion Confusion Low systolic blood Low systolic blood zz Major criteria
Urea ≥7 mmol/L Respiratory rate ≥30/min pressure (<90 mm Hg) pressure (<90 mm Hg) —— Invasive mechanical
Respiratory rate Low blood pressure Multilobar CXR Multilobar CXR ventilation
≥30/min (diastolic blood pressure involvement involvement —— Septic shock with the need
Low blood ≤60 mm Hg or systolic Low albumin (<3.5 g/dL) Respiratory rate (≥25/min) for vasopressors
pressure (diastolic blood pressure ≤90 mm Respiratory rate (≥25/min) Tachycardia (≥125/min) zz Minor criteria
blood pressure Hg) Tachycardia (≥125/min) Confusion —— Respiratory rate
≤60 mm Hg or Age ≥65 years Confusion Poor oxygenation (PaO2 ≥30 breaths/min
systolic blood Poor oxygenation (PaO2 <70 mm Hg; SpO2 <93%) —— PaO /FiO ratio ≤250
2 2
pressure ≤90 mm <70 mm Hg; SpO2 <93%) —— Multilobar infiltrates
Hg) Low pH (<7.35) —— Confusion/disorientation
Age ≥65 years —— Uremia (BUN level
≥20 mg/dL)
—— Leukopenia (WBC count
<4000 cells/mm3)
—— Thrombocytopenia (platelet
count <100,000 cells/ mm3)

—— Hypothermia (core
temperature <36°C)
Recommendations (as per National Pneumonia TABLE 3: Indications for empiric combination therapy in CAP7
Guidelines)1 Presence of comorbid medical conditions
Risk stratification should be performed in two steps
Chronic heart, lung, liver, or renal disease
(Fig. 1) based upon the need for hospital admission
Diabetes mellitus
followed by assessment of the site of admission
(nonICU vs. ICU). Accordingly, patients can be Alcoholism
managed as either outpatient or inpatient (ward or Malignancies

ICU). Use of antimicrobials within the previous 3 months
Initial assessment should be done with CRB-65. If
Severe CAP with or without comorbidities
the score is >1, patients should be considered for
admission. Outpatients should be stratified as those with or
Patients selected for admission can be triaged to the
without comorbidities.
ward (nonICU)/ICU based upon the major/minor Recommended antibiotics are oral macrolides (e.g.
criteria outlined in Table 2 (ATS-IDSA criteria).
azithromycin and others) or oral β-lactams (e.g.
If any major criterion or ≥3 minor criteria are fulfilled,
amoxicillin 500–1000 mg thrice daily) for out patients
patients should generally be admitted to the ICU.
without comorbidities.
For outpatients with comorbidities (Table 3),7 oral
ANTIMICROBIAL THERAPY IN CAP

combination therapy is recommended (β-lactams

Antimicrobial Therapy in plus macrolides).
Outpatient Setting There is insufficient evidence to recommend tetra
Recommendations (as per National Pneumonia cyclines.
Guidelines)1 Fluoroquinolones should not be used for empiric
Therapy should be targeted toward coverage of the treatment.
most common organism, namely Streptococcus Antibiotics should be given in appropriate doses to
pneumoniae. prevent emergence of resistance.
Antimicrobial Therapy in Inpatients, TABLE 4: Doses of drugs used in CAP1
NonICU Drug Doses

Recommendations (as per National Pneumonia Amoxicillin 0.5–1 g thrice daily (PO or IV)
Guidelines)1 Co-amoxiclav 625 mg thrice a day to 1 g twice daily (PO)/1.2 g
The recommended regimen is combination of a
thrice daily (IV)
Azithromycin 500 mg daily (PO or IV)
β-lactam plus a macrolide (preferred β-lactams
Ceftriaxone 1–2 g twice daily (IV)
include cefotaxime, ceftriaxone, and amoxicillin–
clavulanic acid). Cefotaxime 1 g thrice daily (IV)
In the uncommon scenario of hypersensitivity
Cefepime 1–2 g two to three times a day (IV)
to β-lactams, respiratory fluoroquinolones (e.g. Ceftazidime 2 g thrice daily (IV)
levofloxacin 750 mg daily) may be used if tuberculosis Piperacillin- 4.5 g four times a day (IV)
tazobactam
is not a diagnostic consideration at admission.
Imipenem 0.5–1 g three to four times a day (IV)
Patients should also undergo sputum testing for acid-
Meropenem 1 g thrice daily (IV)
fast bacilli simultaneously if fluoroquinolones are
being used in place of β-lactams.
Route of administration (oral or parenteral) should
Diagnostic/therapeutic interventions should be
be decided based upon the clinical condition of done for complications, e.g. thoracentesis, chest tube
the patient and the treating physician’s judgment drainage, etc. as required.
If a patient does not respond to treatment within 48–
regarding tolerance and efficacy of the chosen
antibiotics. 72 h, he/she should be evaluated for the cause of non-
response, including development of complications,
Antimicrobial Therapy in Inpatients, ICU presence of atypical pathogens, drug resistance, etc.
Recommendations (as per National Pneumonia The doses of antimicrobial drugs used in various
Guidelines)1 settings of CAP are outlined in Table 4.1
The recommended regimen is a β-lactam (cefotaxime,
ceftriaxone, or amoxicillin–clavulanic acid) plus Antimicrobial Therapy for CAP According

a macrolide for patients without risk factors for P to International Guidelines
aeruginosa.
The IDSA/ATS consensus guidelines (2007) 7 and
If P. aeruginosa is an etiological consideration, an
the British Thoracic Society guidelines (2009) 2 for
antipneumococcal, antipseudomonal antibiotic (e.g.
antimicrobial therapy in CAP are summarised in
cefepime, ceftazidime, cefoperazone, piperacillin–
Table 5.2,7
tazobactam, cefoperazone–sulbactam, imipenem, or
meropenem) should be used. Combination therapy
may be considered with addition of aminoglycosides/ Treatment Protocol for Antimicrobial
antipseudomonal fluoroquinolones (e.g. cipro Therapy in CAP
floxacin). Fluoroquinolones may be used if Recommendations (as per National Pneumonia
tuberculosis is not a diagnostic consideration at Guidelines)1
admission. Patients should also undergo sputum Switch to oral from intravenous therapy is safe after
testing for acid-fast bacilli simultaneously if clinical improvement in moderate to severe CAP.
fluoroquinolones are being used. Patients can be considered for discharge if
Antimicrobial therapy should be changed according they start accepting orally, are afebrile, and are
to the specific pathogen(s) isolated. hemodynamically stable for a period of at least 48 h.
TABLE 5: International guidelines for the management of pneumonia (CAP)2,7

Outpatient Inpatient (nonICU) Inpatient (ICU)
IDSA/ATS consensus zz Healthy with no use of A respiratory fluoroquinolone zz A β-lactam (cefotaxime, ceftriaxone
guidelines (2007)7 antimicrobials in the previous 3 or a β-lactam plus a macrolide or ampicillin-sulbactam) plus
months: Macrolides or doxycycline azithromycin/a respiratory
zz Comorbidities including chronic fluoroquinolone
heart, lung, liver or renal disease; zz If pseudomonas is suspected: An
diabetes; alcoholism; malignancy; antipneumococcal, antipseudomonal

immunosuppressed state; use of β-lactam (piperacillin-tazobactam,
antimicrobials in the previous 3 cefepime, meropenem or imipenem)
months or in areas with high rate of plus ciprofloxacin or levofloxacin or
infection with high level macrolide Above β-lactam plus aminoglycoside
resistant Streptococcus pneumoniae: and azithromycin or
A respiratory fluoroquinolone or a zz Above β-lactam plus aminoglycoside
β-lactam plus a macrolide and antipneumococcal

fluoroquinolones
zz If MRSA is suspected: Add vancomycin
or linezolid
BTS guidelines Amoxicillin 500–1000 mg thrice a day zz If oral therapy possible: Co-amoxiclav plus clarithromycin (plus
(October 2009)2 or clarithromycin/erythromycin or Amoxicillin plus levofloxacin if legionella is suspected)
doxycycline clarithromycin or or
Doxycycline or Levofloxacin Cefuroxime/cefotaxime/ceftriaxone
or Moxifloxacin plus clarithromycin (plus levofloxacin if
zz If oral therapy not legionella is suspected)
possible: IV amoxicillin or
or benzylpenicillin plus Benzylpenicillin plus levofloxacin/
clarithromycin or IV ciprofloxacin
levofloxacin
Outpatients should be treated for 5 days and in There is no role of other adjunctive therapies
patients for 7 days. (anticoagul ants, immunoglobulin, granulocyte
Antibiotics may be continued beyond this period in colony-stimulating factor, statins, probiotics, chest
patients with bacteremic pneumococcal pneumonia, physiotherapy, antiplatelet drugs, over-the-counter
Staphylococcus aureus pneumonia, and CAP cough medications, β2 agonists, inhaled nitric oxide,
caused by Legionella pneumoniae and nonlactose- and angiotensin-converting enzyme inhibitors) in
fermenting Gram-negative bacilli. Antibiotics may the routine management of CAP.
also be continued beyond the specified period in CAP-ARDS and CAP leading to sepsis and septic
those with meningitis or endocarditis complicating shock should be managed according to the standard
pneumonia, infections with enteric Gram-negative management protocols for these conditions.
bacilli, lung abscess, empyema, and if the initial Noninvasive ventilation may be used in patients with
therapy was not active against the identified pathogen. CAP and acute respiratory failure.
Adjunctive Therapies in CAP Role of Immunization in CAP

Recommendations (as per National Pneumonia Most guidelines recommend immunization with
Guidelines)1 pneumococcal and seasonal influenza vaccines for
Steroids are not recommended for use in nonsevere specific groups. 2,7 However, the adult immunization
CAP. guidelines promulgated by the Association of Physicians
Steroids should be used for septic shock or in in India do not recommend the use of these vaccines on
ARDS secondary to CAP according to the prevalent a routine basis.8 Currently, two pneumococcal vaccines
management protocols for these conditions. are commercially available, namely the polyvalent
TABLE 6: High-risk groups in whom vaccination is recommended7 is not recommended. Pneumococcal vaccine may
Pneumococcal disease be considered for prevention of CAP in special
zz Chronic cardiovascular, pulmonary, renal, or liver disease
zz Diabetes mellitus
populations who are at high risk for invasive pneumo
zz Cerebrospinal fluid leaks coccal disease (Table 6).7
zz Alcoholism
Influenza vaccination should be considered in adults
zz Asplenia
zz Immunocompromising conditions/medications for prevention of CAP.

Influenza Smoking cessation should be advised for all current
zz Chronic cardiovascular or pulmonary disease (including asthma)
zz Chronic metabolic disease (including diabetes mellitus)

smokers.
zz Renal dysfunction
zz Hemoglobinopathies
REFERENCES
zz Immunocompromising conditions/medications
zz Compromised respiratory function or increased aspiration risk

1. Gupta D, Agarwal R, Aggarwal AN, Singh N, Mishra N,
Khilnani GC, et al. Guidelines for diagnosis and management
of community- and hospital-acquired pneumonia in adults:
polysaccharide vaccine (PPV), used predominantly in Joint ICS/NCCP(1) recommendations. Lung India. 2012;
adults and the pneumococcal conjugate vaccine (PCV), 29(Suppl 2):S27-62.
used predominantly in children.9 2. Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C,
PCVs have undergone progressive improvement, Le Jeune I, et al. BTS guidelines for the management of
especially in respect of extended coverage against the community acquired pneumonia in adults: update 2009.
most prevalent and virulent pneumococcal serotypes, Thorax. 2009;64(Suppl 3):iii1-55.
with PCV13 the current leader. Acquisition of this 3. Garau J, Calbo E. Community-acquired pneumonia. Lancet.
2008;371(9611):455-8.
vaccine together with an appreciation of the limitations
4. Ito I, Ishida T, Togashi K, Niimi A, Koyama H, Ishimori T, et
of PPVs, of which PPV23 is the prototype, have resulted
al. Differentiation of bacterial and non-bacterial community-
in updated immunization recommendations. In the acquired pneumonia by thin-section computed tomography.
case of infants and very young children, PCV13 has now Eur J Radiol. 2009;72:388-95.
been included in the National Immunization Programs 5. Ewigs S, Torres A, Woodhead M. Assessment of pneumonia
of many developed and developing countries. With severity: A European perspective. Eur Respir J. 2006;27:6-8.
respect to adults, PCV13 vaccination as a single dose is 6. Shah BA, Ahmed W, Dhobi GN, Shah NN, Khursheed SQ,
recommended by the Food and Drug Administration of Haq I. Validity of pneumonia severity index and CURB-65
the USA for adults aged more than or equal to 50 years, severity scoring systems in community acquired pneumonia
in an Indian setting. Indian J Chest Dis Allied Sci. 2010;52:
while in the case of those aged more than 19 years who
9-17.
have immunocompromising conditions, including HIV
7. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell
infection, a “prime-boost” strategy is recommended for
GD, Dean NC, et al. Infectious Diseases Society of America/
vaccine-naive recipients. This is based on an initial dose American Thoracic Society consensus guidelines on the
of PCV13, followed atleast 8 weeks later by a single dose management of community-acquired pneumonia in adults.
of PPV23, with variations in schedules according to prior Clin Infect Dis. 2007;44(Suppl 2):S27-72.
vaccination and/or the circulating CD4+ T-cell count in 8. India EGotAoPoloAli. The Association of Physicians of
case of HIV infection.9 India evidence-based clinical practice guidelines on adult
immunization. J Assoc Physicians India. 2009;57:345-56.
Recommendations (as per National Pneumonia 9. Feldman C, Anderson R. Community-acquired Pneumonia.
Guidelines)1 In: Jindal SK, 2nd Ed. Text Book of Pulmonary & Critical Care
Routine use of pneumococcal vaccine among healthy Medicine. New Delhi: Jaypee Publications. 2017. pp. 591-
immunocompetent adults for prevention of CAP 607.
CHAPTER
86
Air Pollution and its Health Impact
Vishal Chopra, Prabhleen Kaur, Siddharth Chopra
INTRODUCTION mainly through inhalation and ingestion. Elimination

Air pollution is a well-known risk factor causing human is mainly through excretion. Many studies have
ill health. Health effects of air pollution remain a major shown that air pollution increase the mortality and
public health problem in both the developed and hospital admissions. The systems mainly affected are
developing countries and has both acute and chronic cardiovascular and respiratory. The health effects are
effects on human health affecting many of different vast and can cause nausea and difficulty in breathing
human systems. Climatic change may affect air pollution or skin irritation, cardiac morbidity and cancers. Birth
levels in many different ways. It appears to induce an defects, serious developmental abnormalities, delayed
increase concentration of all health related air pollutants milestones and decreased activity of immune system can
especially potential changes in tropospheric ozone and be attributed to pollution. There are several susceptibility
particulate matter. factors such as age, nutritional status and predisposing
According to WHO report in 2012, 3.7 million deaths conditions. Health effects can be differentiated into
were attributed to ambient air pollution globally which acute, chronic not including cancer and cancerous.
tripled since 2008.1 India ranks 10th in global levels of
ambient particulate matter (PM) with an annual average MECHANISMS LEADING TO
PM10 of 134 μg/m3. Indian cities are listed among the HEALTH EFFECTS
100 most polluted cities worldwide.2 WHO estimates Health impact of the pollutant depend on its type,
that 7 million deaths worldwide are attributable to air concentration, length of exposure, other coexisting
pollution. 3 WHO focuses on four health-related air pollutants and individual susceptibility. Production
pollutants, namely, particulate matter (PM), measured of oxidative stress, free radicals and induction of
as particles with an aerodynamic diameter lesser than inflammatory responses are the various mechanisms
10 μm (PM10) and lesser than 2.5 μm (PM2.5), nitrogen which causes the harmful effects of air pollutants. 8
dioxide, sulfur dioxide and ozone. 4 The WHO report Reactive oxygen free radicals and nitrogen inhibits the
is only one of many reports that have documented the normal function of cellular lipids, proteins and nuclear
problem of the health effects of air pollution in many or mitochondrial DNA. Free radicals are normally
countries.5-7 generated in response to exogenous environmental
Air pollutant can be any substance which harms exposures. It is only when the concentration of free
humans and animals. The entry of various pollutants is radicals increases.
TYPES OF POLLUTANTS 1 mm. The size of the particles determines the site in
1. Gaseous pollutants are produced mainly due to the respiratory tract in which they will deposit. Coarse
combustion of fossil fuels contribute to a great particles deposit mainly in the upper respiratory tract
extent in composition variations of the atmosphere. while fine and ultra fine particles are able to reach
Nitrogen oxides are emitted as NO which reacts with till lung alveoli. The major components of PM are
ozone or radicals in the atmosphere forming NO2. metals, organic compounds, material of biologic
Ozone is formed by a series of reactions involving NO2 origin, ions, reactive gases, and the particle carbon
and volatile organic compounds, a process initiated core in varying composition. There is strong evidence
by sunlight. CO, on the other hand, is a product to support that ultra fine and fine particles are more
of incomplete combustion and its major source is hazardous than coarse particles, in terms of mortality
road transport. SO2 results from the combustion of and cardiovascular and respiratory effects.
sulphur-containing fossil fuels like coal and heavy
oils and the smelting of sulphur containing ores, EFFECTS OF AIR POLLUTION ON
volcanoes and oceans are its major natural sources. DIFFERENT ORGANS
Volatile organic compounds (VOCs) includes
Respiratory System
chemical species of organic nature such as benzene.
Many studies have described the effects of short term
They fuel combustion and especially combustion
exposure to higher concentration and long term exposure
processes for energy production and its major
to lower concentration of air pollutants on respiratory
sources are road transport.
system and airways. Nasal congestion, throat irritation,
2. Persistent organic pollutants are toxic group of
bronchoconstriction and dyspnea are known to occur
chemicals which persist in the environment for long
after exposure to especially to higher levels of SO2, NO2
periods of time, and as they move through the food
chain their effects are magnified, a process known as and heavy metals. Particulate matter has shown to
biomagnification. They include pesticides, dioxins, increase the lung inflammation which deteriorates the
furans and PCBs. Dioxins are produced during disease. Respiratory infections both bacterial and viral
incomplete combustion and whenever materials are shown to increase. Patients having asthma or COPD
containing chlorine (plastics) are burned. deteriorate in lung functions during increased pollution.
3. Heavy metals include lead, mercury, cadmium, silver Long term exposure to heavy metals is also known to
nickel, vanadium, chromium and manganese, are cause lung cancer.
natural components of the earth’s crust. They cannot
be degraded or destroyed, and can be transported by Cardiovascular System
air, and can enter water and human food supply. They Systemic inflammatory changes are known to occur
tend to bio-accumulate in the human body which in patients people exposed to increased particulate
means an increase in the concentration of a chemical matter. Lung inflammation can lead to changes in blood
in a biological organism over time, compared to the coagulation which can lead to clotting in coronary vessels
chemical’s concentration in the environment. causing angina and myocardial infarction. Increased
4. Particulate matter major sources are factories, carbon monoxide concentration binds to hemoglobin
power plants, refuse incinerators, motor vehicles, reducing the transfer of oxygen to all organs leading to
construction activity, fires, and natural windblown impaired concentration, slow reflexes and confusion.
dust, etc. Different categories of particles are defined Heavy metals cause tachycardia, increased blood
based on the particle size: Ultrafine particles, smaller pressure and anemia. The mortality due to ischemic
than 0.1 mm in aerodynamic diameter, fine particles, heart disease is shown to increase due to exposure to
smaller than 1 mm, and coarse particles, larger than organic pollutant.
CHAPTER 86: Air Pollution and its Health Impact 535
Nervous System further vehicular pollution, the Ministry of Petroleum

Nervous system is also affected by heavy metals and and Natural Gas (MoPNG) has adopted the Auto Fuel
dioxins which causes neurotoxicity. Neurotoxicity Policy in 2002 which gave a roadmap for introduction
leads to neuropathies, with symptoms such as memory of cleaner fuels and vehicles in the country upto 2010.
disturbances, sleep disorders, anger, fatigue, hand Auto Fuel Vision Committee was also set up in 2013
tremors, blurred vision, and slurred speech. These have to form the future roadmap on advancement of fuel
been observed after arsenic, lead and mercury exposure. quality and vehicular emission standards upto 2025.
Government has introduced various schemes such as
Gastrointestinal System the Rajiv Gandhi Grameen Vidyutikaran Yojana, the
Dioxins induce liver cell damage as the enzymes in the Village Energy Security Programme, and the Remote
blood are seen to increase. Village Electrification Programme that would facilitate
Gastrointestinal and liver cancer are also known to clean energy use. The Ministry of New and Renewable
increase.9 Energy (MNRE) is promoting setting up of biogas plants
in all the states of the country.10 The participation of the
Effects on Pregnancy community as the whole will probably help in reducing
Both animal and human epidemiological studies the morbidity and mortality of this otherwise avoidable
support the idea that air pollutants cause defects problem.
during gametogenesis leading to a drop in reproductive
capacities in exposed populations. Maternal exposure to REFERENCES
heavy metals like lead, increases the risks of spontaneous 1. Jiang X-Q, Mei X-D, Feng D. Air pollution and chronic airway
diseases: what should people know and do? J Thorac Dis.
abortion and reduced fetal growth, congenital
2016;8(1):E31-40.
malformations,10 and lesions of the developing nervous 2. WHO | Database: outdoor air pollution in cities. World
system. It can lead to impairment in newborn’s motor Health Organization.
and cognitive abilities. 3. WHO | 7 million premature deaths annually linked to air
pollution. WHO. World Health Organization; 2014.
Urinary System 4. TERI. Air Pollution and Health. Discussion Paper by The
Energy and Resources Institute: New Delhi. 2015.
Kidney damage such as tubular dysfunction, evidenced
5. Rice MB, Rifas-Shiman SL, Litonjua AA, Oken E, Gillman
by an increased excretion of low molecular weight MW, Kloog I, et al. Lifetime exposure to ambient pollution
proteins is caused by heavy metals which progresses to and lung function in children. Am J Respir Crit Care Med.
decreased glomerular filtration rate (GFR). 2016;193(8):881-8.
6. Schultz ES, Hallberg J, Bellander T, Bergström A, Bottai
Psychiatry M, Chiesa F, et al. Early-life exposure to traffic-related air
pollution and lung function in adolescence. Am J Respir Crit
Cardiopulmonary effects of air pollution have been well
Care Med. 2016;193(2):171-7.
established, growing concern have focused its effects 7. HEI International Oversight Committee. Outdoor Air
on mental health. Several studies have examined the Pollution and Health in the Developing Countries of Asia:
association between exposure to ambient particulate A Comprehensive Review. Special Report 18. Boston, US;
matter with aerodynamic diameter = 2.5 micronmeter 2010.
and depressive symptoms. 8. Kampa M, Castanas E. Human health effects of air
pollution. Environ Pollut. 2008;151(2):362-7.
To improve air quality and reduce the burden of
9. Mandal PK. Dioxin: a review of its environmental effects
diseases, several interventions have been adopted in
and its aryl hydrocarbon receptor biology. J Comp Physiol B.
India. In order to reduce vehicular pollution, CPCB 2005;175(4):221-30.
set vehicular emission standards in India in 1986 10. Bellinger DC. Teratogen update: lead and pregnancy. Birth
which were later revised in 1987 and 1989. To control Defects Res A Clin Mol Teratol. 2005;73(6):409-20.
SECTION
8
Infections
Infections Causing Cancer Pyrexia of Unknown Origin: Current Concept
Anupam Dey SV Ramana Murty, Chakravarthy DJK
Transfusion Transmitted Infection Approach to a Patient of Meningitis
Apu Adhikary, Tuhin Santra Sanjiv Maheshwari, Vijay Prakash Hawa
Arboviral Infections: Is Effective Leptospirosis: What We Should Know?
Vaccination a Possible Solution? Shantanu Kumar Kar, Paluru Vijayachari,
Ashok Kumar, Shubha Laxmi Margekar, Jayant Kumar Panda
Venugopal Margekar
Kala-azar Elimination in India
MDR-TB and XDR-TB: What are the Options? Shyam Sundar
Bidita Khandelwal
Sickle Cell Crisis: How to go Forward?
Acute Encephalitis: Indian Scenario Srikant Kumar Dhar
Do Not Rash When Fever Coincides with Rash
Tropical Fever: A Case-based Approach Sriprasad Mohanty
Disseminated Intravascular Coagulation:
Vivax Malaria: No Longer Benign! Management Updates
K Nagesh Puneet Saxena, Aradhna Sharma, Madhulata Agarwal,
Sher Singh Dariya, Hitesh Sharma
Newer Modalities in Diagnosis of Tuberculosis
Prem Parkash Gupta Adult Immunization: Current Scenario in India
Resurgence of Yellow Fever: A Great Challenge
Rajib Ratna Chaudhary H1N1 Influenza: 9 Years’ Journey in Gujarat
Asha N Shah
Complicated Dengue
Rajeev Gupta Ebola
Scrub Typhus: Need for Alert
CHAPTER
87
Infections Causing Cancer
Anupam Dey
INTRODUCTION of cell damage can promote neoplasia (Indirect

oncogenesis).
Infection associated cancer are known to account for
2. Inhibition of tumor suppressor genes by oncogenic
about 15–20% of cancer incidence around the world. The
viruses which insert oncogenes in the host (e.g.
International Agency for Research on Cancer (WHO) in
Epstein-Barr virus) (Direct oncogenesis).
2012 stated that infections cause one in six of all cancers
3. Decreased and altered immunosur veillance
around the world and about 2 million (16.1%) of the
secondary to chronic infection and immuno
total 12.7 million new cancer cases were attributable to
suppression (e.g. HIV virus).
infections. Prevalence is higher in developing countries
Cancer viruses have been studied in detail and they
(about 32.7% in sub-Saharan Africa). Advances in
give us an important view on causation theory. It is
molecular biology has helped us understand the process
interesting to note that cancers are not a fundamental
of carcinogenesis and thrown light on the association
part of the life cycles of cancer viruses and tumors occur
of infectious agents with cancer. In 1911, Rous was the
only in a small proportion of infected individuals who
first person to show the association of cancer with an
have multiple coexistent factors such as gene mutations
infectious agent. Sir Anthony Epstein, Bert Achong and
or immune suppression together with infection. Multiple
Yvonne Barr are credited with discovering the first tumor
oncogenic hits (e.g., due to dietary factors, smoking,
virus in humans (later named as Epstein Barr virus)
exposure to environmental oncogenic agents, etc.) are
from African patients with Burkitt’s lymphoma. Tumor
necessary for full-blown transformation. Commensal
formation occurs by a complex multistage process and as
viruses can also cause cancers like EBV and MCV (Merkel
a result of successive genetic changes.
cell polyomavirus). It is difficult to apply Henle Koch’s
criteria for establishing causality as regards the cancer
PATHOGENESIS causing microbial agents, because of multifactorial
Infections can play a role in carcinogenesis by any of these nature of pathogenesis.
three mechanisms:
1. Chronic inflammation by persistence of the agent INTERNATIONAL AGENCY FOR
in the host (e.g. Hepatitis C virus, Helicobacter RESEARCH ON CANCER (WHO)
pylori) releases free radicals thereby damaging DNA, CLASSIFICATION
proteins, cell membranes, and alters gene expression The International Agency for Research on Cancer (IARC)
which can induce carcinogenesis. Repeated cycles has over the time published monographs classifying
540 SECTION 8: Infections
TABLE 1: Groups of association Pathogenesis involves chronic liver injury due to

Group 1 Carcinogenic to humans oxidative stress and subsequent transformation to HCC.
Group 2A Probably carcinogenic to humans
Group 2B Possibly carcinogenic to humans Human T-Lymphotropic Virus Type 1
Group 3 Not classifiable It is a direct carcinogenic agent which causes malignant
Group 4 Probably not carcinogenic to humans transformation by insertional mutagenesis. Tax
oncoprotein is the major agent which inhibits DNA
agents on the basis of their carcinogenic potential in repair. The virus is transmitted by sexual, intravenous
humans. It was last updated in July 2017. The association and breast feeding modes.
has been grouped as below (Table 1).
Helicobacter Pylori
MECHANISMS BY WHICH COMMON H. pylori is postulated to act as a direct carcinogen,
similar to other tumor viruses. Intercellular transport of
AGENTS CAUSE CANCERS (TABLE 2)
bacterial CagA oncoprotein from the bacterium to host
Epstein Barr Virus cells may stimulate an immune surveillance response
Mainly transmitted orally and by blood. B cells are the similar to a direct oncogenesis model for viruses.
main sites of Epstein Barr Virus (EBV) infection. It is
found in a latent state. LMP1 is the oncogenic protein Schistosoma Hematobium
which promotes proliferation and survival of the affected Several mechanisms have been postulated to explain
cell. Others like LMP2 and EBNA proteins also play roles occurrence of bladder cancer in S. hematobium.
in carcinogenesis. S chistos oma e ggs induce fibrosis follow e d by
proliferation, hyperplasia, metaplasia and possible
Kaposi Sarcoma-Associated precancerous lesion. Nitrosamines are released as a
Herpes Virus result of chronic urinary infection and act as bladder
Transmitted through sexual route, blood transfusion carcinogens.
and organ transplantation. Kaposi Sarcoma-Associated
Herpes Virus (KSHV) genes with oncogenic properties Fluke (Opisthorchis and
are v-Cyclin, K1, K5, v-Bcl2, LANA 1, and v-IRF Chlonorchis) Infections
Chronic inflammation caused by the flukes result in
Human Papilloma Virus hyperplasia and changes in the bile duct epithelium
Transmitted by skin contact and by sexual route. The making them vulnerable to certain carcinogens and
main tumor proteins are E6 and E7. Pathology involves leading to malignant transformation.
transition from subtle histological changes to high grade
lesions and finally to carcinoma in situ. DETECTION AND PROVING
ASSOCIATION OF THE INFECTIOUS
Hepatitis B Virus AGENT IN CANCER (TABLE 3)
Transmission is by blood and body fluids as well Detection and proving of causality is often challenging
as vertical transmission. Chronic infection causes because of the latency of the organism. The infectious
hepatocellular carcinoma. agent may not be found in the subsequent tumor. The
need to identify the causal agent is paramount all the
Hepatitis C Virus more because preventive strategies can be instituted
Transmission is by blood and blood products. Core well ahead of time. For example, human papilloma virus
protein has been identified as the viral oncoprotein. (HPV) vaccine has helped prevent cervical cancer caused
CHAPTER 87: Infections Causing Cancer 541
TABLE 2: Detailed information of various groups

Group 1 Group 2a Group 2b Group 3
Epstein-Barr virus (EBV) Merkel cell polyomavirus (MCV) JC polyomavirus (JCV) Opisthorchis felineus
(infection with)
Helicobacter pylori Malaria (infection with Human immunodeficiency Schistosoma mansoni
Plasmodium falciparum in virus type 2 (infection with) (infection with)
holoendemic areas)
Hepatitis B virus (HBV) Schistosoma japonicum Microcystis extracts
(chronic infection with) (infection with)
Hepatitis C virus (HCV) BK polyomavirus (BKV) Fusarium sporotrichioides
(chronic infection with)
Hepatitis D virus Fusarium moniliforme Fusarium graminearum
(Toxin induced) Fusarium culmorum
(Toxin induced)
Human immunodeficiency virus type 1 SV40 polyomavirus
(HIV 1) (infection with)
Human papilloma virus (HPV) types 16, 18,
31, 33, 35, 39, 45, 51
Human T-cell lymphotropic virus type I
(HTLV I)
Kaposi sarcoma herpes virus (KSHV)
Opisthorchis viverrini (infection with)
Clonorchis sinensis
Schistosoma hematobium (infection with)
Aflatoxins (fungal toxin)
TABLE 3: List of infections and associated cancers/tumors

Category Agent Associated tumor(s)
Virus EBV Burkitt’s lymphoma
Hodgkin’s lymphoma
NK cell and T lymphomas
Nasopharyngeal carcinomas
Post transplant lymphoproliferative disease
HPV Cervical cancer
Head and neck area cancer
Genital tract carcinomas
KSHV Kaposi sarcoma
Primary effusion lymphoma
Multicentric Castleman disease
HIV Kaposi sarcoma
(through Lymphomas (including both non-Hodgkin lymphoma and Hodgkin disease), and cancers of the anus,
immunosuppression) cervix, lung, liver, and throat
HBV Hepatocellular carcinoma
HCV Hepatocellular carcinoma
HTLV1 Adult T-cell leukemia/lymphoma
MCPV Merkel cell carcinoma
BK polyomavirus Transplant-related urinary cancers
Contd...
Contd...
Category Agent Associated tumor(s)

Bacteria H. pylori Gastric cancer
Gastric MALT lymphoma
Salmonella typhi* Gallbladder cancer
Streptococcus bovis* Colon cancer
Chlamydia Lung cancer
pneumoniae*
Parasite Schistosoma Urinary bladder cancer
hematobium
S. japonicum Liver and colorectal cancer
S. mansoni Hepatocellular carcinoma (indirect through higher rates of HBV and HCV infection)
Opisthorchis viverrini Bile duct cancer (cholangiocarcinoma)
Opisthorchis felineus
Chlonorchis sinensis
Plasmodium (Malaria) Burkitt lymphoma
Trichomonas Cervical neoplasia
vaginalis*
Toxoplasma gondii* Pituitary adenoma
Fungal Aflatoxin Hepatocellular cancer
toxin (by Aspergillus flavus)
*Association based on published reports. Not proven.
by the same virus, and institution of antiretroviral therapy and effective therapeutic measures for certain cancers.
in AIDS has led to regression of regression of Kaposi’s Further research on pathogenesis and advanced
sarcoma caused by KSHV (a herpes virus). Subtractive molecular detection methods is need of the hour.
methods have been used to demonstrate causality.
Duncan et al. had applied computational subtraction to BIBLIOGRAPHY
search for virus genomes in colorectal cancer. Another 1. Dalton-Griffin L, Kellam P. Infectious causes of cancer and
method known as digital transcript subtraction (DTS) their detection. Journal of Biology. 2009;8(7):67.
2. IARC. Monographs on the evaluation of carcinogenic risks to
uses advanced sequencing methods to identify RNA and
humans, Lyon, France: IARC. 2017.pp.1-119
DNA virus transcripts. However, these methods need to
3. Khurana S, Dubey ML, Malla N. Association of parasitic
be employed in carefully selected tumors to get results. infections and cancers. Indian J Med Microbiol. 2005;23
Bradford Hill’s causation criteria are now considered the (2):74-9.
tool to infer causality of virus and cancer relationship. 4. Liao JB. Viruses and human cancer. The Yale Journal of
These rules along with detection of pathogenic genomes, Biology and Medicine. 2006;79(3-4):115-22.
can help linking an infectious agent with cancers. 5. Mager D. Bacteria and cancer: cause, coincidence or cure?
A review. J Transl Med. 2006;4:14.
6. Moore PS, Chang Y. Common commensal cancer viruses.
CONCLUSION PLoS Pathog. 2017;13(1):e1006078.
The discovery of infectious agents as a cause of cancers 7. Morales-Sánchez A, Fuentes-Pananá EM. Human viruses
has driven our attention towards preventive (vaccines) and cancer. viruses. 2014;6(10):4047-79.
CHAPTER
88
Transfusion Transmitted Infection
Apu Adhikary, Tuhin Santra
INTRODUCTION Trypanosoma cruzi

Transfusion transmitted infections (TTI) are major Babesia microti
limitations of blood transfusion services throughout
the world. Risk of transfusion transmitted infection Bacteria
depends on the prevalence of infections in the donor Gram-negative: Pseudomonas, Escherichia, Klebsiella,
community. In India, infections like hepatitis B, C, HIV, Acinetobacter and Serratia. Yersinia, Proteus
cytomegalovirus, parvovirus B19, malaria, and syphilis Gram positive: Staphylococcus and Enterococcus,
are most prevalent diseases. Although transfusion of Propionibacterium
blood and blood products are much safer than earlier Spirochaete: Treponema pallidum
decades but far from attaining “Zero risk” level at present
days. Only vigilant donor screening, sensitive screening Prion Disease
tests and effective inactivation technique can reduce the Variant Creutzfeldt-Jakob disease (vCJD)
risk associated with transfusion transmitted infections. However, NACO (National Aids Control Organization)
Various agents transmitted through transfusions are recommends testing of 5 TTIs—HIV, HBV, HCV, malaria
as follows: and syphilis.1
Virus HUMAN IMMUNODEFICIENCY VIRUS

Human immunodeficiency virus (HIV) Prevalence of HIV in India is 0.27%.2 Cases of AIDS like
Cytomegalovirus (CMV) illness was first reported in transfused patients in 1982.
Human T-cell lymphotrophic viruses (HTLVs) The responsible virus HIV-1 was identified in 1984. A
Chikungunya virus test for HIV-1 antibody became available in 1985. Over
West Nile virus (WNV) years, HIV antibody sensitivity test was improved, with
Hepatitis viruses—Hepatitis B, C, A and E progressive shortening of the time to detect antibody
Parvovirus B19 from the initial 45 to 55 days to an average of 22 to 25 days.3
Dengue virus In 1996 HIV-1 p24 antigen detection was introduced
for further reduction of this period. This was followed
Protozoa by implementation of minipool nucleic acid testing
Malaria parasite (MP-NAT) which reduced window period to 11 days. At
Leishmania donovani present fourth generation ELISA kit is used as a screening
test which detects both p24 antigen and antibody to HIV MALARIA
(window period 15–18 days). MP-NAT is not a mandatory Malaria is the first reported transfusion transmitted
screening test but still used in some centers in India. infection. It is endemic in India. It is detected by thick
Improvements in donor testing, donor education and and thin peripheral blood smear examination and rapid
questioning processes have led to the selection of a detection tests based on the detection of malaria parasite
blood donor population with an incidence of new HIV antigen in blood. In India, strategies adopted to prevent
infections that is 10-fold lower than that of the general transfusion transmitted malaria are:
population. Deferral of donors with fever (presumably malaria) in
the last 3 months.

HEPATITIS B VIRUS Testing of donated blood for malaria parasite.
It is a DNA virus and Hepatitis B is transmitted sexually,

parenterally or perinatally from infected mothers to their SYPHILIS
infants. Incubation period ranges from 1 to 4 months. In 1915, the first case of transfusion-associated syphilis
Although it is often stated that 5 to 10% of infected adults was reported. Risk of transfusion-transmitted syphilis is
go on to become chronic HBsAg carriers, more recent particularly high in developing countries where blood
studies suggest that the development of chronic infection is collected from family donors and transfused within
is far less common, approximately 1%.5 hours. Prevalence of syphilis among blood donors in
HBsAg detection began in 1970. India is considered India is reported to be 0.7%. For screening of syphilis,
to have intermediate level of HBV endemicity with a rapid plasma reagin (RPR) test or VDRL is used and for
prevalence of 1.18%.6 Early in the course of infection confirmatory Treponema pallidum hemagglutination
IgM anti-HBc antibody can be detected in blood assay (TPHA) or CLIA (Chemiluminescent immunoassay)
even in the absence of HBsAg. Currently enhanced is used. For prevention of transfusion transmission
chemiluminescence and 4th generation ELISA is used following strategies are used:
which detects both HBsAg and antibody to HBV. Nucleic Selection of low-risk donors and screening for the
acid test (NAT) is helpful in situation where HBsAg is disease

negative and anti-HBc is also equivocal.7 Application of pathogen reduction technology
Risk for major transfusion transmissible infections

HEPATITIS C VIRUS continues to decline in India. However, there are some
Hepatitis C causes approximately 90% of cases of infections which have the potentiality to be transmitted
non-A non-B transfusion associated hepatitis.8 Blood through transfusion but their screening is not routinely
components which was a major risk for HCV infection done. Some of these are as follows.
had a prevalence of > 10% in transfusion recipients
in some studies.9 The prevalence of HCV infection in Hepatitis A and Hepatitis E Viruses
general population in India and seroprevalence in blood Both of them are rarely transmitted through blood
donors in India (NACO Annual Report 2009–2010) are transfusion. These viruses are not inactivated by the
<2% and 0.4%. methods like plasma fractionation and processing by
The screening of serum alanine aminotransferase detergent and solvent methods which are commonly
(ALT/SGPT) helps in reduction of transfusion associated used for production of blood components.
of non-A, non-B hepatitis. Screening for anti–HCV
was first available in 1990. However, antibodies are HUMAN T-LYMPHOTROPIC
not reliably detected until an average of 10 weeks after VIRUS I AND II
infection. In 1999, testing for HCV nucleic acid (MP-NAT) HTLV I and HTLVII infect lymphocytes lead to life-long
was implemented. infections. HTLV-I is commonly associated with tropical
CHAPTER 88: Transfusion Transmitted Infection 545
spastic paraparesis (TSP) and adult T-cell leukemia/ BACTERIAL INFECTIONS

lymphoma. HTLV can be detected by antibody testing Transfusion transmitted bacterial infection (TTBI) is
which is of IgG type, therefore having a relatively long a major cause of transfusion-related fatalities. Sources
window period of 51 days. of contamination include the collection system (bags),
a donor with asymptomatic bacteremia, inadequately
CYTOMEGALOVIRUS cleaned skin or a skin core from the collection needles.
Cytomegalovirus can be spread through the infected Most bacteria do not grow well at cold temperatures.
“passenger ” WBCs found in transfused platelet So platelet concentrates rather than PRBCs and FFP
components or PRBCs. As an alternative to screening are the common sources of bacterial contamination.
b l o o d d o nat i o n s f o r C M V a nt i b o d y l e u ko c y t e Approximately 1 in 5,000 for platelets and 1 in 30,000
reduction of cellular components decreases the risk of for RBCs transfusions are bacterially contaminated. 10
transmitting infection regardless of the serologic status
The likelihood of a fatal reaction due to bacterial
of the donor. CMV-seronegative transplant recipients,
contamination was estimated at 1/500,000 platelet
Immunosuppressed patients, and neonates are at higher
units and 1/8 million RBC units. 11 Gram-negative
risk of CMV infection.
bacteria which can grow at 1° to 6°C like Yersinia,
Pseudomonas, Serratia, Acinetobacter, and Escherichia
EPSTEIN–BARR VIRUS
species have been implicated in infections related to
Approximately 90% of blood donors have antibodies
PRBC transfusion.11
against EBV and post-transfusion EBV infection is rare
although has been reported and it can be decreased by
leukocyte reduction of cellular components. Clinical Features of Transfusion
Transmitted Bacterial Infection
WEST NILE VIRUS Recipients of transfusion contaminated with bacteria
In 2003, minipool NAT screening of blood donations for may develop fever and chills, which may occur
West Nile virus RNA was implemented. West Nile Virus abruptly within minutes to hours, can progress to
was first demonstrated to be transmissible by transfusion septic shock and DIC or
in 2002. Increase in heart rate >40/min from baseline or a fall
of blood pressure >30 min.
PARVOVIRUS B19 Severe symptoms are often associated with endotoxin-
The virus is spread chiefly through respiratory secretions producing organisms.
and cause fifth disease (erythema infectiosum). Blood
components and pooled plasma products can transmit
this virus. In individuals with chronic hemolytic anemia, What to do?
it can lead to an acute aplastic crisis due to cessation Stop the transfusion
of RBC production. Individual blood donations are not Resuscitation and adequate hydration of the patient.
currently screened for B19 infection. Parvovirus B19 Repeat the blood group typing and cross-matching
is resistant to the viral inactivation processes usually and collect recipient’s blood for culture and Coombs’
applied to plasma derivatives, such as solvent/detergent test.
treatment and heat. Suspected cases of bacterial contamination should
be reported immediately to the blood supplier so that
ARBOVIRUSES other components made from the same donation can
Dengue viruses, chikungunya virus, and zika virus might be retrieved and quarantined pending the results of
be transmitted through blood transfusion. cultures.
OTHER INFECTIOUS AGENTS blood transfusion from a negatively screened donor but
Various parasites- babesiosis and Chagas disease can have now become positive for an infection
be transmitted by blood transfusion. Tests for some
pathogens are available, such as Trypanosomacruzi, REFERENCES
but not universally required. Prion disease like variant 1. Chandra T, Rizvi N F, Agarwal D. Decreasing Prevalence
Creutzfeldt-Jakob disease (vCJD) can be transmitted of Transfusion Transmitted Infection in Indian Scenario.
Scientific World Journal. 2014;2014:1-4.
through transfusion.
2. Nandi S, Maity S, Bhunia SC, Saha MK. Comparative
PATHOGEN INACTIVATION assessment of commercial ELISA kits for detection of HIV in
India. BMC Res. Notes. 2014;7:436-40.
TECHNOLOGY
3. Petersen LR, Satten GA, Dodd R, et al. Duration of time
The concept of pathogen inactivation in blood
from onset of human immunodeficiency virus type 1
components is to eliminate the risk of known and infectiousness to development of detectable antibody.
unknown pathogens without/minimally interfering The HIV Seroconversion Study Group. Transfusion.
the function the blood components. In India where 1994;34(4):283-9.
infections are rampant this method is desirable. Current 4. Dodd RY. Germs, gels, and genomes: a personal recollection
methods employed are use of methylene blue, solvent of 30 years in blood safety testing. In: Stramer SL, ed. Blood
detergent (SD) plasma and exposure of ultraviolet A safety in the new millennium. Bethesda, MD: American
(UV-A) radiation. Association of Blood Banks; 2001. pp. 97-122.
5. Koff RS. Natural history of acute hepatitis B in adults re
DONOR SCREENING QUESTIONNAIRE examined. Gastroenterology. 1987;92(6):2035-7.
Common questions need to be asked for donor screening. 6. Bobde V, Parate S, Kumbhalkar D. Seroprevalence of viral
Whether currently taking any antibiotic, aspirin or transfusion transmitted infections among blood donors at a
other medication. government hospital blood bank in central India. The Health
Pregnancy within past 6 weeks or current pregnancy. Agenda. 2015;3(1):15-18.
Vaccination in the past 8 week. 7. Offergeld R, Faensen D, Ritter S, Hamouda O. Human
Blood component donation in the past 8 weeks.
immunodeficiency virus, hepatitis C and hepatitis B
A sexual contact with a person who has HIV/AIDS,
infections among blood donors in Germany 2000–2002:
risk of virus transmission and the impact of nucleic acid
gonorrhea, syphilis, hepatitis, hemophilia or has used
amplification testing. Euro Surveill. 2005;10(2):8-11.
clotting factor concentrates, IV drug abuser in the
8. Schreiber GB, Busch MP, Kleinman SH, et al. The risk of
past 1 year.
transfusion-transmitted viral infections. The Retrovirus
An accidental needle-stick or tattoo in last 1 year.
Epidemiology Donor Study. N Engl J Med. 1996;334(26):
Organ, tissue, or bone marrow transplantation in last
1685-90.
1 year. 9. Dodd RY, Notari EP, Stramer SL. Current prevalence and
Any history of lockup, jail, juvenile detention or
incidence of infectious disease markers and estimated
prison for more than 72 hours. window-period risk in American Red Cross blood donor
population. Transfusion. 2002;42(8):975-9.
Donor Deferral Lists 10. Kuehnert MJ, Roth VR, Haley NR, et al. Transfusion-
A list of deferred donor should be kept in blood bank to transmitted bacterial infection in the United States, 1998
make sure not to collect from risky donor. through 2000. Transfusion. 2001;41(12):1493-9.
11. Kleinman SH, Kamel HT, Harpool DR, et al. Two-year
Lookback experience with aerobic culturing of apheresis and whole
It is a programme which helps in identification and blood-derived platelets. Transfusion. 2006;46(10):
notification of recipients who had previously received 1787-94.
CHAPTER
89
Arboviral Infections: Is Effective
Vaccination a Possible Solution?
Ashok Kumar, Shubha Laxmi Margekar, Venugopal Margekar
INTRODUCTION vector (Fig. 1). Sufficiently high titer of virus must be

Arbovirus is an arthropod-borne virus and these viruses present in the blood of the vertebrate host (viremia), to
are transmitted by arthropods, primarily mosquitoes be taken up in the small volume of blood ingested during
and ticks. It is a collective name given to large group of an insect bite for the transmission to be effective. The
diverse viruses (>600 ). Usually, they are named either virus replicates in the gut of the arthropod after ingestion
for the diseases they cause (e.g. yellow fever virus) or of infected blood and then it spreads to other organs like
according to the place of their first isolation (e.g. St. salivary glands. Only the female of the species serves as
Louis encephalitis virus). Most arboviruses are classified the vector of the virus, because only she requires a blood
in three families, namely togaviruses, flaviviruses, meal to produce progeny.
and bunyaviruses. Table 1 shows the classification of The extrinsic incubation period, which ranges from
arboviruses prevalent in India. 7 to 14 days must pass before the virus has replicated
sufficiently for the saliva of the vector to contain
TRANSMISSION enough virus to transmit an infectious dose. Viruses are
Life cycle depends upon the ability of the viruses to transmitted through vertebrates and some by vertical
multiply in the vertebrate host and the blood sucking “transovarian” passage from the mother tick to her
TABLE 1: Classification of arboviruses prevalent in India

Family Genus Virus properties Arthropod Arboviruses in India
Flaviviridae Flavivirus zz Spherical, 40–60 nm in diameter Mosquitoes, ticks Dengue, Japanese
zz Genome: positive-sense, single stranded encephalitis,
RNA, enveloped Kyasanur Forest disease, West
zz All viruses serologically related Nile fever viruses
Bunyaviridae Phlebovirus zz Spherical, 80–120 nm in diameter Sandflies Sandfly fever virus Ganjam,
Nairovirus zz Genome: triple segmented, negative-sense Ticks Crimean Congo hemorrhagic
Orthobunyavirus or ambisense, single stranded RNA, enveloped Mosquitoes viruses Chittoor virus
Togaviridae Alphavirus zz Spherical, 70 nm in diameter-Genome: positive- Mosquitoes Chikungunya, Sindbis viruses
sense, ssRNA, enveloped
zz All viruses serologically related
Rhabdoviridae Vesiculovirus zz Rod- or bullet shaped, 75 × 180 nm Sandflies Chandipura virus

zz Genome: negative-sense, ssRNA, enveloped
with protruding spikes
Fig. 1: Arbovirus transmission cycle
offspring and is important for survival if no vertebrate disease. Arboviral infections, with an estimated high
host is available. As there is low virus concentration and fatality rate of 17 million deaths per year worldwide are
brief duration of viremia in human blood, human behave of major public health concern. The most overpopulated
as dead end hosts. But in diseases like yellow fever and and economically backward countries in Southeast Asia
dengue, humans act as reservoirs of the virus because of are the highly affected areas. In India, the rural, tribal and
high-level viremia. urban slum areas are more prone to develop vector borne
Infection by arboviruses usually does not result disease and are considered as high risk groups. Dengue
in disease neither in the arthropod vector nor in the is considered as the most important human arboviral
vertebrate animal (natural host). Disease (yellow fever) infection and is the leading cause of hospitalization
occurs primarily when the virus infects dead-end hosts, and death among children in the Southeast Asia region.
i.e. human, but it causes harmless infection among the Japanese encephalitis is the leading cause of encephalitis
jungle monkeys in South America. epidemics worldwide, mainly in Korea, China, India, and
Indonesia. More than 3 billion people residing in Asia
CLINICAL FINDINGS AND are at risk, and approximately 30,000–50,000 cases are
EPIDEMIOLOGY reported annually. Chikungunya, a dengue-like disease,
The diseases range in severity from mild to rapidly fatal. started causing epidemics in India and Southeast Asia
The clinical picture is divided into following categories: since 1950s and now it is widely spread in other countries
(1) encephalitis; (2) hemorrhagic fever; or (3) fever with also.
myalgias, arthralgias, and nonhemorrhagic rash. The
pathogenesis involves cytocidal effect of the virus, and a VACCINATION
prominent immunopathologic component. Immunity is Emerging Aedes mosquito-borne viral diseases are
usually lifelong after recovery from the disease. Primarily, public health challenge. Vaccines are essential to limit
arboviral diseases occur in the tropics but are also found disease burden as mosquito control programs are not
in temperate zones (United States, Alaska and Siberia). effective for outbreak containment. Along with yellow
At the interface between human communities and jungle fever vaccines, dengue vaccine is also available, while
or forest areas they tend to cause sudden outbreaks of research has started on vaccines against Zika. Several
CHAPTER 89: Arboviral Infections: Is Effective Vaccination a Possible Solution? 549
vaccine candidates against chikungunya are undergoing may be quarantined for up to 6 days, refused entry,
preclinical studies, and few of them have been tested in or vaccinated on site, if they arrive without proof of
Phase II trials. vaccination. Travelers who are not vaccinated because of
contraindication to YF vaccine or other medical grounds
YELLOW FEVER VACCINE and who cannot avoid travel to a country requiring
Vaccination is an important measure for preventing YF vaccination should request a waiver from a physician
and is available for >60 years. Prompt recognition and before embarking on travel.
control of outbreaks through vaccination is important
to prevent epidemics in high risk areas. Vaccination JAPANESE ENCEPHALITIS
coverage must reach at least 60–80% of the at-risk Japanese encephalitis (JE) is the common cause of viral
population to prevent outbreaks. Two 17D substrain encephalitis in many Asian countries. The infection
vaccines namely 17DD and 17D-204 are manufactured. is caused by the JE virus (a flaviviruses) and it exists
The 17DD YF vaccine is manufactured and used in Brazil in a transmission cycle between mosquitoes, pigs
and also in South American countries. The 17D-204 YF and/or water birds (enzootic cycle). Infected mosquito
vaccine is a freeze-dried, live attenuated, highly effective bite transmits infection to human and is common in rural
vaccine. It is available in single- or multi-dose vials and and periurban region. According to recent literature,
should be stored at 2–8 °C. It should be used within 1 about 30% of cases of Japanese encephalitis result in
hour of reconstitution with normal saline. Dose is 0.5 mL permanent neuropsychiatric sequelae. Transmission is
to be given subcutaneously. People at continued risk of observed throughout the year in tropical climate region
exposure to YF virus require revaccination in every 10 but is endemic with seasonal distribution in temperate
years. The YF vaccine is safe and affordable, providing climate areas of Asia, South and South-East Asia.
effective immunity within one week for 95% of vaccines. Currently, JE is considered hyperendemic in parts of
A single dose provides protection for more than 30 years India and Nepal, where authorities have responded with
and probably lifelong. Serious side effects are extremely immunization campaigns.
rare. The risk related to vaccinations is much less than
death from YF. Japanese Encephalitis Vaccination
JE immunization is recommended by WHO in all regions
Contraindication of YF Vaccine where the disease is identified as public health problem,
Children aged <9 months for routine immunization and for people traveling to endemic regions. Several
(or <6 months during an epidemic) vaccines are available but its use has been limited due
Pregnant women—except during a YF outbreak when to its price, cumbersome immunization schedules, and
the risk of infection is high lack of recognition of the burden of disease. Surveillance
People with severe allergies to egg protein of disease and availability of new vaccines helped in
People with severe immunodeficiency due to control of Japanese encephalitis. Global Alliance for
symptomatic HIV or other causes, or in the presence Vaccines and Immunization (GAVI) has committed to
of a thymus disorder. support JE vaccination in eligible countries once a WHO-
prequalified vaccine is available.
International Certificate of YF Vaccination
Travelers must have a certificate of YF vaccination for Licensed Vaccines
entry to certain countries especially to Africa or Latin The mouse-brain derived inactivated vaccines are
America from Asia, under the International Health p ro d u c e d by s e v e ra l m a n u f a c t u re r s. P r i m a r y
Regulations (IHR) of WHO to prevent importation immunization requires 3 dose of vaccine and boosters.
and indigenous transmission of YFV. Such travellers Vaccines are relatively expensive. Vero-derived
Beijing 1 inactivated vaccine is produced by Japanese particularly with wild type infection. Primary infection
manufacturers for pediatric use and a similar product is with one type of strain provides lifelong immunity to
registered in China as well. Another cell-culture derived that strain and around two years cross protection from
inactivated JE vaccine (attenuated SA 14-14-2 strain) other strains. It has been seen that there is occurrence of
is developed by an Austrian biotech company and is severe dengue in individuals if secondary infection with
available as a traveler’s vaccine. Indian manufacturer other strain occur in them after cross protection due to
has also developed similar product and has received primary infection wanes. The mechanism for this effect
marketing authorization. Research is ongoing on is believed due to antibody-dependent enhancement
pediatric indication. of infection along with other causes. It has been found
A live attenuated vaccine using the SA 14-14-2 strain that symptomatic dengue due to third or fourth infection
manufactured by a Chinese company is the most widely is rare following secondary infection and presumably
used JE vaccine in endemic countries. It is grown on due to reinforcement of nontype specific by secondary
primary hamster kidney cells and only 1–2 doses of infection which provides additional cross protection
vaccine is required to confer long-lasting immunity, also against remaining serotype and this phenomenon
the vaccine is made available at a highly competitive is known as multitypic immunity. This multitypic
price to low-income countries. Another live attenuated, phenomenon has been in consideration for development
chimeric vaccine which uses yellow fever vaccine as of new and effective vaccine against dengue infection.
vector and is combined with E protein encoding gene
from the SA 14-14-2 virus and is grown on Vero cells, has Current Status of Dengue Vaccine
obtained marketing authorization in some JE endemic Currently Dengvaxia® (CYDTDV) is the only licensed
countries. It is given as single dose vaccine, and booster vaccine for dengue infection developed by Sanofi
dose requirement is still to be determined. Pasteur in 2015 in Mexico. The vaccine is a three dose
live recombinant tetravalent dengue vaccine licensed to
Pipeline Vaccines use in individuals of 9–45 years of age who are residing
Various candidate Japanese encephalitis vaccines in endemic areas and administered 0, 6 and 12 month
are under development. These consist of adjuvanted schedule. It has been observed that efficacy of vaccine
inactivated vaccines, candidates using different virus is higher against serotype 3 and 4 than serotype 1 and 2.
strains, and other genetically engineered constructs. Also in the individuals who were already been exposed
to dengue, the vaccine efficacy as higher than infection
DENGUE VACCINE naïve individuals.
Dengue virus belongs to family Flaviridae, genus
Flavivirus, which is single stranded RNA virus, having Status of Vaccine R and D Activities
four serotypes (DENV1–DENV4). Genetic variations in Clinical Pipeline
these serotypes lead to variable pattern of disease and There are two tetravalent live recombinant vaccines
its severity due to variation in virulence, fitness and TV003/TV005 and DENVax are moving towards phase
transmission. Incidence of dengue has been increased 3 clinical trials. The response of these vaccines are
to 30 folds over the period of five decades.4 Diagnosis of encouraging and elicited seroconversion rate are over
dengue can be made by clinical features along with either 90% by one dose of TV005.
isolation of virus, viral serology (MAC-ELISA, IgG ELISA,
NS1 ELISA, and PRNT), or by molecular methods (RT- Preclinical Pipeline
PCR) which is gold standard. There are various approaches in developing effective
Postinfection immunity in individuals recovered vaccine in preclinical pipeline that includes conventional
from dengue infection is not very well understood and novel technological approaches. The various target
CHAPTER 89: Arboviral Infections: Is Effective Vaccination a Possible Solution? 551
for dengue vaccine development includes, recombinant live vectored, chimeric, virus like particle [VLP], subunit
subunit vaccines, DNA vaccines, VLP vaccines, virus- protein, DNA) are currently in preclinical and clinical
vectored vaccines, purified inactivated virus vaccines, development.
live attenuated virus vaccines, heterologous prime-boost
approaches, and simultaneous administration with two KYASANUR FOREST DISEASE
technologically different vaccine candidates. The KFD virus (KFDV) belongs to genus Flavivirus and
For reaching WHO goal of decreasing dengue of family Flaviviridae. Concomitant illness in monkeys
morbidity by at least 25% and mortality by at least 50% by (Semnopithecus entellus and Macacaradiata) and in
2020, a safe, efficacious and cost effective vaccine is the humans leads to discovery of this virus in 1957. This virus
need of time to control of disease. genome is single-stranded, positive sense RNA, spherical
in shape and about 45 nm in diameter. Initially disease
CHIKUNGUNYA VACCINE was seen in some area of Karnataka district Shimoga in
Chikungunya fever, caused by chikungunya virus Sagar, Shikaripur and Sorabtaluks, later on other districts
(CHIKV), is an acute febrile illness characterized by also become endemic like Chikmagalur, Dakshina
high grade fever with severe, debilitating polyarthralgia Kannada, Udipi and Uttar Kanada. Indian council of
and rashes. Disease can progress to chronic stage Medical Research states the annual incidence rate of
in which joint pain can be there for more than three 40–1000 KFD cases with mortality rate of 4–15% in them.
years postinfection in around to third if cases. Disease
occurs across all age groups with similar frequencies Mode of Transmission
and is associated with fever and severe myalgia (90% of Wild monkeys Semnopithecus entellus and Macaca
patients), polyarthralgia and polyarthritis (95%), and radiate gets infected by KFDV through the bites of
rash (50%). The virus belongs to family togaviridae and infected H. spinigera ticks leading to severe febrile illness
its genome is enveloped, positive-sense single stranded in monkeys. After death of infected monkeys, the ticks
RNA. Over the past decade CHIKV has emerged as a shed from their body that help in further spread of the
major cause of vector-borne disease with transmission virus. Humans come in the cycle when bitten by infected
reported in more than 100 countries and territories unfed nymph. No human to human transmission is
worldwide. The estimated case fatality is very low known. But the personnel working on the virus and
(0.1–5%) compared to some other arboviral diseases. Till handling the infected monkeys can develop disease and
date, vector control has been the primary response to around 100 cases were noted.
chikungunya outbreaks but effectiveness has not been
extensively evaluated and may face challenges due to Clinical Features
insecticide resistance in Aedes spp. vectors. Symptoms of KFDV infection in humans are similar
to other viral hemorrhagic illness. There is high grade
Status of Chikungunya Vaccine fever with chills, frontal headaches, photophobia, severe
There are no licensed vaccines for chikungunya. body aches sometimes associated with gastrointestinal
Throughout world there are four lineage of chikungunya symptoms like, nausea, vomiting, and loose motion. An
virus are found, the East, Central, and Southern African important diagnostic sign in some patients is appearance
(ECSA) lineage, the West African lineage, the Asian of papulovesicular lesions on the soft palate. Patients
lineage, and the Indian Ocean lineage (IOL). As all may develop bleeding manifestations in the form of
chikungunya virus lineage appears to single serotype, epistaxis, hemoptysis, malena or bleeding from.
therefore a single vaccine can be expected to protect
all virus strains. The chikungunya vaccine pipeline Vaccination
appears robust. More than 15 vaccine candidates based National Institute of Virology at Pune, India developed
on a range of platforms (inactivated, live attenuated, vaccine against KFDV and is available since 1966.
The vaccine is formalin inactivated and is prepared supported its use, although the drug is not approved by
by growing the virus in chick embryo-fibroblast cells FDA to be use in CCHF cases.
by using modern cell culture techniques. In India,
the vaccine is used nowadays in the endemic regions CONCLUSION
and annually over 50 thousand vaccine doses being There is no doubt that arboviral infections are becoming
administered. Large numbers of new KFDV cases still the dangerous threat to human life in terms of morbidity
occurs from Karnataka questioning the efficacy of the and mortality. Although there are several vaccine
existing vaccine. Therefore, there is need of KFD virus against flaviviruses (i.e. against yellow fever, Japanese
identification and development of highly efficacious encephalitis, TBE and Dengue virus), there are no
vaccine against the KFDV to prevent the epidemics in vaccine available against Zika virus and no vaccines
India. against an important Alphavirus such as chikungunya.
The present licensed dengue vaccine has low pooled
CRIMEAN CONGO HEMORRHAGIC efficacy and very limited data available of its use.
FEVER VIRUS Even after so much technical advancement, there
Crimean Congo hemorrhagic fever virus (CCHFV) appears to be delay in development of effective vaccine.
belongs to family Bunyaviridae, genus Nairovirus Development of vaccine requires huge investments and
containing three negative sensess RNA segment. Its financial resources. A global commitment is needed;
wide geographical distribution, mode of transmission, public/private partnership is essential to develop
severity of the disease, and high mortality rate in humans, vaccine candidates and make them available.
together with therapeutic difficulties and lack of an FDA-
approved vaccine, make CCHFV a significant threat to BIBLIOGRAPHY
public health. Disease is spread in humans by the bite of 1. Broor S, Devi LS. Arboviral infections in India. Indian Journal
of Health Sciences and Care. 2015;2(3):192-202.
ticks, by contact with infected patient during acute phase
2. Dash AP, Bhatia R, Sunyoto T, Mourya DT. Emerging and re-
or bycontact with body fluid secretions, blood or tissues emerging arboviral diseases in Southeast Asia. Journal of
from viremic livestock. There were two major outbreak Vector Borne Diseases. 2013;50(2):77.
of CCHF in India. In 2011 and 2013, few districts and 3. Mourya DT, Yadav PD, Patil DY. Highly infectious tick-borne
viral diseases: Kyasanur forest disease and Crimean–
villages were affected and there were sporadic cases in Congo haemorrhagic fever in India. 2014.
between 2011 and 2012. 4. Smalley C, Erasmus JH, Chesson CB, Beasley DW. Status
The only available vaccine is an inactivated virus of research and development of vaccines for chikungunya.
Vaccine. 2016;34(26):2976-81.
produced on suckling mouse brain (inactivated by
5. Vannice KS, Durbin A, Hombach J. Status of vaccine
chloroform, heated at 58 °C, and adsorbed on aluminum research and development of vaccines for dengue. Vaccine.
hydroxide). This vaccine is currently used in Bulgaria 2016;34(26):2934-8.
and originated from the USSR in 1970. Recently, it has 6. Wallace D, Canouet V, Garbes P, Wartel TA. Challenges
in the clinical development of a dengue vaccine. Current
been found that even after 4 doses of this vaccine the Opinion in Virology. 2013;3(3):352-6.
protective antibody titers are low. Therefore there is great 7. Wilder-Smith A, Gubler DJ, Weaver SC, Monath TP, Heymann
need to find effective vaccine for this deadly disease. DL, Scott TW. Epidemic arboviral diseases: priorities for
research and public health. The Lancet infectious diseases.
At present, there is no safe and effective, commercially
2017;17(3):e101-e6.
available vaccine against CCHFV. There is some role 8. World Health Organization. Dengue vaccine: WHO position
of antiviral drug Ribavirin and Indian CCHFV cases paper—July 2016. WklyEpidemiol Rec. 2016;30:349-64.
CHAPTER
90
MDR-TB and XDR-TB: What are the Options?
Bidita Khandelwal
INTRODUCTION notified pulmonary cases, there are 79,000 MDR-TB

cases but a significant number adds to it by the incident
The burden of tuberculosis and multidrug-resistant
MDR-TB cases.
tuberculosis (MDR–TB) is highest in India, even when
calculated in proportion to its population. The reduction
DEFINING MDR-, PRE-XDR- AND
in the burden has been very slow. Mismanagement of
MDR-TB, i.e. improper treatment, nonadherence to
XDR-TB
guidelines, inappropriate use of second line drugs or MDR-TB: It is defined as TB that is resistant to both
their poor quality has led to emergence of extensively rifampicin and isoniazid.
drug resistant TB (XDR-TB). Drug resistant TB (DR- XDR-TB: It is defined as MDR-TB with additional
TB) is difficult to diagnose and expensive to treat. resistance to any fluoroquinolone (FQ) and to at least
Optimal control of DR-TB cases alone will not control one of three second-line injectable anti-tuberculosis
the global burden. Effective use of first line drug in every drugs (SLID) ie amikacin , capreomycin or kanamycin.
new patient is required to prevent emergence of DR- Pre-XDR-TB: It is defined as a subset of MDR-TB that are
TB. Decentralized rapid diagnostics and DST in field resistant to either FQ or SLID but not to both.
conditions, addressing issues of patient attrition during
case finding and defaults; standardized regimens to MANAGEMENT OPTIONS IN M/XDR-TB
tackle the menace are some of the challenges.
Classes of Anti-TB Drugs
Traditionally, anti-TB drugs have been divided into first
EPIDEMIOLOGY and second line drugs. WHO recommended five groups
Globally in 2015 there were about 480,000 people based on drug class, experience of use, efficacy and
estimated to have MDR-TB and an additional 100,000 safety. Reclassification was done with the realization
people having rifampicin resistant TB (RR-TB), thus that the 1st line ATT drugs might also have a major
bringing the total to 580,000 cases of MDR-TB. XDR-TB role in strengthening DR-TB regimens. Factors taken
constitutes 9.7% of MDR-TB globally. The geographical into consideration while doing the reclassification
factors and epidemic trends are variable. Based on were evidence available, anticipated effects (desirable
estimates reported in Global TB Report 2016, the burden and undesirable) and implementation feasibility. Core
of both TB and MDR-TB is highest in India. Among second line drugs includes Group A, B and C drugs.
REGIMES NEWER DRUGS OPTIONS

The Programmatic Management of Drug Resistant TB Bedaquiline and Delamanid
(PMDT) sets out the integrated algorithm that should be
Bedaquiline which is a diarylquinolines, is the first new
used for the management of MDR/XDR-TB (Table 1).
drug developed specifically to treat TB after four decades.
In the M/XDR-TB regimen Clofazime and Linezolid are
An accelerated approval was granted by USA Federal
now recommended as core second line medicines
Food and Drug Administration (FDA) in December 2012
while p-amino salicylic acid is an add on agent. While
realising the need for a new effective drug. Delamanid
preparing a regimen for M/XDR-TB, at least five effective
inhibits a novel target in mycobacterial tuberculosis cell
TB medicines during the intensive phase including
pyrazinamide is to be used and four core second line wall mycolic acid synthesis. Both are placed in group D
drugs, of which one each from Group A and Group B and as it does not belong to any other TB drug families and
at least two from Group C. If an effective regimen cannot limited data is available regarding its effectiveness and
be composed as recommended above, a drug from Group long-term safety.
D2 and another from Group D3 may be added to have a They are not to be used as a replacement for second
total of five effective drugs. In patients with M/XDR-TB, line drugs. When an effective and well tolerated M/XDR-
further strengthening of the regime can be done with TB regimen is not possible with conventional second
addition of high dose of isoniazid and/or ethambutol. line drugs, then either of the two should be added.
All RR-TB cases are to be considered as MDR-TB cases This situation may arise due to (a) in vitro resistance
and until susceptibility results are confirmed, isoniazid to a drug. (b) Poor tolerance, adverse drug reaction
should be added to the regimen. Even if isoniazid or contraindications and (c) Lack of guarantee supply
susceptibility testing facility is not available and there are or unavailability of a drug. They should not be added
no strong reasons to suspect resistance, isoniazid should alone to an effective regimen and concurrent use of both
remain in the regimen. the drugs is not recommended. In exclusive DR extra-
pulmonary TB disease, they may be added when benefit
TABLE 1: Drugs used for the treatment of M/XDR-TB
outweighs the risk. They can be taken along with other
Group A: Levofloxacin Lfx
Fluoroquinolones Moxifloxacin Mfx
anti-tubercular drugs and after a light meal. Both are
Gatifloxacin Gfx used for a maximum of 24 weeks and from the beginning
Group B: Second- Amikacin Am of the treatment along with other second line drugs.
line injectable (Streptomycin) (S) The dosing schedule for Bedaquiline is:
agents Capreomycin Cm
Week 1–2: 400 mg daily (Seven days per week)
Kanamycin Km
Week 3–24: 200 mg three times per week with atleast
Group C: Other core Ethionamide/prothionamide Eto/Pto
second-line agents Cycloserine/terizidone Cfz 48 hours between doses.
Linezolid Lzd Week 25 onwards: The other second line agents are
Clofazimine Cs/Trd
Group D: Add-on D1 Pyrazinamide Z
continued as scheduled.
agents Ethambutol E The dosing schedule for Delamanid is:
(not part of the core High-dose isoniazid Hh Week 1–24: 100 mg twice daily for seven days a week.
MDR-TB regimen)
T h e re q u i s i t e s f o r s t a r t i n g b o t h t h e d r u g s
D2 Bedaquiline Bdq
Delamanid Dlm includes diligent patient inclusion, adherence to the
D3 p-aminosalicylic acid PAS Ipm recommended regimens, regular monitoring, informed
Imipenem–cilastatin, Mpm consent and active pharmacovigilance. Unregulated
Meropenem (T)
irrational use would inevitably lead to emergence of
Amoxicillin-clavulanate Amx-Clv
(Thioacetazone) resistance.
CHAPTER 90: MDR-TB and XDR-TB: What are the Options? 555
HIGH-DOSE ISONIAZID SURGICAL OPTIONS

High dose isoniazid, with unclear efficacy, is only to All patients of M/XDR-TB should be evaluated for surgery
be used when regimens involving drugs from Groups at the initiation of treatment and or during follow-up.
A, B and C are not possible. High-dose isoniazid 10 Inadequate regimens to treat M/XDR-TB are challenging
mg/kg/day (when the isoniazid minimum inhibitory and have risk of serious sequelae, thus the importance
concentration (MIC) is ≤1 mg/L) or 16–20 mg/kg three of pulmonary surgery needs to be understood. Elective
times per week (when isoniazid MIC is >1 to 5 mg/L) may lobectomy or wedge resection, i.e. partial lung resection
be beneficial but tolerance and safety might be concerns. along with a recommended M/XDR-TB regimen reduces
Evidence from clinical studies regarding its efficacy has the volume of irreversibly damaged lung tissue and
shown mixed results. bacterial load, thus improving outcomes. Bacterial
infection in the surrounding lung tissue can be reduced
DURATION OF TREATMENT M/XDR-TB by giving two months of preoperative therapy In XDR-TB,
The treatment duration for newly diagnosed MDR-TB is 12–24 months of post-operative therapy is recommended.
20–24 months with 8 (6–9) months of an intensive phase. Patients with localized disease, persistent sputum
However, modification may be done based on patients positivity and DR-TB should be offered surgical options.
response to therapy. Whether time past conversion
should determine the duration of therapy is debatable. CONCLUSION
Twelve months past conversion but not less than total The global efforts to control TB has been seriously
20 months, is followed by most. Same recommendations jeopardized by the emergence of XDR-TB. To curb this
holds good for patients with XDR-TB also. iatrogenically created menace, understanding of the
epidemiological and risk factors associated with it is of
Shorter Duration Therapy Option utmost importance. Management of DR – TB is complex
A shorter 9–12 months regimen may be considered in
and challenging. The drugs used have greater toxicities,
those with MDR-TB where second line drugs have not
required for longer duration and have drug-to-drug
been used before and resistance to SLID and FQ has been
interaction. There are several unaddressed operational
excluded or is highly unlikely. An intensive phase for four
challenges and knowledge gap which acts as barrier to
months which may be extended up to a maximum of
good quality PMDT services. Ensuring minimum leakage
six months in case of lack of sputum smear conversion
across the care cascade and maximizing adherence
is used. Drugs used in intensive phase are moxifloxacin
through innovative patient support strategies and real
(or gatifloxacin), prothionamide, kanamycin, high
time monitoring is the need of the hour.
dose isoniazide, pyrazinamide, clofazimine and
ethambutol. The five months continuation phase
BIBLIOGRAPHY
consists of moxifloxacin (or gatifloxacin), pyrazinamide,
1. Katiyar SK, Bihari S, Prakash S, Mamtani M, Kulkarni H. A
ethambutol and clofazimine, randomised controlled trial of high-dose isoniazid adjuvant
There is evidence from studies carried out at therapy for multidrug-resistant tuberculosis. Int J Tuberc
Bangladesh, Niger and Cameroon, that shorter regimens Lung Dis. 2008;12(2):139-45.
are cost effective with good success rate. However more 2. Pai M, Bhaumik S, Bhuyan SS. India’s plan to eliminate
robust trials are required for definite results. Shorter tuberculosis by 2025: converting rhetoric into reality. BMJ
MDR-TB regimen should not be used in patients who Global Health 2017;2:e000326. doi:10.1136/bmjgh-2017-
000326.
have been previously treated for more than a month
3. RNTCP National Strategic Plan for Tuberculosis elimination
with second line drugs or who have documented or
2017-2025.
high likelihood of resistance to the drugs used. However, 4. Standards for TB care in India. 2016.
if DST facilities are unavailable and resistance seems 5. WHO treatment guidelines for drug –resistant tuberculosis.
unlikely, shorter duration regimen may be given. 2016 update.
CHAPTER
91
Acute Encephalitis: Indian Scenario
INTRODUCTION Whereas though West Nile virus encephalitis is a

Acute encephalitis is a group of clinically similar typical example of sporadic encephalitis earlier but
neurologic manifestation caused by several different can also cause outbreak as seen in Assam and Kerala.
viruses, bacteria, fungus, parasites, spirochetes, Enterovirus encephalitis outbreak was detected in
chemical/toxins. In order to get more no of encephalitic eastern Uttar Pradesh (UP). Sporadic viral encephalitis
cases WHO introduced the term Acute Encephalitis and encephalopathies are caused by Herpes simplex
Syndrome (AES). So according to WHO all encephalitic viruses (HSV), rabies, Epstein Barr virus (EBV), measles,
cases are reportable and should be reported as acute mumps, etc. Nowadays, few cases of encephalitis have
encephalitic syndrome. Laboratory confirmation should been detected in recent large outbreak of Chikungunya
be done in all clinical cases of suspected encephalitis. (CHIK) and Dengue viruses.
The following case definition should be used for
reporting of suspected AES cases in endemic areas: ETIOLOGY
The etiology of acute encephalitis syndrome is given in
Case Definition of Acute Encephalitis Table 1.
Syndrome
Clinically, a case of AES is defined as a person of any age, EPIDEMIOLOGY
at any time of year with the acute onset of fever of 5–7 Over the last few decades in India acute encephalitic
days duration and a change in mental status (including syndrome is clinically synonymous with Japanese
symptoms such as confusion, disorientation, inability Encephalitis (JE). JE virus in India was first isolated in
to talk or coma) and/or new onset of seizures (excluding the city of Vellore (previously North-Arcot) Tamil Nadu
simple febrile seizures). in 1955. In 1973 large significant outbreak of JE was
Causitive agents for AES are various and belong to reported in the places of Bankura and Burdwan district
bacterial, parasitic, fungal and viral. Most of them occur of West Bengal. Till 2005 the reporting of JE infection was
as sporadic and few as outbreak form. For example, mainly based on outbreak based surveillance. Thereafter
Japanese encephalitis virus (JEV) and Chandipura virus National Vector Borne Disease Control Program me
(CHPV) cause large scale outbreaks in various parts of (NVBDCP) as the nodal Agency, realized that to control
India. mortality and morbidity due to JE infection there should
CHAPTER 91: Acute Encephalitis: Indian Scenario 557
TABLE 1: Acute encephalitis syndrome northern districts of West Bengal particularly Darjeeling,
Japanese Non-JE—viral Non-JE—nonviral Jalpaiguri and Cooch Behar districts since 2011. After
encephalitis the mass vaccination campaign conducted in late 2013,
Single stranded Enterovirus—Polio Parasitic there were significant decrease incidence of JE cases with
RNA virus of (Malaria)
increase of nonJE AES.
Flaviviridae Non-polio
family (Vector is Japanese encephalitis: Till date Japanese encephalitis
Coxsackie Echo Others
Culex mosquito)
A/B is the leading cause of AES all over India, both in
Chandipura virus Protozoal pediatric and adult population. Japanese encephalitis
(Amoebic)
(JE) is a mosquito borne zoonotic viral disease caused
West Nile virus Spirochetal
by arbovirus (flavi virus). The virus is divided into four
(Syphilis)
genotypes (I, II, III and IV). Genotype III is mostly found
Herpes Scrub typhus
pan India whereas genotype I is found in UP and West
Varicella Trypanosomiasis
Bengal. Genotype II and IV rarely found in India. The JE
Dengue Acute TBM virus is mainly isolated in ardied birds (e.g. cattle egrets,
Toxoplasmosis Bacterial pond herons, etc.) and they are called as natural reservoir,
Tick borne encephalitis Fungal whereas when the virus multiply in body of some animal
(Cryptococcal) particularly Pigs which are called amplifying host.
Venejuelian encephalitis Toxin
Dawson Chemicals Transmission
9 and 10-not found in India Unknown cause The infection is transmitted through the bite of an
infected culicine mosquito. Most important vector
species in India is Culex vishnui group consisting of
be regular reporting of cases and thus establish the
C.tritaeniorhynchus, C. vishnui and C.pseudovishnui.
laboratory based sentinel surveillance in 15 endemic
Culex mosquitoes generally breed in water bodies with
states in India. The system starts reporting separately
luxurious vegetation like irrigated rice fields, shallow
AES and JE cases.
Figure 1 represents the number of AES and JE ditches and pools. Culex mosquitoes are zoophilic, feed
positive cases in India since 2008 collected, collated and primarily on animal and wild birds. In monsoon and
analyzed through this established routine surveillance postmonsoon period, when the vector density is high,
system between 2008 to 2013. It is observed that there is the epidemic of JE usually occur. Female mosquitoes get
a gap between the total AES and JE positive cases over infected after feeding on a viaemic host and can transmit
the years; the percentage of JE cases as proportion of the virus to other hosts after an extrensic incubation
total AES varied from 8.93% to 14.72%. This represents period of 9 – 12 days. The mosquitoes remain infected
that AES is not synonymous with JE, rather in contrast for life. The average life period of a mosquito is about
to earlier belief, AES is a spectrum of diseases with 21 days. Culex mosquito can fly for long distances (1–3
equal contribution of JE and non-JE etiology. Moreover km or even more). The transmission cycle is maintained
after starting the widespread JE vaccination it has been in animals and birds. Infection in man is incidental
observed a paradigm shift of AES from JE to non-JE and occur by bite of infected mosquito when man stays
infections. From the surveillance data it has also been close to the animal reservoir (amplifying host). Man to
observed that more than 90% of the total AES cases have man transmission has not been documented. So man is
been reported from 5 endemic states in the country the dead end of the transmission cycle. The incubation
viz., Assam, Bihar, Uttar Pradesh, Tamil Nadu, and West period in man, following mosquito bite varies from
Bengal. JE cases are increasingly being reported from 5 days to 15 days.
Fig. 1: State-wise mean AES incidence in India (Collected from NVBDCP website)
Clinical Features of AES excludes Japanese encephalitis. AES with symmetrical

Clinically AES including JE presents as encephalitis. Most neurological signs is likely to be cerebral malaria.
of the cases present in younger age groups, although all
age groups can be affected. Initially, there are prodromal Diagnosis of AES
symptoms of fever, headache, nausea, diarrhea, vomiting, Imaging
and myalgia. Those symptoms usually last for few days Imaging in patients with encephalitis may or may not
(1–5 days) followed by irritability, altered behavior, be diagnostic. MRI brain is more specific than CT scan
convulsions and coma. The progression prodromal of brain to detect demyelination in case of encephalitis.
symptoms to full blown disease and complication is very Location of abnormal signal of demyelination in MRI
rapid. Signs of raised intracranial tension are commonly scan can sometime suggest specific etiologies (Fig. 2A
present in acute stage of illness. The patient may develop and Table 2).
aphasis or dysarthria and other neurological deficits Temporal lobe involvement is strongly suggestive of
like ocular palsies, piramidal and extrapyramidal signs HSV encephalitis, although other herpes viruses (e.g.
in the form of hemiplegia, quadriplegia, dystonia, VZV, EBV, human herpes virus 6) can also produce
choreoathetosis and coarse tremors. same clinical picture.
Involvement of the thalamus or basal ganglia is very
Differentiation of Japanese Encephalitis much suggestive of arboviral diseases like JE. Others
and Non-JE, AES may be encephalitis due to respiratory viral infection
During epidemic all cases of acute fever with altered and Creutzfeldt-Jakob disease.
sensorium persisting for more than two hours with The presence of hydrocephalus may suggest nonviral
a focal seizure or paralysis of any part of body, is etiologies, such as bacteria (Tuberculosis), fungal, or
suggestive of encephalitis. Presence of rash with fever parasitic agents.
A B
Figs 2A and B: MRI image of temporal lobe enhancement. (A) In herpes simplex encephalitis;
(B) T2W and flair MRI image in Japanese B encephalitis patient
TABLE 2: Location of abnormal signal of demyelination in MRI viral encephalitis are increased white blood cell count
scan suggesting specific etiologies (usually less than 250/mm3), the differential showing
Disease Japanese Non-JE AES a predominance of lymphocytes (early infection may
encephalitis reveal a predominance of neutrophils), elevated protein
Relation to onset of About 6 weeks after Starts within 3 days concentration (usually less than 150 mg/dL) and normal
rains onset of rain after onset of rain
glucose concentration. Presence of red blood cells in CSF
Pain abdomen No 50%
(in a nontraumatic tap); is suggestive of HSV-1 infection
Diarrhea No 50%
or other necrotizing encephalitis. Specific diagnostic
CSF examination Lymphocytic Normal except in
tests for etiologic diagnosis include polymerase chain
finding pleocytosis increased ICT
reaction (PCR) tests for viruses, culture for bacteria, fungi
CT scan of brain Hypodense in Middle cerebral
thalamus artery infarction and mycobacteria and serology for the arboviruses.
MRI brain Hyperintensity in Middle cerebral
thalamus artery infarction Serology
The detection of virus specific IgM antibody (MAC
CT scan of brain is only useful to rule out space- Elisa) can provide definitive diagnosis rapidly on
occupying lesion or brain abscess. a single specimen of CSF. This class of antibody is
present in body fluids only for 1–3 months and thus
Electroencephalography presence of IgM antibody in body fluid denote acute JE
Electroencephalography usually shows abnormal spicks encephalitis. Viruses for which detection of virus-specific
in acute encephalitis. Spicks in the temporal lobe region IgM antibodies are available include JEV, dengue,
is suggestive of HSV encephalitis. chikungunya, West Nile, measles, rubella, and mumps.
Cerebrospinal Fluid Study Treatment of AES

Analysis of cerebrospinal fluid is an important diagnostic Treatment should be started empirically after making
step in patient with suspected viral encephalitis. Routine clinical diagnosis of viral encephalitis.
examination of the cerebrospinal fluid (CSF), usually A broad spectrum antibiotic such as ceftriaxone (Dose
abnormal in the presence of inflammatory disease of the is 200 mg/kg/day-12 g/day IV Q6h in adult) must be
CNS. The CSF pressure should be usually high in case given, which can be stopped when investigation does
of encephalitis. Other common CSF abnormalities in not reveal bacterial meningitis.
Even though epidemiological data on herpes simplex TABLE 3: Therapeutics agents commonly used in encephalitis
encephalitis from India is lacking, the consensus Indication Typical dosing/administration*
recommendation of the expert group is that acyclovir Cerebral edema Mannitol 0.25 – 1 g/kg bolus every 4–6 hours
(Dose is 10 mg/kg IV Q8h) must be started in all Hypertonic saline
cases of sporadic viral encephalitis, keeping in mind Active brain herniation, 23% daline (30 mL
bolus via central venous access)
that HSE is a treatable disease. Acyclovir should be
Maintenance, 2–3% saline (250–500 mL
stopped if an alternative diagnosis has been made boluses or continuous venous infusion; 3%
like CSF serology positive for ZE, or HSV PCR in the saline via central venous access)
CSF is negative. Seizures status
epilepticus
Increased intracranial pressure: Symptoms and signs
First line, initial Lorazepam 0.1 mg/kg IV up to 4 mg per dose
of increased intracranial pressure include headache,
dosing Midazolam 0.25 mg/kg IM up to 10 mg
vomiting, and a decreased level of consciousness. The maximum
following steps are used in the management of raised Diazepam 0.15 mg/kg IV up to 10 mg
intracranial pressure. The patient should undergo Second line, Fosphenytoin 20 mg PE/kg IV
intubation if the GCS is less than 8, or if there is evidence initial dosing Levetiracetam 1,000–3,000 mg IV
Valproate sodium, 20–40 mg/kg IV
of uncal or cerebellar herniation, or if the patient has
Third line, Propofol 1–2 mg/kg
irregular respirations and inability to maintain airway. If loading dose Phenobarbital 20 mg/kg IV
there are signs of impending herniation, then the patient Pentobarbital 5–15 mg/kg IV
should be hyperventilated to a target PaCO 2 of 30– Herpes simplex Acyclovir, 10 mg/kg IV q8 hours × 14-21 days
35 mm Hg. encephalitis
Mannitol should be given at a dose of initial bolus Autoimmune

encephalitis,
of 0.25 g/kg, then 0.25 g/kg, q6h as per requirement, acute
up to 48 hours. Hypertonic (3%) saline is preferable to First line Methylprednisolone 1,000 mg IV q day × 5 days
mannitol in the presence of hypotension, hypovolemia, IV immunoglobulin, 0.4 g/kg IV q day × days
and renal failure. The dose is 0.1–1 mL/kg/hr by infusion; Plasma exchange, 5–7 exchanges administered
the serum sodium should be targeted to a level of 145–155 every other day
meq/L. The patient should have adequate sedation and Second line Cyclophosphamide, body surface area × 800
analgesia. Noxious stimuli should be avoided; nebulized mg IV
Rituximab, 1,000 mg IV × 1, followed by second
lignocaine should be administered prior to endotracheal dose in 2 weeks
tube suctioning. Relieving elevated ICP is very useful
*Drugs and dosing remmendations are provided only as guide; clinical
to decrease secondary brain injury and the patient will conditions and drug effects must be carefully considered prior to drug
respond better to anti-infective therapy. administration.
Treatment of Japanese encephalitis (JE) mainly
consists of supportive care with emphasis on control of Prevention and Control of AES
intracranial pressure, maintenance of adequate cerebral Prevention carries utmost importance as there is no
perfusion pressure, control of seizure, and prevention specific treatment of JE. Preventive measures usually
of complications. A randomized, placebo-controlled consist of
trial of oral ribavirin in 153 Indian children did not show Surveillance for cases of AES;
any difference in outcome between the treatment and Vector control;
control groups. Studies are ongoing to investigate other Reduction in man-vector contact; and
potential antiviral agents. Vaccination.
An overview of acute management of patients is Control of vectors and prevention of man-vector

provided in the Figure 2B, and typical doses of thera contact are key nonvaccination strategies, but are
peutic agents are listed in Table 3. beyond the scope of the present discussion.
JE Vaccination in India the presence of other agents calls for designing and
Two types of JE vaccines are available in India: implementing novel preventive strategies that would
1. Inactivated vaccine derived from vero cell prepared focus on containment of water-borne enteroviruses and
from an Indian strain of Japanese encephalitis virus vectors for Chandipura virus. This will need a multisector
(JENVAC). This vaccine is very safe and effective for approach involving health, water resources, sanitation
all known strains of Japanese encephalitis. Two doses and rural development departments. Recently, the
of this vaccine given 1 month apart will have sero thought process on such an approach has been initiated.
conversion of around 98% in population of more than In addition, we also need to move from JE surveillance
1 year and up to 55 years of age. to surveillance for the entire spectrum of AES, so that
2. The recently introduced Chinese live attenuated evidence based public health actions can be planned
SA-14-14-2 JE vaccine now available in the routine and carried out.
i m mu n i z at i o n i n c h i l d re n u n d e r Un i ve r s a l
Immunization Program in the 181 endemic districts BIBLIOGRAPHY
of India since 2011. In 3rd July 2014, the Government 1. Gore MM. Acute encephalitic syndrome in India: Complexity
of the problem. J Commun Dis. 2014;46(1):35-49.
of India had announced the introduction of single
2. Guideline of clinical management of acute encephalitic
dose of JE vaccine for adults in endemic districts. syndrome including japanese encephalitis. Directoraye
In the state of Assam, West Bengal and Uttar Pradesh of National Vector Borne Disease Control Programme
NVBDCP has identified 20 hyperendemic districts for Government of India, August 2009.
introduction of adult JE vaccination (>15–65 years). 3. Joshi R, Kalantri SP, Reingold A , Colford JM. Jr.
Till now, eight districts have been covered by the adult Changing landscape of acute encephalitis syndrome in
India: A systematic review. Natl Med J India. 2012;25:212-
vaccination programme.
20.
4. Operational Guideline: National Programme for Prevention
Recent Trends of AES in India and Control of Japanese Encephalitis/Acute Encephalitis
In recent years, investigations into large outbreaks Syndrome; Ministry of Health and Family Welfare, Govt of
of AES have been negative for JEV (or a flavi virus). India; 2014.
Instead outbreaks were found to be due to a rhabdo- 5. Ravi V, Mani R, Govekar S, Desai A, Lakshman L, Ravikumar
BV. Aetiology and laboratory diagnosis of acute encephalitis
virus (Chandipura virus), or water-borne entero viruses.
syndrome with special reference to India. J Commun Dis.
Factor might account for entero viruses replacing JEV 2014;46(1):12-23.
as the major cause of AES is JE vaccination campaigns, 6. Sen PK, Dhariwal AC, Jaiswal RK, Shiv Lal, Raina VK, Rastogi
launched in endemic districts, may have brought A. Epidemiology of acute encephalitis syndrome in India:
about this shift. The introduction of JE vaccination in Changing Paradigm and Implication for Control. J Commun
endemic regions reduced the overall incidence of AES. Dis. 2014;46(1):4-11.
7. Suri V, Narang U, Bhalla A. Viral encephalitis in India:
The emergence of non-JEV etiologies in outbreaks
Management Update: Update on Tropical Fever.
and surveillance studies directly impacts preventive 8. Vashishtha VM, Ramachandran VG. Vaccination Policy for
measures for AES. While vector control programs Japanes Encephalitis in India: Tread with Caution : Indian
and JEV vaccination remain important strategies, Pediatrics; 2015. p. 52.
CHAPTER
92
Tropical Fever: A Case-based Approach
INTRODUCTION Clinical Approach to Tropical Fever

Tropical diseases including tropical fevers are still killer Syndrome
disease in tropics and subtropics. Tropical diseases India being the largest tropical country with high
were defined as diseases that are prevalent in, or prevalence of these deadly tropical infections, difficulties
unique to tropical and subtropical regions. Insect bite is often encountered during diagnosis because of
responsible for transmission of these infectious agents in coinfections and overlapping clinical presentations.
most of the tropical infections.. The prevalence of these Hence, a high degree of suspicion should be there during
infections is on the rise in India, being the largest tropical investigation of all febrile patients in tropical regions as
region. Some of these infections are perennial, some are delay in diagnosis and institution of specific therapy may
seasonal (especially during or following the monsoon) lead to increased morbidity and mortality.
and some are influenced by geography. There is a paucity Detailed medical history is mandatory while
of epidemiological data regarding these infections, evaluating a case of acute febrile illness in tropics.
however the data available from a few selected centers Presence of any underlying conditions associated with
and overall experience of the expert groups indicates that increased risk of infections such as diabetes mellitus,
most common tropical infections are malaria, dengue, HIV infection, neoplastic condition, splenectomy and
typhoid, leptospirosis, rickettsial infections (especially pregnancy should be sought. Sexual exposure, arthropod
scrub typhus), viral infections like influenza and bacterial bites, occupational risks, animal contact, drug and
sepsis. Though these disease conditions are distinct immunization history should be specifically enquired
clinical entities with specific clinical features, sometimes about. The duration of current illness (acute or chronic),
the patients may have concomitant infections, can pattern of fever, association with gastrointestinal
have atypical manifestations, or may also have other manifestations, respiratory tract symptoms, and
distinct medical problems that are unrelated to their genitourinary symptoms should be asked. Prior use of
tropical exposure, including noninfectious diseases, e.g. antibiotics, analgesics and antipyretics may mask the
autoimmune or malignant conditions. Such situations expression of classical pattern of illness described in
may modify the clinical expression or clinical course of the books warranting importance of detailed history
the condition. and careful evaluation to confirm or exclude a tropical
CHAPTER 92: Tropical Fever: A Case-based Approach 563
infection. Like proper history, a quick, judicious clinical TABLE 1: Differential diagnosis of physical findings for some
examination is also equally important in arriving at a tropical infections
provisional diagnosis. Localizing clinical feature like Physical finding Differential diagnosis
headache, seizure, altered sensorium; arthralgia and Lymphadenopathy HIV, rickettsioses, brucellosis, leishmaniasis,
myalgia; photophobia, conjunctivitis; skin rashes, infectious mononucleosis, tuberculosis,
bleeding, localized dermal lesions; lymphadenopathy, toxoplasmosis, melioidosis, lymphatic
filariasis
hepatosplenomegaly; jaundice, and anemia are
Hepatomegaly Malaria, typhoid, viral hepatitis, leptospirosis,
important in making a probable diagnosis (Tables 1
leishmaniasis, schistosomiasis, liver abscess
and 2). The geographic and travel history (inside (amoebic or pyogenic) dengue
the country and abroad, both recent and past) are of
Splenomegaly Malaria, typhoid, typhus, leishmaniasis,
immence importance. Information regarding areas with trypanosomiasis, brucellosis, acute or chronic
recent outbreaks (e.g. HINI/H5NI influenza, dengue) can schistosomiasis, tuberculosis, toxoplasmosis
be of immence help in diagnosing the clinical entity. The Jaundice Viral hepatitis, malaria, leptospirosis, dengue,
onset of illness in relation to known incubation periods scrub typhus
and time of possible exposure can be of great help to
establish or exclude various infectious diseases. Wheezing Löffler’s syndrome, tropical pulmonary
eosinophilia
Since the clinical features of many infections may
overlap with one another and with severe bacterial
sepsis, and sometimes presence of coinfections,
practically it may be very difficult to arrive at a diagnosis TABLE 2: Skin lesions associated with tropical infections
at the time of presentation. Hence, a practical approach Skin lesion Differential diagnosis
is to group these constellations of symptoms and signs
Maculopapular Arbo-viruses, acute HIV, rickettsiae, secondary
in a syndromic fashion so as to enable the physician to rash syphilis, typhus, typhoid, rubeola, rubella,
reach at a probable diagnosis and start emperic therapy disseminated gonococcal or meningococcal
at the earliest. Though it is known that a syndromic infections
approach may not be able to cover atypical or unusual Petechiae/ Rickettsioses, meningococcemia, viral
presentations of common tropical illnesses, yet it can be ecchymoses hemorrhagic fevers, dengue, leptospirosis,
septicemia and disseminated intravascular
of immence value in guiding the physicians for initiating
coagulopathy
therapy in critically ill patients during emergency
Eschars Tick bite fever, scrub typhus, anthrax
hours. The tropical infections may have the following
“syndromic approach”. Nodules Onchocerciasis, leprosy, atypical mycobacteria,
erysipeloid, erythema nodosum
Undifferentiated Fever Vesicles or Rickettsialpox, enteroviruses, varicella, herpes

vesiculopustular simplex, herpes zoster
It is defined as fever without specific symptoms and lesions
localizing signs to arrive at a diagnosis at the time of
presentation. As time progresses, frequent clinical
evaluations will lead to elicitation of clinical clues
Fever with Rash/Thrombocytopenia
or findings to establish the etiology of illness. Very Fever of acute onset with transient skin rash or exanthem,
important infections which need urgent consideration with or without thrombocytopenia (Platelet count
and intervention are malaria (P. falciparum usually), <100,000/cmm). Common causes are dengue, rickettsial
typhoid, dengue, scrub typhus, leptospirosis, and other infections, meningococcal infections, malaria (usually
common viral illness and infections like respiratory tract, P. falciparum), leptospirosis, measles, rubella and other
genitourinary tract and gastrointestinal infections. viral exanthem.
Fever with Acute Respiratory

Distress Syndrome
Fever of acute onset with respiratory distress in the form
of SpO2 <90% at room air or frank ARDS with PaO2/FiO2
ratio <200. Common infections are falciparum malaria,
leptospirosis, scrub typhus, influenza including H1N1,
Hanta virus infection, severe community acquired
pneumonia, meliodosis, and diffuse alveolar hemorrhage
secondary to tropical infections.
Acute Febrile Encephalopathy/Acute Fig. 1: A case of Falciparum malaria with severe anemia and icterus
Encephalitic Syndrome
hepatosplenomegaly may be present. The features of
Acute febrile illness with altered sensorium, the common
severe malaria may be cerebral malaria, severe anemia,
differential diagnoses are:
Encephalitis: Herpes simplex virus, Japanese B,
hypoglycemia, metabolic acidosis, acute kidney injury,
ARDS, shock (algid malaria), DIC, hemoglobinuria,
enterovirus and other viruses.
Meningitis: S. pneumoniae, N. meningitides, H.
hyperparasitemia (>5%) alone or in combination
(Fig. 1). Diagnosis is established by either microscopy
influenzae, enteroviruses.
Others: Cerebral malaria, typhoid encephalopathy,
(Thick smear: parasite detection; thin smear: species
identification), quantitative buffy coat test (QBC) or rapid
scrub typhus.
diagnostic tests (RDTs): histidine rich protein, lactate
Fever with Multiorgan Dysfunction dehydrogenase antigen based immunochromatography.
Possibility of malaria is excluded if two RDTs reports are
The common causes are Falciparum malaria, lepto
negative. Treatment should be antimalarials as per latest
spirosis, scrub typhus, bacterial sepsis, dengue, hanta
WHO recommendations.
virus infection, hepatitis A or E with fulminant hepatic
failure and hepato-renal syndrome, hemophagocytosis
and macrophage activation syndrome.
Dengue Fever
Dengue fever is clinically characterized by an acute
As many infections can have overlapping presen
febrile illness of 2–7 days duration with two or more
tations and there can be coinfections, it is essential
of the following manifestations: headache, retro-
that a physician should be well aware of the common
etiological agents and their epidemiology in the defined orbital pain, myalgia, arthralgia, rash, and hemorrhagic
geographic region to be able to make a provisional manifestations without evidences of capillary leak
diagnosis and initiate treatment. (Fig. 2).
Dengue hemorrhagic fever (DHF): A case with clinical
SPECIFIC INFECTIONS criteria of DF plus hemorrhagic tendencies evidenced
The salient features of common tropical infections are by one or more of the following (positive torniquet test,
discussed below. bleeding from skin, mucosal or gastrointestinal tract)
plus thrombocytopenia (<100,000 platelets/cmm) plus
Malaria Fever evidence of plasma leaking due to increased vascular
Clinically character ized by paroxysm of fever, permeability, manifested by one or more of the following
shaking chills and sweats, occurring every 48 or 72 (a rise in hematocrit for age and sex >20% from baseline,
hours, depending on species. Pallor, icterus and pleural effusion, ascites, hypoalbuminemia).
Fig. 2: Dengue fever with flushed face and suffused conjunctiva Fig. 3: Toxic face of enteric fever
Dengue shock syndrome (DSS): All the above criteria constipation, hepatosplenomegaly, encephalopathy
for DHF with evidence of circulatory failure manifested (2nd week), intestinal bleeding, perforation, multiorgan
by rapid and weak pulse, narrow pulse pressure (<20 dysfunction syndrome (MODS) (3rd week) (Fig. 3).
mm Hg), hypotension, cold and clammy skin and For confirmation of diagnosis, blood culture is the gold
restlessness. standard method during 1st week of fever, positive in
40-80% of patients; bone marrow culture is one of the
Expanded dengue syndrome (EDS): Unusual or atypical
most sensitive method (sensitivity 80–95%), may remain
manifestations of organ dysfunction; encephalitis,
positive after several days of antibiotic treatment or
myocarditis, hepatitis, renal failure, ARDS or associated
regardless duration of illness; widal test is nonspecific.
with various coinfections (e.g. malaria, leptospira), RDT: Typhoid test is also very useful, sensitivity 95–97%,
or associated with comorbidities. For confirmation of specificity >89%. Treatment : Ceftriaxone IV 50–75
dengue infection National Vector Borne Diseases Control mg/kg/day for 10–14 days. Can use azithromycin and
Programme (NVBDCP) recommends use of ELISA-based ciprofloxacin or ofloxacin alternatively.
antigen detection test (NS1) for diagnosing the case from
the first day onwards (usually up to day 5) and antibody Scrub Typhus
dection test IGM capture ELISA (MAC-ELISA) for Clinically characterized by fever, headache, myalgia,
diagnosis the cases after the fifth day of onset of illness. breathing difficulty, jaundice, vomiting, cough, delusion,
DF can be managed symptomatically. As DHF is a maculopapular rash and eschar (Fig. 4). Most important
volume depleted state due to capillary leak, isotonic complicatoins are pneumonia with ARDS, hepatitis,
fluid infusion just sufficient to maintain effective aseptic meningitis, myocarditis, ARF, and DIC. Diagnosis
circulation during the period of plasma leakage guided is established by indirect fluorescent antibody detection
by serial hemotocrit measurements is the cornerstone of test which is the ‘gold stanard’ and specific. Weil-Felix
management. Blood transfusion or platelet transfusion test is of poor sensitivity and specificity, ELISA based
can be done as per WHO/NVBDCP guidelines. detection of IgG and 1gM antibodies are sensitive
and specific in >90% cases. Doxycyline is the drug of
Enteric Fever choice for management. Azithromycin or Rifampicin or
Clinically characterized by fever, headache, relative chloramphenicol can be used as alternatives in children
bradycardia (1st week), abdominal pain, diarrhea or and pregnant women.
Fig. 4: Eschar and maculopapular rash Fig. 5: Icterus and subconjunctival hemorrhage of a case of
of a case of Scrub typhus leptospirosis
Leptospirosis reports, a judicious decision to start emperical treatment

These patients may have a biphasic clinical presentation. is ideal till laboratory reports available. The laboratory
Anicteric leptospirosis or leptospiremic phase: tests can then help to escalating/minimizing the drugs
Characterized by abrupt onset fever, headache, myalgia, after a final diagnosis is established.
abdominal pain, diarrhea, conjunctival suffusion,
transient maculopapular skin rash, calf pain, and TREATMENT STRATEGY
hepatosplenomegaly. Every attempt should be made to arrive at a definite
Icteric leptospirosis (Weil’s disease) is characterized diagnosis at the earliest which may not be possible
by jaundice, proteinuria, hematuria, oliguria and/ always. During emergency the main aim should be to
or anuria, pulmonary hemorrhage, myocarditis, and stabilize a critically ill patient by standard procedures
uveitis (Fig. 5). Diagnosis is established by isolation of to maintain airway, breathing, and circulation. These
leptospira in culture of blood, CSF, or urine; microscopic life saving interventions should preferably be done
agglutination test (single high titer or rising titer/ without invasive monitoring as these patients may have
seroconversion in paired sera), sensitivity 30–63%, thrombocytopenia or coagulopathy. Invasive monitoring
specificity >97% cases; IgM ELISA (sensitivity 52–89%, should preferably be reserved for critically ill patients
specificity >94%). Pencillin G is the preferred first line and should be done carefully after baseline complete
therapy. Alternatively, 3rd generation cephalosporins hemogram and coagulation profile is available. For
can be used and oral doxycycline in uncomplicated control of fever tepid sponging and paracetamol can be
infections. used. Paracetamol in the therapeutic dose of maximum
3–4 g/day in devided doses is safe but higher doses should
INVESTIGATION STRATEGY be avoided to prevent drug induced hepatic dysfunction.
Viewing the complexities of presentation of different Corticosteroids and NSAID’s should be avoided. Isotonic
tropical infections, the laboratory investigation should fluid should be preferred just sufficient to maintain an
be guided towards the common infections prevailing in effective circulation and an ideal hematocrit in patients
that locality and by the local epidemiology. In case, the with evidence of capillary leak syndrome. Blood and
physician is in dilemma, the most life threatening and blood component therapy should be considered under
potentially treatable condition should be investigated in proper indication. Test including rapid diagnostic tests
priority. Expecting a delay in laboratory investigations should be done to exclude malaria.
Emperical use of antimalarials should be discouraged scrub typhus, enteric fever and acute pyogenic meningitis.
as indiscriminate use may potentiate drug resistance. However, if the patient fails to respond to empirical
With the changing pattern of tropical infections, it therapy in ensuing 48 hours, then the patient should
is preferable and safe to use ceftriaxone along with be reviewed for alternative diagnosis, complication and
doxycycline in most cases as they tend to cover management. Table 3 and Flow chart 1 describes the
most common treatable infectins and the results are management protocol for tropical fevers.
encouraging. This combination covers leptospirosis,
TABLE 3: Syndrome based treatment guidelines for critical tropical infections

Fever with thrombocytopenia Antipyretics for control of fever
IV fluids
Avoid aspirin/anticoagulants (Level IV)
Watch for bleeding, dyspnea, shock
Platelet transfusion if the platelet count<20,000 or
clinical bleeding (Level IV)
No role of steroids (Level IB)
Specific therapy once the diagnosis is established
Fever with jaundice Antipyretics for control of fever
Injection ceftriaxone 2 g IV BD
Tablet doxycycline 100 mg BD
IV fluids
Watch for urine output, seizures, encephalopathy,
Bleeding
FFP/cryoprecipitate for bleeding (Level III)
Fever with renal failure Antipyretics for control of fever
Injection ceftriaxone 2 g IV BD*
Tablet doxycycline 100 mg BD*
IV fluids according to CVP
Watch for encephalopathy, bleeding, seizures, ARDS
Renal replacement therapy (intermittent HD/CRRT)
Fever with encephalopathy Antipyretics for control of fever
IV acyclovir 10 mg/kg in adults (up to 20 mg/kg in
children) intravenously every 8 h
IV fluids
IV mannitol for raised ICP
Watch for seizures
Fever with respiratory distress Antipyretics for control of fever
IV fluids
Oxygen by Venturi mask (level IV)
Injection azithromycin 500 mg IV OD*
Tablet oseltamivir 150 mg BD, if H1N1 is a
possibility (Level IA)
Watch for impending respiratory failure, shock,
renal failure, alveolar hemorrhage
Specific therapy once diagnosis is established
Doxycycline is to be taken empty stomach/1 h before or after a meal. It is contraindicated in pregnant women and young children.
*For possible typhoid, leptospirosis and scrub typhus. For possible bacterial meningitis, typhoid and leptospirosis.
Abbreviations: FFP, Fresh frozen plasma; CVP, Central venous pressure; ARDS, Acute respiratory distress syndrome; HD, Hemodialysis; CRRT,
Continuous renal replacement therapy; ICP, Intracranial pressure
Sources: Reproduced with permission, Reference-2
Flow chart 1: An algorithmic approach for the diagnosis and management of critical tropical infections
Source: Reproduced with permission, Reference-2
BIBLIOGRAPHY 2. Frean J, Blumberg L. Tropical fevers part A.Viral, bacterial,

1. Abrahamsen SK, Haugen CN, Rupali P, Mathai D, Langeland and fungal infections. Primer of Tropical medicine. Ch. 5A.
N, Eide GE, et al. Fever in the tropics: Aetiology and Case- Brisbane: ACTM Publication; 2005. Pp 1-18 Available from
fatality – A prospective observational study in a tertiary care HYPERLINK “http//www. tropmed.org/primer/chapter%
hospital in South India .BMC Infect Dis. 2013;13:355. 2005a.pdf” http://www.tropmed.org/Primer/chapter 05a.pdf.
3. Hai Err, Viroj Wiwanitkit. “Syndromic approach” to diagnosis M Chugh TD, Rungta N. Tropical Fevers: Management
and treatment of critical tropical infections. Indian J Crit guidelines. Indian J Crit Care Med. 2014;18(2):62-9
Care Med. 2014;18(7):479. (Reproduced with Permission)
4. John TJ, Dandona L, Sharma VP, Kakkar M. Continuing 6. WHO, India. National Guidelines for Clinical Management
challenge of infectious diseases in India. Lancet. 2011; of Dengue Fever, National Vector Borne Disease Control
377:252-69. Programme; 2015.
5. Singhi S, Chaudhari D, Varghese GM, Bhalla A, Karthi N,
Kalantri S, Peter JV, Mishra R, Bhagchandani R, Munjal
CHAPTER
93
Vivax Malaria: No Longer Benign!
K Nagesh
INTRODUCTION EPIDEMIOLOGY
Historically, malaria is as old as the mankind itself. King In the 21st century, malaria still continues as the greatest
Alexander in 323 BC developed fever during a war, which killer in the tropical countries including India. It ranks
increased day by day and finally he drifted into coma one among the ten leading killer diseases in the world.
and died. This 33-years-old warrior, who had conquered Half of the world’s population across hundred countries
almost all the known world, at the height of his power are still living under the dark shadow of malaria (Fig. 1).
died of a disease called ‘Malaria’. In the ancient wars, About 300–500 million cases are being reported every
malaria has killed more people than the actual weapons; year across the globe, killing around one million people
but for malaria, the results of many wars, the destiny of per year.
many kings and the geographical boundaries would have In India, malaria is prevalent all over except Jammu
been different. and Kashmir (Fig. 2). 77% of the burden of malaria in
Fig. 1: World scenario of malaria

CHAPTER 93: Vivax Malaria: No Longer Benign! 571
Fig. 2: Malaria endemic areas in India
South East Asia is from India, 40% of the global Malaria Plasmodium ovale
death outside Africa is in India. Plasmodium malariae
It is very unfortunate that, though malaria is pre Plasmodium knowlesi
ventable and potentially curable; in the battle between Plasmodium vivax and Plasmodium falciform are the
malaria and mankind, malaria still has the upper hand two dominant species in India. Plasmodium knowlesi is
(Fig. 3).1 not reported in our country.
MALARIA PARASITE VIVAX MALARIA

Malaria is caused by a parasite belonging to the genus Plasmodium vivax threatens almost 40% of the world’s
Plasmodium, the important species that causes human population, resulting in 132–391 million clinical
infection are: infections each year. Most of these cases originate from
Plasmodium falciparum South East Asia and western Pacific region,2 50% of the
Plasmodium vivax malaria burden in South East Asia including India is
Fig. 3: Global mortality due to malaria for the last three decades1
contributed by Vivax malaria. Compared to Plasmodium TABLE 1: Comparison of organ involvement (Severe P. vivax vs P.
falciparum, Plasmodium vivax has got slightly longer falciparum malaria)5
incubation period (12 days to several months), similar Organ system Vivax malaria Falciparum malaria
N=488 N=233
erythrocytic cycle (42–48 hrs) and produces fewer
Thrombocytopenia 435 (89.13%) 178 (79.82%)
merozoites per schizont. As Plasmodium vivax require
Hepatic 95 (9.46%) 81 (36.32%)
duffy antigen to invade host erythrocytes, it is less
Renal 156 (31.96%) 123 (55.15%)
common in sub Saharan Africa. Recently, this has been
Cerebral 40 (8.19%) 32 (14.35%)
challenged by the observation that Plasmodium vivax
Lungs 8 (1.63%) 5 (2.24%)
transmission in a population found to be duffy antigen
Deaths 44 36
negative,3 however further studies are needed in this
% Deaths 9.01% 16.14%
regard. Plasmodium vivax has apparent preference for
invading young red cells in contrast to falciparum, which
vivax malaria has started showing its malignant face.
invades broader range of erythrocyte ages. A proportion
The severe complications with organ involvements like
of sporozoites persistently remains in the hepatocytes
ARDS, acute renal failure, hepatitis, coma, severe anemia,
as hypnozoites, which can cause relapse of infections in
thrombocytopenia, DIC have been reported in vivax
few weeks to many years. This ability to relapse renders
malaria from all across the endemic countries including
Plasmodium vivax resilient to eradicate from human
India” (Table 1).2,4-7,15
host.
In asia, Plasmodium vivax is emerging as a dominant
species, with chloroquine resistance starting to spread,
MALIGNANT BEHAVIOR OF makes it an important health issue. Severe fatal drug
PLASMODIUM VIVAX resistant severe vivax malaria challenges our perception
For centuries, Vivax malaria was called as ‘benign of vivax malaria as a benign disease. It has been neglected
tertian malaria’, it was believed as, it does not cause under the shadow of Plasmodium falciparum by the
organ involvement, no mortality, can be managed on researchers, policy makers and the funding bodies.
outpatient basis with oral medication. “Of late this benign Although the emphasis on Plasmodium falciparum is
appropriate the burden of vivax malaria should not be polyarthralgia, dry cough, acute abdomen, psychosis,
under appreciated.2 frequent urination, ataxia, acute GE, jaundice, coma, etc.
Plasmodium vivax has started punching above its weight. Malaria can mimic anything and everything, physicians
practicing in endemic areas should develop a high degree
PATHOPHYSIOLOGY of suspicion.
The exact pathogenesis of this malignant behavior
of Plasmodium vivax remains unclear and poorly CLINICAL CLASSIFICATIONS
understood, because of paucity of researches in this field, Uncomplicated malaria
however the possible postulations are: Severe malaria
Although cytoadherence and sequestration is known Uncomplicated malaria is one where the patient does
to be the main mechanism for severe falciparum not exhibit any organ involvement, generally does not
malaria, the same is not a feature in Plasmodium carry any mortality. The term complicated malaria has
vivax. Recently, this paradigm has been challenged been given up and has been replaced by the term “severe
suggesting that Plasmodium vivax infected red cells malaria”.
can also sequestrate in organs such as lung.8
Few studies have clearly demonstrated that severe Severe Malaria
Vivax malaria is strongly associated with potent Patient who is found positive for malaria parasite
proinflammatory response and ‘cytokine storm’. and if has any one of the feature listed in Table 2, is
Interferon gamma (IFN) is also implicated in disease supposed to be suffering from severe malaria.
severity. Conversely plasma interleukin-10 (IL-10), Severe malaria is a medical emergency.
a cytokine that down regulates inflammation, was If untreated/missed, carries mortality near to 100%.
lower with increased disease severity.9 All deaths in malaria are due to severe malaria.
The direct lytic effect, immunological reaction, splenic Urgency and aggressiveness is the key to success.
sequestration and oxidative stress are some of the IV antimalarial should be used in preference.
suggested mechanism for severe thrombocytopenia
in Vivax malaria.10 Lab Diagnosis
Altered rheological properties of parasitized red Parasitological confirmation is mandatory before starting
cells and vascular endothelial changes contribute antimalarial treatment.12
to the microvascular obstruction. New evidence Microscopy
also suggests that, at molecular level, localized Rapid diagnostic test
and generalized ischemic hypoxia may enhance Quantitative buffy coat (QBC)
cytokine induced nitric oxide synthetase, resulting in

detrimental nitric oxide generation.11 TABLE 2: Features of severe malaria12
zz Impaired consciousness/coma. zz Severe anemia (Hb<5 mg%)
Both sequestration related and nonsequestration related
zz Multiple convulsions >2 in zz Hypoglycemia
complications may occur in Vivax malaria. 24 hours (RBS <40 mg%)
zz Circulatory zz Hemoglobinuria
CLINICAL FEATURES zz Collapse/shock (Systolic BP zz Hyperparasitemia
<70 mm Hg) (>5% parasitized RBCs)

Classically, malaria may present with intermittent chills/
zz Jaundice (Serum bilirubin >3 zz Hyperpyrexia (temperature
rigors, fever, sweating (cold stage, hot stage, sweating mg%) 106°f )
stage) with malaise, body ache, head ache and vomiting zz Renal failure (Serum creatinine zz Hyperlactemia
as associated symptoms, but these classical symptoms >3 mg%)

zz Abnormal bleeding/DIC Metabolic acidosis
may be absent in good number of patients, instead zz
zz Pulmonary edema/ARDS zz Prostration

they may present with atypical fever, only headache,
Bone marrow studies ACT should be given for at least three days.
Polymerase chain reaction (PCR) Primaquine: single dose of 0.75 mg/kg body weight
Microscopy with thin and thick smear is still the on day 2, 13 and 0.25 mg/kg body weight in low
gold standard for the parasitological confirmation of transmission area.12
malaria. One can identify the species and also quantify
the paracytemia. The disadvantages are it is time Second Line Treatment
consuming, needs skilled personnel. A negative smear Alternative ACT
does not rule out malaria in a strongly suspected case, or
repeated smear examination may be needed. Rapid Oral Artesunate + Doxycycline/Clindamycin for
diagnostic tests (RDT) are simple, easy to perform, yields 7 days
quick and reliable results, has been fully approved by or
WHO for the confirmation of malaria. The disadvantages Oral Quinine + Doxycycline/Clindamycin for 7 days
of RDT are, one cannot quantify and may remain positive
Oral Artesunate monotherapy has been banned in India.
for several weeks after the acute infection, hence should
not be used to detect recrudescence. The QBC is almost
Management of Severe Malaria12,13
equalent to a good thick and thin smear examination.
IV artesunate 2.4 mg/kg, 0 hr, 12th hr and 24th hr,
Bone marrow studies are not routinely recommended
then once daily.
except in a desperate situation to prove the diagnosis
IV quinine may be used if only IV artesunate is not
in a rare case. PCR tests should be reserved for research
available in the dose of 20 mg/kg stat and then 10 mg/
purposes considering its cost and nonavailability in
kg every 8th hrly, (IV infusion in dextrose over 4 hrs).
peripheral centers.
Artimether 3.2 mg/kg IM on admission then 1.6 mg/kg
IM OD.
MANAGEMENT
Alpha-beta artether 150 mg IM, OD for three days.
Treatment of uncomplicated P. vivax malaria:12
IV antimalarial should be given for a minimum of
Chloroquine 25 mg base/kg body weight divided over
24 hrs, thereafter ACT may be started
three days.
Supportive measures like antipyretics, anti
Primaquine 0.25 mg/kg once daily for 14 days.
convulsants, good oral and intravenous hydration,
Chloroquine resistant vivax should be treated with
should be taken care. Artificial ventilation, blood
Artemisinin based combination therapy (except AS
transfusion and dialysis may be considered if
+SP) + Primaquine.
indicated.
Primaquine is contraindicated in pregnancy, infancy,
mothers breast feeding infants less than six months of Revised dose recommendation for parenteral Artesunate in
age and in patients with G6PD deficiency. young children:12
Children weighing <20 kg should receive a higher dose of
Treatment of uncomplicated PF malaria: Artesunate (3 mg/kg bw per dose) than larger children and adults
ACT is the treatment of choice (Table 3) (2.4 mg/kg bw per dose) to ensure equivalent exposure to the drug.
TABLE 3: Artemisinin based combination therapy (ACT)12 TREATMENT OF MALARIA

zz Artemether + Lumefantrine (AL) IN PREGNANCY
zz Artesunate + Amodiaquine (AS+AQ) Uncomplicated P. vivax
zz Artesunate + Mefloquine (AS+MF) Chloroquine is used in all trimesters. As Primaquine
zz Artesunate + Sulfadoxine Pyrimethamine (AS+SP) is contraindicated, chloroquine in the dose of 300 mg
zz Dihydroartemisinin + Piperaquine (DHA+PQ) weekly should be administered to prevent relapse, till the
complication of pregnancy and thereafter primaquine REFERENCES

should be given. 1. Christopher JL Murray, Lisa C Rosenfield, Stephen S Lim,
Kathryn G Andrews, Kyle J Foreman, et al. Global malaria
Uncomplicated P. falciparum mortality between 1980 & 2010: A systematic analysis, The
Lancet. 2012;379(9814):413-31.
First trimester: Oral Quinine, 10 mg/kg body weight three
2. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, et al.
times daily, plus oral Clindamycin 10 mg/kg body weight, Vivax malaria: neglected not benign. Am J Trop Med Hyg.
two times daily should be administered for seven days. 2007;77(6 suppl):79-87.
3. Ryan JR, Stoute JA, Amon J, Dunton RF, Mtalib R, et al.
Second and third trimesters: ACT is the treatment of
Evidence for transmission of P vivax among a duffy antigen
choice. negative population in western Kenya. Am J Trop Med Hyg.
Severe malaria: 2006;75:575-81.
First trimester-IV Quinine plus Clindamycin
4. Kochar DK, Das A, Kochar SK, et al. Severe Plasmodium
vivax malaria: A report on serial cases from Bikaner in North
Second and third trimester-IV Artesunate
western India. Am J Trop Med Hyg. 2009;80:194-98.
5. Nadkar MY, Huchche AM, Singh R, Pazare AR. Clinical
CLINICAL MALARIA13,14 profile of severe Plasmodium vivax malaria in a tertiary
A case of suspected malaria without lab confirmation care centre in Mumbai from june 2010-january 2011.JAPI.
in endemic area. 2012;60(10):11-3.
6. Zubairi ABS, Nizami S, Raza A, Mehraj V, Rasheed AF, et al.
All efforts should be made to confirm parasitologically
Severe Plasmodium vivax malaria in Pakistan. Emerging
by repeated smear and RDT examination infectious diseases. 2013;19(11):1851-4.
All other prevailing infections to be ruled out 7. Limaye CS, Londhey VA, Nabar ST. The study of complications
Should be treated with chloroquine in full therapeutic of Vivax malaria in comparison with Falciparum Malaria in
dose Mumbai. JAPI. 2012;60(10):15-8.
Severe malaria without any alternative explanation 8. Anstey NM, Handojo T, Pain MC, Kenangalem E, Tjitra E.
Lung injury in vivax malaria: pathophysiological evidence
should be treated accordingly.
for pulmonary vascular sequestration and post treatment
Presumptive treatment with single dose of chloroquine alveolar-capillary inflammation. J infect Dis. 2007;195:589-
has been banned.13 96.
9. Hemmer CJ, Holst FG, Kern P, Chiwakata CB, Dietrich M, et
al. Stronger host response per parasitized erythrocyte in
CONCLUSION Plasmodium vivax or ovale than in Plasmodium falciparum
Plasmodium vivax malaria is neglected, underestimated malaria. Trop Med Int Health. 2006;11:817-23.
and mistakenly considered as benign. Despite its 10. Goel A, Mangla A, Singh T. Changing pattern of Vivax
huge prevalence, researches in this regard lacks malaria. Pediatrics & Therapeutics, 2014;4(4). http://
dx.doi.org/10.4172/2161-0665.1000e124.
disproportionately. Vivax malaria with increasing
11. Mohanty D, Ghosh K, Nandwani SK, Shetty S, Philips C,
chloroquine resistance, coupled with its malignant
et al. Fibrinolysis, inhibitors of blood coagulation and
behavior, we may be looking a disaster in making. monocyte derived coagulant activity in acute malaria. Am J
Clinicians should become more aware of this paradigm Hematol. 54:23-9.
shift and make a strong note that vivax malaria is no 12. WHO 2015: Guidelines for the treatment of malaria.
longer benign and treat accordingly. 13. National Drug Policy 2014: Guidelines for diagnosis and
treatment of malaria in India.
14. White NJ. Malaria, Manson’s Textbook of tropical diseases.
2015;23:532-600.
15. Genton B, Mueller I. Vivax malaria-More severe and more
resistant. Therapy. 2010;7(1):39-48.
CHAPTER
94
Newer Modalities in
Diagnosis of Tuberculosis
Prem Parkash Gupta
INTRODUCTION country and in other resource limited countries. The

The causative agent of tuberculosis (TB), Mycobacterium significant advantages of sputum microcopy are its
tuberculosis, was discovered by Henirich Herman Robert being a rapid and inexpensive test. The advantages are
Koch around 135 years back in 1882. Since then there particularly negated by its poor sensitivity, ranging from
have been tremendous efforts to wipe the disease from 45–80% in culture confirmed pulmonary tuberculosis
global scenario, however, till today, there is a huge global and, additionally, its poor positive predictive value
burden of TB in term of morbidity and mortality and ranging from 50–80% in settings where nontuberculous
likely to remain so in near future. Globally, over 9 million mycobacteria are commonly isolated. Fluorescence
new tuberculosis occur annually leading to more than 1.7 microscopy has been found to be 10% more sensitive, as the
million deaths annually. A great majority of these cases slide examination may be done at a lower magnification
are fully preventable and treatable. covering more area. LED microscopy showed 84%
As tuberculosis is an infectious disease, the most sensitivity and 98% specificity against culture as the
significant control strategies include timely diagnosis reference standard. LED microscopy was significantly
and the appropriate treatment of diseased subjects more sensitive by 6%, with no appreciable loss in
to prevent spread in close contacts. Worldwide, case specificity, when compared with direct Ziehl-Neelsen
detection rate of tuberculosis remains unacceptably microscopy. LED microscopy was 5% more sensitive
low being only 64%. The diagnosis of tuberculosis can and 1% more specific than conventional fluorescence
be decisively made using various laboratory tests and microscopy. LED microscopy is recommended by the
adopting the appropriate one amongst the plethora of World Health Organization (WHO) over conventional
the tests available require judicious decision making. and fluorescence microscopy.
As newer tests become reality, strengthening the
existing laboratory capacity and improvement in their
CULTURE-BASED METHODS FOR
performance is essential. THE DIAGNOSIS OF TUBERCULOSIS
Conventional Solid Media
DIRECT SPUTUM SMEAR Until early nineties, mycobacterial cultures were
MICROSCOPIC EXAMINATION usually done on solid egg-based media and were
For over last 100 years, microscopic examination of regarded as Gold Standard Test for confirmation of
sputum specimens has been the mainstay for detection the tuberculous etiology. The most common culture
of pulmonary tuberculosis, and still remains so in our medium employed was Lowenstein Jensen medium. In
CHAPTER 94: Newer Modalities in Diagnosis of Tuberculosis 577
addition of being able to isolate the M. tuberculosis, other

alternate mycobacterial species could be detected using
appropriate laboratory tests. Culture is still considered
as a key tool in the diagnosis of tuberculosis, despite
the onslaught of new modalities including polymerase
chain reaction. The major drawback is time required;
it takes up to 6 weeks before the mycobacterial growth
may becomes identifiable over a solid medium culture
and further up to 6 weeks may be required for drug
susceptibility testing.
Liquid Culture
At present liquid cultures are regarded as the “Gold
Standard” for detection of mycobacterial susceptibility
Fig. 1: BACTEC MGIT 960 system (BD, USA)
to anti-tubercular drugs. The significant advantages of
liquid medium are:
—— MB Redox (biotest diagnostics, USA)
The sensitivity for the growth of M. tuberculosis has
Semiautomated system
seen a significant increase (up to 20%), and
—— BACTEC 460TB (BD, USA)
A significant reduction in detection time (10–14
Fully automated systems
days compared with up to 4 weeks). The drawback
—— BACTEC 9000 MB (BD, USA)
is a higher rate of contamination of liquid medium.
—— BACTEC MGIT 960 (BD, USA) (Fig. 1)
For primary isolation of mycobacteria, WHO has
—— ESP culture system II (Trek Diagnostics, USA)
recommended the use of traditional solid media
—— MB/BacT ALERT 3D system (BioMerieux, NC)
along with liquid media.
Liquid medium most frequently used is Middlebrook
RAPID DETECTION OF DRUG
7H9 broth. It is supplemented with 10% OADC (oleic
acid, albumin, dextrose, and catalase) and, to prevail
RESISTANCE: IN-HOUSE METHODS
over contamination with other microorganisms, PANTA Advantages of these in-house methods are rapid
(an antibiotic mixture of polymyxin, amphotericin detection of drug-resistance under low-income settings.
B, nalidixic acid, trimethoprim, and azlocillin) is Some of these methods are as shown below:
Microscopic observation of drug susceptibility
added. Mycobacteria Growth Indicator Tube (MGIT) is
considered as the best tool with regard to sensitivity, (MODS)
Thin layer agar (TLA)
while LJ solid medium sets the current standard for
Colorimetric redox indicator (CRI) methods
specificity. Liquid media may provide positive results
Nitrate reductase assay (NRA)
in about half of time that is required for those in case of
solid media. All types of clinical specimens, pulmonary
as well as extra-pulmonary (except blood and urine), Microscopic Observation Drug
can be processed for primary isolation in the MGIT tube Susceptibility (MODS) Assay
using conventional methods. At present, a number of The microscopic observation drug susceptibility (MODS)
commercially available elaborate culture systems are in assay is a low-tech as well as a low-cost tool for detection
existence: of tuberculosis and drug resistance tuberculosis. The
Simple system underlying principles being:
—— MGIT (BD diagnostic systems, USA) The growth of M. tuberculosis (MTB) is faster in liquid
—— Septi-Chek AFB (BD, USA) media than on solid media.

M. tuberculosis growth in liquid media is characterized propensity to reduce nitrate to nitrite which is detected
by microscopic appearances of cording, strings or by adding a specific reagent like Griess reagent.
tangles making them to be noticed much earlier than These low cost in-house methods have almost
waiting for the macroscopic appearance of colonies comparable precision to commercial liquid culture
on solid media. systems. These methods can be implemented in high-
It is possible to integrate the antitubercular drugs burden, low-income settings as an intermediate solution
like isoniazid and rifampicin into the MODS assay to significantly reduce the cost of overall national
to have a concurrent confirmation of drug resistance programs. There drawbacks include the requirement
tuberculosis directly. of extensive operator training, standardization and
MODS culture offers faster and more sensitive results quality assurance before implementation. WHO
than existing gold-standard methods. It provides side- has recommended MODS as an interim solution for
by-side detection of drug resistance tuberculosis and developing countries with low incomes that are waiting
being a low cost in-house tool may become feasible in for the regular implementation of liquid culture methods
a resource-limited settings. The disadvantages of the in their respective National Tuberculosis Control
MODS include Programmes.
1. requirement of an inverted microscope, which is
costly and not routinely available in laboratories,
DIAGNOSIS OF TB BASED
2. microscopically, differentiation between micro ON DNA TOOLS
colonies of Mycobacterium tuberculosis and those of For over two decades, numerous tools have been
rapidly growing mycobacteria may be difficult, and develop e d and des cr ib e d for the dete ction of
3. the assay requires daily examination, is time- M. tuberculosis using technology of polymerase chain
reaction (PCR) assay. The principle is to amplify a DNA
consuming, and carries a risk of laboratory trans
fragment specific for M. tuberculosis using appropriate
mission.
oligonucleotide primers that vary from tool to other tool.
One method incorporates polymerase chain reaction
COLORIMETRIC REDOX
(PCR) and restriction enzyme analysis (PRA) of the gene
INDICATOR METHODS
coding for the heat shock protein hsp65.
The method employs a preincubation of M. tuberculosis
Other method uses the amplification of the 16S
containing clinical specimen for several days in vitro rRNA gene specific for M. tuberculosis. This can be done
added with different antitubercular drugs and in different either by an in house methods or using a commercially
drug concentrations. This is followed by culture in a available kit : the MicroSeq 500 16S ribosomal DNA
liquid media to which added a colored indicator (Alamar (rDNA) bacterial sequencing kit (Applied Biosystems,
blue and Resazurin) in a microtiter plate. Colorimetric Foster City, Calif.).
redox indicator (CRI) methods are characterized by A commercially available method named as
the reduction of this colored indicator. Mycobacterial AccuProbe (Gen- Probe Inc.) uses a chemiluminescent
resistance to antitubercular drugs lead to a change in label that hybridizes to the ribosomal RNA of the targeted
color of the indicator. The change of color is proportional mycobacteria in clinical specimen. The results of the test
to the number of viable mycobacteria in the medium. are read using a luminometer and rapid diagnosis can be
achieved. Separate tools for the identification of various
Nitrate Reductase Assay mycobacteria species are available.
Nitrate reductase assay (NRA) requires culture of clinical
specimen containing mycobacteria over a solid media Nucleic Acid Amplification Tests
(conventional Lowenstein-Jensen medium) into which The nucleic acid amplification (NAA) tests are noteworthy
potassium nitrate has been added. M. tuberculosis has due to rapidity to provide the results within 6 hours.
A comparison with smear microscopy highlights the contamination and no requirement for biosafety facilities.
importance of NAA tests in term of having (1) better Diagnostic accuracy of this technique in term of sensitivity,
positive predictive value (over 95%) in settings in which specificity, positive predictive value and negative
non-tuberculous mycobacteria are common, and (2) predicted value for diagnosis of pulmonary tuberculosis
ability to detect M. tuberculosis in 50–80% of smear- were 79.5%, 100%, 100% and 94%, respectively and those
negative, culture-positive clinical specimens. for the detection of rifampicin resistance were 57.1%,
NAA tests are superior to culture methods in term 100%, 100% and 94.9%, respectively. The WHO has
of detecting M. tuberculosis weeks earlier than culture
endorsed the use of nucleic acid amplification tests in
in up to 90% of patients suspected with pulmonary
resource-limited settings since 2008.
tuberculosis in whom TB is ultimately confirmed by
culture. Still, a recent meta analysis considering accuracy
Loop-mediated Isothermal Amplification
of commercially available NAA tests in over 125 studies
noted an unacceptably high degree of variability in Test (LAMP)
accuracy across the studies. The meta-analysis noted The method is commercially made available by Eiken
a need for improvement in diagnostic accuracy of Chemical Co., Japan. This technology amplifies target
NAA tests. This was assessed that presently available DNA under isothermal conditions (at 65°C) and is
commercial NAA tests cannot replace “Gold Standard” intended to detect mycobacterial DNA visually in less
culture and microscopy for diagnosing pulmonary TB. than two hours. The step to denature double stranded into
Current US recommendation is “NAA testing should be a single stranded form is not required. Amplification and
performed on at least one respiratory specimen from detection of the DNA takes place in the same microfuge
each patient suspected with pulmonary TB for whom a tube (Fig. 3). WHO is conducting independent studies to
diagnosis of TB is being considered but has not yet been assess the feasibility and cost-effectiveness of the assay
established, and for whom the test result would alter case and whether it can replace sputum smear microscopy.
management or TB control activities.”
Various NAA tests commercially available are: Line Probe Assays
Amplified Mycobacterium tuberculosis Direct Test
The individual anti-tubercular drug resistance in M.
(MTD, Gen-Probe, San Diego, California)
Amplicor Mycobacterium tuberculosis Test (Amplicor,
tuberculosis is often characterized by mutations in well
described genes. The extensive knowledge regarding
Roche Diagnostics, Basel, Switzerland)
GeneXpert (Xpert MTB/RIF)
genes associated with drug resistance enabled the
Loop-Mediated Isothermal Amplification Test
development of line probe assays, which allow for the
(LAMP) (Eiken Chemical Co., Japan) simultaneous detection of multiple resistances rapidly
within 24–48 hours. Line probe assays have proven
GeneXpert (Xpert MTB/RIF) efficacy in detecting drug resistance tuberculosis in
This is a commercially available cartridge-based system a variety of geographical settings. It is observed to be
to detect M. tuberculosis as well as rifampicin resistance cost-effective when compared with mycobacterial
in a clinical specimen in flat 2 hours. The fully automated culture followed by DST. Two of the commercial systems
system purifies, concentrate, detect and identify available for the rapid identification are:
targeted nucleic acid sequences and do not require any 1. INNO-LiPA MYCOBACTERIA v2 (Innogenetics NV,
preprocessing of clinical samples. It utilizes real-time Ghent, Belgium),
PCR (rt-PCR) technology. 2. GenoType mycobacterium CM/AS tests (Hain
The test is module based and machines with 1, 4, Lifesciences, Nehren, Germany).
16 and 48 modules are available, with each module The WHO has recommended LiPA for the rapid
independently processing one cartridge at a time; diagnosis of MDR-TB in high TB-burden, low-income
(Fig. 2). The system is fully closed so there is no risk of settings.
Fig. 2: GeneXpert MTB/RIF four module system. Placing of GeneXpert cartridge is shown here; and GeneXpert MTB/RIF cartridge
Mantoux test being one of the commonly used TSTs.

TSTs can not differentiate between latent infection and
active disease; additionally they have poor sensitivity
and specificity. A false-positive TST may result due to
contact with nontuberculous mycobacteria or due to
BCG vaccination in past. Inspite of its limitations, TSTs
remain the most widely used supportive method to add
the probability of mycobacterial infection. The test is
done by injecting intradermally a small dose of a purified
protein derivative of M. tuberculosis (PPD) into the skin
on the forearm. A positive TST means an induration of 10
Fig. 3: Loop-mediated isothermal amplification test (LAMP); mm (5 mm in HIV seropositive subjects) at the injection
P represent a positive result and N represent a negative result
site within 2 days.
LATENT TUBERCULOUS INFECTION
Interferon Gamma (IFN-γ) Release Assays
DIAGNOSIS
The interferon gamma (IFN-g) release assays (IGRAs)
Tuberculin Skin Test are in vitro blood tests to detect cell-mediated immune
Persons with latent TB infection are usually infected response. They measure release of interferon (IFN)
with mycobacterial bacilli, without having a full blown gamma from T cells following stimulation of blood
disease. Conventionally, diagnosis of latent tubercular sample by the mycobacterial specific antigens: (1)
infection is made using a tuberculin skin test (TST), early secretory antigenic target, ESAT-6 and (2) culture
filtrate protein, CFP-10. These antigens are are unique to and IgM against M. tuberculosis antigens in serum. They
M. tuberculosis. Two commercially available IGRAs include: have been in use in some parts of the world in past mainly
1. Quantiferon TB Gold tests, Cellestis, Victoria, due to commercial interests. Recent meta-analyses and
Australia systematic reviews after extensive deliberations over the
2. T-SPOT TB, Oxford Immunotec, Abington, UK. subject concluded against serological tests for providing
Superior efficacy of IGRA tests over the TSTs for the inconsistent results due to issues of cross reactivity with
detection of tubercular infection has been described by other mycobacterial antigens and poor sensitivity.
various past studies. IGRAs is not intended to distinguish The WHO recommends against their use for the
between latent infection and active tubercular disease diagnosis of pulmonary as well as extrapulmonary
and should not be used as a biomarker for the diagnosis
tuberculosis and Government of India, through a Gazette
of active TB. This is particularly so in high tubercular
notification, has banned them as diagnostic tests for
infection prevalence regions like India and isolated
tuberculosis disease.
positive IGRA without any clinical and other laboratory
findings cannot be a basis to diagnose active tuberculosis
CONCLUSION
warranting the start of antitubercular drugs.
The diagnostic modalities presently available for clinical
SEROLOGICAL DIAGNOSIS OF TB management of tuberculosis diagnosis and identification
There have been numerous studies in past aimed at of drug resistance tuberculosis are concisely summarized
detection of antibodies like immunoglobulins IgG, IgA in Table 1.
TABLE 1: A summary of tuberculosis diagnostic modalities

Diagnostic tool Methodology Advantages Weakness Sensitivity Cost Time delay
Direct smear Ziehl-Neelsen, Minimal equipment Operator-dependent, no DST, Low Inexpensive Rapid
microscopy Auramine/Rhodamine required; low cost inadequate sensitivity,
particularly for extrapulmonary
tuberculosis, HIV coinfection,
and in children
Conventional Lowenstein-Jensen Low cost; simple; Biosafety hazards; quality Moderate Moderate Very Slow
solid culture gold standard; can control essential; DST possible
provide DST only after detection
Recent culture BACTEC MGIT, Sensitive; DST; Biosafety hazards; cross- High Moderate-to- Intermediate
using synthetic Thin-layer agar Extrapulmonary contamination; manpower expensive
media tuberculosis training; equipment
requirements; DST only
after detection; cold chain
requirements
MODS In-house protocol; Concurrent DST and Biosafety concerns; training and High Moderate-to- Intermediate
Hardy kit rapid culture equipment requirements; cold expensive
chain requirements
NAAT GeneXpert Amplicor, Concurrent DST; Genotypic DST with Moderate Moderate/ Rapid
Gen-probe, biosafety; simple questionable clinical expensive
LAMP, implications; moderate
sensitivity
Line probe INNO-LiPA Rif, MTBDR Rapid DST for Expensive; complex; Genotypic Low Expensive Rapid
tuberculosis DST with questionable clinical
implications; cold chain
requirements
Serological LAM TB ELISA Nonsputum based Low sensitivity in Low Undefined Rapid
HIV-uninfected patients
Low specificity
Abbreviations: DST, drug-susceptibility testing; HIV, human immunodeficiency virus; LAM, liproarabinomannan; LAMP, loop-mediated
isothermal amplification; MODS, microscopic-observation drug susceptibility; NAAT, nucleic acid amplification tests
BIBLIOGRAPHY 6. Simner PJ, Doerr KA, Steinmetz LK, Wengenack NL.

1. Brady MF, Coronel J, Gilman RH, Moore DA. The MODS Mycobacterium and aerobic actinomycete cultures: are two
method for diagnosis of tuberculosis and multidrug medium types and extended incubation times necessary? J
resistant tuberculosis. J Vis Exp. 2008;17:845. Clin Microbiol. 2016;54:1089-93.
2. Centers for Disease Control and Prevention. Updated 7. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC,
Guidelines for Using Interferon Gamma Release Assays Dendukuri N. Xpert® MTB/RIF assay for pulmonary
to Detect Mycobacterium tuberculosis Infection, United tuberculosis and rifampicin resistance in adults. The
States, 2010. MMWR. 2010;59:1-25. Cochrane Database of Systematic Reviews. 2014;1:1-166.
3. Gray CM, Katamba A, Narang P, Giraldo J, Zamudio C, 8. Update: Nucleic acid amplification tests for tuberculosis.
Joloba M, et al. Feasibility and operational performance MMWR Morb Mortal Wkly Rep. 2000;49:593-4.
of tuberculosis detection by loop-mediated isothermal 9. WHO. Fluorescent light-emitting diode (LED) microscopy for
amplification platform in decentralized settings: Results diagnosis of tuberculosis policy. Policy statement. http://
from a multicenter study. Journal of Clinical Microbiology. www.who.int/tb/publications/2011/led_microscopy_
2016;54:1984-91. diagnosis_9789241501613/en/ (Accessed on August 14,
4. Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic acid 2017)
amplification tests for diagnosis of pulmonary tuberculosis 10. WHO. Global tuberculosis report 2014. Geneva: World
in respiratory specimens: meta-analysis and meta- Health Organization, 2014. http://www.who.int/tb/
regression. PLoS One. 2008;3:e1536. publications/global_report/en/ (accessed August 06,
5. Person AK, Pettit AC, Sterling TR. Diagnosis and treatment of 2017).
latent tuberculosis infection: an update. Current respiratory
care reports. 2013;2:199-207.
CHAPTER
95
Resurgence of Yellow Fever:
A Great Challenge
Rajib Ratna Chaudhary
Yellow fever is an arthropod-borne viruses (arboviruses) TRANSMISSION OF YELLOW

disease which has recently reemerged, and rapidly FEVER VIRUS
spreading through populations that had not previously Yellow fever virus is an RNA virus that belongs to the
been exposed to yellow fever virus, causing substantial genus Flavivirus. West Nile, St. Louis encephalitis,
morbidity and mortality. The first arthropod-borne and Japanese encephalitis viruses are related to it.
vius disease was dengue, which reemerged and caused The infected Aedes or Hemagogus species mosquitoes
widespread disease predominantly in South America transmits yellow fever virus to human through its bite.
and the Caribbean in the 1990s. This epidemic was Mosquitoes acquire the virus by feeding on infected
followed by West Nile virus in 1999 and chikungunya in primates (Human or nonhuman) and then transmit
2013, which continues to cause disease, and Zika virus the virus to other primates (Human or nonhuman).
recently emerged in Brazil in 2015 and spread through Human infected with yellow fever virus are infectious
infected travelers to many parts in the world. to mosquitoes (referred to as being “viremic”) after the
Yellow fever is a fifth arbovirus virus disease which onset of fever and upto 5 days after onset.
has reemerged in Brazil and the majority of the infections There are three transmission cycles of yellow fever
occurring in rural areas of the country. Yellow fever virus.
is a zoonotic flavivirus infection transmitted by Aedes
mosquitoes. Yellow fever was imported in to the South Sylvatic (Jungle)
Americas in the 1600 from Africa through slave trade, The sylvatic (jungle) cycle involves transmission of the
this has been suggested by genetic studies. Cuban virus between mosquito species found in the forest
epidemiologist Carlos Finlay in 1881 proposed that canopy and nonhuman primates (e.g. monkeys). The
yellow fever was a mosquito-borne infection and the virus is transmitted by mosquitoes when humans are
fact was verified by the US Army physician Walter Reed visiting or working in the jungle.
and a Yellow Fever Commission in 1900. Later on,
better sanitation practices and mosquito-control efforts Intermediate
virtually eliminated yellow fever from Americas but An intermediate (savannah) cycle exists in Africa that
sporadic outbreaks of varying magnitude continued in involves transmission of virus to humans living or
tropical regions. working in jungle border areas from infected mosquitoes.
to distinguish from other flulike diseases. Symptoms

includes malaise, headache, fever, retroorbital pain,
nausea, vomiting, and photophobia. There may be
relative bradycardia, conjunctival injection, and facial
flushing. A clue to diagnosis may be provided by high
fever associated with bradycardia, leukopenia, and
transaminase elevations, and patients will be viremic
during this period.
Stage of Remission
This initial stage is followed by a period of remission with
clinical improvement and most patients recover fully.
Fig. 1: Aedes aegypti
Stage of Intoxication
The virus can be transmitted from monkey to human or
The symptoms may recur after 24–48 hours in 15 to 20%
from human to human via mosquitoes bite in this cycle.
of patients and progress to intoxication stage which is
Urban characterized by high fever, relative bradycardia (Paget
In this cycle, transmission of the virus occurs between a sign), hypotension, hemorrhagic manifestations (nasal,
viremic humans infected in the jungle or savannah and oral, gastrointestinal), severe hepatic dysfunction
urban mosquitoes, primarily Aedes aegypti (Fig. 1). and jaundice (hence it is called “yellow fever”), renal
People cannot spread yellow fever among themselves failure, cardiovascular dysfunction, delirium and central
through casual contact, although the infection can be nervous system dysfunction which may progress to
transmitted directly into the blood through contaminated coma, and shock. Antibodies may be detected during
needles. this stage and viremia has usually resolved in this stage.
There may be 20–60% case fatility range in patients with
PATHOGENESIS severe disease as the treatment is supportive, because no
The viruses replicate in the lymph nodes and antiviral therapies are currently available.
infect dendritic cells after the bite of an infected mosquito.
They reach the liver and infect hepatocytes via Kupffer LABORATORY FINDING
cells, which leads to eosinophilic degradation of cells There may be leukopenia but it may not be present at the
and cytokines are released. Councilman bodies appear onset. Proteinuria as high as 5–6 g/L with kidney disease
in the cytoplasm of hepatocytes after apoptosis. is present, sometimes, and usually disappears completely
with recovery. Bilirubin can be remarkably abnormal
CLINICAL PRESENTATION with the levels of liver enzymes (AST usually doubling
The clinical manifestations may be difficult to recognize those of ALT). Prothrombin time may be elevated as well.
in early stage by most physicians who have never seen Serologic diagnosis is made by using capture ELISA to
a case of yellow fever. Yellow fever is suspected on the measure IgM during the acute and convalescent phases.
basis of clinical presentation and, a definitive diagnosis is Viral culture is used in epidemic settings. Rapid test
confirmed later which requires specialized laboratories. involving PCR and monoclonal antibody assays against
circulating viral antigens are available in specialized
Clinical Illness Manifests in Three Stages laboratories. The plaque reduction neutralization assay
Stage of Infection is the most frequently used test. IgM antibodies are
The incubation period is 3–6 days during which patients shown to persist in up to 73% of recipients 3–4 years after
present with a nonspecific febrile illness that is difficult vaccination.
CHAPTER 95: Resurgence of Yellow Fever: A Great Challenge 585
DIFFERENTIAL DIAGNOSIS mosquito density is high and there is risk of exposure, it

It is difficult to distinguish yellow fever on clinical is possible that travel related cases of yellow fever could
evidence alone from dengue, malaria, leptospirosis, occur, with brief periods of transmission in warmer
louse-borne relapsing fever, hepatitis, and other regions, due to prevalence of A. aegypti mosquitoes.
hemorrhagic fevers. Albuminuria is a constant feature in In an era of frequent international travel there are
yellow fever patients and its presence helps differentiate possibility of travel-related cases and local transmission
yellow fever from other viral hepatitides. Serologic in regions where yellow fever is not endemic. In the
confirmation is often required. light of the serious nature of this historically devastating
disease, public health awareness and preparedness are
TREATMENT AND PREVENTION critical, even for individual cases.
No specific antiviral therapy is available. Treatment is
directed toward symptomatic relief and management of CONCLUSION
complications. Yellow fever is an acute viral hemorrhagic disease
Max Theiler, a virologist developed a live attenuated transmitted by infected A. aegypti mosquitoes
yellow fever vaccine in 1937, that is still in use today and presenting with jaundice.
that provides lifetime immunity in up to 99% people The virus is endemic in tropical areas of Africa and
vaccinated, according to the World Health Organization Central and South America.
(WHO). Extensive vaccination campaigns combined Epidemics of yellow fever occur when infected people
with effective vector-control strategies have significantly introduce the virus into heavily populated areas with
reduced the number of yellow fever cases worldwide. high density of A. aegypti and where most people
have little or no immunity.
PROGNOSIS The vaccine provides effective life-long immunity
The death occurs most commonly between the sixth and within 30 days for 99% of persons vaccinated.
the tenth days in severe cases and the mortality rate is 20– Supportive treatment improves survival rates. There
50%. The temperature returns to normal by the seventh or is currently no specific antiviral drug available for
eighth day in survivors. There may be intractable hiccups, yellow fever.
copious black vomitus, melena, anuria, jaundice, and
elevated AST and these are unfavorable signs. There BIBLIOGRAPHY
may be 1–2 weeks of asthenia and convalescence may be 1. Brazilian Ministry of Health. Surveillance update. February
prolonged. Lifelong immunity is conferred to those who 2017.
recover from infection. 2. Fauci AS, Morens DM Zika virus in Americas – yet another
arbovirus threat, N Engl J Med. 2016;374:601-4.
As have been seen with dengue, chikungunya, and
3. Gardner CL, Ryman KD, Yellow fever: a reemerging threat.
Zika, A. aegypti-mediated arbovirus epidemics moved Clin Lab Med. 2010;30:237.
rapidly through populations with little pre-existing 4. Monath TP, Vasconcelos PF. Yellow fever. J Clin Virol.
immunity and spread due to increased aviation facility 2015;64: 160-73
to the people. A. aegypti also occurs in tropical and 5. World Health Organization. Vaccine and Vaccination
subtropical regions of Asia, the Pacific, and Australia, against yellow fever: WHO Position Paper, June 2013 –
recommandations.
yellow fever has never occurred in these parts of the
6. Wu JT, Peak CM, Leung GM, Lipsitch M. Fractional dosing
globe until the introduction of 11 cases by jet travel from
of yellow fever vaccine to extend supply: a modeling study.
an outbreak in Africa in 2016. Lancet. 2016;388:2904-11.
Although it is highly likely that yellow fever outbreaks 7. Yellow fever in Africa and the Americas, 2014. Wkly
in India, or Asia pecific may occur where A. aegypti Epidemiol Rec. 2015;90(26):323-34.
CHAPTER
96
Complicated Dengue
Rajeev Gupta
INTRODUCTION clinical manifestations ranging from myalgias, myositis,

rhabdomyolysis and hypokalemic paralysis. Guillain-
Overview
Barr Landry’s syndrome (GBS) can also be seen in
Dengue is an mosquito-borne infectious disease caused
patients who have neuromuscular involvement. Dengue
by any of the four dengue virus serotypes: DENVs. It is
associated Guillain-Barré syndrome responds very well
primarily transmitted to humans by the female Aedes
to treatment in form of intravenous immunoglobulins
mosquito. The disease is mainly seen in tropical and
(IVIG). Mononeuropathies can devlop in dengue. phrenic
subtropical regions. Infection with DENV results in
nerve dysfunction due to dengue mononeuropathy can
varying degrees of clinical conditions. It can manifest lead to diaphragmatic paralysis. Similarly plexopathies
as either of the following syndromes—asymptomatic are fairly common neurologic complications, brachial
dengue fever (DF) or dengue hemorrhagic fever (DHF) plexopathy, occurs more frequently than lumbo-sacral
or dengue shock syndrome (DSS) which can be fatal. plexopathy.
A dramatic worldwide increase in DENV has occurred
due to rapid urbanization, and increase in international CVS: About 34–75% of patients have electrocardiographic
travel, lack of effective mosquito-control measures, and (ECG) abnormalities because of dengue infection. These
globalization. are predominantly sinus bradycardia and conduction
defects, all of which are transient. On the other hand,
Complications although tachycardia is a well-known physiological
Usual complications: Thrombocytopenia (<100,000/L), response to febrile illness, it is less commonly observed,
bleeding tendencies in some cases severe ecchymoses with AF being a rare entity during dengue infection. Viral
and gastrointestinal bleeding, maculopapular rash, low myocarditis, leading to left ventricular dysfunction can
be seen in dengue patients.
pulse pressure
Cyanosis, hepatomegaly and acute hepatitis, Skin: Morbilliform, petechial rashes can be seen,
polyserositis - pleural effusions, ascites. mucosal involvement occurs in 15–30% of patients.
Unusal complications : CNS- Up to 4% of dengue ARDS: Hematological complications—thrombocytopenia,
patients can have involvement of neuromuscular leukopenia, hemoconcentration and hemophagocytic
system. Involvement of muscles can lead to various syndrome, risk of concurrent bacteremia.
CHAPTER 96: Complicated Dengue 587
Hyperferritinemia (Secondary failure. Mainly hepatocytes and Kupffer cells are affected
Hemophagocytic-Lymphohistiocytosis by the virus.
It is a life-threatening condition, it may be seen in primary Heparin sulphate, an acidic glucosaminglycan found
and secondary infection of dengue—it can present as in liver itself, is central to intrusion of the virus in liver cells.
following signs and symptoms: persistent fever, rash, When hepatocytes are infected by DENV hepatocellular
hepatitis, liver failure, seizures, altered sensorium. It apoptosis sets in. This can manifest as liver enzymes
is a dreadful complication and usually unrecognized elevation or fulminant hepatic failure. Management,
condition of dengue fever. just like any other hepatitis case, is primarily supportive.
Prognosis is usually good. However, one must be careful
Diagnostics Guidelines for HLH-2004 regarding the drugs being used in treatment as many
HLH can be diagnosed, if one of either of two criteria (see drugs can worsen the liver damage.
below) is fulfilled.
1. Molecular diagnosis confirmatory of HLH.
2. Diagnostic criteria for HLH fullfilled (5 out of 8 BIBLIOGRAPHY
criteria below) 1. Bhatt S, Gething PW, Brady OJ, et al. The globaldistribution
A. Initial diagnostic criteria: and burden of dengue. Nature. 2013;496(7446):504-7.
Clinical criteria: Fever, splenomegaly 2. Brady OJ, Gething PW, Bhatt S, et al. Refining the global
Laboratory criteria: Cytopenias (affecting ≥ 2 of 3 spatial limits of dengue virus transmission by evidence-
based consensus,” PLoS Neglected Tropical Diseases.
lineages in the peripheral blood)
2012;6(8):Article ID e1760.
Histopathologic criteria: Hemophagocytosis in
3. Chen R, Vasilakis N. Dengue-Quo Tu et Quo Vadis?” Viruses.
bone marrow or spleen or lymph nodes.
2011;3(9):1562-608.
No evidence of malignancy. 4. Gubler DJ. Dengue/dengue haemorrhagic fever: history
B. New diagnostic criteria low or absent NK-cell and current status, Novartis Foundation Symposium.
activity ferritin > 500 mg/L Soluble CD25 (i.e. 2006;277:3-16.
soluble IL-2 receptor) ≥ 2400 U/mL 5. Malavige GN, Fernando S, Fernando DJ, Seneviratne SL.
Dengue viral infections. Postgraduate Medical Journal.
Treatment 2014;80(948):588-601.
Exclusion of SIRS and secondary infection is important 6. Murphy BR, Whitehead SS. Immune response to dengue
before initiation of corticosteroids. Early recognition virus and prospects for a vaccine. Annual Review of
has a significant impact on the management and Immunology. 2011;29:587-619.
7. Sanofi Pasteur Media Release, http://www.sanofipasteur.
outcome. Dengue-associated HLH may indicate a
com/en/articles/First-Vaccinations-against-Dengue-Mark-
severe form dengue infection. The role of steroids, IVIG
Historic- Moment-in-Prevention-of-Infectious-Diseases.aspx.
and therapeutic plasma exchange in HLH have been
8. Stanaway JD, Shepard DS, Undurraga EA, et al. The global
described and used, however, convincing data is not burden of dengue: an analysis from the Global Burden
available. of Disease Study 2013. The Lancet Infectious Diseases.
2016;16(6):712-23.
HEPATIC COMPLICATIONS 9. World Health Organization, Dengue: Guidelines for
Hepatic involvement can range from asymptomatic Diagnosis, Treatment, Prevention and Control, WHO, Geneva,
elevation of hepatic transaminases to fulminant hepatic Switzerland; 2009.
CHAPTER
97
Scrub Typhus: Need for Alert
INTRODUCTION variants or strains of O. tsutsugamushi (Karp, Gilliam,

Scrub typhus is one of the three most common causes of and Kato). Infection with one strain does not preclude
prolonged fever in Southeast Asia and Pacific affecting reinfection with a different strain. Seasonality of the
almost 1 million people annually worldwide out of disease is determined by the appearance of larvae. In
1 billion exposed. Its distribution is limited to a triangle the Southeast Asia, scrub typhus season is observed mainly
in summer and autumn (July to November) after growth
so called” Tsutsugamushi triangle” extending between
of scrub vegetation particularly after rains.
Northern Japan, Western Australia, and Central Russia
that includes the Indian subcontinent, eastern Russia,
EPIDEMIOLOGY AND TRANSMISSION
China, and the Far East. Scrub typhus is a mite-borne
Scrub typhus is a common disease in endemic areas.
infectious disease caused by Orientia tsutsugamushi,
Although most cases of scrub typhus occur in rural areas,
distinct from other rickettsial infections. The disease has
a number of cases have been acquired in settings such as
been known since ancient times and was first described
suburban Bangkok, where the seroprevalence exceeds
by the Chinese in the third century (313 AD), but the first
20%, as well as urban areas, such as Beijing and Seoul.
description of its classic features came to surface when
It is also common in India but is apparently grossly
it showed a dramatic emergence in soldiers fighting on
under reported. Hotspots of Scrub typhus (termed ‘Mite
both sides in the Pacific theater during World War II. Island’) are associated with secondary vegetation and an
abundance of Trombiculid mites.It is transmitted by the
ETIOLOGY bite of trombiculid mite (genus-Leptotrombidium) larvae
O. tsutsugamushi is a rickettsial (Gram –ve intracellular (chiggers), infected by O. tsutsugamushi which serves
Cocobacillus) organism, formerly (until 1995) named as both vector and reservoir. The larvae typically bite
Rickettsia tsutsugamushi, which multiplies freely in the humans on the lower extremities or in the genital region.
cytoplasm of the host cells. The target cells in humans Transmission of O. tsutsugamushi may occur in sharply
are endothelial cells or monocytes and vasculitis is the delineated “mite islands” that consist of focal locations
most prominent clinical manifestation. This bacterium of scrub vegetation as small as a few square meters. The
exhibits a wide heterogeneity, which explains several ease of air travel and relatively long incubation period of
species in this genus. It lacks both lipopolysaccharide scrub typhus (up to two weeks) allow the disease to occur
and peptidoglycan in its cell wall. There are three in tourists returning to regions, where it is not endemic.
CHAPTER 97: Scrub Typhus: Need for Alert 589
CLINICAL MANIFESTATIONS The symptoms also var y according to organ

The disease occurs in patients exposed to rural or urban involvement. Gastrointestinal symptoms, including
foci of scrub typhus which usually occurs 7–10 days after abdominal pain, vomiting, and diarrhea, occur in up
the bite of an infected chigger (range 6 to 19 days). Scrub to 40% of children at presentation. Severe forms can be
typhus may begin insidiously with headache, anorexia, manifested as septic shock. Abortion commonly occurs
and malaise, or start abruptly with chills and fever. in pregnant women. In severe cases, evolution to a
Respiratory complaints are often present; cough occurs multiorgan dysfunction syndrome with hemorrhage can
in about 45% of patients. be observed.
Approximately, one-half of all patients develop a Elderly patients are more likely to have severe illness
characteristic nonpruritic, macular or maculopapular, and complications compared with younger patients.
pale, transient rash. The rash typically begins on the Acute kidney injury (AKI), mental confusion and
abdomen and spreads to the extremities. The face is also dyspnea are more common in older patients, whereas
often involved. Rarely, petechiae may develop. the frequency of fever, rash, and eschars is similar in both
Attentive examination may reveal an inoculat ion groups. A delay in therapy is associated with a higher risk
eschar at the site of the chigger bite and if present of complications.
is pathgnomic. Tender draining lymph nodes are Complications of scrub include interstitial pneu
sometimes present and limited to the site proximal to monia (20–35%), pulmonary edema, myocardial
the mite bite. A painless papule often appears at the site dysfunction, reversible complete heart block, congestive
of the infecting chigger bite. Subsequent central necrosis heart failure, circulatory collapse, CNS dysfunctions
then occurs, which in turn leads to the formation of a (delirium, confusion, and seizures), scrub cerebellitis,
characteristic eschar with a black crust (Figs 1 and 2). meningoencephalitis (15%), acute disseminated
The frequency of eschars in patients with scrub typhus encephalomyelitis (ADEM), AKI, transverse myelitis,
is highly variable (7–68%). One or multiple eschars opisthotonus and tetanic spasms and reversible
may develop before the onset of systemic symptoms. pancytopenia.
Hepatomegaly and splenomegaly can be observed. Mortality rate varies widely by location and is more in
Neuromeningeal symptoms are relat ively common older patients. In addition, the presence of myocarditis,
and range from slight intellectual blunting to coma or delirium, and pneumonitis is associated with a fatal
delirium. outcome (0–35%).
Fig. 1: A tough black scab surrounded by elevated red areola neither Fig. 2: A tough black healing scab mimicking a cigarette burn mark
painful nor pruritic
TABLE 1: Scrub typhus: Prevalence of signs and symptoms As these laboratory findings are relatively nonspecific,
Varghese, et al Sharma R, et al to confirm the presence of O. tsutsugamushi infection
Year of study 2005–2010 2012–2013 four methods can be used more definitively: serology,
Number of cases 623 125 biopsy, culture, and polymerase chain reaction. Serology
Location South India North India is the most used diagnostic tool. Immunofluorescence
Population Local residents Local residents and immunoperoxidase studies are the most reliable.
Signs and symptoms (%) The Weil-Felix test detects cross-reacting antibodies
Fever 100 100
to Proteus mirabilis OX-K and is still used because of
Headache 46 81.6
its low cost but it lacks sensitivity and specificity and
Cough and dyspnea 38 58.4
should be replaced by IFA or ELISA. Polymerase chain
reaction assay carried out on blood, eschar material,
Myalgias — 48
or lymph node samples are useful. Histopathology of
Nausea/vomiting 54 46.5
eschar or generalized rash reveals intense vasculitis with
Altered sensorium 26 20.8
perivascular collection of lymphocytes and macrophages.
Adenopathy — 29
Hepatosplenomegaly — 59.4
DIFFERENTIAL DIAGNOSIS
Eschar 43.5 17.6
The differential diagnosis includes fever of unknown
MODS (Multiorgan Dysfunction) 34 28.86
origin, enteric fever, dengue, dengue hemorrhagic
Case-fatality rate % 9 10.4
fever, malaria, other rickettsioses, tularemia, anthrax,
leptospirosis and infectious mononucleosis.
Varghese et al in South India studied 623 cases of
scrub, in which MODS occurred in (34%) and the overall TREATMENT
case fatality rate was 9%. Sharma R, et al. in North India Owing to the potential for severe complications, diagnosis
studied 125 cases with MODS occurring in 28.86% and a and decision to initiate early treatment should be based
mortality rate of 10.4%. (Table 1) on clinical suspicion or confirmation by serological
Paradoxically, scrub infection has been reported testing.
to lead to a diminution of viral load in human The recommended treatment regimen for scrub
immunodeficiency virus (HIV)-1–infected patients and typhus is doxyc ycline (4 mg/kg/day PO or IV divided
to help restore the immune status of infected patients. every 12 hours, 100 mg BD; maximum 200 mg/day for
7 days).
DIAGNOSIS Alternative regimens include tetracycline (25–50 mg/
As with all rickettsial diseases, no laboratory test is kg/day PO divided every 6 hours, 500 mg QID; maximum
diagnostically reliable in the early phases of scrub 2 g/day) or chloramphenicol (50–100 mg/kg/day divided
typhus. The disease is usually recognized when clinicians every 6 hr IV or PO, 500 mg QID; maximum 4 g/24 hr) or
correlate the presence of compatible clinical signs, Azithromycin (500 mg OD for 7 days).
symptoms, and laboratory features, with epidemiologic Azithromycin is also the drug of choice in pregnancy
clues. and children.
Patients with scrub typhus may develop the following Cases resistant to doxycycline have been reported,
laboratory abnormalities: and rifampin (600–900 mg orally daily) is a reasonable
The lymphocyte count is decreased and the T4 : T8 alternative often in combination with doxycycline in
ratio is diminished; lymphocytosis can also occur; such cases.
Liver enzyme levels, serum bilirubin and creatinine are Quinolones are not effective and should be avoided.
increased in 60% of cases and thrombocytopenia may be Duration of treatment should be at least 5–7 days or
present which is sufficient to cause bleeding. until the patient has been afebrile for ≥ 3 days to avoid
CHAPTER 97: Scrub Typhus: Need for Alert 591
relapse. Scrub typhus is so responsive to treatment that leads to a lot of confusion. Clin Infect Dis. 2007;44:391-
if patient does not become afebrile within 48 hours, 401.
2. Chapter 221, Scrub Typhus (Orientiatsutsugamushi)
diagnosis of Scrub typhus is unlikely or presence of other
by Megan E. Reller and J. Stephen. Textbook of Nelson
concomitant infection should be thought of. Pediatrics, 19th edn.
After apparent recovery, relapses frequently occur 3. Mandell, Douglas andBennette’s PPID, 8th edn. 2015.
and may also follow short treatment courses. Relapse is 4. Parola P, Watt G, Brouqui P. Orientia tsutsugamushi (scrub
usually less severe than the first attack. typhus). In: Yu VL, Weber R, Raoult D (Eds). Antimicrobial
Therapy and Vaccine, 2nd edn. New York: Apple Trees
Productions; 2002:883-7.
PREVENTION
5. Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline
Prevention is based on avoidance of the chiggers that versus azithromycin for treatment of leptospirosis and scrub
transmit O. tsutsugamushi. Protective clothing is the next typhus. Antimicrob Agents Chemother. 2007;51:3259-63.
most useful mode of prevention. No vaccine is available 6. Phongmany S, Rolain JM, Phetsouvanh R, et al. Rickettsial
till date. infections and fever, Vientiane, Laos. Emerg Infect Dis.
2006;12:256-62.
Mite control: The use of insect repellants and miticides 7. Scrub typhus: Clinical features and diagnosis- UptoDate
such as N,N-diethyl-3-methylbenzamide (DEET) are 2017; www.uptodate.com.
highly effective when applied to both clothing and 8. Sharma R, Krishana VP, et al. Analysis of Two Outbreaks of
Scrub Typhus in Rajasthan: A Clinico-epidemiological Study.
skin. Permethrin and benzyl benzoate are also useful
J Assoc Physician India. 2014;62:24-29.
agents when applied to clothing and bedding. 9. Varghese GM, Trowbridge P, Janardhanan J, et al. Clinical
profile and improving mortality trend of scrub typhus in
BIBLIOGRAPHY South India. Int J Infect Dis. 2014;23:39-43.
1. Blacksell SD, Bryant NJ, Paris DH, et al. Scrub typhus 10. Watt G, Kantipong P, de Souza M, et al. HIV-1 suppression
serologic testing with the indirect immunofluorescence during acute scrub-typhus infection, Lancet. 2000;356:
method as a diagnostic gold standard: a lack of consensus 475-9.
CHAPTER
98
Pyrexia of Unknown Origin:
Current Concept
SV Ramana Murty, Chakravarthy DJK
INTRODUCTION TABLE 1: Classification of FUO (Durack DT & Street AC, 1991)
Benjamin Felson in his prologue to his famous book Category of Definition

FUO
“Chest Roentgenology” states that “All of us have a
Classical zz Temperature > 38.36°C (101°F)
tendency to make a diagnosis on the basis of past zz Duration of > 3 weeks
experience with similar shadows. But remember; many zz Evaluation of at least 3 outpatients visits or 3
dissimilar conditions cast similar shadows.” So too with days in hospital

fevers… many dissimilar conditions may cause fevers Nosocomial zz Temperature > 38.3°C
zz Patient hospitalized 24 hours or longer but no
which appear to be similar. fever or incubating at admission
“Humanity has three great enemies: fever, famine and zz Evaluation of at least 3 days
wars. Of these by far the greatest and the most terrible is Neutropenic zz Temperature > 38.3°C
fever”. —Sir William Osler (1849–1919). zz Neutrophil count less than or equal to 500/mm3
zz Evaluation of at least 3 days
Note: HIV- zz Temperature > 38.3°C, duration of > 4 weeks for

The terms Pyrexia of Unknown Origin (PUO) and associated outpatients > 3 days for inpatients
zz HIV infection confirmed
Fever of Unknown Origin (FUO) are used synonymously.
system for classification of FUO that better accounts

Etymology
for nonendemic and emerging diseases, improved
Pyrexia is from the Greek origin “ pyr “ meaning fire
diagnostic technologies
Febrile is from the Latin word “ febris “ meaning fever,
Classification and revised definition of FUO according
to Durack DT and Street AC (Table 1)
Definition
PUO was defined by Petersdorf and Beeson in 1961 as EPIDEMIOLOGY
temperature > 38.3°C (101°F) lasting for more than 3
The prevalence of various causes of PUO varies according
weeks and failure to reach a diagnosis even after 1 week
to geographic areas (Table 2)
of inpatient investigations.
Note : Indian Perspective

While this definition has stood for more than 30 years, Infectious diseases preferably tuberculosis has been
in 1991 Durack and Street have proposed a revised found to be the most common cause of PUO in India.
CHAPTER 98: Pyrexia of Unknown Origin: Current Concept 593
TABLE 2: Etiology of PUO/FUO over the past twenty years Malignancies

Individual entity West Other geographic locations Hepatocellular carcinoma,colonic carcinoma, etc.
Percentage Percentage Hodgkin’s disease, non-Hodgkin lymphoma, multiple
Infections 22 43
myeloma, etc.
Non infectious non 23 23
inflammatory diseases
Neoplasms 11 16 Vasculitis
Miscellaneous 9 4
Polymyalgia rheumatic, Takayasu’s arteritis, polyarteritis
Unknown 36 13
nodosa, allergic vasculitis, etc.
Source: Derived from Harrison’s principles of internal medicine 19th
edition page 136, table 26-1
Systemic Autoimmune Disorders
However different geographical Jones will have Autoimmune hemolytic anemia, Systemic lupus
specific problems. To mention a few… erythematosus, acute rheumatic fever, rheumatoid
Residents of Bihar and Jharkhand present with arthritis, autoimmune hepatitis, antiphospholipid anti-
pancytopenia and massive splenomegaly suggesting body syndrome, reactive arthritis, Bachets disease, etc.
visceral leishmaniasis.
Inhabitants of Karnataka, North India or Kashmir Miscellaneous
with history of exposure to animals presenting with Factitious fever, atrial myxoma, pulmonary embolism,
hepatosplenomegaly and multiple joint involvement sarcoidosis, etc.
would suggest brucellosis.
North East Indians presenting with oral ulcers, skin Approach
lesions, and adrenal enlargement would suggest Comprehensive history
disseminated histoplasmosis. Physical examination
Appropriate laboratory testing
Etiology Management
Some important causes of PUO.
Comprehensive History
Infections
Enquire about:
Tuberculosis (especially extrapulmonary), malaria, Possible recent visit to an endemic area like agency
typhoid, leishmaniasis, toxoplasmosis, brucellosis,
(malaria)
Q-fever, scrub typhus, hiv, actinomycosis, asprgillosis, Possible recent exposure to sexually transmitted
cytomegalo virus infection, Epstein-Barr virus, disease, injected illicit drug use predisposing to
histoplasmosis, candidasis, trypanisomiasis. hepatitis B and C, HIV and infective endocarditis
Occupational histor y with exposure to birds
Nonspecific Bacterial (psittacosis) or animals (toxoplasmosis, brucellosis)

Infections at Different Sites General complaints: Fever, weight loss, night sweats,
Urinary tract infection, septic phlebitis, mastoiditis, headache and rashes

sinusitis, mediastinitis, lung abscess, endocarditis, Previous illness: Surgeries, zoonoses, malignancies,
liver abscess, abdominal abscess, osteomyelitis, pelvic immune disorders

inflammatory disease, appendicitis, cholangitis, Previous: Family history, immunization status,
cholecystitis, diverticulitis, etc. nutrition and drug history.

Fig. 1: Chronic osteomyelitis Fig. 2: Tuberculous choroiditis
Physical Examination
Look carefully
For skin rash, conjunctival petechiae, clubbing and
splinter hemorrhages (infective endocarditis)

Jaundice, edema, thyroid status, lymph nodes,
tongue-coating, boils or furuncles

Chronic nonhealing deep seated ulcers like chronic
osteomyelitis (Fig. 1)
Migratory asymmetric arthritis: Cardiovascular
examination may reveal: tic-tac rhythm, murmurs,

pericardial rub, suggestive of acute rheumatic fever
Skin rashes coupled with alopecia, oral ulcers,
poly-arthritis hepato splenomegaly; may be

suggestive of SLE.
For bronchial breathing, infiltrative rales, pleural rub,
Fig. 3: CMV retinitis
(underlying pulmonary TB).

Enlarged liver or spleen, ascites, any abdominal
Roth spots in infective endocarditis, choroid
mass, para-aortic lymph nodes, (abdominal TB or tubercules in miliary tuberculosis (Fig. 2) or lesions
lymphomas) of CMV retinitis (Fig. 3) (fundus examination).
For UTI or TO mass in females (Genitourinary
Investigations
examination)
Signs of meningeal irritation, focal seizures, or
Principles
Investigations must be individualized based on the
paraplegia (Acute demyelinating encephalomyelitis)
Digital rectal examination may suggest the cause most probable suspected diagnosis
Differential diagnosis will depend upon the
occasionally may suggest inflammatory bowel
disease, local sepsis or abscess, rectal carcinoma, geographical area, age of the patient, and co-morbid
prostatic malignancy. conditions.
In general noninvasive investigations should be done early in the disease. It is specific and reliable but false
first before resorting to invasive investigations such as positive results may occur.
biopsy, endoscopy and others.
Gene Xpert MTB/RIF
Urinary A cartridge based nucleic acid amplification test automated
Mid stream urine is to be collected for microscopy and diagnostic test that can identify Mycobacterium
culture. tuberculosis DNA and resistance to rifampicin by nucleic
acid amplification test (NAAT).
Hematological
A complete blood count and ESR in all cases. (ESR Imaging Studies
above 80 mm/1st hour is seen in TB, malignancy, X-ray: When pneumonia and TB, paranasal sinuses,
connective tissue diseases and temporal arteritis) bones and joints and others. Suspected, chest for lung
A peripheral smear for abnormal cells, malaria abscess (Fig. 4)
parasite and atypical lymphocytes. Skeletal survey in suspected cases of multiple
myeloma.
Microbiological
Ultrasound to detect organomegaly, free fluid in
Blood culture in all fevers persisting for more than a
pleural, peritoneal or pericardial sac, may detect
week. repeated blood cultures may have to be done to
abnormalities hepatic tumor or abscess, biliary
isolate the organism, e.g. infective endocarditis.
system disease, retroperitoneal lymphadenitis, or TO
Blood Biochemistry mass
Rise in serum uric acid level in malignancies like Echocardiography: To detect intracardiac vegetations,
lymphomas. atrial myxoma, the most valuable tool to confirm or
Rise in serum alkaline phosphatase indicates liver rule out infective endocarditis.
cell involvement. CT scan brain for lesions like cerebral abscess (Fig. 5)
and liver (Fig. 6)
Polymerase Chain Reaction (PCR) Gallium 67scan to detect infection/malignancy
PCR is very valuable in detecting the nuclear or Indium labeled leukocytes to detect occult septic
cytoplasmic components of infecting organisms focus
Fig. 4: Lung abscess Fig. 5: CT scan brain cerebral abscess

Fig.6: CT scan liver abscess Fig. 7: MRI of brain T2 weighted tuberculous granuloma of brain
Fig. 8: MRI of TB spine D1 tuberculous granuloma of brain Fig. 9: MRI T1w and T2w images showing TB spine a female patient
from Orthopedic department.
Technetium Tc 99m to detect acute and chronic Selected Serological Tests

infection of bones and soft tissues
Infections
MRI brain to detect malignancy and autoimmune
Detection of specific antibodies against infecting
conditions, tuberculoma (Fig. 7) MR spectroscopy to
organisms or their products, e.g.
differentiate various etiologies (Fig. 7) Widal reaction (Salmonella), leptospiral antibodies
MRI spine for TB (Figs 8 and 9) multiple myeloma

Antistreptolysin-O (ASO) titer (streptococcal toxin)
(Fig. 10) FDG-PET scan to detect malignancy and Malarial antigen (malaria)
inflammation HIV1 and 2, HBsAg, HCV and CMV
Transthoracic/transesophageal echocardiography to
Diseases of connective tissue and vasculitis when
detect bacterial endocarditis suspected
Venous Doppler study to detect venous thrombosis. Rheumatoid factor, ANA profile, ANCA
Among infections visceral leishmaniasis or military

tuberculosis.
Management
Principles
Unless the patient is acutely ill, no specific therapy is
started
Because nonspecific therapy is ineffective and mostly
delays the diagnostic process
An exception is neutropenic FUO for which delay
could lead to severe complications
Hence after blood samples for cultures are taken,
Fig. 10: MR spectroscopy tuberculous granuloma of brain aggressively treated with higher antibiotics in addition
to granulocyte colony stimulating factor.
Gastrointestinal Endoscopy Note:
May suggest inflammatory bowel disease, tuberculous Many undiagnosed cases of PUO may spontaneously
enteritis, carcinoma colon, intestinal diverticulitis. resolve

For accurate and early diagnosis of cases of prolonged
Bronchoscopy and Bronchoalveolar fever, an algorhythm may be followed (Flow chart 1).
Lavage
For culture of organisms and cytology for malignant and Certain Important Conditions
bacterial/fungal/parasitic infections.
Temporal/giant cell arteritis: Elderly female with
Fine Needle Aspiration Cytology temporal headache, jaw claudication, fever, weight
Ultrasoundguided FNAC form suspected tissues loss, visual disturbances, anorexia, fatigue, and cough,
mediastinal lymph nodes, intrahepatic lesions. elevated ESR.
Biopsy Fungal infections: History of immunosuppressive

therapy, use of broad spectrum antibiotics, presence
Liver biopsy: This procedure may help to diagnose
of intravascular devices, total parenteral nutrition—all
miliary TB, sarcoidosis, lymphomas, or histoplasmosis,
these predispose to disseminated fungal infections.
if the lesions are generalized and tumors or localized
granulomatous lesions if large enough (ultrasound/CT Vasculitis: Vasculitis are characterized by inflammation
guided). of blood vessel walls and the surrounding interstitium.
Lymph node biopsy: Useful when lymph nodes are They may affect large, medium or small sized vessels.
enlarged as in lymphomas, tuberculosis, secondary ANCA, Cryoglobulin estimation are required in the
malignant deposits and others. diagnostic work-up.
Muscle biopsy: In cases of suspected polymyositis and Drug related fever: Eosinophilia and rash in only 1/5th
Dermatomyositis muscle biopsy will clinch the diagnosis of the patients, fever usually begins in 1–3 weeks after
starting the drug and, remits 2–3 days after the drug is
Bone Marrow Aspiration and Biopsy withdrawn, virtually all drug classes can cause fever.
Useful in case of hematological disorders such as However betalactum antibiotics, quinidine, anti-
leukemias, myeloma. neoplastic drugs, neuroleptics are more prone.
Flow chart 1: Clinical approach to PUO nulomas in one or more organ systems, irreversible
fibrosis and honeycombing of lungs with mediastinal
lymphadenopathy, musculoskeletal system involvement
and hepatosplenomegaly.
Lymphoma: Occurs at any age but common at 60s
multicentric in origin and spreads rapidly to non
contiguous areas discrete, painless, firm, lymph nodal
enlargement is the most.
Common presentation Waldeyer’s ring and epitroclear
lymph nodes are frequently involved, bone marrow
involvement is common and early; and can produce
cytopenias.
Osteomyelitis: Osteomyelitis usually causes localized
swelling, pain and tenderness which are deep seated,
treated with systemic higher antibiotics, surgical
debridement.
Systemic Lupus Erythematosus

Malar rash, discoid rash, oral ulcers, convulsions,
serositis, thrombocytopenia, ANA positive, treated with
corticosteroids and disease modifying drugs.
Factors Defining PUO!!

Time era of the study (diagnostic means), geographic
factors, patient’s age, duration of the fever.
Why PUO Commonly Missed!!!

Uncommon manifestations of common diseases, partial
or inappropriate treatment, minimal or absent localizing
features, drug fever, newer or unfamiliar diseases, after
effects of interventions, immune- compromized status.
Factitious fever: Evidence of psychiatric problems, history

CONCLUSION
of multiple hospitalizations at different institutions,
In India extrapulmonary TB may be considered as
rapid changes in body temperature without associated
first possibility of PUO, followed by connective tissue
shivering or sweating, large differences between rectal
disorder and than malignancy.
and oral temperatures, discrepancies between fever,
In all cases adequate history, scrupulous examination
pulse rate, or general appearance typically observed in
and relevant investigations will become the sheet
patients who manipulate
anchor of the diagnostic approach.
Sarcoidosis: Age group 20–40 years, occurs in non However, considering the patients’ suffering, one may
smokers, highly varying clinically, noncaseating gra have to resort to the therapeutic trial.
BIBLIOGRAPHY 6. Mueller PS, Terrell CL, Gertz MA. Fever of unknown origin
1. Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: caused by multiple myeloma: a report of 9 cases. Arch
a clinical approach. Am J Med. 2015;128:1138. intern Med. 2002;162:1305.
2. Dejaco C, Duftner C, Buttgereit F, Matteson EL, Dasgupta 7. Petersdorf RG, Beeson PB. Fever of unexplained origin:
B. The spectrum of giant cell arteritis and polymyalgia report on 100 cases. Medicine (Baltimore). 1961;40:1-30.
rheumatica: revisiting the concept of the disease. 8. Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A,
Rheumatology (Oxford). 2016;(1) [MEDLINE]. Wernsdorfer WH. A review of malaria diagnostic tools:
3. Durack DT, Street AC. Fever of unknown origin- reexamined microscopy and rapid diagnostic test (RDT). Am J Trop Med
and redefined .Curr Clin Trop Infect Dis. 1991;11:35-51. Hyg. 2007;77(6 Suppl):119-27 [MEDLINE].
4. Grace E Max, Edward D Chan. Tuberculosis Research and 9. Zinzani PL, Gandolfi L, Broccoli A, et al. Midtreatment
Treatment. Volume 2011 (2011), Article ID 798764, 9 18F-fluorodeoxyglucose positron-emission tomography in
pages http//dx doi org/10. 1155/2011/798764. aggressive non-Hodgkin lymphoma. Cancer. 2011;1:117(5):
5. Horowitz HW. Fever of unknown origin or fever of too many 1010-8 [MEDLINE].
origins ? N Engl J Med. 2013;366:197.
CHAPTER
99
Approach to a Patient of Meningitis
Sanjiv Maheshwari, Vijay Prakash Hawa
INTRODUCTION Subacute meningitis is meningitis that develops

Meningitis is a inflammation of arachnoid membrane, over days to few weeks and chronic meningitis is slowly
pia mater and intervening cerebrospinal fluid. Meningitis developing meningitis that lasts four weeks or longer.
can be caused by bacteria, viruses, fungi, parasites, Tuberculosis is one of the important infectious cause
bleeding into meninges, neoplasia or chemical irritation. of subacute and chronic meningitis in developing nation
Currently about 1.2 million sporadic cases of bacterial like India. In developed nation, tubercular meningitis
meningitis occur annually with approximately 1, 70,000 is usually associated with immunocompromised state
deaths worldwide. The incidence in India is not known most commonly HIV.
but bacterial meningitis is a frequent medical emergency. Aseptic meningitis is an inflammation of meninges
Although all human microbes have the potential to cause with mononuclear pleocytosis without any pyogenic
meningitis, only a few organism account for most cases bacterial infection on gram staining or culture.
of bacterial meningitis among which Streptococcus Important causes are viral meningitis [Enterovirus,
pneumoniae (50%), Neisseria meningitides (25%), VZV, herpes simplex virus type 2 (HSV-2), Arbovirus,
Listeria monocytogenes (10%), Haemophilus influenzae CMV, HIV, etc.], atypical and nonpyogenic bacteria,
(<10%) more common. Listeria is important cause of fungal (most common Cryptococcus neoformans),
Meningitis in neonates, pregnant women, elderly and chemical (following myelography, endogenously due
immunocompromised individuals. Staph. aureus, to epidermoid tumor, craniopharyngioma), neoplasm
CONS, gram negative bacilli (E.coli, Klebsiella, etc.) are (metastatic carcinomatous meningitis, CNS tumor like
important cause of meningitis following invasive neuromeningeal gliomatosis, ependymoma, dysgerminoma,
surgical procedures like shunting, craniotomy, use of etc.), drug induced and meningitis associated with
Ommaya reservoir. autoimmune and hypersensitivity disease. It is usually
Recurrent bacterial meningitis is deifined as two subacute or chronic in course.
or more episodes of meningitis caused by a different
bacterial organism or a second episode caused by the CLINICAL PRESENTATION
same organism more than 3 weeks after completion of A patient with meningitis can either present as acute
therapy. It may be an indicative of either host defect in fulminant and rapidly progressive illness or subacute/
local anatomy or in immunologic defence. chronic infection which worsen over several day. The
CHAPTER 99: Approach to a Patient of Meningitis 601
Flow chart 1: Approach to a patient of suspected meningitis
classical clinical features as fever, headache, projectile Fulminant meningococcal septicemia can cause
vomiting and nuchal rigidity may not be present in all cases Waterhouse-Friderichsen syndrome (hemorrhage within
but almost all patients (~95%) with bacterial meningitis adrenal glands) characterized by sudden onset high
present with at least two of these four features (Flow chart 1). grade fever, large petechial hemorrhage, cardiovascular
Altered sensorium and photophobia are also common. collapse and DIC.
Seizure can also occur as a part of initial presentation Along with the above symptoms other symptoms of
or during course of disease in 20–40% of cases. It may be predisposing conditions like discharge from ear (otitis),
focal or generalized.
chronic headache (sinusitis), cough (pneumonia),
Focal neurological deficit can be found in 33% of
weight loss, fatigue, recurrent infection (immuno-
cases.
compromised state) can also be found.
In meningococcemia rash may be present which
begin as diffuse enythematous, maculopapular rash
resembling viral exanthems. They rapidly become EXAMINATION
petechial. They are found on trunk, lower extremities, Initially all the efforts should be directed to differentiate if
mucus membrane, conjunctiva and occasionally palm the infection is predominantly in the subarachmoid space
and soles. (meningitis) or it is generalized or focal involvement of
brain tissue in the cerebral hemispheres, cerebellum or bradycardia, chaotic respiration, etc.) may be present in
brainstem. patient of meningitis with varying degree and percentage.
Evidence of meningeal irritation is usually present as
evidence by a stiff neck, Kernig’s sign, Brudzinski’s sign, INVESTIGATION
etc. Nuchal rigidity caused by meningitis resists passive Whenever bacterial meningitis is suspected lumbar
flexion but can be rotated easily from side to side while in puncture should always be performed as soon as possible
cervical spine disease resistance present in all direction for CSF examination. Neuroimaging (CT and/or MRI
of neck movement. Neck stiffness disappears during head) is indicated prior to lumbar puncture if patients
coma. In elderly, patients neck stiffness may be difficult has focal neurological deficit, seizures, papilloedema,
to evaluate because of osteoarthritis in neck or stiffness coma or is in an immunocompromised state.
of neck muscles secondary to based ganglia disorders. It
is falsely positive in subarachnoid hemorrhage, tetanus, CSF EXAMINATION
strychnine poisoning, cervical spondylosis and hysteria.
Findings on CSF examination suggest the cause of
Kernig’s sign can be elicited in supine patient when
meningitis even before the results of culture are available
the thigh is flexed on abdomen with the knee flexed
(Table 1).
and attempt to passively extend the knee cause pain in
Initial CSF pressure is usually found elevated (>180
presence of meningeal irritation.
mm H2O in 90% patients).
Brudzinski’s sign is again elicited in supine patient
Examining the gram stained smear of the sediment
and considered positive when passive flexion of the neck
of CSF reveals the etiologic agent in 60–80% cases of
causes spontaneous flexion of the hips and knees.
bacterial meningitis. Aerobic culture of antibiotic naïve
Although a lot is said about these tests on physical
examinations, the sensitivity and specificity of Kernig’s CSF shall reveal the etiologic agent in 80–90% cases
and Brudzinski’s sign are approximately 30% or lower. of bacterial meningitis. Broad range PCR on CSF may
Both of them may be absent or reduced in very young be a better option in diagnosing bacterial meningitis
or elderly patients, immunocompromised persons, or in patients in whom antimicrobial therapy was begun
patients with a severely depressed mental status. before lumbar puncture or when culture are negative and
Physical findings suggesting multiple cranial nerve a bacterial origin is still suspected.
involvement (third, fourth, sixth, or seventh nerves), focal For diagnosing CNS viral infections, amplification of
neurological signs (visual field defects, gaze preference, viral specific DNA or RNA from CSF by PCR amplification
dysphasia, hemiparesis, etc.), signs of increased CSF is the most important method now a day. Suspicion of
pressure (obtund consciousness, papilloedema, sixth intraventricular rupture of a cerebral abscess should
and third nerve dysfunction, abnormal reflexes, Cushing always be kept if one finds extremely high cell counts
response of decerebrate prostuning, hypertension, (>50,000/µL).
TABLE 1: Common CSF finding in patient with meningitis

Parameter Normal Bacterial meningitis Tuberculous meningitis Viral meningitis
Pressure (mmH2O) 50–180 >180 >180 <180
Gross appearance Clear Turbid Clear (cob web formation on Clear
standing)
Glucose (mg/dL) 40–70 Very low (even zero) Low Normal
Protein (mg/dL) 20–50 High Very high Normal to slightly high
Cells/µL 0–5 Raised 100–10,000 Raised 10-1000 cells pleocytosis Raised 5–500 cells predominantly
predominantly neutrophils predominantly lymphocytosis lymphocytosis
CHAPTER 99: Approach to a Patient of Meningitis 603
Bacterial species like Borrelia burgdorferi, Trepo When bacterial meningitis is suspected blood culture
nema palladium, Leptospira sp., Francisella sp., should be immediately obtained.
Brucells sp., mostly do have lymphocytic pleocytosis. Serum procalcitonin level is mostly increased in
Polymorphonuclear leukocytosis may predominate bacterial meningitis.
in the first 48 hours of illness with infections due to
Mycobacterium tuberculosis, or in echovirus 9, West Nile NEUROIMAGING
virus, eastern equine encephalitis virus or mumps. PMN Although not always required but whenever indicated,
pleocytosis with low glucose may also be a feature of MRI is preferred over CT scan because of its superiority
CMV infection in immunocompromised patients. in demonstrating areas of cerebral edema and ischemia.
A large number of test measuring level of various CSF Diffuse meningeal enhancement is often seen after
proteins, enzymes and mediators including C-reactive the administration of gadolinium in patients with
protein, lactic acid, lactate dehydrogenase, neopterin, meningitis, but it is not diagnostic because it can occur in
quinolinate, Il-lβ, Il-6, soluble Il-2 receptor, β 2 – any CNS disease associated with increased blood brain
microglobulin and TNF have been proposed as potential barrier permeability.
discriminators between viral and bacterial meningitis
but due to unproved sensitivity and specificity they are TREATMENT
not routinely used for clinical diagnostic purposes. Maintaining the vital parameters of the patient is
Extreme elevation of CSF protein (>1000 mg/dL) may
always the first and foremost aim.
indicate CSF flow obstruction (Froyn’s syndrome).
Diagnose and treat the cause of meningitis. If any
Traumatic lumbar puncture will have rise in both
delay in lumbar puncture, empirical antibiotic
protein and cells and should be corrected:
therapy should be started after taking sample for
CSF protein level is corrected by subtracting 1 mg/dL
blood culture.
for every 1000 red blood cells.
Provide adequate supportive measures.
Corrected WBC in CSF
= Measured WBC in CSF – {(WBC in blood × RBC in

BIBLIOGRAPHY
CSF) × 10 lakh/RBC in blood}
1. Anderson NC, Koshy AA, Ross KL. Bradley’s neurology in
The limulus amebocyte lysate assay is a rapid clinical practice, 7th edition; Elsevier; 2012. pp. 1147-58.
diagnostic test for the detection of gram-negative 2. Gill FMc, Others. Acute bacterial meningitis in adults; The
endotoxin in CSF with approximately 85–100% specificity Lancet. 2017;388;3036-47.
and ~100% sensitivity. 3. K o p p e l B S , H a y a n a T. C u r r e n t d i a g n o s i s a n d
treatment Neurology, 2nd edition; McGraw Hill; 2012. pp.
OTHER LABORATORY STUDIES 401-8.
4. Maguire J. Adams and Victor’s principles of neurology, 10th
Routine investigations like complete and differential
edition; McGraw Hill; 2014. pp. 698-708.
blood counts, blood glucose, liver and renal function 5. Nath A. Goldman-Cecil Medicine, 25th edition; Elsevier;
tests, ESR, CRP, electrolytes, creatine kinase for associated 2016. pp. 2480-94.
comorbidity, etc. are must in all patients with suspicion 6. Roos KL, Tyler KL. Harrison’s principles of internal medicine,
of meningitis. 19th edition; McGraw Hill; 2015. pp. 883-93.
CHAPTER
100
Leptospirosis: What We Should Know?
Shantanu Kumar Kar, Paluru Vijayachari, Jayant Kumar Panda
INTRODUCTION and the CFR in the range of 10–15%. Leptospirosis was

Leptospirosis is an emerging direct zoonoses that first reported in Andaman Islands in 1929. Following
poses important public health problem globally due to several subsequent isolated reports on the disease in
increasing incidence, epidemic potential and high-case India and its re-emergence that appeared with increased
fatality in severe cases. The disease is caused by any frequency of cases covering newer areas, making it
of the serovars of the pathogenic species of Leptospira endemic in states such as Kerala, Tamil Nadu, Karnataka,
interrogans while Leptospira biflexa another species Maharashtra, Gujarat, Odisha and Andaman Islands.
include the saprophytic strains/serovars. The infection During last two decades, several outbreaks were reported
exhibits wide clinical spectrum from asymptomatic stage from Odisha, Mumbai, Konkan region of Kerala, Tamil
at one end to mild clinical form of undifferentiated fever Nadu and Gujarat in the aftermath of natural disasters
to severe clinical form involving multiorgans injury. such as cyclones and floods. The disability adjusted life
Antigenically, Leptospira are divided into nearly years (DALY) lost per 1 lakh population in these states
300 serovars arranged in 26 serogroups and 23 during 2013-14 varies between 0.091–2.905. There is
genomospecies, naturally carried by several species of wide variation between states in terms of DALY lost
rodents, wild and domestic animals. Morphologically, due to leptospirosis. Males suffer more frequently than
these are thin spirals of 6–20 µm length, highly motile, females. It is a seasonal disease that starts at the onset
stained by silver impregnation technique visualized of the rainy season and declines as the rain recedes,
under darkground microscope. Because of diversity however, sporadic cases may occur throughout the year.
of Leptospira, leptospirosis possesses a challenge in In India, it is more commonly associated during post
tropical settings lacking adequate facilities for isolation monsoon period, natural disasters such as floods and
and typing. cyclones that can assume epidemic form.
In humans, leptospirosis is transmitted by exposure
EPIDEMIOLOGY to water or soil contaminated by the urine of infected
The estimated number cases globally in the recent past animals or by direct contact with infected animals.
were 1.03 million annually. Around 300,000–500,000 Domestic animals such as cattle, buffalo, goat, sheep
severe cases observed and case fatality ratio (CFR) and pigs are considered as carriers of the infection.
varying between 5–20%. The estimated incidence of Rodents harbor Leptospira in their renal tubules lifelong
the disease in India is 19.7 cases per 1 lakh population are considered as reservoir hosts and usually do not
CHAPTER 100: Leptospirosis: What We Should Know? 605
exhibit any signs of infection whereas temporary carriers presence of leukoc ytes, er ythroc ytes in ur ine,
may suffer from disease. Leptospira shed in urine of albuminuria, increases in blood urea and creatinine can
carrier animals remain in the environment and probably be observed.
multiply. Biofilm formation by Leptospira alone or in In more severe form with liver and kidney involvement
combination with other bacteria may aid in its survival is known as Weil’s disease. Hepatic features marked by
in the environment as well as in renal colonization of mild-to-severe Jaundice, tender hepatomegaly and may
reservoir and carrier animals. progress to hepatic encephalopathy. Renal involvement
Direct transmission from animals to humans is may manifest as acute tubular necrosis (ATN), interstitial
common in occupational groups that handle animals necrosis and renal failure. RBC casts are common in
and animal tissues such as butchers, veterinarians, cattle urine microscopy.
and pig farmers and rodent control workers, whereas Renal dysfunction worsens during 1st to 2nd week
and complete recovery may occur by 4th week in
indirect transmission is common in workers exposed to
cases with appropriate renal support. Pulmonary
wet environment such as rice farmers, sewage workers,
involvement includes cough, respiratory distress with
minors or in subjects engaged in water-related sports.
signs of crepitation in basal regions spreading upwards.
The most common portal of entry is through intact
Radiological signs of basal and mid zone opacity may
skin or mucous membrane of potential hosts where
accompany. Hemorrhagic pneumonitis, interstitial,
penetration is aided by the rotational movement of
intra-alveolar hemorrhages are commonly observed in
bacteria. After entry, Leptospira spreads by hematogenous very severe cases. Cardiovascular system may present
dissemination and initiate infection. Vascular endothelial with shock, and arrhythmias. Central nervous system
damage is the primary lesion in leptospirosis, caused abnormalities commonly present with features of
either by direct physical injury, by bacteria or as a result meningitis, irritability and restlessness that may lead
of some immune mechanism. to seizures, encephalitis and focal neurological deficits
macular, maculopapular erythematous skin irruptions
CLINICAL PRESENTATION are commonly observed in face, trunk and extremities.
While asymptomatic infections go unnoticed, the Pregnancy with leptospirosis accompany bad prognosis.
symptomatic cases may present with mild form of The death due to leptospirosis occurs in large
disease that lasts for 5 to 7 days is called anicteric phase proportion of cases presenting with alveolar hemorrhage
of leptospirosis. This phase corresponds to phase of and renal complication. The case fatality varies between
leptospirosis. It presents with sudden onset of remittent 0–15%.
fever, chills, severe myalgia, intense headache and Laboratory results show, elevated total WBC and
bilateral conjunctival suffusion. This may accompany neutrophilia, high ESR, thrombocytopenia increased
asymptomatic urinary abnormalities in the form of BUN and marked increase in serum creatinine
mild proteinuria with few casts and cells in urine, and phosphokinase. These clinical features needs to be
chest manifestation such as cough and chest pain. differentiated from other diseases such as falciparum
Hemorrhagic features are not common in this stage. malaria, dengue, scrub typhus, typhoid, viral hepatitis,
The clinical features either decrease or disappear in acute encephalitis syndrome and pylonephritis.
two to three days and then may reappear or progress in
few cases to severe leptospirosis. DIAGNOSIS
The icteric phase represents severe form of disease, Laboratory based diagnosis includes conventional
where leptospires transfer from blood vessels to the methods such as dark-field microscopy, immuno
organs. Here patients present with fever, myalgia, fluorescence, culture, histopathological staining
headache, conjunctival suffusion, acute renal failure assay and molecular methods such as PCR, real-
manifesting as oliguria/anuria, nausea, vomiting, time quantitative PCR, loop-mediated isothermal
diarrhea, abdominal pain, and hypotension. During this amplification that assist in early diagnosis and are
phase, laboratory features of eleveted aminotransferases, more specific. Serological tests such as microscopic
agglutination test (MAT), ELISA and other serological test irregular pulse, alternative consciousness should be
such as indirect hemagglutination (IHA), microcapsule immediately shifted to higher centers. Elevations of serum
agglutination test and lateral flow assays aid in diagnosis potassium and serum phosphorus are common, and if
after one week of onset of disease, when antibodies are potassium and phosphorus level gets too high special
formed ELISA and MAT are used to confirm the diagnosis. measures should be taken. Corticosteroid administration
Single MAT titer more than or equal to 1:400 has been in gradual doses (prednisolone) during 7–10 days in case
considered as a test to consider probable diagnosis since of severe hemorrhagic may be considered.
it can persist for a long time. IgM ELISA and other rapid Chemoprophylaxis may be used in deserving
tests are simple sensitive and specific tests for diagnosis. subjects at high risk with doxycycline 200 mg, once a
MAT is the gold standard test for detection of serovar/ week. Control measures such as rodent control, health
serogroup specific antibodies. Culture and isolation, education, personal protection and animal vaccination
MAT test are said to be gold standard. While PCR and may be undertaken as protection measures.
immune-chromatography tests are sensitive and used
to help early diagnosis. MAT and ELISA (four-fold rise BIBLIOGRAPHY
of antibody titer in convalescent samples compared to 1. Himani D, Suman MK, Mane BG. Epidemiology of
initial titer) shows result after a week of disease onset. leptospirosis: an Indian perspective. J Foodborne Zoonotic
Dis. 2013;1:6-13.
2. Oliveiraa MAA, Leal EA, Correia MA, Filho JCS, Dias RS,
TREATMENT AND PREVENTION
Serufo JS. Human leptospirosis: occurrence of serovars of
Treatment with effective antibiotics should be initiated as Leptospira spp. in the state of Minas Gerais, Brazil, from
soon as the diagnosis of leptospirosis is made, preferably 2008 to 2012. Brazilian J Microbiol. 2017;48:483-8.
before the 5th day after onset of disease. Clinicians 3. Programme for Prevention and Control of Leptospirosis.
should never wait for results of laboratory test before National Guidelines; Diagnosis, case management
starting treatment with antibiotics because serological prevention and control of leptospirosis. National Centre for
test do not become positive until about a week after the Disease Control (Directorate General of Health Services);
2015.
onset of disease (5th–7th day of onset). Leptospira are
4. Sethi S, Sharma N, Kakkar N, Taneja J, Chatterjee SS,
susceptible to most of the antibiotics such as penicillin,
Banga SS, Sharma M. Increasing Trends of Leptospirosis in
doxycycline, cephalosporins, tetracyclines, macrolides Northern India: A Clinico-Epidemiological Study. PLo S Negl
and fluoroquinolones. Antibiotic therapy should start Trop Dis. 2010;4:e579.
very early after onset of disease to prevent progression. 5. Shivakumar S. Indian Guidelines for the Diagnosis and
The drug of choice for outpatient treatment is Management of Human Leptospirosis. Infectious Dis. 2013.
doxycycline 100 mg twice daily for seven days and that 6. Shivakumar S. Leptospirosis: Current Scenario in India.
for inpatient (severe cases) treatment is crystalline Medicine Update. 2008;18.
7. Suppiah J, Chan SY, Ng MW, Khaw YS, Ching SM, et
penicillin 20 lakhs IU, IV six hourly should be initiated
al. Clinical predictors of dengue fever coinfected with
early. Pregnant and lactating mothers should be given
leptospirosis among patients admitted for dengue fever: a
ampicillin 500 mg every six hourly. Cases sensitive pilot study. J Biomed Sci. 2017;24:40.
to penicillin be given ceftriaxone or cefotaxime 1 gm 8. V i j a y a c h a r i P, S u g u n a n A P, S h a r m a S , R o y S ,
intravenously six hourly for seven days. Natarajaseenivasan K, Sehgal SC. Leptospirosis in the
In disease progression affecting multiple organs Andaman Islands, India. Trans R Soc Trop Med Hyg. 2008;
such as kidney, lungs, liver, CNS and CVS the patients 102:117-22.
may require dialysis, assisted ventilation, and case 9. Vijayachari P, Sugunan AP, Shriram AN. Leptospirosis:
an emerging global public health problem. J Biosci.
management does not differ then that of non-leptospirosis
2008;33:557-69.
causes. All suspected leptospirosis cases, whether
10. Vijayachari P, Sugunan AP, Singh SS, Mathur PP.
positive or negative with immunodiagnostic test having Leptospirosis among the self-supporting convicts of
features of organ dysfunction such as hypotension, Andaman Island during the 1920s: the first report on
oliguria (<400 mL/day), jaundice serum billirubin >3.0 pulmonary haemorrhage in leptospirosis? Indian J Med Res.
mg % hemoptysis or breathlessness, bleeding tendency, 2015;142:11-22.
CHAPTER
101
Kala-azar Elimination in India
Shyam Sundar
INTRODUCTION have been continuous decline in number of cases. Till

Visceral leishmaniasis (VL) is caused by intracellular now around 70% of endemic blocks have achieved the
protozoan parasites of the Leishmania donovani elimination target. In Bangladesh, number of visceral
complex. Around 20,000–40,000 deaths occur annually leishmaniasis endemic upazilas decreased from 140
in VL and associated with high morbidity. India, initially in 2005 to 16 in 2012 and six in 2014 and has
Bangladesh, Sudan, South Sudan, Ethiopia, and Brazil achieved the elimination targets in 90% of their endemic
constitute more than 90% cases of VL. The governments upazilas. In Nepal, elimination has been reached at
of India, Bangladesh, and Nepal took a regional initiative district level, and has been sustained for the past 2 years.
in 2015 by launching VL elimination programme Although all three countries have made encouraging
which targeted to eliminate VL by 2015. Elimination progress towards elimination but still target of
was defined as reducing incidence to a level at which elimination is not attained. Consequently, as countries
it would cease to be of public health importance— remain committed to the goal of visceral leishmaniasis
i.e. less than one per 10,000 inhabitants per year at elimination, the original date was extended from 2015 to
subdistrict levels (known as blocks in India and Nepal, 2017.
and Upazilas in Bangladesh). Elimination of visceral Various challenges in path of achieving the target is
leishmaniasis was considered to be an achievable goal discussed below:
for the following reasons: L. donovani, the causative
species, is transmitted in a human-to-human cycle in Asymptomatic Carrier
this region, without animal reservoir; there is only a For every clinical case of VL, there are 8–9 cases of
single sand fly vector species, Phlebotomus argentipes, subclinical/asymptomatic. Although less infectious
which is susceptible to insecticides; transmission is these asymptomatic patients do have the potential
geographically restricted to a well-defined number of to spread the disease. Therefore, the dynamics of
districts; and recent breakthroughs in diagnosis and asymptomatic visceral leishmaniasis infection and
treatment have resulted in a rapid diagnostic test and an its potential risk in disease transmission should be
oral drug, miltefosine. The annual incidence of visceral deciphered in order to target elimination. Infectivity of
leishmaniasis was as high as 22 per 10,000 people in 2005 these carrier asymptomatic person may present a major
in some endemic districts of Bihar, India which peaked challenge to VL elimination strategies. Further, detection
in 2007 with 44,533 cases reported. Thereafter, there of antibody and PCR positivity in domestic animals
suggest that apart from humans animals could act as Control of Vector
reservoir. The infectiousness of these animals to sand fly Effective vector control management strategy is
vector if confirmed, will pose a major hindrance in path cornerstone in VL elimination programme. Although
of VL elimination. effective insecticides, indoor residual spraying is effective,
Treatment of Post-kala-azar Dermal the use of this procedure to decrease VL transmission
remains controversial. This might not affect outdoor
Leishmaniasis
sandfly populations, which may be an important aspect
Post-kala-azar dermal leishmaniasis (PKDL) is cha
of VL transmission as most of people from endemic
racterized by macular, popular and nodular lesions or
areas in Bihar sleep outside their houses. In a cluster
a mixture of these. It is mainly seen in Sudan and India,
randomised trial in India and Nepal medicated nets did
in 50% and 5–10% of VL treated cases, respectively.
Infectivity of these lesions especially nodular variety to reduce indoor sandfly density by 25%, although no effect
sand fly has been found. So how much infectivity and was seen on disease transmission.
from which type of lesion need to be found out. It further
complicates the vision of VL elimination. Uninterrupted Supply of Drugs
As the patients coming from endemic area cannot afford
HIV-VL Coinfection treatment antileishmanial drugs are provided free of
HIV changes the nature of the human VL infection, charge so that a full course of treatment is completed.
the response to treatment, and the epidemiology. Therefore, a strong commitment from government is
The HIV/VL coinfected patients have a high parasite essential for continuos supply of drugs. Single dose
burden and a weak immune response, respond poorly LAmB is excellent option as it does not require admission
to treatment, and have a high relapse rate. Therefore, however requirement of cold chain and cost remains a
they are the ideal candidates to harbor and spread drug constraint for its wide availability.
resistant parasites. With the growing burden of HIV
in India, HIV/VL coinfection could become a major CONCLUSION
problem. In India about 5.6% of over 2000 adult patients For making a sustained and successful VL elimination
with visceral leishmaniasis in Bihar, India, were found to of VL we need a better understanding of transmission,
be coinfected with HIV. optimal use of existing resources, and development of
Treatment of VL new, more effective tools to interrupt the progression of
After a landmark study on treatment of VL by miltefosine, the disease, and proper treatment of PKDL cases which
it was adopted as first line treatment of VL in Indian act as reservoir of infection. Role of domestic animals
subcontinent. Being an oral drug, it became the backbone through xenodiagnosis studies are also required. More
of VL elimination programme started by India, Nepal sensitive, cheap, and easily available rapid diagnostic
and Bangladesh. Unfortunately, the relapse rates with and epidemiological tools to monitor L. donovani
miltefosine doubled when studied after decade of its infection needs to be explored. Various methods of
use. Relapse rates of up to 20% were reported in Nepal in diagnostics like DNA-based diagnostic tests, portable
2013. Single dose liposomal amphoterecin B (LAmB) also and field-friendly molecular testing kits that could
recommended as first line treatment after revolutionary identify all Leishmania species at low densities and
trial on LAmB on Indian VL patients. Its use it however whole blood interferon gamma release assay tools
limited by cost and need of cold chain. Other effective still warrants further validation. Single-dose drug
combination therapy of paramomycin and miltefosine regimens offer great opportunities for better control
is used when there is difficulty in maintain cold chain. but mechanisms of drug action and resistance need
However the assumption of having an oral effective drug to be explored further for designing better and more
for elimination no more exist. effective drug regimens. Apart from this, targeted vector
CHAPTER 101: Kala-azar Elimination in India 609
control-related research should be intensified, including 3. Singh OP, Hasker E, Boelaert M, Sundar S. Elimination of
the identification of new insecticides to combat the visceral leishmaniasis on the Indian subcontinent. Lancet
Infect Dis. 2016;16(12).
resistance of available insecticides. Despite the various
4. Singh OP, Singh B, Chakravarty J, Sundar S. Current
challenges and obstacles the commitment towards challenges in treatment options for visceral leishmaniasis
VL elimination by Governments of India, Nepal and in India: a public health perspective. Infectious Diseases of
Bangladesh is tremendous which has lead to decrease in Poverty. 2016;5(1):2016.
incidence of new cases and hopefully soon will achieve 5. Sundar S, Singh A, Singh OP. Strategies to overcome
antileishmanial drugs unresponsiveness. Journal of Tropical
the target of VL elimination.
Medicine, vol. 2014, Article ID 646932.
6. WHO-SEARS. Health Ministers commit to eliminate kala-
BIBLIOGRAPHY azar [press release]. Dhaka: World Health Organization
1. Bhattacharya SK, Sur D, Sinha PK, Karbwang J. Elimination Regional Office for southeast Asia; 2014.
of leishmaniasis (kala-azar) from the Indian subcontinent 7. WHO. Kala-azar elimination programme: Report of a
is technically feasible & operationally achievable. Indian J WHO consultation of partners. Geneva: World Health
Med Res. 2006;123:195-6. Organization; 2015.
2. NVBDCP. National Road map for kala-azar elimination. New 8. WHO. Regional strategic framework for elimination of kala-
Delhi, India: Directorate of National Vector Borne Disease azar from the South-East Asia Region (2005–2015). New
Control Programme; 2014. Delhi: World Health Organization; 2012.
CHAPTER
102
Sickle Cell Crisis: How to go Forward?
Srikant Kumar Dhar
Sickle cell disease (SCD) is an autosomal recessive waiting for investigations. Different type of crisis with
disorder of the b-globin gene in which hemoglobin S which SCD presents are vaso-occlusive, hemolytic,
polymerizes in erythrocytes in deoxygenated conditions aplastic, sequestration and acute chest syndrome (ACS)
causing occlusion of small blood vessels. Pain is the out of them ACS is most fatal.
hallmark of presentation in patients presenting as
painful vaso-occlusive crisis. HOW TO MANAGE?
Initial medical assessment does not need to be
HOW TO DIAGNOSE? exhaustive but should focus on detection of the medical
The diagnosis of a pain crisis is only on clinical diagnosis complications requiring specific therapy such as
where no laboratory test can be of assistance for infection, dehydration, acute chest syndrome (fever,
diagnosis. History taking of a suspected case of a sickle tachypnea, chest pain, hypoxia, other chest signs),
cell pain crisis is most useful tool. Past history of sickle severe anemia, splenic enlargement, abdominal crisis,
cell hemoglobinopathy, no of hospitalization, drugs, cholecystitis, neurological events (cerebral infarct,
infection, blood transfusions, joint involvements that cerebral hemorrhage, transient ischaemic attack,
provide clue to diagnosis and further management. seizure) and priapism. During sickle cell crisis, when
Careful physical examinations helps to know cause of the severity of the episode is assessable, self-treatment
crisis. Adjuvant investigations such as CBC (complete at home with bed rest, oral analgesia, and hydration
blood count) and peripheral smear showing hemolytic is possible. Individuals with SCD often present to the
picture, reticulocytosis, target cells, polychromasia, hospital after self-treatment is ineffective or fails. Clinical
Howell Jolly bodies, and specific hematological tests, presentation is usually the pain of which may appear
e.g. sickling test, Hb electrophoresis, HPLC (high anywhere in your body and in more than one body sites,
performance liquid chromatography) as well as tests such e.g. arms and legs, abdomen, chest, hands and feet (more
as, LFT (liver function test) LDH (lactate dehydrogenase), typical in young children), lower back. Adult present with
RFT (renal function test), ABG (arterial blood gas), serum large joint pain, e.g. knee, hip, ankle, elbow, etc. Or rarely
iron profile, CRP (C-reactive protein), D-dimer, urine may present with breathlessness, headache, priaprism,
analysis will yield for definite diagnosis. Radiological or stroke.
Investigations such as chest X-ray, USG abdomen, CT Treatment strategies should include goals to manage
brain and thorax, guide for management. However, sickle of vaso-occlusive crisis, pain syndromes, hemolytic
cell crisis warrants immediate management without anemia, treatment and prevention of infections and
CHAPTER 102: Sickle Cell Crisis: How to go Forward? 611
complications and the various organ damage syndromes as paracetamol, ibuprofen and diclofenac should be
associated with the disease. Therapy should also take prescribed if there are no contraindications. Ketorolac is
care for prevention of stroke as well as detection and also a preferred agent which can be given both IM or IV
treatment of pulmonary hypertension. but it should not be given more than 5 days. Aspirin to
be avoided. Codeine containing analgesics or Tramadol
PRINCIPLES OF MANAGEMENT may be used for mild-to-moderate pain and which are
Effective analgesia should be given within 30 minutes of useful for weaning patients off the stronger opiates. PCA
the patient presenting to hospital. Adequate hydration (patient control analgesia) can be considered, if break-
(60 mL/kg/24 hrs) to be maintained taking care of through pain is occurring. Pethidine should be avoided.
anemia, cardiac status and fluid overload. Oxygenation
plays a vital role in management. Prophylactic or FLUID REPLACEMENT
therapeutic antimicrobials to prefer, if fever, to be chosen Increased plasma osmolarity from a reduced plasma
according to site of infection. Incentive spirometry is volume can worsen a vaso-occlusive crisis by causing
reserved for acute chest syndrome in recovery. Re- intracellular dehydration, hemoglobin polymerization
assessment and titration of analgesia have been done for and further sickling. During dehydration, the affinity of
maintenance and non responders. hemoglobin S for oxygen is increased so aggravates crisis.
Nitrous oxide (50%) and oxygen (50%) (Entonox, If tolerated, oral rehydration should be used in patients
Equanox) can be used in the ambulance and for the first with milder vaso-occlusive crises, patient should take
30–60 min in hospital not beyond. 60 mL/kg/day. The parenteral route of rehydration
The aim of treatment is to break the vicious cycle of is indicated in patients with severe pain, vomiting or
sickling, hypoxia and acidosis leading to more sickling all volume depletion.
of them exacerbated by dehydration.
TREATMENT OF ACUTE
ANALGESIA CHEST SYNDROME
Pain is the most common mode of presentation and Defined clinically as an acute pulmonary illness along
management of pain is mainstay of crisis treatment.
with body pain and chest discomfort characterized by a
Opiate analgesia is usually drug of choice for painful
new radiographic pulmonary infiltrate, fever, hypoxemia,
crises and should be administered within 30 minutes
of presentation to hospital aiming to achieve effective chest pain, cough and wheezing which is leading
analgesia by 60 minutes. A pain chart should be cause of mortality. Special investigations may yield
commenced for all patients as drug response varies in clue to diagnosis, e.g. ABG analysis, chest X‐ray, blood
different individuals. cultures, sputum cultures, respiratory atypical serology
Morphine is the opiate of choice for the management (Chlamydia, Legionella, Mycoplasma), complete blood
of sickle cell crisis wherever available. Morphine 5 mg count and reticulocyte count, renal and liver function
intravenously should be given initially as loading dose. tests.
This can be diluted in normal saline to give a 1 mg/mL
solution which can be given over the next 10 minutes. For Initial Management
effective analgesia, initial dose can be repeated after one
Intravenous fluids with close monitoring of fluid
hour. Closely monitor for hypoxia every 30 minutes until
balance is mainstay of treatment, oxygen therapy to
pain settled and then every 2 hours. If respiratory rate
<10/second stop opiates, with further drop to < 6 give 100 increase oxygen saturations >95% monitoring pO2 on
ug naloxone intravenous repeated every 2 minutes when air, pulse, respiratory rate, arterial blood gases and
required. Hb. Antibiotics given preferably IV co‐amoxiclav (plus
In Indian conditions where morphine is not easily clarithromycin 500 mg bd, if atypical pneumonia
available NSAIDs can be useful adjunctive therapy such suspected), bronchodilators preferred, if there is
evidence of wheeze or reversible airways disease, or blood and exchange transfusion .Corporeal aspiration,
a history of asthma. Additional supportive and pain and phenylephrine injection to induce smooth muscle
management (analgesia as per painful crisis) to continue. contraction to be instituted initially and shunt surgery to
Consider positive pressure ventilation for patients with be performed if conservative therapy fails.
poor respiratory effort or reduced ventilation however
Incentive spirometry (10 deep breaths 1–2 hourly) when Stroke
awake and stable. Frusemide 0. 5–1 mg/kg if signs of fluid Stroke is a manifestation of cerebral sickling. Patient
overload to introduce. Prophylatic low molecular weight may manifest with neurodeficit or convulsion. Mainstay
heparin may be instituted. Transfusion has major role, if of management is exchange transfusion along with
the patient’s hemoglobin has fallen to <6. 0 g/dL, initial usual treatment for stroke. Other agents such as anti-
transfusion to be given. Simple transfusion is given for inflammatory agents, hydroxyurea also play important
moderately severe illness, but do not transfuse acutely to role in therapy. For secondary prevention in stroke
patient with Hb%>10g/dL, or take the hematocrit above suggest that lifelong blood transfusions may be necessary,
30%. Other useful method is exchange blood transfusion as there is a high risk of recurrence relatively soon after
with an aim to bring HbS <30%. With no improvement transfusion cessation.
and further detoriation consider noninvasive ventilation,
or subsequent invasive ventilation (CPAP). Review Role of Hydroxyurea
analgesia protocol, if needed. Hydroxyurea is a novel agent with robust clinical evidence
to be used for SCD. It causes fetal hemoglobin induction
Sequestration Crisis through soluble guanylyl cyclase activation and altered
It is characterized by sudden massive pooling of red erythroid kinetics. It lowers neutrophil and reticulocyte
cells in spleen, liver resulting in pain, hypoxemia, counts from ribonucleotide reductase inhibition and
hypovolemic shock and cardiovascular collapse. Main
marrow cytotoxicity, decreased adhesiveness circulating
treatment is packed cell or exchange transfusion along
neutrophils and reticulocytes. It also reduces hemolysis
with usual management.
through improved erythrocyte hydration, macrocytosis,
and reduced intracellular sickling; and causes NO
Hyperhemolytic Crisis
release leading to local vasodilatation and improved
Described as episodes of accelerated hemolysis
vascular response. indications of hydroxyurea are acute
characterized by decreased blood Hb, increasing
chest syndrome, Painful dactilitis (mostly children), low
reticulocytes and other markers of hemolysis, it occurs
HbF, elevated TLC, LDH, chronic hypoxemia. Patient
in resolving phase of vasocclusive crises. DHTR (delayed
instituted with hydroxyurea to be monitored CBC weekly-
hypersensitive transfusion reaction) may occur in
for first 4 weeks, fortnightly for next 8 weeks, monthly
multiply transfused, alloimmunized patients producing
thereafter, if counts stable followed by 3 monthly unine,
accelerated hemolysis. Concurrent G6PD deficiency is
LFTs, urate, LDH and HBF% with regular review. Dose of
other factor to be ruled out.
hydroxyurea to start initially at 15–20 mg/kg/day orally,
Aplastic Crisis if there is a good clinical response continue on this dose.
Whenever any disruption in rapid production of red cells If clinical response is suboptimal, check adherence,
in SCD as in parvo virus B 19 infection it leads to aplastic then increase by 2.5–5 mg/kg/day every 8 weeks until
crisis. Treatment is conservative with blood transfusions. limited by toxicity. If there is a significant rise in Hb (>11
g/dL in HbSS) stop the hydroxycarbamide and consider
Priapism venesection. Common toxicities are bone marrow
Painful persistent penile erection for hours may be suppression and cytopenias, hyperpigmentation of nails
benefited by hydration, hyperbaric oxygen, analgesia, and skin, Nausea and vomiting, diarrhea, skin rash and
CHAPTER 102: Sickle Cell Crisis: How to go Forward? 613
uncommon toxicities are alopecia, teratogenicity, and more DHTR characterized by fever pain and signs
leg ulcer. of hemolysis occurring few days to 2 weeks after a
transfusion. Iron overload is factor to be observed.
Role of Transfusions
There are two types of transfusions: RECOMMENDATIONS FOR
1. Episodic simple transfusion VACCINATION
2. Exchange transfusion In adults, the pneumovax should be re-administered
every 5 years. Other vaccines recommended are Hib,
Episodic Simple Transfusion hepatitis B, and annual influenza vaccination.
It is considered in sequestration crisis, aplastic crisis,
hyperhemolysis, when Hb less than 5 g%, or more CONCLUSION
than 20% decline in Hb% from baseline. And in acute Sickle cell disease is a chronic, debilitating disorder
complications of pregnancy. with diverse symptoms that make disease treatment
challenging. Pain is the most common mode of
Exchange Transfusion presentations to hospital. Gene therapy and bone-
It is administered in ACS, priaprism, prevention of stroke, marrow transplant remains definite treatment of SCD,
preoperative, leg ulcers refractory to conservative therapy, however patients attending to emergency department
critically ill patients. Exchange transfusion is a potentially with different crisis needs aggressive but watchful
life-saving procedure that allows correction of anemia treatment.
without increasing blood viscosity and may improve
tissue oxygenation while reducing microvascular BIBLIOGRAPHY
sickling. The aim of exchange transfusion is to lower the 1. Byrne J. Sickle Cell Disease, Guideline for the Management,
HbS level to 30% or less while keeping the hemoglobin Author Dr Jennifer Byrne.
close to 10 g/dL. It has advantage of decreased iron 2. Guidelines for the management of the acute painful
overload. crisis in sickle cell disease. Rees, et al. British Journal of
Transfusion may lead to complication such as TRBC Haematology. 2003;120:744-52.
3. Nice guideline CG143 Sickle cell acute painful episode;
alloimmunization (19–30% with <15 units transfusion)
June 2012.
due to extensive antigenic phenotyping. It may cause 4. The management of Sickle Cell Disease, NIH Publication
hemolytic reactions and decreases RBC survival of 2/2117N22?NIH Publication No. 02-2117IH Publication
infused RBCs, further warranting transfusion. Further No. 02-2117.
CHAPTER
103
Do Not Rash When
Fever Coincides with Rash
Sriprasad Mohanty
INTRODUCTION presenting features of these diseases are nonspecific and

Fever with rash encompasses a large number of very often, clinical features fit into diagnostic criteria of
causes. Viral hemorrhagic fevers constitute a major the disease. In that situation, it becomes more important
part. However drug rash, collagen vascular disorders to rule out viral hemorrhagic fevers. The following
(vasculitis), rickettsial infection, leptospirosis, etc. are clinical features are important ones for that purpose:
Hemorrhage is almost never seen in the first few days
also important causes. Different geographical areas
have different problems and season of the year also has of illness in case of viral hemorrhagic fever.
Although, conjunctival injection and subconjunctival
important consideration.
hemorrhages are frequent in viral hemorrhagic fever,
APPROACH TO DIAGNOSIS they are not accompanied by itching discharge or
rhinitis.
When There is Epidemic With the exception of yellow fever, jaundice at
It is important to consider whether any epidemic is
presentation is not typical of viral hemorrhagic fever.
going on or not. Since the organism will be in circulation Prominent pulmonary symptoms or the presence
during the epidemic, it comes to forefront as the
of productive sputum are not typical of viral
provisional diagnosis. If there is no epidemic at the time,
hemorrhagic fever.
all etiological factors should be given due weightage.
The following information are quite useful to arrive at a When There is no Epidemic
diagnosis.
In order to arrive at a diagnosis, type of lesions,
Medications taken during the previous month
configuration and pattern of distribution should be
Specific travel history
carefully noted. Lesions can be of following types:
Immunization status
Immune status Macules Flat lesion defined by area of changed color

Exposure to domestic pets and other animals Papules Raised, solid lesions <5 mm in diameter
History of animal bite/possibility of arthropod bites Plaques >5 mm, flat surface
Recent dietary exposure Nodules >5 mm, rounded configuration
Contact with ill individual Urticaria/wheals Papules or plaques that look pink, classically
During an epidemic, all febrile patients appear to lasting for <24 hours in any defined area
be suffering from that viral hemorrhagic fever. Because Vesicles <5 mm, lesions containing fluid
CHAPTER 103: Do Not Rash When Fever Coincides with Rash 615
Bullae >5 mm in diameter, containing fluid are more intensely erythematous and pruritic. There is
Pustules Lesions containing purulent exudates history of new drug intake and absence of prostration.
Purpura Bleeding into skin. <3 mm is petechiae>3 mm is Rashes may persist up to 2 weeks after the offending drug
echymosis. Papable purpura is due to vasculitis. is discontinued.
Ulcer Defect in the skin surface Rickettsial illness presents with centrally distributed
Escher Necrotic lesion covered with a black crust maculopapular eruptions. Epidemic typhus is usually
seen in a setting of war or natural disaster when the
Most of the febrile rashes are centrally distributed people are exposed to body lice. In scrub typhus, there is
maculopapular eruptions. However, some can have eschar at the site of mite bite.
other patterns. Examples are as given here: Rash of measles stats at the hairline 2–3 days after
Centrally located maculopapular eruptions: Measles,
onset fever. Then they spread downwards sparing palms
rubella, drug reaction, acute meningococcemia, and soles. The rash begins as discrete erythematous
infectious mononucleosis, primary HIV infection, lesion; but become confluent later. Koplik’s spots
rickettsial infection, leptospirosis, dengue fever are white or bluish lesions of 1–2 mm size with an
erythema marginatum, still’s disease. erythematous halo on the buccal mucosa. They are seen
Peripheral eruptions: Chikungunya, hand-foot-mouth
within first 2 days of illness and are pathognomonic.
disease, secondary syphilis, bacterial endocarditis, Rubella rash also starts from hairline and spreads
erythema multiforme. downwards. But unlike measles, they tend to clear from
Confluent desquamatic erythema: Scarlet fever,
the originally affected areas as they spread down. It may
kawasaki disease, streptococcal toxic shock syndrome, be pruritic. Postauricular and suboccipital adenopathy is
staphylococcal toxic shock syndrome, Stevens- common as is arthritis.
Johnson syndrome, toxic epidermal necrolysis Leptospirosis presents with centrally distributed
(TEN), drug reaction with eosinophilia and systemic ma cu la p o pu la r e r u p t i o n w i t h su b c o n ju c t i va l
symptoms (DRESS). hemorrhage. Patients may have renal, hepatic disfunction
Vesiculobullous or pustular eruptions: Hand-foot- or aseptic meningitis; persons exposed to animal urine
mouth syndrome, staphylococcal scalded skin usually suffer from this Weil’s disease.
syndrome, TEN, DRESS, vericella, variola, herpes,
eyethema gangrenosum. VIRAL HEMORRHAGIC FEVERS
Urticaria-like eruptions: Vasculitis, serum sickness,
Viral hemorrhagic fever is an acute systemic febrile
drugs, connective tissue disorder. syndrome caused by over 30 viruses. Microvascular
Nodular eruptions: Fungal infection, erythema instability with capillary leak and impaired hemostasis
nodosum, sweet syndrome. are the pathogenic hallmarks. The viruses that cause
Purpuric eruption: Arbo-virus infections including hemorrhagic fever are zoonotic. Consequently, the
dengue, meningococcal infection, DIC, hemolytic endemic areas of the various viral HF are limited to
uremic syndrome, thrombotic thrombocytopenia distribution of their mammalian reservoirs and/or
purpura, cutaneous small vessel vasculitis. arthropod vectors. Ebola is a nightmare, especially for
Eruptions with ulcers and/or escher: Scrub typhus, health workers. Hantavirous has spread worldwide. It
rickettsial-spotted fevers, erythema gangrenous, can present as hemorrhagic fever with renal syndrome
anthrax, tularemia. or hantavirous pulmonary syndromes. The first case of
Since, the patient has to take medicines, drug rash Crimean-Congo hemorrhagic fever of India was detected
poses a common and difficult differential diagnosis. Drug in Sanand, Gujurat in January, 2011. Kyasanur forest
reaction can manifest in many forms but exanthematous disease is endemic in Karnataka. However, the most
drug induced eruptions are most common and they important causes of febrile rash in India are dengue and
resemble viral exanthems. However, the former ones chikungunya at present. Both are transmitted by the
same vector (Aedes aegypti), both are seen at the same Symptoms Chikungunya Dengue
season and both have joint pain as a major complain Thrombocytopenia Infrequent Common
in addition to fever and rash. But in Dengue mortality Hematocrit Normal High
is high which is not so in chikungunya. In the later, the
morbidity may be prolonged. Following few points are In dengue NSAIDs should not be used. Whereas
useful in differentiating them. they can be useful to control the severe pain seen in
chikungunya. But unlike NS1Ag for dengue, we do not
Symptoms Chikungunya Dengue
have antigenic marker for chikungunya. We have to wait
Abdominal pain 31.6% 50%
for 5–7 days till IgM antibody appears or depend upon
Conjuctival injection 55.6% 32.8%
RT-PCR for laboratory diagnosis.
Maculopapular rash 59.6% 12.1%
Myalgia/Arthralgia 40% 12% BIBLIOGRAPHY
Coma 0 3% 1. Harrison’s Principle of Internal Medicine, 19th edition;
Fever onset Acute Gradual 2015.
Duration 2–4 days 5–7 days 2. Manson’s tropical Disease, 23rd edition; 2014.
3. National guideline for clinical management of chikungunya;
Hypovolumic shock Rare Common
Directorate of National Vector Borne Disease Control
Leukopenia Common Infrequent
Programme, Govt. of India; 2016.
CHAPTER
104
Disseminated Intravascular Coagulation:
Management Updates
Puneet Saxena, Aradhna Sharma, Madhulata Agarwal, Sher Singh Dariya, Hitesh Sharma
INTRODUCTION and how to diagnose and manage DIC. Many conditions

Disseminated intravascular coagulation (DIC) also cause DIC, therefore it is difficult to determine its overall
called “consumption coagulopathy” or “Defibrination incidence.
syndrome” is acquired clinicopathological syndrome
characterized by disturbance in hemostatic balance PATHOGENESIS (FIG. 1)
primarily due to excess thrombin formation resulting DIC exemplifies multifaceted interactions between
in microvascular thrombi and depletion of platelets innate immune system, inflammatory and coagulation
and coagulation factors. Spectrum ranges from florid, pathways at the blood endothelial interface. Two
acute DIC, giving rise to life-threatening emergency; hallmark features of DIC are continuous generation of
massive hemorrhage and multiple organ dysfunction fibrin and consumption of procoagulants and platelets;1
syndrome (MODS) to subclinical chronic DIC with accomplished by three main steps:
positive hemostatic markers, depending on the 1. Initiation of thrombin generation by activation
coexisting comorbidities and the severity of the of coagulation cascade by procoagulants such as
underlying process (Table 1). It is harbinger of death micro-particles released from cell apoptosis, histones
and independent predictor of mortality in morbidly ill and DNA, lipopolysaccharide from microbes and
patients, thus it necessary to understand pathophysiology neutrophil extra-cellular traps (NET’s).
TABLE 1: Etiology of disseminated intravascular coagulation

Acute DIC Chronic DIC
zz Medical: Sepsis, heat stroke, hypothermia, acute fulminant hepatic failure, snake zz Medical: Liver cirrhosis, vasculitis, Kasabach-Merritt
bite, allergic reaction, transplantation, homozygous protein C deficiency, Shock, syndrome, adenocarcinoma (pancreas, ovary, stomach
acute respiratorpy deficiency syndrome (ARDS), leukemia lung and prostate), leukemia
zz Surgical: Polytrauma, major surgeries, brain injury, cardiac bypass surgery, zz Surgical : Aortic aneurysm, organ transplantation,
thermal injury, fat embolism, peritoneovenous shunt, extracorporeal shunt vascular tumors
zz Obstetrics: Abruptio placentae, septic abortion, acute fatty liver, uterine rupture, zz Obstetrics: HELLP syndrome, retained dead fetus
toxemia of pregnancy, amniotic fluid embolism
zz Immunological disorders: Hemolytic transfusion reaction, massive transfusions
zz Drugs: Fibrinolytics, aprotinin, warfarin, amphetamines
2. Amplification and sustained generation of thrombin bleeding is the most common manifestation of acute
due to inhibition of anticoagulant pathway and DIC, most common whereas chronic thromboembolic
activation of coagulant pathways complications are the most common manifestation of
3. Propagation of fibrin deposition and thrombus chronic DIC; as thrombin generation and procoagulant
formation due to inhibition of fibrinolytics. factor production go hand inhand.
DIAGNOSIS First Order Tests2

Platelet count: Decreased due toconsumption.
Clinical and Laboratory Features (Table 2) Prothrombin time (PT): Measure of extrinsic and
Acute versus chronic DIC (also called decompensated common coagulation, pathways, prolonged in 50–
and compensated DIC, respectively) are two ends of the 70% of patients with DIC.
pathogenic spectrum of consumption coagulopathy. Due Fibrinogen : Decreased due to excessive–con
to consumption of platelets and procoagulant factors; sumption.
Fig. 1: Pathogenesis of DIC (Disseminated Intravascular coagulation);

There is increased coagulation and suppressed anticoagulation and fibrinolysis.
Abbreviations: LPS, lipopolysaccharide; NETs, neutrophil extracellular traps; HMGB-1, high mobility group box-1; TF, tissue factor; TFPI, tissue
factor pathway inhibitor; AT, antithrombin III; TM, thrombomodulin; APC, activated protein C; PAR, protease activated receptor; FDPs, fibrin
degradation products; SMF, soluble fibrin monomer; tPA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor; TAFI, thrombin
activated fibrinolysis inhibitor; MODS, multiorgan dysfunction syndrome
CHAPTER 104: Disseminated Intravascular Coagulation: Management Updates 619
TABLE 2: Clinical and laboratory features of DIC

Acute DIC Chronic DIC
zz Bleeding 64% includes petechiae, ecchymoses, blood oozing from zz Venous or arterial thromboembolism especially in absence of other
wound sites and IV lines, catheters, mucosal surfaces, accumulation precipitating factors
of blood in serous cavities postsurgery. Life-threatening bleeding zz Most of them are asymptomatic
can occur, if it involves GIT, lungs or CNS zz Nonbacterial thrombotic endocarditis (Libman-Sacks endocarditis,
zz Renal dysfunction (25%) Marantic endocarditis)

zz Hepatic dysfunction (19%) zz Superficial migratory thrombophlebitis (Trousseau’s syndrome)
zz Respiratory dysfunction (16%)
zz Shock (14%), thromboembolism (7%), CNS (2%)
zz Adrenal dysfunction form of waterhouse Friderichsen syndrome
zz Purpurin fulminans: Rare, life-threatening condition characterized
by DIC with extensive tissue thrombosis and hemorrhagic skin

necrosis
D-dimer/Fibrin degradation products: Evidence TABLE 3: ISTH-SSC diagnostic scoring system for DIC
of plasmin-mediated biodegradation of fibrin and Risk assessment: Is there an underlying disorder associated with
fibrinogen, elevated in patients with DIC overt DIC
zz If “Yes” proceed
Activated partial thromboplastin time (aPTT):
zz If “No” , do not use this algorithm
Measure of intrinsic andcommon coagulation
pathways, prolonged in 50–60% of patients with DIC. Order global coagulation tests: PT, platelet count, fibrinogen, fibrin
related marker
Imaging and other studies: Depending on underlying
Score the test results
disorder and areas of thrombosis and hemorrhage. 9 9 9
zz Platelet count (>100 × 10 /L = 0, <100 × 10 /L = 1, <50 × 10 /L =
Other markers of hemostasis: Thrombin time (measures 2)

zz Elevated fibrin marker (e.g. D-dimer, fibrin degradation products)
conversion of fibrinogen to fibrin) is prolonged;
(no increase = 0, moderate increase = 2, strong increase = 3)
Protamine test (detects fibrin monomers in plasma) is zz Prolonged PT (<3 s = 0, >3 but <6 s = 1, >6 s = 2)
positive. Levels of V, VIII, X, XIII are decreased. zz Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
Emerging tests for DIC: Levels of AT and protein C Calculate score:

zz >=5 compatible with overt DIC: repeat score daily
are frequently decreased in DIC and have prognostic zz <5 suggestive for non-overt DIC: repeat next 1–2 days
significance, but their availability is still limited due to

lack of standardized methods of estimation. Other tests
are D-dimer monoclonal antibody test, Fibrinopeptide
DIFFERENTIAL DIAGNOSIS
A and Prothrombin fragments 1 and 2 levels which are Severe liver disease; present with signs of liver failure
increased. Thromboelastography (TEG) is used to assess and have known source of liver injury (e.g. acute
hypercoaguable state in chronic DIC and early stages of hepatitis, alcohol) and abnormal liver function tests.
traumatic DIC. Other is FVIII, which is low in DIC and high in liver
Subcommittee of International Society of Thrombosis disease.
and Hemostasis (ISTH), Scientific and Standardisation Thrombotic thrombocytopenic purpura (TTP) or
Committee (SSC);3 has devised a scoring system, the other thrombotic microangiopathy (TMA); unlike
ISTH SSC diagnostic score of DIC (Table 3). Score has in DIC, TTP and other TMA have microvascular
specificity of 97% and sensitivity of 91%. The odds ratio thrombin rich in platelet and fibrin poor and do not
for mortality was 0.29 for each point in the scoring have consumption coagulopathy.
system. The rapidly changing physiology in DIC makes it Heparin induced thrombocytopenia (HIT); have
essential to clinically observe the patient and repeat the history of UFH exposure and positive laboratory
laboratory tests at frequent intervals. testing for heparin-PF4 antibodies (HIT antibodies),
also patients with HIT do not have global coagulation receive coagulation factor replacement. Options
abnormalities. include fresh frozen plasma(FFP; contains 0.7-1
HELLP syndrome; occurs 28 weeks after gestation, in U/mL of factors II, V, VII, VIII, IX, X, XI, XII and
cases with severe pregnancy induced hypertension. 2.5 mg/mL of fibrinogen), Plasma frozen within
Presents with elevated liver enzymes, low platelet, 24 hrs of phlebotomy (PF24) and Cryoprecipitate
hemolysis and normal FDP and negative D-dimer (Fibrinogen 150 mg/bag, Factor VIII 80–120 units/
and Coombs’ positive. bag and factor XIII and vWF). FFP is the first agent
of choice for coagulation factor replacement and
TREATMENT cryoprecipitate and fibrinogen concentrates are
Cornerstone of treatment is to treat the underlying cause second-line alternatives. Rapid infusion of platelets,
to stop the excess generation of thrombin by removing FFP, cryoprecipitate and fibrinogen concentrate can
the inciting injury.1,2 For example, in Abruptio placentae, lead to hypotension.
placenta has to be delivered, snake bite, administer Treatment of chronic DIC: Dominant thrombotic
snake anti-venom and sepsis initiate antibiotics. signs—In chronic DIC of malignancy with venous
Supportive measures: Mechanical ventilation to maintain or arterial thromboembolism or Purpura fulminans
airway and respiration. Restoration of physiological with acral ischemia; heparin in therapeutic doses
coagulation pathways:1,2 By suppressing coagulation and shall be considered. In cases with increased risk
facilitating anticoagulation using agents such as Heparin. of bleeding use continuous infusion of UFH at 4–5
U/kg/hour with aPTT being in range of 1.5–2.5
Hemodynamic support or replacement therapy:1,2 Only
times control. Direct thrombin inhibitors that do
in cases of ongoing hemorrhage or at risk of bleeding
not require antithrombin (AT-III) for there action
as assessed by DIC diagnostic scoring system, about to
are better than heparin which requires AT for its
undergo invasive procedures or deficient in coagulation
action which is reduced in DIC. But use of direct
factors or platelets.
In case of acute hemolytic transfusion reaction
thrombin inhibitors is not yet recommended due to
lack of RCT’s demonstrating there benefits in DIC.
aggressively hydrate the patient.
In case of massive blood loss RBCs need to be
Drotrecogin alpha (recombinant human activated
Protein C) used in the past for treatment of sepsis, has
transfused urgently.
Treatment of acute DIC: Low risk of bleeding: Treat the
been withdrawn in 2011 due to lack of efficiency in
clinical trials (PROWESS-SHOCKTrial).4
underlying cause. Patients who are not at increased
Underlying hyperfibrinolysis: Administration of
risk of bleeding and have platelet counts well above
antifibrinolytics5 such as tranexemic acid or Epsilon
>20 × 109/L there is no need of prophylactic platelet
amino caproic acid are to be used with extreme
administration.
caution as they inhibit fibrinolysis. Used occasionally
High risk of bleeding: Patients with platelet count
in case of severe refractory bleeding resistant to
<20 × 10/L, or having ongoing hemorrhage or at
conventional therapy (Grade C, Level IV). Similarly
increased risk of bleeding or those about to undergo
Prothrombin complex concentrates (PCC) are also
invasive procedures and platelet count < 50 × 109/L
avoided for the same reason.
should be given platelet transfusion. Give two units of
RDP/10 kg body weight or one single donor apheresis Emerging therapies: Antithrombin III; 6 Is an anti-
unit daily. One unit of RDP (contains 5.5 × 10 10 inflammatory and anticoagulant molecule which is
platelets) increases platelet count by 5,000–10,000/L decreased in DIC. Goal is to achieve 125–150% of normal
and one SDP (contains 3 × 1011 platelets) = 6 units of levels of AT III. However it is efficacy is not yet confirmed
RDP. and use not recommended at present.
Patients with severe bleeding and prolonged PT Inhibitor of tissue factor pathway (Tifacogin); 7
and aPTT as well as fibrinogen levels <1 g/L should complexes with TF, FVIIa and FXa; tested in phase III
CHAPTER 104: Disseminated Intravascular Coagulation: Management Updates 621
trial in severe sepsis revealed no benefit on mortality and 2. Levi M, De Jong E, van dear Poll T. New treatment strategies
increased the risk of bleeding. for disseminated intravascular coagulation based on
current understanding of the Pathophysiology. Ann Med.
Recombinant human soluble thrombomodulin
2004;36:41-9.
(ART-123);8 has anticoagulant and anti-inflammatory 3. Taylor FB Jr, Toh CH, Hoots WK, et al. Scientific Subcommittee
properties and is showing efficacy in Sepsis with DIC in on Disseminated Intravascular Coagulation (DIC) of the
phase IIb trial. Recombinant F VIIa (rFVIIa);9 new agent International Society of Thrombosis and Haemostasis
for severe refractory hemorrhage in DIC. Recombinant (ISTH). Towards definition, clinical and laboratory criteria,
and a scoring system for disseminated intravascular
Hirudin (r-hirudin); Direct thrombin inhibitor and
coagulation. Thromb Haemost. 2001;86:1327-30.
Recombinant Nematode Anticoagulant c2 (NaPc2); 10 4. Lowes R. Sepsis Drug Xigris Pulled from worldwide
Discrete inhibitor of complex between TF/FVIIa and market. Medscape Medical News. Available at http://www.
Fxa has been tested in animal models in DIC and proven medscape.com/viewarticle/752169. Accessed: 14,2014.
effective. 5. Avvisati G, ten Cate JW, Buller HR, et al. Tranexemic acid
for control of hemorrhage in acute promyelocytic leukemia.
Recombinant IL-10; anti-inflammatory cytokine,
Lancet. 1989;2:122-4.
modulates coagulation and abrogates endotoxin- 6. Warren BL, Eid A, Singer P, et al. Caring for the critically
induced effects on coagulation. ill patient. High-dose Antithrombin III in severe sepsis: a
Similarly, protease inhibitors of thrombin and randomized controlled trial. JAMA. 2001;286:1869-78.
plasmin such as Gabexate mesylate and C1- Inhibitors 7. Abraham E, Reinhart K, Demeyer I, et al. Efficacy and safety
of Tifacogin (recombinant tissue factor pathway inhibitor)
all proved of no efficacy in management of DIC.
in severe sepsis: a randomized controlled trial. JAMA.
2003;290:238-47.
Prognosis:1,2 DIC does not resolve as soon as inciting
8. Vincent JL, Ramesh MK, Ernest D, et al. A randomized,
injury is removed, as resolution requires synthesis of double-blind, placebo- controlled, Phase IIb study to
coagulation factors, clearance of anticoagulant factors evaluate the safety and efficacy of recombinant human
and fibrin degradation products from circulation soluble thrombomodulin, ART-123, in patients with sepsis
which can take several days. Mortality rate ranges from and suspected disseminated intravascular coagulation. Crit
Care Med. 2013;41:2069-79.
40–80% in patients with severe sepsis, trauma or burns
9. Franchini M, Manzato F, Salvagno GL, et al. Potential role
and depends on degree of coagulation impairment and of recombinant activated factor VII for the treatment of
treatability of the underlying condition. severe bleeding associated with disseminated intravascular
coagulation: a systematic review. Blood Coagul Fibrinolysis.
2007;18:589-93.
REFERENCES 10. Moons AH, Peters RJ, Cate H, et al. Recombinant nematode
1. Franchini M, Lippi G, Manzato F. Recent acquisitions in the anticoagulant protein c2, a novel inhibitor of tissue factor-
Pathophysiology, diagnosis and treatment of Disseminated factor VIIa activity, abrogates endotoxin-induced coagulation
intravascular coagulation. J Thromb; 2006. p. 4. in chimpanzees. Thromb Haemost.2002;88:627-31.
CHAPTER
105
Adult Immunization:
Current Scenario in India
Achieving resistance to infection is immunization. This with increased life expectancy, the chance of adults
is can most commonly achieved artificially by vaccines, developing communicable disease has increased.
which are biologic agents that stimulate one’s adaptive Adults with immunosuppression, those with chronic
immunity. It has been shown that immunization has diseases of the liver, lung and kidneys, vulnerable
led the control and elimination of various diseases of groups such as healthcare workers are more prone to
infectious etiology, many of which are life threatening. It develop many infectious diseases which are basically
has also been estimated that successful vaccination can preventable by vaccination, thereby reducing morbidity
prevent 2 to 3 million deaths annually. Vaccination is and mortality significantly in these groups of people.
cost effective, does not require any lifestyle modification Additionally, diseases that are common in childhood
and can be effectively delivered to vulnerable and hard when manifested in adulthood tend to be more severe
to reach populations through appropriate outreach with worse outcomes, which also depend on the prior
activities; a clear example is the ‘Pulse Polio programme’, immunization status in childhood. 1 Further, adult
which led to the WHO declaring India ‘Polio free’ on 27th immunization coverage in India is negligible, with no
March 2014. national governmental policy guideline in existence.
Immunization in the pediatric group has been a Even in the USA, where the Centre for Disease Control
major thrust area for all national and international (CDC) releases a yearly guideline, adult vaccination
agencies for a long time. The National Immunization data for 2015 revealed that only about one third of adults
Schedule of India, supported by the Indian Association were adequately vaccinated.2,3 The latest CDC guidelines
of Pediatrics (IAP) has been a success in our country, have been brought out in 2017. The Indian guidelines
with the latest ongoing programs being the ‘Mission for immunization in adults have been published in 2009
Indradhanush’—seven colors of the rainbow to represent under the initiatives of the API and have been updated
seven diseases such as tuberculosis, hepatitis B, polio, in 2014.4,5 Table 1 summarizes the indications and dose
tetanus, diphtheria, whooping cough and measles which schedule of different of different vaccines which are
can be prevented by immunization through vaccines. recommended in adults in our country.
This programs covers all pregnant women and children
aged less than two years. HEPATITIS B VACCINE
However, adult immunization has never been The vaccine that is recommended for all adults in India
included so far in any national programs of the country. is the recombinant Hepatitis B vaccine. 4 Patients at
In the current era of globalization and urbanization, high risk for infection include Intravenous (IV) drug
CHAPTER 105: Adult Immunization: Current Scenario in India 623
TABLE 1: Indications and dose schedule of different vaccines recommended for use in India in adults
Vaccine Indication Schedule
Hepatitis B All adults 20 μg (1 mL) IM at 0,1 and 6 months. For patients
with CKD and immunosuppression, 40 μg (2 mL)
IM at 0, 1, 2, and 6 months. Routine boosters only,
if high chance of reinfection, e.g. CKD on dialysis
DPT/DT/TdaP/Td All adults 0.5 mL intramuscular (IM) dose, booster once
every 10 years till age 65
MMR May be given in HIV if CD4 count >200 cells/µL 2 doses 0.5 mL SC 28 days apart
HPV Female: 13–26 Years 0.5 mL IM at 0, 1 and 6 months
Male: 13–21 Years, may also be given in 22 to 26 years
Other vaccines indicated in specific groups
Hepatitis A (Havrix/vaqta) High-risk individuals only - IV drug users, haemophilias Vaqta IM 1 mL—2 doses at 0 and at 6–18 months
and as post-exposure prophylaxis. Infection with other of first dose
hepatitis viruses, awaiting/received liver transplant, food Havrix IM 1 mL—2 doses at 0 and at 6–12 months
handlers and CKD of first dose
Varicella vaccine Adults without prior varicella infection/immunization, HIV 2 SC doses (0.5 mL) given 4 to 8 weeks apart
with CD4 count >200 cells/µL, outbreak control and for
post exposure prophylaxis within 3 to 5 days of exposure
to varicella rash
Zoster vaccine Age >60 years, chronic illness including HIV with CD4 single 0.65 mL dose SC
count >200 cells/µL
Pneumococcal vaccine PPSV23 in adults between 19 to 64 years with COPD, CLD, Both 0.5 mL IM/SC
(PPSV23 and PCV13) diabetics and in smokers. All adults >65 years: single dose Single dose of PCV13 2 weeks prior to elective
PCV13 followed by PPSV23 after 1 year. splenectomy
People >19 years with immunocompromise, CSF leak,
asplenia: PCV13 followed by a dose of PPSV23 after 8
weeks with PPSV23 booster after 5 years
Meningococcal vaccine Health care workers, close contacts of cases, Both 0.5 mL SC single dose. 2 doses at 2 months
(MPSV4 and 2, MCV4) immunocompromised, asplenia, outbreaks, travellers apart for asplenia
to epidemic areas and crowded fairs/festivals and Haj For travel, single dose bivalent polysaccharide
piligrims 10–14 days before travel
Haemophilus inflenzae type High risk only—asplenia, immunosuppression including Single 0.5 ml dose IM
b Vaccine HIV and transplant recepients
Influenza Vaccine (TIV/LAIV) Adults >50 years, diabetes, COPD, CKD, healthcare TIV single IM 0.5 mL dose
personnel and immunosuppressed. LAIV nasal spray
Not recommended in India
users, healthcare workers, people living with HIV/ four doses are given, the second, third and fourth doses
AIDS, diseases requiring multiple blood transfusions, being administered at one, two and six months form the
patients of chronic liver and kidney disease and those first injection and the dose per injection is doubled to
with other sexually transmitted diseases or high-risk 40 μg (2 mL). Routine boosters are not recommended
behavior. It is contraindicated only if there is known except in patients with repeated risk of reinfection
yeast hypersensitivity. It is given as three doses of like CKD patients on maintenance haemodialysis.6-9 A
intramuscular injections, the second and third doses combination vaccine with hepatitis A is also available
being administered at one and six months from the first with the same dosing schedule.
dose. The standard regimen consists of three doses of Appropriate protection levels are said to be achieved
20 μg (1 mL) each, but in patients with chronic kidney when Anti-HBs levels are above10 mIU/mL. If the Anti-
disease (CKD) and those with immunosuppression, HBs levels, after a full schedule of vaccination with
20 μg/1 mL vaccine are suboptimal in persons with a booster of Td irrespective of previous immunization
normal immunity, then three more doses, given status. Contraindications for use of this vaccine include
atleast one month apart is recommended and anti- a history of anaphylaxis and any acute neurological
HBs levels should be retested atleast one month after conditions. The conventional vaccines for diphtheria,
the last dose. If the anti-HBs level is stall less than pertussis and tetanus used in pediatric immunization
10mIU/mL, then another three doses with double the are whole cell (wp) and diphtheria toxoid (DT) vaccines
strength of the vaccine, i.e. 40 μg is to be repeated, respectively. These are not used in adults because of
the second and third doses being administered one higher risk of neurological complications.10,11
and six months, respectively after the first dose. Post- Post-exposure prophylaxis: For minor/unconta
exposure prophylaxis can be provided with hepatitis-B minated wounds, one dose of tetanus toxoid (TT) should
immunoglobulin, which should be administered as early be given, if the last dose of TT was taken more than 10
years ago. However, for major/contaminated wounds, a
as possible, within 72 hours of exposure, to be followed
dose of TT should be given, if last dose of TT was given
by a full course of vaccination.
more than 5 years ago.
HEPATITIS A VACCINE In pregnant women, if Td has been received in the
past 10 years, a single booster immediately after delivery
In India, inactivated Hepatitis A vaccine (Havrix and
must be given. During pregnancy, plain TT is preferred
Vaqta) is available. A combination vaccine with Hepatitis
over Td. If more than 10 years have passed since the last
B (twinrix) is also available. As per the Indian guidelines,
dose of TT/Td, a single dose of TT vaccine must be given
universal immunization is not recommended in India
in the second or third trimester. If previous immunization
by the API expert panel.4 The vaccine is only indicated
is incomplete or status unknown, then a full course of
in high-risk individuals live IV drug users, hemophiliacs
3 doses of TT must be given in the second or third trimester
and as post exposure prophylaxis. Hepatitis A is known
with a gap of at least 3 weeks between each dose.
to be more severe if it occurs as a coinfection with other
hepatitis viruses or in case of chronic liver disease, hence MEASLES, MUMPS AND
it is mandatory in such patients,especially in post liver RUBELLA VACCINE
transplant cases or those awaiting a liver transplant.8It is It is available as an attenuated vaccine. The usual
also essential for food handlers. However, caution is to be adult dose comprises of 2 doses of 0.5 mL vaccine
exercised for its use in pregnancy. The standard schedule given subcutaneously 28 days apart. It is not required
comprises 2 intramuscular doses: the first dose followed in those who have already been vaccinated with
6-18 months later by a second dose. MMR in childhood. Despite being a live attenuated
vaccine, it can still be given in HIV-infected persons,
DIPHTHERIA, PERTUSSIS AND
if CD4 count is above 200 cells/µL. 3 The vaccine is
TETANUS VACCINES
contraindicated in individuals with earlier history of
The available vaccines in adults are the acellular
hypersensitivity to gelatin or neomycin, pregnancy,
pertussis (ap), tetanus toxoid (TT), reduced diphtheria
Severe immunodeficiency and fever. Precautions for use
with tetanus toxoid combination (Td) and combination
include a recent history of antibody containing blood
of acellular pertussis, reduced diphtheria and tetanus
product transfusion and conception must be avoided for
toxoid (Tdap). These are indicated in all adults who did
at least 3 months after vaccination.
not have any prior immunization. A single dose of Tdap
is recommended for all adults up to the age of 65 years.
All adults must receive a booster dose of Td once every VARICELLA AND ZOSTER (SHINGLES)
10 years till the age of 65 years. Adults in close contacts VACCINES
with infants, particularly those suffering from diphtheria Both are live-attenuated vaccines (Oka strain). The
or tetanus must be vaccinated with Td, if not done in difference between the two vaccines is that the zoster
the past 2 years. Health-care professionals must receive vaccine has 18 times the viral content of the varicella
vaccine. The zoster vaccine has been demonstrated to immunocompromised, or are having cerebrospinal leak,
reduce the incidence of herpes zoster and post-herpetic cochlear implants or anatomical/functional asplenia
neuralgia and by 51% and 66% respectively.5 should receive a single dose of PCV13 followed by a
Varicella vaccine is indicated in all adults without a single dose of PPSV23 after at least 8 weeks.
prior varicella infection. It is strongly indicated in patients In patients planned for elective splenectomy, a single
with high-risk including in HIV patients with CD4 count dose of PCV13 must be given 2 weeks before the surgery,
>200 cells/µL.3 The vaccine is also recommended for followed by a booster dose of PPSV23 after 5 years.3
postexposure prophylaxis in case of adults with no prior
history of infection or immunization. In such a case, a MENINGOCOCCAL VACCINE
single dose of vaccine must be given within 3 to 5 days
It is available as polysaccharide and conjugate
of exposure to patients with varicella.5 Varicella vaccine
vaccines. Polysaccharide vaccine may be quadrivalent,
is administered as 2 doses (0.5 mL) subcutaneously
containing four antigens—A, C, Y, and W135 (MPSV4)
4 to 8 weeks apart. It is contraindicated in pregnancy,
or bivalent with A and C antigens. MPSV4 has no effect
severe immunodeficiency, history of allergy to gelatine
on nasopharyngeal carriage. The conjugate vaccine
or neomycin, or if the patient has received blood
is quadrivalent (MCV4), and is more immunogenic
transfusion within the past 5 months.
Zoster vaccine is recommended in elderly people with immune protection starting 28 days following
above the age of 60 years and persons with any chronic immunization. It is not recommended for use above
illness including HIV infection with CD4 count of more the age of 55 years. MCV4 reduces mucosal carriage in
than 200 cells/µL.3 Zoster vaccine is given as a single the nasopharynx and promotes herd immunity.None of
subcutaneous injection of 0.65 mL. It is contraindicated these vaccines protect against group B meningococci. 14
in pregnancy, severe immunodeficiency and age Meningococcal vaccine is recommended for
below 60 years. The use of Zoster vaccine has not been health care and laboratory workers, contacts of cases,
recommended in India due to lack of strong evidence in people living in crowded spaces such as jail inmates,
this regard.5 immunocompromised persons and persons with
anatomical or functional asplenia. Patients with
PNEUMOCOCCAL VACCINE deficiency of late complements, e.g. C8, C9 are prone
Two types of pneumococcal vaccine are available. The to meningococcal infections and should therefore be
first is a polysaccharide vaccine containing 23 serotypes
vaccinated.
(PPSV23), which is associated with a lesser immune
During outbreaks of meningococcal meningitis,
response and lack of mucosal protection. The other form
or as pre-exposure prophylaxis in people travelling to
is a conjugate vaccine containing polysaccharide capsules
epidemic areas (e.g “meningitis belt” of central Africa),
from 13 serotypes (PCV13) bound to diphtheria toxoid.
or for people visiting crowded fairs or festivals, a single
The latter is more immunogenic and provides lifelong
dose of bivalent polysaccharide vaccine should be
immunity along with mucosal protection. 12,13 Both
vaccines can be given intramuscularly or subcutaneously given 10–14 days before the planned visit. As per Indian
at a dose of 0.5 mL. national policy, a single dose of MPSV4 vaccine is given
As per the CDC guidelines, adults above 65 years to all Haj pilgrims. Both vaccines are given as a 0.5 mL
of age with normal immune status should receive a subcutaneous single dose injection. For people with
single dose of PCV13 followed at least one year later functional or anatomical asplenia 2 doses of MCV4
by a single dose of PPSV23.3 For adults below 65 years, must be given 2 months apart. These vaccines are
those who are smokers or are suffering from chronic contraindicated only if there is a history of allergic to
diseases of the liver, heart or lungs should receive latex. MCV4 is to be used with caution if there is a history
a single dose of PPSV23. 3Adults of all ages, who are of GBS.
HAEMOPHILUS INFLUENZAE VACCINE JAPANESE ENCEPHALITIS VACCINE

The antigenic component of this vaccine resides in The vaccine used is a live-attenuated cell culture vaccine
the outer membrane protein of the H. influenzae of strain SA 14-14-2. It is given as single 0.5 mL SC dose
type B bacterium, which is conjugated to tetanus followed by a booster dose after at least one year.4 The JE
toxoid for its administration. 4 Adults at high risk of vaccine is presently not recommended for use in adults.
infection with H. influenzae, such as those with asplenia, Currently, there is also no recommendation on the issue
immunosuppression including HIV and transplant of outbreak immunization.
recipients should receive this vaccine. The vaccine is
given as a single 0.5 mL IM dose.4 YELLOW FEVER VACCINE
It is available as a live-attenuated vaccine (17D strain).
HUMAN PAPILLOMA VIRUS VACCINE It is indicated in persons below the age of 60 years who
It is available in India as quadrivalent vaccine against intend to travel to an area where yellow fever is endemic
HPV types 6, 11, 16 and 18 (Gardasil) and bivalent or to a country which requires vaccination prior to entry.
vaccine against HPV types 16 and 18 (Cervarix). As per The vaccine is administered in a single subcutaneous
the latest 2017 CDC recommendations, all females aged dose of 0.5 mL. Booster doses of the vaccine are
13–26 years and males aged 13–21 should receive a recommended every 10 years. “International Certificate
3-dose course of HPV vaccine, with the second and third of Vaccination or Prophylaxis” or the “yellow card” is
doses spaced 2 and 6 months from the first dose.3 The issued that becomes valid 10 days after vaccination up to
vaccine are contraindicated in pregnancy and in people 10 years.5
with hypersensitivity to yeast.
CHOLERA VACCINE
INFLUENZA VACCINE Cholera vaccine, which is an oral vaccine (WC-rBS/
In India, a trivalent inactivated virus vaccine (TIV) is Dukoral), is an inactivated killed monovalent vaccine
available which is given in a single dose of 0.5 mL IM. containing whole cells of Vibrio cholerae O1 strain bound
The other available vaccine is a nasal spray containing to recombinant cholera toxin B subunit, and is available
live attenuated virus (LAIV). Since there is continuous in India. This vaccine is still not recommended for use in
mutation of the Influenza virus a fresh vaccine is required adults or in outbreak control/prevention.4
every year or with each epidemic. Both vaccines provide
protection only after 2 weeks of administration. TYPHOID VACCINE
Vaccination is required only in individuals with risk Two vaccines are available. The live oral Ty21a vaccine
of severe infection including adults over 50 years of age, is available as an enteric-coated capsule or as a liquid
chronic kidney and lung conditions, diabetes mellitus, suspension. An injectable Vi capsular polysaccharide
hematological diseases, during pregnancy, healthcare antigen vaccine (Vi CPS) is also available. Both vaccines
personnel and immunosuppressed individuals. are equally efficacious (51% for Ty21a vs 55% for ViCPS at 3
Contraindications to TIV include history of Guillian– years).11 Currently, these vaccines are not recommended
Barre syndrome after previous vaccination and history for routine adult immunization or for pre/postexposure
of hypersensitivity reaction to eggs, formaldehyde prophylaxis,5 but are recommended only for household
and gentamicin. Contraindications to LAIV include contacts of known Salmonella typhi carriers. Oral
people aged more than 50 years, pregnancy and Ty21a is given in 3 doses on alternate days with a single
immunosuppression. Currently, the use of this vaccine dose booster administered every third year. Ty21a is
is not recommended in India due to lack of sufficient contraindicated in pregnancy, immunosuppression
epidemiologic data.5 and young children below 6 years of age. Vi CPS is
administered as a single 0.5 mL IM/SC dose with booster communicable diseases and improve the general
given every 3 yearly. Vi CPS is contraindicated below the well-being and productivity of the most economically
age of 2 years. significant component of the population—the Adults.
NEWER VACCINES REFERENCES

Dengue: One dengue vaccine, Dengvaxia (CYD-TDV), 1. Barness LA. Childhood Disease in Adults. American
has been licensed and five additional dengue vaccines Association of Industrial Nurses Journal. 1963;11(2):8-10.
2. Williams WW, Lu P, O’Halloran A, et al. Surveillance of
are in clinical development (DENVax, Tetra Vax-
Vaccination Coverage among Adult Populations—United
DV, TDENV PIV, V180), with two in Phase III trials. 15 States, 2015. MMWR Surveill Summ. 2017;66(No. SS-
Dengvaxia was first approved in Mexico and at present 11):1-28.
is licensed in 9 countries. It is given in a three dose 3. Kim DK, Riley LE, Harriman KH, Hunter P, Bridges CB,
intramuscular schedule at 0,6 and 12 months. The WHO– on behalf of the Advisory Committee on Immunization
Practices. Recommended immunization schedule for adults
SAGE recommends that use should be limited to areas
aged 19 years or older, United States, 2017*. Annals of
where the disease is common because vaccination may Internal Medicine. 2017;166(3):209-19.
increase the risk of dengue fever in people who have not 4. API Guidelines “Executive Summary. The Association
been previously infected with the dengue virus.15 of Physicians of India Evidence-based Clinical Practice
Guidelines on Adult Immunization”. Expert Group of the
Malaria: At present, there are no approved vaccines Association of Physicians of India on Adult Immunization in
for Malaria. Mosquirix (RTS, S/AS01) acts against India JAPI. 2009; 57:345-56.
P. falciparum, and is the most promising vaccine. More 5. Muruganathan A, Mathai D, Sharma SK, editors. Adult
than 20 other vaccines are either in trials or in various Immunization. J Assoc Physicians India. 2014. pp. 1-270.
phases of development.16 Mosquirix requires 4 injections 6. Guidelines for Vaccinating Dialysis Patients and
Patients with Chronic Kidney Disease. Summarized
and has an efficacy of only about 26 to 50%. Further,
from Recommendations of the Advisory Committee on
the WHO does not recommend the use of Mosquirix in Immunization Practices (ACIP) 2012 Dec.
babies between 6 to 12 weeks of age.16 7. Guidelines for the Management of CKD. Indian J Nephrol.
2005;(Suppl 1):S72-4.
Hepatitis E: There is only one hepatitis E vaccine (HEV
8. Danzinger-Isakov L, Kumar D. AST Infectious Diseases
239 vaccine, Hecolin) in use which was first approved Community of Practice. Guidelines for vaccination of
in China. It has demonstrated a high efficacy in trials in solid organ transplant candidates and recipients. Am J
healthy subjects aged 16 to 65 years in China. 17 However, Transplant. 2009;9(Suppl 4):S258-62.
data on the global burden and morbidity of hepatitis E 9. Kidney Disease: Improving Global Outcomes (KDIGO) CKD
virus infection and disease is still limited. At present the Work Group. KDIGO 2012 Clinical Practice Guideline for the
Evaluation and Management of Chronic Kidney Disease.
WHO has made no recommendation on this vaccine.17
Kidney Inter. 2013;(Suppl 3):1-150.
HIV/AIDS: Since 1987, more than 30 HIV candidate 10. Centers for Disease Control and Prevention (CDC). Updated
recommendations for use of tetanus toxoid, reduced
vaccines have been tested in approximately 60 Phase
diphtheria toxoid and acellular pertussis (Tdap) vaccine
I/II trails, involving more than 10,000 healthy volunteers,
from the Advisory Committee on Immunization Practices,
however no significant breakthrough has been reported 2010. MMWR Morb Mortal Wkly Rep. 2011; 60:13-5.
to date.18 11. Centers for Disease Control and Prevention (CDC). Updated
recommendations for use of tetanus toxoid, reduced
CONCLUSION diphtheria toxoid, and acellular pertussis (Tdap) vaccine in
adults aged 65 years and older – Advisory Committee on
Adult immunization is a long forgotten but pressing
Immunization Practices (ACIP), 2012. MMWR Morb Mortal
issue that requires further governmental policy thrust Wkly Rep. 2012; 61:468-70.
and implementation such as the pediatric programs. 12. Nuorti JP, Whitney CG. Centers for Disease Control
This will in the long term, reduce the burden of many and Prevention (CDC). Prevention of pneumococcal
disease among infants and children—Use of 13-valent and guidance for use: Advisory Committee on Immunization
p n eumococ c a l c on j uga te va c c i ne and 23-val en t Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep.
pneumococcal polysaccharide vaccine. Recommendations 2010;59:273.
of the Advisory Committee on Immunization Practices (ACIP) 15. Dengue vaccine: WHO position paper—July 2016; Weekly
MMWR Recomm Rep. 2010;59:1-18. Epidemiological. Record, No 30, 2016;91:349-64.
13. Ku m a r D , We l s h B , S i e g a l D , C h e n M H , H u m a r 16. Malaria vaccine: WHO position paper—January 2016.
A. Immunogenicity of pneumococcal vaccine in renal Weekly Epidemiological Record. 2016;91(4):33-52.
transplant recipients: Three-year follow-up of a randomized 17. Hepatitis E vaccine: WHO position paper – January 2016.
trial. Am J Transplant. 2007;7:633-8. Weekly epidemiological record. No. 18, 2015;90:185-200.
14. Centers for Disease Control and Prevention (CDC). 18. WHO–HIV/AIDS Vaccine resource. www.who.int/hiv/topics/
Licensure of a meningococcal conjugate vaccine (Menveo) vaccines/Vaccines/en/.
CHAPTER
106
H1N1 Influenza: 9 Years’ Journey in Gujarat
Asha N Shah
Swine influenza is a disease affecting pigs and it is caused PB1, polymerase PA, followed by hemagglutinin, nuclear
by virus. There are regular outbreaks of swine influenza protein, neuraminidase and then matrix proteins and
among pigs. H1N1 swine flu is a strain of the flu virus non-structural proteins.
that jumped from pigs to humans in 2009 and was then
transmitted from human to human. WHO declared Antigenic Shift/Drift
on June 2009 that H1N1 2009 influenza pandemic had The virus undergoes mutation that can take place within
attained level 6 criteria and it was the first flu pandemic the genome (Antigenic drift)/or re-assortment among
the genetic materials of subtypes (antigenic Shift)
in 41 years.1 This H1N1 flu virus spread to every continent
resulting in a new virus.
except Antarctica involving almost 200 countries though
Antigenic drift is responsible for new seasonal strains
disease was not severe. Actually term “swine flu” has
that make necessary surveillance to detect these strains
recently been used incorrectly to refer to the seasonal
and to prepare new seasonal influenza vaccine.
influenza A (H1N1) pdm09 virus, which infects humans.
Antigenic shift may result in a new virus easily
A new swine flu virus was detected in some areas of
transmissible from man to man for which the population
world in 2011 which was named influenza A (H3N2)v. It
has no immunity: Results in Pandemics
infected few people (mainly children). As per CDC, more
Researchers from the MIT (Massachusetts Institute
people were infected in the 2012-2013 flu season but
of Technology) detected the mutation—named K166Q in
at present, not many people are infected with H3N2v.1 Indian samples and they observed that it affects middle-
Another virus which was H3N2 (but not with “v” ) which aged people as it lowers these people’s immunity to
was different then H3N2v was also detected and it also circulating influenza strains but as per NIV Pune, there is
caused flu. So it can be said that, all influenza A strains slight antigenic drift.
have a structure similar to the H1N1 virus (Fig. 1). Influenza viruses basically are from the family of
Orthomyxoviridae viruses. They are divided into three
HISTORY OF REASSORTMENT EVENTS main types—A, B and C.2
IN THE EVOLUTION OF THE 2009 Influenza A is the most virulent group, causes
INFLUENZA A (H1N1) VIRUS pandemics, epidemics, seasonal outbreaks and sporadic
There are eight segments within each virus code. The cases. It has following surface antigens:
following are the proteins of the influenza A virus (which Hemagglutinin (H or HA)
are from top to bottom): polymerase PB2, polymerase Neuraminidase (N or NA)

Fig. 1: Influenza A strains with a structure similar to the H1N1 virus
There are 18 Hemaglutinin (H) 11 neuraminidase Category B1

(NA) antigens in influenza A. The hemagglutinin Over and above all the signs and symptoms mentioned
antigen’s functions is attachment to host cells. under Category-A , if the patient has severe sore
Neuraminidase antigen acts to remove neuraminic acid throat with high grade fever may need treatment with
from mucin and thereby allows the virus to be released Oseltamivir and home isolation.
from the cell.
Category B2
GOVERNMENT OF INDIA GUIDELINES Over and above the signs and symptoms mentioned
ON CATEGORIZATION OF SEASONAL under Category-A, patients having one or more of the
INFLUENZA A H1N1 CASES (REVISED below mentioned high-risk conditions should be treated
ON 11-2-2015)3 with Oseltamivir:
Children having mild illness but who have
Category- A predisposing risk factors.

Patients having mild fever with cough/sore throat which Pregnant women;
may be associated with or without headache, bodyache, People aged 65 years or more;
vomiting and diarrhea. They do not need Oseltamivir Patients who are having heart disease, lung diseases,
and they should be given symptomatic treatment. All chronic kidney diseases, liver disease, any blood
patients should be observed for their progress and they disorders, diabetes, patients having neurological
have to be reassessed at 24 to 48 hours. They should be disorders, patients suffering from cancer or patients
advised to be confined to home. having HIV/AIDS;
They do not require testing for H1N1. Patients who are on long-term steroids.
CHAPTER 106: H1N1 Influenza: 9 Years’ Journey in Gujarat 631
Fig. 2: Mortality in H1N1 patients with different comorbidities in 2017
Fig. 3: Mortality of H1N1 patients with different comorbidities—2009
Tests for H1N1 are not required for the Category-B1 Children with ILI (influenza like illness) with severe
and Category B2. disease as manifested by the red flag signs (high and
Category-B patients should have home isolation. persistent fever, somnolence, inability to feed well,
The other change from 2009 guidelines is that seizures).
all these patients, Broad-spectrum antibiotics for Deterioration of any underlying chronic medical
Community-acquired pneumonia may be prescribed as conditions.

per the guidelines. All the patients belonging to Category C require
testing for H1N1, and they also require urgent

Category C hospitalization and treatment.
Over and above the signs and symptoms of Category It is evident from Figures 2 and 3 that maximum
A and B, patient having one or more of the following mortality due to H1N1 influenza is seen in patients
are included in category C; having diabetes mellitus and cardiac disorders.
Chest pain, breathlessness hypotension, drowsiness, Source of infection is case or subclinical case and
hemoptysis, cyanosis; spread is through large-particle respiratory droplet
transmission. Incubation period is average 1-2 days . The patients also require hematological, biochemical,
People are contagious 1 day prior to symptoms and as radiological and microbiological tests.
long as they have symptoms. Children, especially infants,
may remain contagious for two weeks or longer. Collection of Specimen
Antibodies appear 7 days after an attack; reach Nasopharyngeal swab, throat swab, nasal swab and
maximum Level in 2 weeks; drops to pre-infection tracheal aspirate for intubated patients.
level in 8-12 months. German researchers observed
and calculated that when around 33% of a population Treatment
becomes immune to the virus, herd-immunity would Isolation ward with dedicated team, early implementation
develop and transmission would stop. This may have of infection control Prompt treatment to prevent severe
happened in 2010. But people with no immunity are illness and death. Early identification and follow-up of
born everyday and people with old age may lose their persons at risk.
immunity to a particular strain every few years. Another Oseltamivir for weight <15 kg 30 mg BD for 5 days
factor is the phenomenon of antigenic drift. along with supportive therapy is given.
Zanamavir: Treatment of 7 year and older patients 10
CYTOKINE STORM IN YOUNG mg (2puffs). BID 5 days, IV Zanamavir and IV Paramavir
It is the systemic expression of a healthy and vigorous is an option in western countries for severe cases.
immune system resulting in the release of more than Cases in Gujarat (mostly category C cases as testing
150 inflammatory mediators. Both pro-and anti- was done in only C category as per GOI guidelines).
inflammatory cytokines are elevated in serum with lethal As can be seen from Table 1, 2009 pandemic cases
interplay of these cytokines referred to as a “Cytokine started in July but peaked in December 2009 and January
Storm”. The primary contributors are TNF-a and IL-6. 2010. This pattern was consistent with increase cases
The end result of cytokine storm is MODS (multiple in rainy seasons and persisting in winter. Because of
organ dysfunction syndrome) acquiring herd immunity, there were hardly any cases in
Diagnosis is by RT-PCR, virus isolation in culture or 4 2011 and 2012.Interestingly the pattern changed in 2013
fold rise in virus specific neutralizing antibodies (ELISA). and maximum cases occurred in February and March
TABLE 1: Pandemic cases

2009 2010 2011 2012 2013 2014 2015 (28th Oct)
Month Positive Death Positive Death Positive Death Positive Death Positive Death Positive Death Positive Death
January 0 0 564 119 3 0 0 0 38 9 4 1 270 38
February 0 0 215 49 0 1 0 0 306 58 3 0 4098 227
March 0 0 38 9 2 0 2 0 496 93 25 5 2160 168
April 0 0 5 2 0 1 5 2 127 31 30 13 57 6
May 0 0 2 0 1 0 0 0 9 0 21 7 9 0
June 0 0 7 1 0 0 1 0 4 1 18 6 1 0
July 7 0 31 11 1 1 4 3 3 1 7 3 5 1
August 111 8 307 46 0 0 4 2 1 1 11 6 69 13
September 78 25 454 99 0 0 27 7 4 1 21 7 274 26
October 87 7 56 17 0 0 31 10 0 1 14 4 154 20
November 32 6 2 0 0 0 18 4 0 0 2 3
December 382 71 1 0 0 0 12 4 1 0 2 0
Fig. 4: Seasonal trend over the years
and in 2015, there was a heavy outbreak reaching all time spike in 2015 in the same way it happened in 2013
high cases in February and March. in US and Mexico epidemics. So it is probable that
It can be clearly seen that the number H1N1 cases middle-aged people who were affected in 2015 were
record 2 spikes every year. In the 2009-10, 2014-15 more vulnerable to the mutated strain of H1N1, and
and 2016-17 seasons, the largest spike was seen from cytokine storm which probably affected younger
January to April (Fig. 4). population in 2009 was less observed.
Whereas in 2010-11 months of July–September In recent years, the agewise mortality has seen a
recorded most number of cases and same trend is significant change with emergence of probable
being observed this year. K166Q strain or antigenic drift. In 2009, CFR in
We published original article in JAPI for 2009-2010 6-15 and >46 years age group was 13.6% and 7.4%
pandemic cases.4 A total of 965 (64.9%) cases were respectively (Fig. 5). Whereas in 2017 the >46 years
seen amongst the young age group of 13 to 45 years.5 age group registered a CFR of 16.6%.
We also observed that case fatality in nonpregnant RECOMMENDED NORTHERN HEMISPHERE
women was 25.9% while in pregnant women it was VACCINE (2017–18) INFLUE N Z A TRIVAL E N T
53.3%. VACCINE:
Surprisingly, mortality in 2015 outbreak was high Contains:
in age group of >45 years. In 2016 also CFR was high —— An A/Michigan/45/2015 (H1N1) Pdm09-like
in the same age group (19%) and same trend is also virus,
seen in 2017 (Tables 2 and 3). Proving that this is —— An A/Hong Kong/4801/2014 (H3N2)-like virus,
seasonal influenza or possible antigenic drift (K166Q) —— A B/Brisbane/60/2008-like (B/Victoria lineage)
and the K166Q may have contributed to the Indian virus

TABLE 2: Age-and sexwise H1N1 Report, 2017 (1st January to 31 TABLE 3: Age-and sexwise H1N1 Report, 2016 (1st January to 8
December 2016) August 2017)
Male Female Male Female
Age Positive Death CFR% Positive Death CFR% Age Positive Death CFR% Positive Death CFR%
0 to 5 20 3 15.0 7 0.0 0 to 5 44 3 6.8 29 4 13.8
6 to 15 5 1 20.0 5 1 20.0 6 to 15 23 0 0.0 13 4 30.8
16 to 30 15 1 6.7 37 6 16.2 16 to 30 51 4 7.8 72 8 11.1
31 to 45 57 5 8.8 69 10 14.5 31 to 45 163 17 10.4 159 20 12.6
46 and 97 9 9.3 99 19 19.2 46 and 255 32 12.5 225 44 19.6
above above
Total 194 19 9.8 217 36 16.6 Total 536 56 10.4 498 80 16.1
Fig. 5: Age-wise CFR over the years

REFERENCES 4. Study of outcome of young H1N1 females in tertiary care

1. www.cdc.gov/h1n1flu/ centre admitted in Jan 2010 Original study Indian medical
2. http://www.who.int/ith/diseases/si_iAh1n1/en/ Gazette; Nov 2010.
3. http://mohfw.nic.in/basicpage/technical-guidelines 5. Epidemiology and clinical outcome of H1N1 in Gujarat
from July 2009 to March 2010 in Journal of Associations of
Physicians of India. 2012;60:95-97.
CHAPTER
107
Ebola
BACKGROUND the largest and most complex Ebola outbreak since the
In August 1976, a 44-year-old headmaster named virus was first discovered in 1976. There were more cases
Mabalo Lokela arrived back in the town of Yambuku and deaths in this outbreak than in all others combined.
in the Democratic Republic of the Congo, after two It also spread between countries, starting in Guinea then
weeks spent touring with a local mission. A few days moving across land borders to Sierra Leone and Liberia.
after his return, he checked into the local hospital with The virus causing the 2014–2016 West African outbreak
nosebleeds, dysentery, and a fever. The doctors treated belonged to the Zaire ebola virus species (Table 1).
him for malaria, but to no avail. Lokela got worse. In
early September, two weeks after his first symptoms, he TRANSMISSION
died. And meanwhile, other people who had come into Natural reservoir host of Ebola viruses has not yet
contact with him started getting sick. been identified. Fruit bats are believed to be carriers of
Over the next three months, 318 people became disease and are able to spread the disease without being
infected, and 280 of them died. That outbreak, and affected by it. Scientists believe that the first patient in
another that took place simultaneously in South Sudan, an outbreak becomes infected through contact with an
alerted the world to the existence of a lethal new disease, infected animal, such as a fruit bat or primate (apes and
which eventually took the name of the waterway on monkeys), and it is called a spillover event. Ebola then
which Yambuku is situated—the Ebola river. spreads through human-to-human transmission via:
Ebola virus disease (EVD), which was previously 1. Direct contact (through broken skin or mucous
known as Ebola hemorrhagic fever, is a rare and membranes) with the blood, secretions, organs or
deadly disease. It is caused by infection with one of other bodily fluids of infected people.
the Ebola virus species. The virus family Filoviridae 2. Surfaces and materials (e.g. syringes, needles,
includes three genera: Cuevavirus, Marburgvirus, and bedding, clothing) contaminated with these fluids.
Ebolavirus. Within the genus Ebolavirus, five species 3. Possibly from contact with semen from a man who
have been identified: Zaire (now known as Ebola virus), has recovered from Ebola (e.g. by having oral, vaginal,
Bundibugyo, Sudan, Taï Forest and Reston. Apart or anal sex).
from reston virus, which causes disease in nonhuman Only a few species of mammals (e.g. humans, bats,
primates, the rest four viruses are known to cause disease monkeys, and apes) have shown the ability to become
in humans. The 2014–2016 outbreak in West Africa was infected with and spread Ebola virus. In Africa, Ebola
CHAPTER 107: Ebola 637
TABLE 1: Ebola outbreaks in reverse chronological order

Year(s) Country Ebola Reported no. of Reported no.
subtype human cases (%) of deaths
(suspected, possible among cases
or confirmed)
May-July 2017 Democratic Republic of the Congo Ebola virus 8 4 (50%)
August-November 2014 Democratic Republic of the Congo Ebola virus 66 49 (74%)

Outbreak occurred in multiple villages in the Democratic
Republic of the Congo. The outbreak was unrelated to the
outbreak of Ebola in West Africa
March 2014-2016 Multiple countries Ebola virus 28616 11310 (39%)
Outbreak primarily in Guinea, Liberia and Sierra Leone.
Thirty-six confirmed cases were reported from Italy, Mali,
Nigeria, Senegal, Spain, the United Kingdom, and the
United States
November Uganda Sudan virus 6 3 (50%)
2012-January 2013
June-November 2012 Democratic Republic of the Congo Bundibugyo 36 13 (36.1%)
virus
June-October 2012 Uganda Sudan virus 11 4 (36.4%)
May 2011 Uganda Sudan virus 1 1(100%)
December Democratic Republic of the Congo Zaire virus 32 15(47%)
2008-February 2009
November 2008 Philippines Reston virus 6 (asymptomatic) 0
December 2007-January Uganda Bundibugyo 149 37 (25%)
2008 virus
2007 Democratic Republic of the Congo Zaire virus 264 187(71%)
2004 Russia Zaire virus 1 1(100%)
2004 Sudan (South Sudan) Sudan virus 17 7(41%)
November-December Republic of the Congo Zaire virus 35 29 (83%)
2003
December 2002-April Republic of the Congo Zaire virus 143 128 (89%)
2003
October 2001-March Republic of the Congo Zaire virus 57 43 (75%)
2002
October 2001-March Gabon Zaire virus 65 53 (82%)
2002
2000-2001 Uganda Sudan virus 425 224 (53%)
1996 Russia Zaire virus 1 1 (100%)
1996 Philippines Reston virus 0 0
1996 USA Reston virus 0 0
1996 South Africa Zaire virus 2 1 (50%)
1996-1997 (July- Gabon Zaire virus 60 45 (74%)
January)
1996 (January-April) Gabon Zaire virus 37 21 (57%)
Contd...
Contd...
Year(s) Country Ebola Reported no. of Reported no.

subtype human cases (%) of deaths
(suspected, possible among cases
or confirmed)
1995 Democratic Republic of the Congo (formerly Zaire) Zaire virus 315 250 (81%)
1994 Côte d’Ivoire (Ivory Coast) Taï Forest 1 0
virus
1994 Gabon Zaire virus 52 31 (60%)
1992 Italy Reston virus 0 0
1989-1990 Philippines Reston virus 3 (asymptomatic) 0
1990 USA Reston virus 4 (asymptomatic) 0
1989 USA Reston virus 0 0
1979 Sudan (South Sudan) Sudan virus 34 22 (65%)
1977 Zaire Zaire virus 1 1 (100%)
1976 England Sudan virus 1 0
1976 Sudan (South Sudan) Sudan virus 284 151 (53%)
1976 Zaire (Democratic Republic of the Congo – DRC) Zaire virus 318 280 (88%)
may also spread as a result of handling bush meat (wild People remain infectious as long as their blood or
animals hunted for food) and contact with infected bats. bodily secretions contains the virus.
Ebola virus has been found in the semen of some
men who have recovered from Ebola. However, it is CLINICAL SYMPTOMS
not known if Ebola can be spread through sex or other The incubation period is about 2–21 days. Humans
contact with vaginal fluids from a woman who has had are not infectious until they develop symptoms, which
Ebola. Viral load decreases, in the semen over time and includes sudden onset of fever fatigue, muscle pain,
eventually disappears. The time it takes for Ebola virus to headache and sore throat. This is followed by vomiting,
leave the semen is different for each man. Contact with diarrhea, rash, symptoms of impaired kidney and liver
semen from a man who has had Ebola should be avoided function. Internal and external bleeding (e.g. oozing from
or barrier contraceptive should be used, until semen is the gums, hematemesis, melena, petechiae, purpura,
negative for virus on two ocassions. ecchymosis or hematomas), may be seen in many cases.
Burial ceremonies that involve direct contact with the Death is due to low blood pressure caused by fluid
body of the deceased also contributes significantly in the loss. Bleeding from any site worsens the prognosis.
transmission of Ebola. In 2014–16 outbreak about 60% Survivors may have muscular and joint pains, liver
cases were caused by observing such rituals. inflammation, lethargy, fatigue, decreased appetite and
Health-care workers have frequently been infected difficulty in regaining pre-illness weight.
while treating patients with suspected or confirmed In some people who have recovered from EVD, the
EVD. Exposure to Ebola can occur in health care virus is seen to persist in immune privileged sites. These
settings where hospital staff are not wearing appropriate sites include testicles, the central nervous system and the
personal protective equipment and infection control eye. The virus also persists in placenta, amniotic fluid
precautions are not strictly followed. Infected needles and fetus of infected pregnant women. The virus may
and syringes should be properly cleaned and disposed, persist in breast milk of infected women.
virus transmission can continue and amplify if adequate Viral persistence studies indicate that in a small
sterilization of the instruments is not done. percentage of survivors, some body fluids may test
TABLE 2: Diagnosis of Ebola Oral fluid specimen stored in universal transport

Time line of infection Diagnostic tests available medium collected from deceased patients or when
Within a few days after zz Antigen-capture enzyme-linked blood collection is not possible.
symptoms begin immunosorbent assay (ELISA) All biological specimens should be packaged using
testing
the triple packaging system when transported, as they
zz IgM ELISA
zz Revere transcription polymerase

carry extreme biohazard risk.
chain reaction (RT-PCR) Current WHO recommended tests include:
zz Virus isolation by cell culture
Automated or semiautomated nucleic acid tests
Later in disease course or zz IgM and IgG antibodies (NAT) for routine diagnostic management.
after recovery
Rapid antigen detection tests for use in remote
Retrospectively in deceased zz Immunohistochemistry testing
patients zz RT-PCR
settings where NATs are not readily available. These
zz Virus isolation by cell culture tests are recommended for screening purposes as
part of surveillance activities, however reactive tests
positive on reverse transcriptase polymerase chain should be confirmed with NATs.
reaction (RT-PCR) for Ebola virus for longer than 9
months. Symptomatic illness in someone who has TREATMENT AND VACCINES
recovered from EVD due to increased replication of At present no FDA-approved vaccine or medicine (e.g.
the virus in a specific site is a rare event, but has been antiviral drug) is available for Ebola. Good supportive
documented. care and patient’s immune response play a significant
role in recovery.
DIAGNOSIS The following basic interventions, when used early,
can significantly improve the chances of survival:
Suspecting Ebola in a person, initially is difficult because
Providing adequate oral hydration or intravenous
the early symptoms, such as fever, are nonspecific
fluids and electrolytes.
to Ebola infection and are also seen in patients with
Maintaining oxygen status and blood pressure.
more common diseases like meningitis, malaria and
Treating other infections if they occur.
typhoid fever. However, person should be isolated and
In a trial led by WHO, in Guinea, an experimental
public health authorities notified if they have the early
Ebola vaccine proved highly protective against the virus.
symptoms of Ebola and have had contact with
the trial involved 11,841 people the vaccine, called rVSV-
Blood or body fluids from a person sick with or who
ZEBOV, was studied during 2015. Among the 5837 people
has died from Ebola who received the vaccine, no Ebola cases were recorded
Infected fruit bats and primates (apes and monkeys)
10 days or more after vaccination. In comparison, there
Objects that have been contaminated with the blood
were 23 cases 10 days or more after vaccination among
or body fluids of a person sick with or who has died those who did not receive the vaccine.
from Ebola
Semen from a man who has recovered from Ebola
LESSONS LEARNT
Ebola virus is detected in blood only after onset of EVD has got high mortality rate. Killing between
symptoms. It may take up to three days after symptoms 25–90% of these infected by it, with an average of
start for the virus to reach detectable levels (Table 2). about 50%. However, when proper and advanced
For diagnosis the preferred specimens include: medical support was available to the patients, the
Whole blood collected in ethylenediaminetetraacetic mortality figures dropped very significantly. The last
acid (EDTA) from live patients exhibiting symptoms. and biggest outbreak was extremely challenging as
it involved urban and densely populated areas. In screening helped to identify those at risk for Ebola
contrast to predominantly rural and remote area and prevent disease transmission to other countries
outbreaks in past even after providing some medical More than 339,000 people were screened before
care the mortality was about 40%. leaving Guinea, Liberia and Sierra Leone. Enhanced
Now, there are many EVD survivors and many entry screening was also implemented globally.
are experiencing the sequelae of the disease. Adequate hydration/IV fluids/electrolytes/blood
As ebola virus can persist for several months in transfusion and use of life support system can bring
immunologically privileged sites like testis, eyes, down the mortality rates significantly.
CNS. This persistence of virus is responsible for many Control of outbreaks requires coordinated medical
smaller outbreaks so more caution and appropriate services, alongside a certain level of community
infection control practices should be adhered til engagement. There should be rapid detection of
ebola virus testing is negative on two occasions. cases of disease, contact tracing of those who have
Cost of Ebola epidemic to the resource poor African come into contact with infected individuals, quick
countries is enormous. Besides the devastating health access to laboratory services, proper health care for
effects, the Ebola epidemic also had a pronounced those who are infected, and proper disposal of the
socio-economic impact in Guinea, Liberia, and Sierra dead through cremation or burial.
Leone. Lower investment and a substantial loss in The potential for widespread infections in countries
private sector growth were also a result of the disease. with medical systems capable of observing correct
Health-care workers caring for patients with Ebola medical isolation procedures is considered low.
were among those at highest risk for contracting the Usually when someone has symptoms of the disease,
disease. Guinea, Liberia, and Sierra Leone, reported they are unable to travel without assistance. Human-
a total of 881 confirmed health worker infection to-human transmission of Ebola virus through
along with 513 reported deaths from the start of the air has not been reported to occur during
the outbreak to November 2015. Liberia lost 8% of EVD outbreaks. The apparent lack of airborne
its doctors, nurses, and midwives to Ebola; Sierra transmission among humans is believed to be due
Leone and Guinea lost 7% and 1% of their healthcare to low levels of the virus in the lungs and other parts
workers, respectively. of the respiratory system of primates, insufficient to
Nearly 20% of all Ebola cases occurred in children cause new infections.
under 15-years-old. In June 2014, all schools in People who care for those infected with Ebola
Guinea, Liberia, and Sierra Leone closed because should wear protective clothing including masks,
of the epidemic. By the time the schools reopened gloves, gowns and goggles. Centers for Disease
in 2015, due to school closures, students had lost Control (CDC) recommends that the protective
approximately 1,848 hours of education, ranging gear should leave no skin exposed. These measures
from around 33 weeks in Guinea to 39 weeks in are also recommended for those who may handle
Sierra Leone. A gap in vaccination schedules was objects contaminated by an infected person’s body
also seen as routine immunizations decreased by fluids. In 2014, the CDC recommended that medical
30% as the funding and logistics previously dedicated personnel receive training on the proper suit-up and
to vaccination campaigns were redirected to fight removal of personal protective equipment (PPE). In
the epidemic or were postponed to avoid public addition, a designated person, appropriately trained
gatherings. More than 17,300 children have been in biosafety, should be watching each step of these
orphaned because of Ebola. procedures to ensure they are done correctly. The
Travelers leaving West Africa were screened at infected person should be in barrier-isolation from
airports to prevent Ebola from crossing borders. Exit other people. All equipment, medical waste, patient
waste and surfaces that may have come into contact TABLE 3: Details of various outbreaks post West Africa 2014
with body fluids need to be disinfected. outbreak
Eb o l a v i r u s e s ca n b e e l i m i nat e d w i t h h e at Country Time Cases Contacts
(heating for 30–60 minutes at 60 °C or boiling Liberia March 2015 1 192
for 5 minutes). To disinfect surfaces, some lipid Liberia June 2015 7 126
solvents such as some alcohol-based products, Sierra Leone August 2015 6 840
detergents, sodium hypochlorite (bleach) or calcium Sierra Leone Sept 2015 1 780
hypochloride (bleaching powder), and other Liberia Nov 2015 3 165
suitable disinfectants may be used at appropriate Sierra Leone Jan 2016 2 >150
concentrations. Guinea and Liberia March 2016 13 >1200
Bushmeat, an important source of protein in the
diet of some Africans, should be handled and but it is difficult to predict whether these antibodies
prepared prepared and thoroughly cooked before will protect from reinfections, or infection with
consumption. another Ebola species. Further studies with these
When a person with Ebola disease dies, direct contact survivors are warranted to answer these questions.
with the body should be avoided. Certain burial
r i t u a l s, w h i c h m a y h av e i n c l u d e d m a k i n g BIBLIOGRAPHY
various direct contacts with a dead body, require 1. Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M,
Sanchez A, Nichol ST, Ksiazek TG, Rollin PE. Assessment of
reformulation such that they consistently maintain a
the risk of Ebola virus transmission from bodily fluids and
proper protective barrier between the dead body and fomites. J Infect Dis. 2007;196(Suppl 2):S142-7.
the living. 2. CDC. 2016. 2014 Ebola Outbreak in West Africa – Case
The World Health Organization (WHO) is responsible Counts. January 20. Accessed January 22, 2016. https://
for determining when a country will be declared www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/
case-counts.html.
free of Ebola virus transmission. Public health
3. CDC. 2016. Outbreaks Chronology: Ebola Virus Disease.
authorities in these countries should maintain active January 20. Accessed January 22, 2016. https://www.cdc.
surveillance for new cases of Ebola and identify, gov/vhf/ebola/outbreaks/history/chronology.html.
locate, and monitor any potential contacts. 4. Ebola virus disease Fact sheet No. 103. World Health
WHO now declares a country free of Ebola virus Organization. September 2014.
transmission after 42 days since last Ebola patient 5. Evansa DK, Goldstein M, Popova A. 2015. “Health-
care worker mor tality and the legacy of the Ebola
(two incubation periods).
epidemic.” The Lancet Global Health 3 (8): e439–e440.
Seven documented clusters as shown below Accessed December 22, 2015. doi:10.1016/S2214-
have occurred following control of the epidemic 109X(15)000650. http://www.sciencedirect.com/science/
(Table 3). Recent outbreaks appear to be related to article/pii/S2214109X15000650.
viral persistence in survivors. Rapid and coordinated 6. Qureshi AI, Chughtai M, Loua TO, Pe Kolie J, Camara
HF, Ishfaq MF, N’Dour CT, Beavogui K. Study of Ebola
efforts controlled all 7 flare-ups.
Virus Disease Survivors in Guinea. Clin Infect Dis.
In 2017, Anne Rimoin and her team tracked down 2015;61(7):1035-42.
14 survivors of the 1976 Ebola epidemic. Rimoin’s 7. Ruzek, edited bySingh SK, Daniel. Viral hemorrhagic fevers.
team showed that the immunity against Ebola virus Boca Raton: CRC Press, Taylor & Francis Group. 2014.
extended for decades. All of the 14 people they p. 444.
8. UNDP. 2014. “Assessing the socio-economic impacts of
studied still carried antibodies that recognize at
Ebola Virus Disease in Guinea, Liberia and Sierra Leone:
least one of the Ebola virus’s proteins, and four had The Road to Recovery.” Accessed December 22, 2015.
antibodies that could completely neutralize the virus. 9. World Health Organization. 2015. Ebola Situation Report –
Ebola infections can lead to long-lasting antibodies, 4 November 2015.
SECTION
9
Human Immunodeficiency Virus
90-90-90 Strategy in HIV Epidemic Neurological Manifestations of HIV
R Sajith Kumar Dipanjan Bandyopadhyay, Amit Adhikary
ART in HIV Infection: State-of-the-Art Cardiopulmonary Manifestations of HIV
BB Rewari, Manish Bamrotiya, Suman Singh Alaka K Deshpande
Opportunistic Infections in HIV: Changing Scenario Immune Reconstitution Inflammatory Syndrome
Amar R Pazare Vinay Rampal
CHAPTER
108
90-90-90 Strategy in HIV Epidemic
R Sajith Kumar
INTRODUCTION TREATMENT TARGET

Ever since the acquired immuno deficiency syndrome In December 2013, the UNAIDS Programme Coordinating
(AIDS ) was descr ibed (1981) and the Human Board called on UNAIDS to support all country efforts to
immunodeficiency virus (HIV) identified (1983), the establish new targets for HIV treatment scale-up beyond
progress in the field of managing the epidemic has been 2015 (Figs 1 to 3). As HIV treatments are becoming
phenomenal. The virus is expected to have infected more successful, new targets have been defined which
many millions in the world. The 39 million people have is ambitious but achievable. This new narrative aims to
already died of the disease. Any strategy that is used achieve the following.
to control the epidemic is meant for a healthier future By the year 2020, 90% of all people in the world living
generation. Global solidarity, evidence-based action
with HIV will know their HIV status.
and multi sectoral partnerships have been showing
By 2020, 90% of all such people with detected HIV
good results across continents. Antiretroviral therapy
infection are given antiretroviral therapy.
has become the mainstay of the management of the
epidemic in addition to the behavioral interventions By 2020, 90% of all such people receiving antiretroviral
suggested. The efficacy of drug therapy has literally therapy will have viral suppression.1
made us think of a visible silverline in the control of Once this three-part target is achieved, it is expected
the epidemic. If the antiretroviral drugs can make the that across the globe, at least 73% of all people living
viruses undetectable for an indefinite period of time, its with HIV will be virally suppressed—a two- to three-
implications are unimaginable. It makes the life of the fold increase over current rough estimates of viral
affected far better and AIDS in reducing transmission to suppression. Various models developed suggests that if
the unaffected significantly. That being the case, the goal these targets are achieved by 2020 the world will be able
now is to make the benefit available to the masses in a to end the AIDS epidemic by 2030, which will generate
structured way. Whereas previous AIDS targets sought to explicit benefits in health and economics. The only
achieve incremental progress in the response, the aim in way to achieve this highly ambitious target is through
the post-2015 era is nothing less than the end of the AIDS approaches based on principles of human rights, mutual
epidemic by 2030. respect and inclusion.
646 SECTION 9: Human Immunodeficiency Virus
Fig.1: Graphic representation of the 90-90-90 targets (Courtesy: UNAIDS)
Fig. 2: Graphic representation of the gaps in 90-90-90 targets (Courtesy: UNAIDS)
It is certain that HIV treatment is a critical tool services for people who inject drugs, and programming
towards ending the AIDS epidemic, but it is not the only focused prevention for other key populations. To put
one. While taking action to maximize the prevention in place an all inclusive response to end the epidemic,
by way of HIV treatment, urgent efforts are needed concerted efforts will be needed to eliminate stigma,
on similar grounds to scale up other core prevention discrimination and social exclusion based on sero status.
strategies, including total elimination of mother-to- AIDS will disappear, perhaps only with uninterrupted
child transmission, condom programming, pre/postdelivery of lifelong antiretroviral drugs for of millions
exposure antiretroviral prophylaxis, voluntary medical of people. This in turn is possible only with strong,
male circumcision in priority countries, harm reduction flexible health and community systems, protection of
CHAPTER 108: 90-90-90 Strategy in HIV Epidemic 647
Fig. 3: Status of India in the 90-90-90 target (Adopted from NACO materials)
Note: Diagnosed, PLHIV ever registered–(PLHIV dies + PLHIV Permanent LFU)
Source: Monthly progress Report (Aug 2017)
human rights, and self-financing that is able to support Brief July 2017 also states that ART initiation should be
treatment programmes across the world and throughout offered the same day to people who are ready to start.
the lifespan of people living with HIV. Just as prophylaxis
for Pneumocystis carinii pneumonia served in the early HIV Treatment Averts AIDS-related Deaths
years of AIDS as a life-saving bridge to the antiretroviral The initial worry about shortened survival for HIV
treatment era for millions of people living with HIV, the infection is also gradually waning off. In the pretreatment
world needs to improvise the existing tools aimed at era, someone who acquired HIV infection could expect
extending lives towards a day when a cure or simpler to live only between 2 and 12.5 years. But today a
treatment options will become standard. young person becoming infected can expect to live for
25–50 years with the use of uninterrupted therapy. The
difference in survival between people with HIV infection
HIV Treatment Prevents HIV-related in developed countries and low income countries
Illness is also decreasing, as the cost of therapy is coming
As years passed by, the threshold for starting ART in HIV down. A major contributor for this development is the
infected people kept on changing. The initial cut off value pharmaceutical industry in India that made generic
of 200 CD4+ cells per cmm quickly got replaced with, 350 drugs at costs far below their multinational counterparts.
and later 500 CD4+ cells per cmm. In the last ten years, Thus more and more people could afford ART.
many studies have shown the definite benefit of starting
ART at higher levels, and as of now all agencies across HIV Treatment Prevents New HIV
the globe have accepted the ‘Treat All’ policy, which Infections
implicates initiation of ART in all patients, irrespective of Ever since the epidemic started, there has been lot of
CD4+ cell count. Many HIV related and non HIV related focus on preventive strategies. Many interventions
causes of morbidity and mortality can be efficiently have been instituted. But HIV treatment by itself has
prevented by this strategy. The Treat All policy also been shown to be the most effective of all. It is common
ensures definite treatment initiation. The WHO Policy knowledge that if the number of replicating or active
organisms in any infection is directly related to infectivity. REACHING TARGET 2

In HIV infection, it goes without saying that suppressing
the virus from thousand or millions of copies per mL
90% of All People with Detected HIV
to undetectable levels will make the transmission Infection will Get Proper Antiretroviral
routes inefficient, thus preventing new infections to a Therapy (90% on HIV Treatment)
significant extent. Interim findings from the PARTNER One major hindrance to initiation of therapy was the
study indicate that among 767 serodiscordant couples, cost of drugs. The availability good quality generic drugs
no case of HIV transmission occurred when the person from many middle income economies and widespread
living with HIV had suppressed virus – after an estimated acceptance of the same by many other countries are
40,000 instances of sexual intercourse. The concept of positive achievements in this direction. Research has
‘Treatment As Prevention’ (TAP) has to be extensively also led to better therapeutic options like Single Tablet
agreed upon as a major preventive tool. regimens. Abolition of CD 4 cut off value also will ease
the initiation of therapy in all. The direction to start
HIV Treatment Saves Money standard ART in pregnant women will put an increasing
Many modelling exercises have shown clearly that early number of persons who would have been subjected to
ART is also a cost effective tool in the long run. According dangerous therapeutic options otherwise.
to a modelling exercise, investments in HIV treatment Adequately high treatment coverage has been
scale-up generate returns more than two-fold greater achieved in many countries and regions, putting them
when averted medical costs, averted orphan care and on pace to reach the second part of the 90-90-90 target
labour productivity gains are taken into account. The if progress continues. Many countries as varied as
initial increase in cost attributed to cost of infrastructure, Botswana and Colombia, 70% or more people detected
logistics, drugs, testing laboratories etc. will definitely to have HIV infection are on proper antiretroviral therapy
pay in the long run to reduce total cost of decreased even now. More than 60% of people with HIV infection
morbidity and survival. in Brazil were receiving antiretroviral therapy as early
as 2013. Strategic action will be needed to achieve and
REACHING TARGET 1 sustain high treatment coverage. Countries will need
to align national treatment guidelines with evidence
90% of All People Living with HIV will documenting the clear benefits of early treatment
know their HIV Status (90% Diagnosed) initiation and ensure use of preferred, optimized
In order for this to happen, all countries should have regimens. Recommending antiretroviral therapy to
a proper estimate of people living with HIV. This is the all people with diagnosed HIV infection, without the
major determinant based on which all calculations are requirement of a prior CD4 test, has the potential to
made. Testing has to be extensive and frequent, and enhance treatment uptake by reducing loss to follow up.
strategies for early testing has to be in place. Point of In order to achieve and maintain such high treatment
care testing for detection has to be adopted with all coverage, it is needed to ensure that HIV treatment and
antecedent challenges that may be posed. Human rights care and support, including diagnostic tests and other
issues, confidentiality, stigma and discrimination issues treatment-related items, is offered free to all. However,
have to be addressed properly. Proper pre-test and post- the affluent should be able to buy also. Countries will also
test counselling and simple integration with care has need to address implementation issues that have often
to be in place. Every testing facility should act as points slowed scale-up, including frequent drug stockouts,
of entry for care and support. Encouraging voluntary barriers to procurement of optimally affordable
testing, self referral can be tools to achieve the increased medicines and diagnostics, and inadequate availability
detection rate. of second- and third-line regimens.
REACHING TARGET 3 challenge, countries have already demonstrated the

feasibility of achieving high retention rates.
90% of All People Receiving Antiretroviral Operationalization of the third component of the
Therapy will have Viral Suppression new treatment target will require concerted efforts to
(90% Suppressed) improve access to viral load testing technologies. To
Once ART has been intiated, persistency and adherence ensure that the third part of 90-90-90 target is achieved
issues arise. Even in free roll out of the ART patient and thereby to end the AIDS epidemic, every person
compliance and adherence issues are important. The starting HIV treatment will have to be ensured access to
toxicity of many antiretroviral drugs was and continues viral load testing. Regular HIV viral load monitoring is
to be a limiting factor. Newer simpler regimens with safer essential for optimized HIV treatment, and every person
drugs, availability of better predictors and improved with detected HIV infection has the right to know her
awareness and institution of regular monitoring or his viral load. Viral load testing optimizes treatment
systems help a lot to reduce ineffective therapy. Use outcomes, and may also help lower expenses for therapy.
of pharmacokinetic enhancers also reduce failure Where viral load tests are unavailable, clinicians are
and toxicity rates. Countries and program have also unable to identify early treatment failure and intervene
succeeded in achieving high levels of viral suppression, to support patients who are having difficulty adhering to
demonstrating the feasibility of a target of 90% viral prescribed regimens. As a result, individuals whose less
suppression among all people receiving antiretroviral expensive first-line regimens might have been preserved
therapy by 2020. When we examine individual low with effective adherence support interventions may be
income countries, example of Rwanda, is interesting. prematurely switched to more expensive second- and
There 83% of people receiving antiretroviral therapy were third-line regimens.
virally suppressed at the end of 18 months of therapy in
as early as 2009. Accumulated information tell that high Special Groups
rates of viral suppression are attainable in individual It is clear that the HIV epidemic affected populations
countries and across regions. According to data from are not uniform. Due to the persistence of stigma,
17 countries in Latin America and the Caribbean, the discrimination and social exclusion, members of
median rate of viral suppression among recipients of key populations experience inequitable access to
HIV treatment is 66%, with more than 80% of individuals care and suboptimal health outcomes. Many factors
receiving antiretroviral therapy having achieved viral undermine effective responses in achieving the 90-
suppression in at least five countries (Barbados, Brazil, 90-90 targets for key populations. These have to be
Honduras, Mexico and Uruguay). addressed separately. Special problems related to caring
These impressive rates of viral suppression are of children, adolescents and marginalized groups like
encouraging. However, they do not account for AIDS- IV drug abusers, transgender, etc. may require intensive
related mortality or loss to follow up, highlighting approaches to be diagnosed and enrolled for the strategy
the essential need for intensified efforts to ensure to become successful. Stigma and discrimination, in
long-term retention in care among those who enrol the broader social environment but especially in health
in HIV treatment. The third approach to treatment care settings, deter many members of key populations
targeting is cascading in that it requires sustained use from learning their HIV status or accessing life-saving
of HIV treatment and ongoing virologic monitoring to prevention and treatment with HIV Stigma Index
verify treatment success and to intervene to support indicate that members of key populations commonly
treatment adherence and re-engage those who fall out experience disapproval, rejection and sub-optimal
of care. Although retention in care remains an important services in health care settings. Certain laws and policies
that interfere with free testing and treatment efforts for treatment protocols. This considerable loss to follow
certain key populations are to be amended to achieve the up, underscores the need for efficient interventions to
90-90-90 target. enable retention in therapeutic services. In collaboration
A global consultation convened by UNAIDS on the with partners, WHO has identified key research and
adolescent treatment challenges found that adolescents development priorities, including the development of
living with HIV confront innumerable obstacles to age-appropriate fixed dose combinations for children
meaningful treatment access and thereby ensuring and prioritized development of fixed dose combinations
favorable health outcomes. Some of these challenges that include especially promising new antiretroviral
are well known and include stigma, discrimination drugs, such as dolutegravir or TAF.
and problematic laws and policies, including parental At a societal level–whether broadly defined for high-
consent laws. Many of them limit young people’s ability prevalence countries, or at a population level for key
to access HIV testing and other health care services on populations–knowledge of HIV status has often yet to be
their own. Like adults and younger children, adolescents established as a fundamental social norm. While working
often struggle with health care linkage and retention, to leverage every available strategy–community-centered
with particular challenges experienced as adolescents testing campaigns, full implementation of provider-
transition from paediatric to adult services. Many young initiated HIV counseling and testing, social marketing,
people often have poor access to sex education and selftesting and the like–specific efforts are needed to
limited exposure regarding their sexual and reproductive elements of the 90-90-90 target, a rights-based educate
health and rights. Many adolescents living with HIV communities regarding the HIV testing approach that
struggle with disclosure of their HIV status, in part rejects coercion and stigmatization is imperative.
because they are frequently left on their own to navigate Augmented release of funds are required to end the
the complexities of living with HIV as a young person. AIDS epidemic by 2030, but the resources needed for
Without HIV treatment, half of children living with such rapid scale-up towards the 90-90-90 target are not
HIV will die by age two. Even with continued progress in so unmanageable. It has been estimated that to reach the
prevention of mother-to-child transmission, WHO and ambitious 90-90-90 target, HIV treatment, including drug
UNICEF project that 1.9 million children will require HIV expenses, service delivery, community mobilization to
treatment in 2020. For children born to women living ensure access to testing and retention in treatment, and
with HIV who are not effectively linked to diagnostic preART costs, will require an enormous total of USD 14
services through systems to prevent mother-to-child billion by 2016. In 2016–2020, funding will need to ramp
transmission, HIV testing is not routinely offered in up incrementally each year, reaching USD18 billion
child-focused programmes. This failure represents a by 2020. From peak spending in 2020, it is definite that
major missed opportunity, as there is often very high treatment costs will come down through 2030, when the
prevalence among children with needs addressed by same will total USD16.9 billion
other service systems. Children today suffer from the
reality that after detection of HIV infection, treatment ENDING THE AIDS EPIDEMIC
options available are limited. Most of the antiretroviral The tools and strategies that exist now are sufficient in
medicines approved for use in adults are not approved themselves to see the end of the AIDS epidemic by 2030.
for use in children. The few medicines available for use in However, achieving these requires unprecedented action
very young children tend to be unpalatable and require now to scale up early antiretroviral therapy, as delay
regimens than are more complicated than those for adults. will merely allow the epidemic to continue to outpace
There is an urgent need for pediatric-specific fixed-dose the response. Inspired by what has been achieved to
combinations that reduce medication burdens and help date and undaunted by the challenges ahead, the entire
improve treatment adherence. Children are frequently global community should resolve not to allow this
lost to follow up even after getting enrolled into HIV historic opportunity to pass by.
BIBLIOGRAPHY 8. Resch S, et al. Economic returns to investment in AIDS

treatment in low and middle income countries. PLoS One.
1. Collaborative Group on AIDS Incubation and HIV Survival.
2011;6:e25310.
Time from HIV-1 seroconversion to AIDS and death before
9. Rodger A, et al. HIV transmission risk through condomless
widespread use of highly-active antiretroviral therapy: a
sex if HIV+ partner on suppressive ART: PARTNER study.
collaborative re-analysis. Lancet. 2000;355:1131-7.
21st Conference on Retroviruses and Opportunistic
2. Granich R, et al. Expanding ART for treatment and
Infections, Abstrract 153LB, Boston, USA, 2014.
prevention of HIV in South Africa: Estimated cost and cost-
10. Samji H, et al. Closing the gap: Increases in life expectancy
effectiveness 2011-2050. PLoS ONE. 2012;7:e30216.
among treated HIV-positive individuals in the United States
3. Grinsztejn B, et al. Effects of early versus delayed initiation
and Canada. PLoS ONE, 2013;8:e81355.
of antiretroviral treatment on clinical outcomes of HIV-1
11. Tanser F, et al. High coverage of ART associated with decline
infection: results from the phase 3 HPTN 052 randomised
in risk of HIV acquisition in KwaZulu-Natal, South Africa.
controlled trial. Lancet Infect Dis. 2014;DOI:10.1016/ Science, 2013;339:966-71.
S1473-3099(13)70692.3. 12. UNAIDS: 90-90-90. An ambitious treatment target to help
4. Karim SAS, Karim QA. Antiretroviral prophylaxis: a defining end the AIDS epidemic, October 2014. (Majority of the
moment in HIV control. Lancet, 2011;378:e23-e5. material is based on this publication).
5. Montaner JSG, et al. The case for expanding access to 13. UNITAID, HIV/AIDS medicines market and technology
highly active antiretroviral therapy to curb the growth of the landscape, 2014.
HIV epidemic. Lancet. 2006;368:531-6. 14. Ventelou B, et al. The macroeconomic consequences of
6. Montaner JSG et al. Expansion of HAART coverage is renouncing to universal access to antiretroviral treatment
associated with sustained decreases in HIV/AIDS morbidity, for HIV in Africa: a micro-simulation model. PLoS ONE.
mortality and HIV transmission: the “HIV treatment as 2012;7:e34101.
prevention” experience in a Canadian setting. PLoS ONE. 15. Walensky RP, et al. Cost-effectiveness of HIV treatment
2014;9:e87872. as prevention in serodiscordant couples. New Eng J Med.
7. Newell ML, et al. Mortality of infected and uninfected infants 2013;369:1315-25.
born to HIV-infected mothers in Africa: a pooled analysis. 16. WHO, Consolidated guidelines on the use of antiretroviral
Lancet, 2004;364:1236-43. drugs for preventing and treating HIV infection, 2013.
CHAPTER
109
ART in HIV Infection: State-of-the-Art
BB Rewari, Manish Bamrotiya, Suman Singh
ANTIRETROVIRAL THERAPY TABLE 1: Goals of ART
FOR HIV INFECTION Clinical goals Increased survival and improvement in quality
of life
There has been a rapid decline in HIV related mortality
and morbidity with the wider availability of affordable, Virological goals Greatest possible sustained reduction in viral
load
more efficacious and less toxic antiretroviral (ARV)
drugs over last two decades. Antiretroviral therapy Immunological Immune reconstitution, that is both
goals quantitative and qualitative
(ART) consists of use of combination of at least three
antiretroviral drugs from different classes to inhibit the Therapeutic Rational sequencing of drugs in a manner that
goals achieves clinical, virological and immunological
replication of HIV and reduce viremia to undetectable goals while maintaining future treatment
levels. Durable suppression of viral replication leads options, limiting drug toxicity and facilitating
to a restoration of immune response reflected by adherence
an increase in CD4 count leading to slowing of the Preventive goals Reduction of HIV transmission by suppression
disease progression, reduced frequency of opportunistic of viral load
Infections, improvement in the quality of life and
increased longevity. Successes achieved by antiretroviral cells and fluids (e.g. brain, liver and lymphoid tissue)
therapy (ART) have now transformed the perception despite prolonged suppression of plasma viremia to
about HIV infection from being a ‘virtual death sentence’ <50 copies/mL by ART. The primary goals of ART are
to a ‘chronic manageable illness’. ART was earlier known maximal and durable reduction of plasma viral levels and
as Highly Active ART (HAART) and as combination restoration of immunological functions. The reduction
ART (cART). in viral load also leads to reduced transmissibility and
reduction in new infections. The defined goals of ART are
GOALS OF ANTIRETROVIRAL depicted in Table 1.
THERAPY Due to continued viral suppression, the destruction
ART cannot cure HIV infection as the currently of CD4 lymphocyte cells is reduced and over time there
available ARV drugs cannot eradicate the virus from is an increase in CD4 count, which is accompanied
the human body. This is because a pool of latently by partial restoration of pathogen-specific immune
infected CD4 cells is established during the earliest stages function. This leads to a reduction in opportunistic
of acute HIV infection and persists within the organs/ infections, reduced morbidity and mortality.
CHAPTER 109: ART in HIV Infection: State-of-the-Art 653
TABLE 2: Classes of ARV Drugs

Nucleoside reverse Non-nucleoside reverse Protease inhibitors (PI)
transcriptase inhibitors (NsRTI) transcriptase inhibitors (NNRTI)
Zidovudine (AZT/ZDV)* Nevirapine* (NVP) Saquinavir (SQV)**
Stavudine (d4T)* Efavirenz*(EFV) Ritonavir* (RTV)
Lamivudine (3TC)* Delavirdine (DLV)** Nelfinavir (NFV)**
Etravirine Amprenavir (APV)**
Didanosine (ddl)** Fusion inhibitors (FI) Indinavir (INV)**
Zalcitabine (ddC)** Enfuvirtide (T-20) Lopinavir (LPV)*
Abacavir (ABC)* Integrase inhibitors Fosamprenavir (FPV)
Emtricitabine (FTC) Raltegravir (RGV)* Atazanavir (ATV)*
Dolutegravir (DTG) Tipranavir (TPV)
Nucleotide reverse transcriptase inhibitors (NtRTI) CCR5 entry inhibitor Darunavir (DRV)*
Tenofovir (TDF)* Maraviroc
*Available in National Programme
**No longer used
Principles of Antiretroviral Therapy transcriptase and preventing the conversion of RNA to

A continuous high level of replication of HIV takes place DNA. These drugs are called “non-nucleoside” inhibitors
in the body right from the early stages of infection. At because, even though they work at the same stage as
least one billion viral particles are produced during nucleoside analogues, as chain terminators, they inhibit
active stage of replication. The antiretroviral drugs act the HIV reverse transcriptase enzyme by directly binding
on various stages of replication of virus in the body to it.
and interrupt the process of viral replication. The
most commonly used drugs target the virus mainly by Protease Inhibitors
inhibiting the enzymes reverse transcriptase (RT) and Protease inhibitors (PIs) work at the last stage of the
protease and they are depicted in Table 2. viral reproduction cycle. They prevent HIV from being
successfully assembled and released from the infected
CLINICAL PHARMACOLOGY OF CD4 cell. All PIs can produce GI intolerance, altered
COMMONLY USED ARV DRUGS taste, abnormal liver function test and bone disorder and
all have been associated with metabolic abnormalities,
Nucleoside/Nucleotide Reverse such as hyperglycemia, insulin resistance and increase
Transcriptase Inhibitors in triglycerides, cholesterol and body fat distribution
The first effective class of antiretroviral drugs discovered (lipodystrophy).
was the Nucleoside analogues, which act by incorporating
themselves into the DNA of the virus, thereby stopping Integrase Inhibitors
the building process. The resulting DNA is incomplete Integrase inhibitors block the action of integrase, a viral
and cannot create new virus. Nucleotide analogues enzyme that inserts the viral genome into the DNA of
work in the same way as nucleosides, but they have a the host cell. Since integration is a vital step in retroviral
nonpeptidic chemical structure. replication, blocking it can halt further spread of the
virus. Raltegravir was the integrase inhibitor approved
Non-nucleoside Reverse for use in 2007. Dolutagrevir (DTG) and Elvitegravir
Transcriptase Inhibitors (ELV) are the other approved drugs in this class.
Non-nucleoside reverse transcriptase inhibitors The dosage and common adverse effects of commonly
(NNRTIs) stop HIV production by binding onto reverse used ARV drugs are given in Table 3.
TABLE 3: Commonly used ARV drugs

Generic name Dose Adverse effects
Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTI)
Tenofovir (TDF) 300 mg once daily Renal toxicity, bone demineralization
Zidovudine (ZDV, 300 mg twice daily Anemia, neutropenia, bone marrow suppression, gastrointestinal intolerance,
AZT) headache, insomnia, myopathy, lactic acidosis, skin and nail hyperpigmentation
Lamivudine (3TC) 150 mg twice daily Minimal toxicity, rash (though very rare)
or
300 mg once daily
Abacavir 300 mg twice daily Hypersensitivity reaction in 3–5% (can be fatal), fever, rash, fatigue, nausea,
(ABC) or vomiting, anorexia, respiratory symptoms (sore throat, cough, shortness of
600 mg OD breath); Rechallenging after reaction can be fatal
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Efavirenz (EFV) 600 mg once daily (bed time CNS symptoms (dizziness, somnolence, insomnia, confusion, hallucinations,
administration is suggested to agitation) and personality change. Rash occurs, but less common than NVP.
decrease CNS side-effects) Avoid taking after high fat meals
Nevirapine (NVP) 200 mg once daily for 14 days, Hepatitis (usually within 12 weeks); sometime life-threatening hepatic toxicity.
followed by 200 mg twice daily Skin rash occasionally progressing to severe conditions, including Stevens
Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Patients who
develop severe hepatic toxicity or grade 4 skin rashes should not be re-
challenged
Protease inhibitors(PI)
Atazanavir/ritonavir 300 mg Atazanavir + 100 mg Hyper bilirubinemia. Less lipid problems than LPV/r hyperglycemia, fat
(ATV/r) ritonavir once daily maldistribution, nephrolithiasis
Interaction with acid blocking agents. Do not coadminister with H2 receptor
antagonist. Give 12 hours gap when using proton pump inhibitors
Lopinavir/ritonavir 200 mg Lopinavir/50 mg Ritonavir Diarrhea, nausea, vomiting, abnormal lipid profiles, glucose intolerance. Any
(LPV/r) Fixed dose tablet PI should not be prescribed with Simvastatin as they significantly increase the
Heat stable tablets 2 tablets twice daily level of Simvastatin leading rhabdomyolysis, resulting in severe kidney failure
Darunavir (DRV) 600 mg twice a day (when used Hepatotoxicity, skin rash (10%), diarrhea, nausea, headache, hyperlipidaemia,
with Ritonavir 100 mg twice daily) serum transaminase elevation, hyperglycemia
Ritonavir (RTV) 100 mg Twice daily (used only to Common-gastrointestinal (diarrhea, nausea, vomiting, abdominal pain (upper
boost another PI) and lower)), rarely neurological disturbances (including paraesthesia)
Integrase inhibitors
Raltegravir (RAL) 400 mg twice daily Rhabdomyolysis, myopathy, myalgia, diarrhea, fever, rash, Stevens-Johnson
syndrome, toxic epidermal necrolysis, hepatitis and hepatic failure
insomnia
Dolutagrevir (DTG) 50 mg once daily Insomnia and headache; Dolutagrevir can cause serious, life-threatening side
effects. These include hypersensitivity (allergic) reactions and liver problems.
To be used with caution in people with a history of hepatitis B virus (HBV) or
hepatitis C virus (HCV) infection or deranged LFT
CONSIDERATIONS BEFORE opportunistic infections, treatment preparedness

INITIATION OF ART counselling and timely ART initiation.
All people with confirmed HIV infection should undergo The following principles need to be kept in mind:
a comprehensive clinical and laboratory evaluation Treatment should be started based on a person’s
to assess baseline status, treatment of pre-existing informed decision and preparedness to initiate
ART on the benefits of treatment, understanding of comprehensive prepared ness counseling for the patient.
lifelong medication, adherence issues and positive In general, the clinical management of an HIV infected
prevention patient revolves around optimizing the treatment
All patients with CD4 less than 350 cells/cmm need to regimen, reducing drug toxicity, reducing the pill burden
be put on co-trimoxazole preventive therapy (CPT). and increasing adherence to the treatment.
All patients need to be screened for TB, using the
4-symptom tool (current cough, fever, night sweats When to Start ART in Adults
and weight loss) and those who do not have TB need and Adolescents?
to be started on isoniazid preventive therapy (IPT) in The guidelines on When to start ART have been evolving
addition to ART. over the years towards earlier initiation of ART; CD4
ART should not be started in the presence of an active
count off point moving for ART initiation from less than
OI: In general, OIs should be treated or stabilized 200 cells/cmm in 2004 to less than 350 cells/cmm in 2010
before commencing ART. Mycobacterium avium and then to less than 500 cells/cmm in 2013. The current
complex (MAC ) and progressive multifocal recommendation is to TREAT ALL, regardless of clinical
leukoencephalopathy (PML) are exceptions, in which stage or CD4 count. These changes have been based on
commencing ART may be the preferred treatment, evidence from various randomized clinical trials (RCT)
especially when specific MAC therapy is not available. and large observational cohorts which have revealed that
Some conditions which may regress following the with the earlier ART initiation, there was a significant
commencement of ART include candidiasis and delay in progression to AIDS and reduction in incidence
cryptosporidiosis. For those with HIV TB coinfection, of TB. These studies are summarized in Figure 1.
start antitubercular treatment first and start ART as
soon as possible after 2 weeks of ATT but definitely zz As per DHHS, WHO 2016 and NACO 2017 Guidelines
before 2 months. For those with CD4 less than zz All HIV positive persons (adults. adolescents, children, pregnant
50/cmm, start ART and ATT simultaneously. women, those with coinfections like TB, hepatitis, etc.) are eligible
Once the evaluation of patient is completed, the for ART initiation regardless of CD4 count, viral load or WHO
clinical staging
following guidelines for ART need to be followed after a
Fig 1: Evolution of CD4 cut-offs for ART initiation over time

Ensuring good adherence to the treatment is imperative recommended that all PLHIV with HIV-1 infection be
for the success of treatment as well as for the prevention of initiated on a regimen consisting of
drug resistance. To achieve this, counseling must start from
TENOFOVIR (TDF 300 mg) + LAMIVUDINE (3TC 300 mg)
the first contact of the patient with the clinical team and
+ EFAVIRENZ (EFV 600 mg) (TLE) as Fixed Dose
should include preparing the patient for treatment and
Combination (FDC) in a single pill once a day.
providing psychosocial support through an identified
caregiver/guardian/treatment buddy and through support This regimen has the advantage of harmonization of
networks. All patients should undergo at least two counseling treatment for all adults, adolescents, pregnant women
sessions (preparedness counseling) before the initiation and those with HIV-TB and HIV hepatitis coinfections. It
of ART. The period of waiting for investigations and their is the simplest, most potent and least toxic regimen that
results should be utilized for counselling, cotrimoxazole offers the advantage of a decentralized service delivery
prophylaxis and isoniazid preventive therapy (in eligible and monitoring. It also simplifies the supply chain and
patients) and treatment preparation. minimizes the monitoring requirements.
In cases where the preferred first line ARV regimen of
What to Start: Antiretroviral Therapy TDF+3TC+EEV cannot be used, the alternative regimen
Regimens of AZT+3TC+EFV, TDF+3TC+NVP, ABC+3TC+EFV or
Fixed-dose combinations (FDCs) of ARVs are preferred ABC+3TC+NVP can be used.
because they are easy to prescribe and easy for patients to
take, which facilitates improved and desirable treatment Note: The patients with HIV-2 and both HIV-1 and HIV-2
adherence. This is essential for PLHIV as treatment co-infections need to be initiated on a PI containing
is life-long and we need to minimize the chances of regimen, as NNRTIs (EFV/NVP) are not active against
developing drug resistant mutants in their body and the HIV-2 virus. For patients with HIV-2 infection, the
resultant treatment failure. preferred first line ART regimen shall be Tenofovir
(300 mg) plus Lamivudine (300 mg) plus Lopinavir/
RECOMMENDED CHOICE OF Ritonavir (800/200 mg)
FIRST LINE REGIMEN A summary of different ARV regimens with specific
The basic principle for first line ART for treatment naïve indications are given below in Table 4.
adult and adolescent patients is to use a triple drug
combination from two different classes of ARVs. The MONITORING OF PATIENTS ON ART
first line ART essentially comprises of a NRTI backbone, Follow-up and monitoring is essential in patients
preferably nonthymidine (Tenofovir plus Lamivudine) initiated on ART to track clinical progress, monitor
and one NNRTI, preferably EFV. Based on evidence wellbeing and to identify adverse drug reactions and
supporting better efficacy and fewer side effects, it is now toxicities.
TABLE 4: First line ARV regimen guidance

ART regimen Recommended for
Tenofovir + Lamivudine + Efavirenz First line ART regimen for: All ARV naive patients except those with known renal disease
Or HIV-2 or HIV-1 and 2 infections Or women with single dose Nevirapine exposure in past
pregnancy
Abacavir + Lamivudine +Efavirenz First line ART regimen for: All patients with known renal disease
Tenofovir + Lamivudine + Lopinavir/ First line ART regimen for: All women with single dose Nevirapine exposure in a past
Ritonavir pregnancy;
All confirmed HIV-2 or HIV- 1 and HIV-2 co-Infection
Zidovudine + Lamivudine + Nevirapine All patients who are on either of these first line regimens initiated earlier in the program need
Zidovudine + Lamivudine + Efavirenz to be continued on the same
TABLE 5: Laboratory monitoring for individual ARV drugs

For all patients on ART, need to do CD4, Hb, TLC, DLC, ALT (SGPT), serum creatinine once in every six months
Tests for monitoring patients on ART (Follow-up tests) Drug specific tests frequency as below
Monitoring ARV drug in regimen Monitoring test Baseline 15th day First Second Third Sixth Then every
month month month month 6 months
On Zidovudine based ART CBC Yes Yes Yes Yes Yes Yes Yes
On Tenofovir based ART Serum creatinine Yes Yes Yes Yes Yes Yes Yes
Nevirapine containing ART ALT Yes Yes Yes Yes Yes Yes Yes
(SGPT)
Efavirenz containing ART Lipid profile Yes Yes Yes Yes Yes Yes Yes
Atazanavir containing ART LFT Yes Yes Yes Yes Yes Yes Yes
Lipid profile
Lopinavir containing ART Lipid profile and Yes Yes Yes Yes Yes Yes Yes
Blood sugar
ART monitoring includes clinical monitoring and inter-current illnesses and drug-drug interactions and
laboratory monitoring. Clinical monitoring includes other metabolic abnormalities. The summary of the
monitoring of ART adherence as well. The client should laboratory monitoring recommended under the program
be monitored every month for clinical progress, for the is presented in the Table 5. Additional laboratory tests
side effects of the ARV/s and for the treatment adherence. outside this schedule may be performed as clinically
The various monitoring indicators are listed below: indicated.
Clinical monitoring
—— Monthly clinical evaluation Antiretroviral Drug Toxicity

Body weight, overall wellbeing, any new symptoms/ Antiretroviral drugs have a broad range of toxicities,
signs, four symptom screening for TB on every visit ranging from low-grade intolerance which may be self-
—— Monthly treatment adherence-evaluation--pill limiting to life-threatening side-effects and are depicted
count, self-reported adherence in Table 6. Differentiating between complications
—— For adverse reactions of ART/OI drugs of HIV disease and ART toxicity is very important.
—— For drug-drug interactions, look for all conco Considerations should also include intercurrent illness
mitant drug use (prescribed and over the counter) (e.g. hepatitis A, malaria, etc.) or reactions to medications
—— For IRIS (Immune Reconstitution Inflammatory other than ARVs, e.g. isoniazid-induced hepatitis or rash
Syndrome) induced by cotrimoxazole. However, most of the toxicity/
Immunological monitoring: CD4 counts should be effects can be adequately co-managed with good clinical
monitored every 6 months in all patients on ART. monitoring at all the levels of the health care system.
Frequency of Cd4 testing can be reduced in patients As a general principle, mild toxicity does not require
who are virologically suppressed after one year on discontinuation of ART or substitution. Symptomatic
ART. treatment may be given. Moderate or severe toxicities
Virological monitoring: At 6 months and 12 months may require substitution with a drug of the same ARV
after ART initiation and then every 12 months. class but with a different toxicity profile. Severe life-
The laboratory monitoring of PLHIV on ART is also threatening toxicity requires discontinuation of all ARV
very important. Regular monitoring of patients’ laboratory drugs until the patient is stabilised and the toxicity is
parameters is crucial to identify ARV related toxicities, resolved.
TABLE 6: Common ARV drug toxicities and overlapping toxicities

Drugs Short-term Medium-term toxicities Long-term toxicities
toxicities
Zidovudine zz Headache, nausea, vomiting, malaise, zz Bone marrow suppression
diarrhea zz Anemia (Macrocytic)
zz Bone marrow suppression zz Hyperpigmentation
zz Anemia (Macrocytic) zz Lactic acidosis
zz Proximal myopathy
Tenofovir zz Nephrotoxicity (low incidence),

zz Fanconi syndrome and rarely acute renal failure
Efavirenz zz Drowsiness, dizziness
zz Confusion, Vivid dreams
zz Skin rashes
zz Hepatotoxicity (very rare)
Nevirapine zz Skin rashes

zz Hepatotoxicity
Overlapping toxicities Drugs

Bone marrow suppression Zidovudine, Cotrimoxazole, Dapsone, Pyrimethamine, Ganciclovir, Amphotericin B, Ribavirin
Hepatotoxicity Nevirapine, Atazanavir, Lopinavir, Ritonavir, Isoniazid, Rifampicin, Pyrazinamide, Fluconazole, Cotrimoxazole
Peripheral neuropathy Stavudine, Isoniazid, Alcohol
Pancreatitis Stavudine, Cotrimoxazole, Alcohol
TREATMENT FAILURE: WHEN TO guidelines and should be started as soon as the patient
CHANGE AND WHAT TO CHANGE is stabilised on ATT. In HIV-infected patients with TB
The adherence to ART is one of the most crucial who are not currently on ART, and who are provided
determinants of success of ART on long term basis. The Rifampicin-based anti-TB treatment, initiate ART directly
adherence of 95% or more is crucial for patients to achieve with EFV. No lead in dose is required for EFV. Nevirapine
desirable suppression of viral replication. However even or PIs should not be administered along with Rifampicin
with good adherence levels, resistance occurs to ARV because of the enzyme inducing effect of Rifampicin
drugs over a period of time due to viral mutation and which renders NVP levels sub-therapeutic. EFV blood
this requires change of ARV drugs. The virological failure levels are also decreased in presence of Rifampicin,
appears first followed by immunological failure which but remain at therapeutic levels. It is recommended to
finally leads to clinical failure. It is desirable to switch use the standard dose of EFV (usually 600 mg/day) in
the entire regimen from first to second line as soon as patients receiving EFV and Rifampicin or use Rifabutin
virological failure is detected. Table 7 depicts the criteria if patient is on LPV/r based ART. Details on initiation
for suspecting and confirming treatment failure. guidelines have already been discussed.
The second line regimen for patients failing on first
line ART is AZT + 3TC + ATV/r for those on TDF in first CONCLUSION
line regimen (and TDF+3TC+ATV/r for those on AZT or Antiretroviral therapy is quite effective in suppressing
d4T based regimen in first line). viral replication, delaying the progression of disease
and has changed the management of HIV disease
HIV/Tuberculosis Coinfection dramatically. Millions of lives and millions of new
Initiation of treatment for active TB should always be on infections have been saved due to ART. Present day ART
priority followed by initiation of ARV therapy as per the with initiation with single pill FDC regardless of CD4
TABLE 7: Defining antiretroviral failure. WHO definitions of clinical, immunological and virological failure for the decision to switch ART
regimens
Failure Definition Comments
Clinical failure Adults and adolescents New or recurrent clinical event The condition must be differentiated from immune
indicating severe immunodeficiency (WHO clinical stage 4 reconstitution inflammatory syndrome occurring after
condition)a after 6 months of effective treatment initiating ART
For adults, certain WHO clinical stage 3 conditions
(pulmonary TB and severe bacterial infections) may also
indicate treatment failure
Immunological failure Adults and adolescents CD4 count at or below 250 cells/ Without concomitant or recent infection to cause a
mm3 following clinical failureb or persistent CD4 levels transient decline in the CD4 cell count
below 100 cells/mm3 Current WHO clinical and immunological criteria
have low sensitivity and positive predictive value for
identifying individuals with virological failure
Virological failure Viral load above 1000 copies/mL based on two consecutive An individual must be taking ART for at least 6 months
viral load measurements in 3 months, with adherence before it can be determined that a regimen has failed
support following the first viral load test
a & b
Previous guidelines defined immunological failure based on a fall from baseline, which is no longer applicable in the context of CD4-
independent treatment initiation. The option of CD4 cell count at or below 250 cells/mm3 following clinical failure is based on an analysis of
data from Uganda and Zimbabwe
count offers an hope to reach out to more and more BIBLIOGRAPHY

people, decentralise the delivery of ART and with 90- 1. Guidelines for Management of HIV-Infected Adults and
90-90 strategy we can hope to begin the end of AIDS Adolescents Including Post-exposure Prophylaxis, NACO.
epidemic. As people live longer on ART, the issues of Ministry of health and Family Welfare, 2013). Available
at http://naco.gov.in/NACO/Quick_Links/Publication/
adherence, toxicity, emerging resistance and cost of
Treatment_Care__Support/. including draft 2017
newer drugs will emerge as newer challenges. The future
2. National Guidelines on Second line ART for adults and
options include new group of drugs, better strategies adolescents, December 2014, National AIDS Control
but the correct usage of these agents, their timings of Organisation, Ministry of Health and Family Welfare
initiation and proper monitoring is of utmost importance (updated draft 2017)
if we want these drugs to remain effective. The therapy 3. Panel on Antiretroviral Guidelines for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1-
is no doubt panacea for those already infected, but HIV
infected adults and adolescents. Department of Health and
prevention messages and probably AIDS vaccines are
Human Services, USA. July 2016. Available at http://www.
the keys to halting the progression of the epidemic of this aidsinfo.nih.gov/guidelines
dreaded disease. The reports about “sterilizing cure” of a 4. WHO consolidated Guidelines on Antiretroviral Therapy
Berlin patient and “functional cure” of a US infant home for HIV Infection: Recommendations for a public health
encouraged researchers to look beyond controlling the approach July, 2016. Available at http://www.who.int/hiv/
pub/guidelines
virus with ART. The “end of AIDS” talks have began and
offer an opportunity for renewed and heightened interest
into further research of HIV molecular biology to find a
cure for the dreaded infection.
CHAPTER
110
Opportunistic Infections in HIV:
Changing Scenario
Amar R Pazare
INTRODUCTION not only ART drug resistance responsible for increased

Acquired immune deficiency syndrome (AIDS) was incidence, but there is increased resistance to standard
diagnosed by the presence of opportunistic infections PCP treatment like sulfa- or sulfone-containing anti-
like PCP (OIs) in 1981 in healthy young males. Since then Pneumocystis regimens. Despite the declines in death
AIDS patients usually present with one or other OIs. In and disease from HIV in the United States and Western
75% of HIV patients present with ‘aids-defining’ OIs Europe, PCP remains an important disease and is
before ART era. But due to early ART initiation in recent unlikely to be eradicated.
years, presentations of OIs changed drastically. And Since Pneumocystis cannot be cultured, the diagnosis
these patients admitted to the hospital for conditions relies upon the visualization of the cystic or trophic forms
other than OI like coronary artery diseases or side effects in appropriate specimens. Polymerase chain reaction
of the anti-retroviral therapy (ART). Although there is (PCR) of respiratory fluid (BAL) can make the diagnosis.
tremendous decrease in OIs in HIV positive patients, Various treatment modalities are trimethoprim-
prevalence of tuberculosis is still remained high. sulphamethoxazole (TMP-SMZ), Or TMP and Dapsone.
Both the regime has equal efficacy (86%) but later has
COMMON OPPORTUNISTIC less side effect. Pentamidine is another alternative ( 61%
INFECTIONS IN HIV-INFECTED efficacy) but it is less effective and more toxic.
PATIENTS IN THE PAST Studies also revealed that there is improved
oxygenation in the steroid-treated patients, hence expert
Pneumocystis Carinii Pneumonia (PCP) panel advice corticosteroids.
Pneumocystis carinii pneumonia (PCP) is the AIDS
defining illness occurred in about 65% of cases with Toxoplasmosis
very high mortality before ART era. With introduction Up to half of the world’s population is infected by toxo
of ART incidence of PCP is reduced to 3.4%. in 1992 and plasmosis but have no symptoms. 11% of the population
0.3% in 1998 in developed world. But, it is still high in in the United States it is infected with Toxoplasma.
developing nations (13–29%). A CD4 cell count less than Reactivation of a chronic Toxoplasma infection is
200 cells/mL is the risk factor for PCP even in HAART responsible for encephalitis in HIV-infected patients
era. With rising resistance to anti-retroviral drugs, it is especially when CD4 drops below 100/mL. Toxoplasma-
likely that incidence of PCP will rise in developed world. seropositive AIDS patients may develop toxoplasmic
And it is already rose to 11% in developed countries. It is encephalitis in 24–47% of cases. Primary prophylaxis
CHAPTER 110: Opportunistic Infections in HIV: Changing Scenario 661
against Toxoplasma and anti-retroviral therapy decreases population) possibly due to increased number of HIV
the risk of toxoplasmosis. cases. While in hospital base study shows incidence
Ver y few adults and children (10–20%) are of 1.09 cases/1,000 admissions in 2009. Patch in the
symptomatic for toxoplasmosis, but it is life-threatening mouth, trachea or esophagus are of three main types
for HIV/AIDS patients. Toxoplasmic encephalitis is like pseudomembranous, erythematous (atrophic) and
the most common manifestation of toxoplasmosis in hyperplastic. It presents as painless lesion or burning
HIV/AIDS patients. Clinical findings include altered sensation in mouth or bad taste due to the presence of
mental state, seizures, hemiparesis, cranial nerve palsies, the membranes. Sometimes there may be dysphagia due
movement disorders, neuropsychiatric manifestations. oropharynx or esophageal candidiasis. The trachea and
Most aids patients with cerebral toxoplasmosis the larynx may also be involved may cause hoarseness of
respond to pyrimethamine and sulphadiazine therapy the voice. Treatment with fluanazole for 10–15 days cures
but relapses are very common once therapy is stopped. the candidiasis. And there is no need for prophylaxis.
Hence maintenance therapy is advised reduced dose.
Cytomegalovirus
Cryptococcosis Fifty to eighty percent of the adult population is infected
One million cases of cryptococcal meningoencephalitis by cytomegalovirus (CMV) but disease is found in
and 600,000 deaths occurs each year globally and most immuno-compromized patients. CMV infection was the
of them are HIV/AIDS patients with CD4 is less than most common OI in AIDS patients (25–40%) with a CD4
100 cells/mL. With an introduction of ART incidence less than 50/mL.
of cryptococcal meningoencephalitis has declined Incidence of CMV retinitis decreased by 55–83% with
considerably. To diagnose cryptococcal infection, serum introduction of ART. Common presentation of CMV is
and CSF cryptococcal antigen (CrAg) and CSF culture is the chorioretinitis, (80–90%) which may start unilaterally
the ideal test. and then progresses bilaterally. Decreased visual acuity
Cryptococcal meningoencephalitis is the most or/and visual field loss are the common symptoms of this
common presentation and manifest with fever, headache, disease and blindness may occur if left untreated.
vomiting, stiff neck, photophobia, altered mental status. CMV colitis may occur in 5–10% of HIV/AIDS patients
Cryptococcal pulmonary disease may be with CD4 less than 50 cells/mL and presents as diarrhea,
asymptomatic or present with acute respiratory distress weight loss, abdominal pain, anorexia, and fever.
syndrome. Rarely, it may manifest as a mass that may Submucosal ulceration and hemorrhages and may be
compress superior vena cava. Fever, malaise, cough, seen on endoscopy and vasculitis and CMV inclusions
pleuritic pain, and hemoptysis are the manifestation body may be seen on biopsy. Patients may sometimes
of pulmonary cryptocosis. There may be cavity, hilar suffer from esophagitis and presents with dysphagia.
lymphadenopathy, and pulmonary fibrosis on X-ray Rarely these patients present with radiculopathy,
chest. transverse mylitis, encephalitis or pneumonia.
Myocarditis, chorioretinitis, hepatitis, peritonitis, These patients may be treated with ganciclovir and
renal abscess, prostatitis, myositis, adrenal involvement foscarnet
may be the other presentation of cryptococal infection.
Treatment includes amphotericin B with or without Tuberculosis
fluconazole or flucytosine for 2 weeks. Tuberculosis (TB) and HIV are closely associated and
incidence of TB has increased with a advent of HIV
Candidiasis infection. TB is the most common OI and main cause of
Incidence of candidiasis in population study have death in HIV/AIDS patients. 30% world’s population is
increased in Europe and USA in 1990s (7.28/100,000 infected with Mycobacterium tuberculosis (WHO) and
900000 new cases of active TB occurs every year. HIV and and HIV negative patients when CD4 is more than
TB coinfection present in 50–80% sub-Saharan African 350 cells/mL. However, when CD4 drops below 350,
patients while 8.6% in the United States patients. presentation becomes atypical (extrapulmonary and
As per HPTN 052 study, initiation of early ART (CD4 disseminated disease).
more than 350 cells mL) was associated with a 47%
reduction in the risk of active TB versus ART started Mycobacterium Avium Complex
when CD4 below 250 cells/mL. Incidence of multidrug-
Mycobacterium avium complex (MAC) usually occurs
resistant TB (MDRTB) is fluctuates in the USA (0.4% in
in immunocompromised patients like AIDS, leukemia
1980, 3.5% in 199, 1% in 1997, 1.3% in 2010). MDRTB
and patients receiving chemotherapy, steroids. MAC
and XDRTB are a increasing problem in developing
is primarily a pulmonary pathogen but it may present
countries.
TB may occur early as well as any stage of HIV disease. with osteomyelitis; synovitis; and lymphadenitis.
Incidence of TB increases as CD4 decreases. Risk of TB Common environmental sources of MAC are aerosolized
remains high in HIV/AIDS patients with normalization water, house dust, birds, farm animals, etc. Treatment
of CD4 count even after ART, compare to the general includes macrolides (clarithromycin or azithromycin),
population. The presentation of TB also depends on ethambutol, rifampin or rifabutin or streptomycin or
CD4 counts. Presentation of TB is similar in HIV positive amikacin for at least 12 months.
CHAPTER
111
Neurological Manifestations of HIV
Dipanjan Bandyopadhyay, Amit Adhikary
INTRODUCTION DIRECT VIRAL INVASION

All levels of the central nervous system (CNS) may be
HIV Associated Neurocognitive
affected in patients with HIV infection. Neurological
involvement in HIV may be due to multiple pathogenetic
Disorder (HAND)
mechanisms, all of which are briefly discussed in this HAND is a major neurological complication of HIV, and
chapter. has been increasingly diagnosed following prolonged life
Neurological involvement in HIV may be grouped expectancy from effective ART. The American Academy of
under the following headings: Neurology (AAN) nomenclature (2007) classifies HAND
Acute seroconversion illness by clinical severity into asymptomatic neurocognitive
Direct invasion by HIV impairment (ANI), mild neurocognitive disorder (MND),
Opportunistic infections and HIV-associated dementia (HAD). The diagnosis of
HIV associated malignancies HAD is based on assessment of 3 domains, motor speed,
Associated with HAART use psychomotor speed, and memory recall (Table 1).
MR spectroscopy reveals a reduction of NAA (n-acetyl
ACUTE SEROCONVERSION ILLNESS aspartate) in the cortex and frontal white matter and
A symptomatic flu-like syndrome occurs in up to 70% of elevated levels of Cho (choline) and mI (myo inositol).
cases at HIV seroconversion. Acute HIV infection may The International HIV Dementia Scale appears to be
present with headache, photophobia and occasionally clinically useful for bedside assessment of HAND.
frank encephalitis. The syndrome usually resolves
within 2 to 4 weeks. Immune activation triggered by MYELOPATHY DUE TO HIV
HIV infection may lead to aseptic meningitis, acute HIV associated myelopathy may be vacuolar myelopathy
disseminated encephalomyelitis, acute inflammatory which clinically simulates subacute combined
demyelinating polyneuropathy, transverse myelitis, degeneration of spinal cord, pure sensory ataxia arising
polymyositis, brachial neuritis or a cauda equina out of dorsal column involvement or HIV myelitis
syndrome. In the appropriate clinical setting, all these per se. HIV associated vacuolar myelopathy typically
neurologic entities should raise the suspicion of acute presents as progressive painless leg weakness, stiffness,
HIV infection. sensory loss, imbalance, and sphincter dysfunction.
TABLE 1: International HIV Dementia Score

Memory Registration: Give four words to recall (dog, hat, bean, red) (1 second to say each. Then ask the patient to say all four words, after
you have said them. Repeat words if the patient does not recall them all immediately. Tell the patient you will ask for recall of the words again
a bit later.
Motor Speed: Have the patient tap the first two fingers of the non-dominant hand as widely and as quickly as possible.
Score: 4 = >15 in 5 sec, 3 = 11–14 in 5 sec, 2 = 7–10 in 5 seconds, 1 = 3–6 in 5 seconds, 0 = 0–2 in 5 seconds
Psychomotor Speed: Have the patient perform the following movements with the non-dominant hand as quickly as possible. 1) Clench
hand in fist on flat surface. 2) Put hand flat on surface with palm down. 3) Put hand perpendicular to flat surface on the side of the 5th digit.
Demonstrate and have patient perform twice for practice.
Score: 4 = 4 sequences in 10 seconds, 3 = 3 sequences in 10 seconds, 2 = 2 sequences in 10 seconds, 1 = 1 sequence in 10 seconds, 0 = unable
to perform.
Memory - Recall: Ask the patient to recall the four words. For words not recalled, prompt with a semantic clue as follows: animal (dog); piece
of clothing (hat); vegetable (bean); color (red). Give 1 point for each word spontaneously recalled.
Score: 0.5 points for each correct answer after prompting maximum –4 points.
Total International HIV Dementia Scale Score: The maximum possible sum of the three scores is 12. A score of <10 necessitates further
assessment for possible dementia.
Pathogenetic mechanisms include infiltration by HIV- CNS-TB

infected mononuclear cells that secrete neurotoxic TB affecting the CNS may manifest as TB meningitis
factors, impaired ability to utilize vitamin B12 and (TBM), TB vasculitis, single or multiple space-occupying
direct invasion of astrocytes and neurons by HIV. The lesions (Tuberculoma or Tuberculous abscess), Pott‘s
spinal cord shows extensive spongiform changes in spine, Tuberculous arachnoiditis (presenting as
the white matter. Physical examination reveals slowly myeloradiculopathy), intramedullary spinal tuberculoma
progressive spastic paraparesis, hyperreflexia, extensor
or spinal meningitis.
plantar responses, sensory ataxia and incontinence. A
discrete sensory level strongly suggests other causes of
Toxoplasma Encephalitis
myelopathy. Vacuolar myelopathy is suspected when
TE presents as focal or diffuse nercotizing encephalitis
cord atrophy or symmetric hyperintense signals is seen
with multiple intracerebral SOLs, usually at CD4 <200
on T2-weighted MRI.
cells/µL. Clinical features include focal neurological
PERIPHERAL NEUROPATHY signs, headache, altered sensorium and seizures.
Peripheral neuropathy PN is unusual at CD4 counts Imaging shows multiple ring-enhancing lesions
>500/µL. The characteristic pattern is of distal sensory characteristically located at the basal ganglia, thalami,
polyneuropathy (DSPN) causing loss of pain, touch and at the gray-white matter junction, and rarely brainstem
temperature in a stocking distribution. Radiculopathy, (Fig. 1). Spectroscopy reveals marked elevation of
cranial neuropathy and autonomic neuropathy might lipid and lactate peaks. All other brain metabolites are
occur, and HIV vasculitis can present as mononeuritis markedly diminished. TE is treated with Pyrimethamine
multiplex. Treatment includes correction of nutritional 200 mg PO on the first day, followed by 75 mg/day
abnormalities and institution of HAART, while avoiding PO, Sulfadiazine 4–6 g/day PO in four divided doses,
neurotoxic drugs like stavudine (d4T), zalcitabine (ddC) and folinic acid 10 to 25 mg/day, for 4–6 weeks.
and didanosine (ddI). Clindamycin 600 mg IV or 450 mg PO four times daily
is an adequate alternative to sulfadiazine for patients
OPPORTUNISTIC INFECTIONS (OI) allergic to sulfonamides. Secondary prophylaxis with
AFFECTING THE CNS Co-trimoxazole is continued till CD4 >200/µL for
CNS-TB, cryptococcal meningitis (CM) and Toxoplasma >6 months. Absence of clinical improvement at the
encephalitis (TE) are the major OI in India, although a end of 1 week demands consideration of an alternative
host of other pathogens might be involved. diagnosis. Short-term dexamethasone to reduce life
CHAPTER 111: Neurological Manifestations of HIV 665
TABLE 2: Treatment protocol for Cryptococcal meningitis

Treatment for cryptococcosis includes induction, consolidation, and
maintenance phases
Induction Therapy (For At Least 2 Weeks, Followed by
Consolidation Therapy)
Preferred Regimens:
zz Liposomal ampho B (LAB) 3–4 mg/kg IV/d plus flucytosine 25
mg/kg PO QID; or
zz Ampho B deoxycholate (ABDC) 0.7–1.0 mg/kg IV/d plus
flucytosine 25 mg/kg PO QID

Note: Flucytosine dose should be adjusted in renal impairment
Alternative Regimens:
zz Ampho B lipid complex (ABLC) 5 mg/kg IV daily plus flucytosine
25 mg/kg PO QID; or
zz LAB 3–4 mg/kg IV daily plus fluconazole 800 mg PO or IV daily or
zz ABDC 0.7-1.0 mg/kg IV daily) plus fluconazole 800 mg PO or IV
Fig 1: Multiple CNS toxoplasma lesions in MRI brain daily; or

zz LAB 3–4 mg/kg IV daily alone; or
threatening mass effects and medications to control or zz ABDC 0.7–1.0 mg/kg IV daily alone; or
zz Fluconazole 400 mg PO or IV daily plus flucytosine 25 mg/kg PO

prevent seizures may be co-prescribed.
QID; or
zz Fluconazole 800 mg PO or IV daily plus flucytosine 25 mg/kg PO
CRYPTOCOCCAL MENINGITIS QID; or

CM usually presents as a sub-acute meningoencephalitis zz Fluconazole 1200 mg PO or IV daily alone
with fever and headache (65–90%), neck stiffness (30%), Consolidation Therapy (For At Least 8 Weeks, Followed by
altered sensorium (20%) and seizure/focal deficit Maintenance Therapy)
zz Begin after >2 weeks of successful induction therapy
(<10%). The diagnosis is based on elevated opening
Preferred Regimen:
pressure of CSF with lymphocytic pleocytosis, CSF India zz Fluconazole 400 mg PO or IV OD
Ink preparation (70% positivity) and CSF cryptococcal Alternative Regimen:

zz Itraconazole 200 mg PO BID
antigen (>90% positivity). Treatment of CM is detailed in
Table 2. Maintenance Therapy
zz Fluconazole 200 mg PO for at least 1 year
Treatment for cryptococcosis includes induction,
consolidation, and maintenance phases. The induction Maintenance therapy may be discontinued, if the following
criteria are fulfilled
therapy continues for at least 12 weeks and includes, zz Completed induction, consolidation and at least 1 year of
liposomal ampho-B plus flucytosine OR ampho-B maintenance therapy, and

deoxycholate. Consolidation therapy continues for at zz Remains asymptomatic from cryptococcal infection, and
zz CD4 count ≥100 cells/μL for ≥3 months, and

least 8 Weeks with either fluconazole and itraconazole.
zz Suppressed HIV RNA in response to effective ART
Maintenance therapy includes fluconazole 200 mg PO
for at least 1 year. Cessation of maintenance therapy
may be considered after 1 year if the patient remains
myelopathies. A flaccid paraparesis with urinary retention
asymptomatic, has a CD4 count ≥100 cells/μL for ≥3
raises the suspicion of CMV polyradiculomyelopathy.
months and/or viral suppression is documented on lab
CSF demonstrates neutrophilic pleocytosis, hypo
tests.
glycorrhachia and elevated proteins. CSF, CMV, PCR is
CMV Neurologic Disease positive in >95% cases. The treatment of CMV disease
This occurs usually at CD4 < 100 cells/µL presenting with includes induction with ganciclovir, preferably with
dementia, ventriculo-encephalitis, and polyradiculo foscarnet, and maintenance with valganciclovir.
PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY
Progressive multifocal leukoencephalopathy (PML) is
an OI of the CNS, caused by the polyoma virus JC virus
(JCV) and characterized by focal demyelination. PML
manifests as insidious and progressive focal neurological
deficits. Any region of the CNS can be involved, but
favored areas include the occipital lobes (hemianopsia),
frontal and parietal lobes (aphasia, hemiparesis, and
hemisensory deficits), cerebellar peduncles and deep
white matter (dysmetria and ataxia) (Fig. 2). MRI shows
distinct white matter lesions which are hyperintense on
T2 - weighted and fluid attenuated inversion recovery
(FLAIR) sequences and hypointense on T1- weighted Fig 2: PML in a PLHIV with CD4 36
sequences. In contrast to cerebral toxoplasmosis and
primary CNS lymphoma, no mass effect or displacement NEUROLOGICAL DISEASE ARISING
is seen in PML. FROM ART
Stavudine, didanosine and zalcitabine all cause
HIV ASSOCIATED MALIGNANCIES peripheral neuropathy. Somnolence, insomnia, vivid
AFFECTING THE CNS dreams and depression are caused by Efavirenz, while
Primary CNS Lymphoma depression and suicidal ideation are related to Rilpivirine.
Primary CNS lymphoma (PCNSL) without extra-cranial Insomnia, depression and suicidality have been reported
involvement occurs in <5% of AIDS patients. These with the integrase strand transfer inhibitors (INSTI),
tumors are usually aggressive, high-grade, diffuse B-cell albeit rarely. However, it must be emphasized that
neoplasms, which consist of either large immunoblastic immune reconstitution arising with effective ART may
or small non-cleaved cells. Symptoms evolve slowly and lead to a wide spectrum of OI affecting the nervous
include headaches, confusion, lethargy, focal signs and system, with TBM, CM and TE, being the most common
seizures. The CD4 is usually <50 cells/µL. CSF changes in India.
are non-specific with pleocytosis and hypoglycorrhachia,
but CSF, EBV, DNA positivity is almost diagnostic. BIBLIOGRAPHY
Periventricular solitary mass lesions are seen on MR. 1. Manji H, Miller R. The Neurology of HIV infection. J Neurol
Elevated choline and lipid/lactate peaks combined with Neurosurg Psychiatry. 2004;75:i29-i35.
2. Satishchandra P, Mathew T. Neurological manifestations
high Cho/Cr ratios is seen on MRS. NAA peak is reduced.
associated with HIV infection: Indian Perspective. In: Rao
Cho/NAA and lactate/Cr ratios are also increased when
MS, Ed. Medicine Update 2010. Mumbai: Ass Phy India.
compared to normal gray matter, thus differentiating 2010;760-5.
from CNS toxoplasmosis. Treatment consists of whole 3. Tan IL, Smith BR, Geldern GV, Mateen FJ, McArthur JC.
brain irradiation, steroids to reduce edema and mass HIV-associated opportunistic infections of the CNS. Lancet
effect, and HAART. Neurol. 2012;11:605-17.
CHAPTER
112
Cardiopulmonary Manifestations of HIV
Alaka K Deshpande
The first case reports of a new disease entity appeared in —— Dilated cardiomyopathy
June 1981 which was later called as acquired immuno- —— Isolated left or right ventricular dysfunction
deficiency syndrome caused by human immuno Endocardial involvement:
deficiency virus (HIV) infection. —— Non-bacterial thrombotic (marantic) endo
It is a chronic infectious disease affecting various carditis

organ systems. Autran et al. in 1983 reported the first case Infective endocarditis:
of cardiac involvement in AIDS who noticed myocardial —— Fung al: Candida albicans, Cr ypto co ccus
Kaposi sarcoma of heart at autopsy. Since then several neoformans and Aspergillus Fumigates
reports recognized cardiac involvement in HIV infection. Pulmonary hypertension:
The Veterans affairs study is the largest study of CVS —— HIV-related pulmonary hypertension (HRPH)
complications related to HIV/HAART which did not Cardiac malignancies—Kaposi’s sarcoma (KS)
reveal significant increase in CVS disease compared to Malignant lymphomas
age adjusted, non-infected US population. As against, Cardiac arrhythmias
the French hospital data base study and Data Collection Vascular lesions:
on adverse effects of anti-HIV drugs (DAD) showed —— Coronary artery disease
increase in rates of MI with prolonged exposure to —— Arteriopathy
protease inhibitors ( PI) and Abacavir. —— Aneurysms
Cardiac involvement in HIV disease may be classified Inflammatory vascular diseases—PAN, Kawasaki,
as follows: Takayasu’s arteritis.
Pericardial disease
Pericarditis PERICARDIAL DISEASE

—— Staph. aureus, Strept. pneumoniae, H. influenzae Spectrum of pericardial disease varies from asymptomatic
—— Pericardial effusion effusion to fatal cardiac tamponade.
—— Cardiac tamponade In India, the most common cause of pericardial
—— Constrictive pericarditis effusion is M. tuberculosis. Cases due to Nocardia,
—— Heart muscle disease Chlamydia, Listeria, NTM, as well as various fungal
—— Myocarditis infections have been reported. The incidence is reduced
after HAART, however, treatment defaulters can present most sensitive technique. Speckled appearance and
with any of the osteogenesis imperfectas. heterogenicity of myocardium indicates infiltration of
lymphoma.
Myocardial Disease
Myocarditis due to various causes is common. HIV Arrhythmias
directly or by autoimmunity, other viral infections, Various rhythm disturbances due to myocarditis,
bacterial causes, toxoplasmosis result into myocarditis. electrolyte disturbances, autonomic dysfunctions have
Dilated cardiomyopathy (DCM) is common due to been documented.
multiple factors. HIV per se has been incriminated. Other
factors include OIs, nutritional deficiencies, metabolic CARDIOTOXIC DRUGS
abnormalities, autonomic dysfunctions. Pathogenesis is Amphotericin DCM, HTN, bradyarrhythmix
complex and is related to cytokine imbalance. Foscarnet Cardiomyopathy
DCM in HIV disease has a poor prognosis with Gancyclovir VT
median survival of about 101 days in presence of poor Doxorubicin DCM
cardiac parameters. Erythropoietin HTN
Interferon Arrhythmia, MI, DCM, AV blocks,
Endocardial Disease sudden death
Pre-HAART era reported 3–5% of AIDS patients with HAART CHD, PVD, DCM
marantic endocarditis with systemic embolization. Pentamidine, Septran QT prolongation, Torsade de
Infective endocarditis of various etiologies is common Pointes
frequently associated with IVDUs.
HIV-related pulmonary hypertension is being CORONARY ARTERY DISEASE
increasingly recognized as cardiovascular complication H I V- i n f e c t e d i n d i v i d u a l s h a v e l o w l e v e l s o f
related to lung infections, LV dysfunction and venous HDL cholesterol while LDL levels are raised. This
thromboembolism. derangement is further contributed by therapy with
HIV-related primary pulmonary hypertension is protease inhibitors. Various studies have shown that 74%
thousand times more common in HIV/AIDS compared HIV cases receiving protease inhibitors as therapy have
to general population. It is common in younger age lipid abnormalities which may precede lipodystrophy.
group, without much disability, however, mortality at the Endothelial dysfunction is reported in HIV disease due
end of one year is reported to be more than 50%. to increased susceptibility to cytomegalovirus infection
or may be by HIV per se.
Malignancies Patients may remain asymptomatic or may have
HAART has increased survival time with increased serious complications with fatal results. Baseline
longevity, which is associated with rise in the malignant investigations should include cardiac evaluation by
disorders related to chronic HIV infection. Although echocardiography. HIV patients may present with acute
Kaposi’s sarcoma is commonly seen in other countries. coronary syndromes or other vascular complications at
It is a rarity in India. The various lymphoid malignancies younger age.
are increasing. B-cell lymphomas and NHL involving Management of these conditions is same as in non-
heart have been reported. The cardiac involvement in HIV cases.
lymphoma may present with congestive heart failure, A wide variety of inflammatory vascular diseases
superior vena cava syndrome, complete heart block have been reported in HIV-infected individuals, such
due to lymphomatous infiltration, pericardial effusion as polyarteritis nodosa, Henoch-Schönlein purpura,
and cardiac tamponade. Echocardiography is the Takayasu’s arteritis and a Kawasaki-like syndrome.
CHAPTER 112: Cardiopulmonary Manifestations of HIV 669
With more effective and safer antiretroviral drugs, the In addition, immune status needs to be assessed by
longevity is increasing as a result of which one is likely to CD4 estimation.
see more cardiac events due to OIs, immunosuppression,
drug therapies of HIV as well as OIs . BACTERIAL INFECTIONS
Post-cARV the OIs are declining and bacterial
PULMONARY MANIFESTATIONS pneumonias are occurring more frequently.
The first report in MMWR in June 1981 was of patient Strept. pneumoniae, H. influenzae, Klebsiella,
with Pneumocystis carinii pneumonia in young patients
Pseudomonas aeruginosa and Staph. aureus are
with evidence of deficiency of cell-mediated immunity.
common pathogens. Fever, cough, shortness of breath
The experience of managing OIs in HIV disease led
are presenting features.
to chemoprophylaxis studies. The guidelines directed
In 2012, the Advisory Committee on Immunization of
use of daily one tablet of TMP-SMX as chemoprophylaxis
CDC and updated DHHS Guidelines recommend that all
against PCP when CD4 declined to less than 200. This
strategy resulted in dramatic decrease in cases of PCP. HIV-infected patients aged 19 years or greater, regardless
The advent of cARV further controlled the disease of CD4 counts, receive pneumococcal vaccination.
process by acting on the virus, which improved the Individuals who are pneumococcal vaccine-naïve
immune status of the patient increasing his CD4 cell should first receive one dose of pneumococcal conjugate
count. Most of the OIs decreased with rising CD4 counts. vaccine PCV 13. It should be followed by one dose of 23
However newer challenges appeared. valent polysaccharide pneumococcal vaccine 23 PPV in
P o s t-A RT e ra, t h e s p e c t r u m o f p u l m o n a r y patients with CD4 counts ≥200 cells/μL at least 8 weeks
manifestations of HIV/AIDS changed in the developed after receiving PCV13. For patients with CD4 counts
world. PCP declined but bacterial pneumonias are <200 cells/μL, 23 PPV could be offered 8 weeks after
dominating. In other countries with paucity of health receiving PCV13, or deferred until the CD4 counts
care resources, illiteracy and poverty still reigning increase to >200 cells/μL with cART
supreme; various OIs affect the lungs, tuberculosis cARV and pneumococcal vaccine together have
dominating the clinical picture. The OIs are caused by decreased the risk of bacterial pneumonias, however,
various pathogens including bacteria, viruses, fungi, and there is no unequivocal evidence to suggest its efficacy
parasites. In addition to OIs the lungs are involved in in prevention of pneumonias caused by nonvaccine
various malignancies like NHL, lung cancers (smoking serotypes.
being additional risk factor) and Kaposi’s sarcoma.
Mycobacterial infections are the most common OIs
The main obstacle in diagnosis of these conditions
in developing world including India. The presentation
is lack of rapid diagnostics and need of extensive
depends on the immune status of the patient. At higher
investigations. The investigations include:
CD4 counts >350, the tubercular manifestations are
Sputum smear
Appropriate culture/PCR
similar to non-HIV cases. Upper lobe infiltrations,
Chest radiography
cavitations are common. With declining CD4 counts the
HRCT
extra-pulmonary tuberculosis as well as disseminated
Bronchoscopy
TB is seen more frequently. Despite adequate anti-TB
BAL treatment the relapse rates are 9 to 10 folds higher in
CT-guided biopsy presence of HIV infection compared to non-HIV cases.
Thoracoscopy The incidence of MDR and XDR-TB is increasing in HIV
Open biopsy cases similar to non-HIV patients. South Africa reports
S. LDH alarmingly high prevalence of MDR (39%) and XDR-TB
Arterial blood gases (6%) in HIV patients.
The present strategy of treating all HIV-infected cases Epstein-Barr virus may cause lymphoproliferative
with cARV irrespective of the CD4 counts is expected to disease of the lung, which manifests as multiple nodules
successfully control the various OIs including TB. of peribronchovascular or subpleural distribution.
Parasitic infections are rare and they occur in
Non-tubercular Mycobacteria patients with advanced HIV disease. The most common
Atypical mycobacterial infections are seen with an parasitic infections include pulmonary toxoplasmosis,
increased frequency in AIDS patients. The most common strongyloidosis, Cryptosporidium and Microsporidia.
atypical mycobacterial infection is with M. avium or M.
intracellulare species the Mycobacterium avium complex FUNGAL INFECTIONS
(MAC). It has been suggested that prior infection with Pneumocystis carinii pneumonia was an AIDS-defining
M. tuberculosis decreases the risk of MAC infection. The illness in the early part of epidemic. With effective
most common presentation is disseminated disease chemoprophylaxis and with the advent of cARV the
with fever weight loss and night sweats. At least 85% of prevalence has drastically reduced. Earlier it was thought
patients with MAC infection are mycobacteremic, and to be a parasite but now it has been shown to be an
large numbers of organisms can often be demonstrated atypical fungus—Pneumocytis jirovecii.
on bone marrow biopsy. The chest X-ray reveals Clinically, patient presents with fever, non-productive
lower lobe infiltrates, miliary shadows,mediastinal cough, rapidly increasing dyspnea, and hypoxemia.
lymphadenopathy. Therapy consists of macrolides, Bilateral crackles are noted. Plain radiographs may be
usually clarithromycin with ethambutol. Rifabutin is normal in 10% of cases but HRCT may reveal ground-
used. cARV has changed the scenario. glass infiltrate, perihilar reticular opacities. Cystic
lesions are seen in few patients particularly those
Nocardiosis receiving prophylaxis with aerosolized pentamidine and
The etiological agent is Nocardia asteroides, currently trimethroprim-sulfamethoxazole. It is the most common
considered as a bacterium (formerly thought to be a reason for hospitalization of AIDS patient to ICU.
fungus). Infection appears with low CD4 counts < 200 Other fungal infections include aspergillosis,
cell/mm 3. Cough is prominent and produces small histoplasmosis, and pulmonary cryptococcosis.
amounts of thick, purulent sputum that is not malodorous.
Fever anorexia weight loss are common; Remissions MALIGNANT NEOPLASMS
and exacerbations over several weeks are frequent. Kaposi sarcoma is the most common AIDS-associated
Roentgenographic findings include pneumonia, nodular malignancy. It is affecting almost exclusively adult
densities. Culture isolates the organism. Patients are homosexual or bisexual men and their partners, with
treated with minocycline, linezolid, imipenam, amikacin. a male/female ratio of 50 to 1. The course is variable—
Long-term use of TMP-SMX is also recommended. slowly progressive or aggressive. It is a rarity in this
Viral infections are rare and are associated with country.
marked immunosuppression. Of the 8 types of human Malignant lymphomas, both Hodgkin’s and non-
herpes viruses, 6 are associated with substantial morbidity Hodgkin’s lymphomas are seen more frequently in India
in patients with AIDS. They include cytomegalovirus, particularly after universal access to ART which has
herpes simplex virus type 1 and type 2, varicella zoster resulted in the increased survival.
virus, Epstein-Barr virus and human herpes virus Carcinoma of the lung is also reported frequently.
type 8. Pulmonary infection by any of these viruses Non-infectious, non-neoplastic lesions such as
may manifest as diffuse interstitial pneumonitis, while lymphocytic interstitial pneumonitis in children,
herpes simplex virus may also produce focal necrotizing bronchiolitis obliterans, nonspecific interstitial
tracheobronchitis. Cytomegalovirus causes pneumonitis. pneumonitis are other reported lesions.
CHAPTER
113
Immune Reconstitution
Inflammatory Syndrome
Vinay Rampal
BACKGROUND if immune competent cells are maintained in a state

Although mortality in acquired immune deficiency of chronic activation and also that an improvement
syndrome (AIDS) has reduced much after the initiation in immune function could result in pathological
of highly active antiretroviral therapy (HAART), by virtue inflammation. The so called “paradoxical responses”
of its direct action on the human immune deficiency were well described among non-HIV infected patients
virus (HIV) as well as on the warding off HIV related being treated for Mycobacterium tuberculosis associated
opportunistic infections (OIs), but almost 1/3 rd of with clinical worsening. Inflammatory reactions during
patients with HIV and certain other OIs experience a treatment are also common among patients infected
flare up or worsening of their condition within days to with M. leprae. Finally recovery of immune cells following
years of starting their first antiretroviral (ARV) regimen.1 bone marrow transplantation or chemotherapy has
Often there is little detectable evidence of the underlying been clearly associated with clinical deterioration
OI surviving in the affected tissues or body fluids and in some patients. 4,5 Because clinical deterioration
there are expected increases in CD4+ T lymphocyte occurs during immune recovery, this phenomenon has
counts and more than expected decrease in HIV-I viral been described as immune restoration disease (IRD).
load. This “paradoxical” clinical deterioration is a result Immune reconstitution syndrome (IRS) and paradoxical
of an inflammatory response or “dysregulation” of the reactions. Since there is host inflammatory response
immune system to both intact subclinical pathogens and hence the term immune reconstitution inflammatory
residual antigens.2 Resulting clinical manifestations of syndrome (IRIS) has been proposed and is the most
this syndrome are diverse and depend on the infectious widely accepted.
or noninfectious agent involved. These manifestation
incl u de myc o bate r ia l - i n d uce d ly mp ha de nitis, DEFINITION
paradoxical tuberculosis reactions, worsening of Initially considered as an aftermath of highly active
progressive multifocal leukoencephalopathy, recurrence antiretroviral therapy (HAART) till mid nineties, IRIS has
of Cryptococcosis and Pneumocystis jirovecii pneumonia finally been defined as “Signs and symptoms consistent
Cytomegalovirus retinitis, shingles and viral hepatitis as with an inflammatory and/or typical presentation of
well as noninfectious phenomena.3 opportunistic infections (OIs) or tumors, that is not a
We know that the ability of immune system to respond side effect of HAART, and which occurs after initiation,
to a broad spectrum of antigens may be compromised reintroduction or change in HAART in a patient who
has evidence of HIV viral RNA suppression”. Though TABLE 1: Infectious and noninfectious causes of IRIS in HIV-
no specific risk factors have been described till date, infected patients 6-17
however some of the following risk factors are supposed Infectious etiologies Noninfectious etiologies
to have a positive relation with the development of zz Mycobacteria zz Rheumatoid arthritis
IRIS.3,10 zz Mycobacterium tuberculosis zz Systemic lupus
zz Mycobacterium avium erythematosus (SLE)
complex zz Graves disease
CLINICAL FACTORS ASSOCIATED WITH zz Cytomegalovirus zz Autoimmune thyroid disease
THE DEVELOPMENT OF IRIS zz Herpes viruses zz Sarcoidosis and
zz Herpes zoster virus granulomatous reactions

Male sex
zz Herpes simplex virus zz Tattoo ink
Younger age
zz Herpes virus-associated zz AIDS-related lymphoma
Lower CD4 cell count at ART initiation

Kaposi’s sarcoma zz Guillain-Barré syndrome
Higher HIV RNA at ART initiation zz Cryptococcus neoformans (GBS)

zz Pneumocystis jirovecii zz Interstitial lymphoid
Lower CD4+ T-cell percentage at ART initiation
pneumonia pneumonitis
Lower CD4/CD8 ratio at ART initiation
zz Histoplasmosis capsulatum
More rapid initial fall in HIV RNA on ART zz Toxoplasmosis
Antiretroviral naïve at time of OI diagnosis zz Hepatitis B virus
zz Hepatitis C virus
Shorter interval between OI therapy initiation and
zz Progressive multifocal
ART initiation2,10 leukoencephalitis
Similarly, a classification has been proposed: zz Parvovirus B19
Post-OI IRIS: When in a case of IRIS the opportunistic zz Strongyloides stercoralis
process was diagnosed prior to the initiation of infection and other parasitic
infections
HAART zz Molluscum contagiosum and
Coincident OI IRIS: When the opportunistic process

genital warts
zz Sinusitis
was first diagnosed (coincident with) at the time of
zz Folliculitis
IRIS presentation.6
To date no prospective therapeutic trials concerning
the management of IRIS have been conducted. All proposed infectious and non infectious causes of IRIS are
evidence regarding the management of IRIS in the given in the Table 1.3-10
literature relates to case report and small case series The most frequently reported IRIS symptoms in
reporting on management practices. response to previously treated or partially treated
infections include reports of clinical worsening and
Pathogenesis of IRIS: Despite numerous descriptions of recurrence of clinical manifestations of Mycobacterium
manifestations of IRIS, its pathogenesis remains largely tuberculosis (TB) and cryptococcal meningitis following
speculative, and at present three theories concerning the initiation of ART7-10. In noninfectious causes of IRIS,
pathogenesis of the syndrome propose (i) a combination autoimmunity to innate antigens plays a likely role
of underlying antigenic burden, (ii) the degree of in the syndrome. Examples include exacerbation of
immune restoration following HAART and (iii) the host rheumatoid arthritis and other autoimmune diseases.
genetic susceptibility. These pathogenic mechanisms Potential mechanisms for the syndrome include a
may interact and likely depend on the underlying burden partial recovery of the immune system or exuberant
of infectious or noninfectious agent because an antigenic host immunological responses to antigenic stimuli
stimulus is a must for the development of this syndrome, and the theory that the syndrome is precipitated by
which may be an intact, “clinically silent” organism or the degree of immune restoration following ART. Some
dead or dying organism and their residual antigens. The studies suggest differences in the baseline CD4 profiles
CHAPTER 113: Immune Reconstitution Inflammatory Syndrome 673
or quantitative viral load at ART initiation or their rate treatment for OI and starting ART, a rapid fall in HIV-1
of change during HAART between IRIS and non-IRIS RNA after ART, and being ART-naïve at the time of OI
patients, while other studies demonstrate only trends diagnosis. Other significant predictors have also included
or no significant difference between IRIS and non-IRIS younger age, a lower baseline CD4 cell percentage, a
patients. An alternative immunological mechanism lower CD4 cell count at ART initiation, and a lower CD4
may involve qualitative changes in lymphocyte function to CD8 cell ratio at baseline. Future epidemiologic and
or lymphocyte phenotypic expression. For instance, genetic studies conducted within diverse cohorts will
following ART an increase in memory CD4 cell types be important in determining the importance of host
is observed possibly as a result of redistribution from susceptibility and underlying opportunistic infections on
peripheral lymphoid tissue. This CD4 phenotype is the risk of developing IRIS.
primed to recognize previous antigenic stimuli, and thus
Manifestations: Although commonly the patients present
may be responsible for manifestations of IRIS seen soon
with severe prostration, with onset of high grade fever,
after ART initiation. After this redistribution, naïve T cells
fresh lymphadenopathy, severe dehydration with
increase and are thought to be responsible for the later
leukocytosis and altered renal and liver functions but the
quantitative increase in CD4 cell counts.12
disease specific manifestation are:
The third purported pathogenic mechanism for
IRIS involves host genetic susceptibility to an exuberant
MYCOBACTERIUM TUBERCULOSIS IRIS
immune response to the infectious or noninfectious
Mycobacterium tuberculosis (TB) is among the most
antigenic stimulus upon immune restoration. Although
frequently reported pathogens associated with IRIS,
evidence is limited, carriage of specific 1-ILA alleles
presenting with fever, lymphadenopathy and worsening
suggest associations with the development of IRIS and
respiratory symptoms. Pulmonary disorders, such as new
specific pathogens. Increased levels of interleukin-6 (lL-6)
pulmonaiy infiltrates, mediastinal lymphadenopathy,
in IRIS patients may explain this exuberant response to
and pleural effusions are also common. Extrapulmonary
mycobacterial antigens in subjects with clinical IRIS.
presentations are also possible, including disseminated
Such genetic predispositions may partially explain why
tuberculosis with associated acute renal failure, systemic
manifestations of IRIS differ in patients with similar
inflammatory responses (SIRS), and intracranial
antigenic burden and immunological responses to ART.13
tuberculomas, persistent fever, weight loss, and
Epidemiology of IRIS: Large retrospective studies have worsening respiratory symptoms. Abdominal TB-IRIS
been carried out on IRIS in John Hopkins (1996– can present with nonspecific abdominal pain and
2006) 6 Houston (1997–2000) 10 AND North Carolina obstructive jaundice.
and Johansberg, South Africa.3 The authors studied the In most studies, TB-IRIS occurs within two months
phenomenon prospectively in 450 patients over a period of ART initiation, the median onset of IRIS was 12–15
of 5 years (2004–2009).14 In a large retrospective analysis days (range 2–114 days), with only four of these cases
examining all forms of IRIS 25% of patients exhibited occurring more than four weeks after the initiation of
one or more disease episodes after initiation of ART. antiretroviral therapy. These studies suggest the onset
Other cohort analyses examining all manifestations of mycobacterial-associated IRIS is relatively soon after
of IRIS estimate that 17–23% of patients initiating ART initiation of ART, and clinicians should maintain a high
will develop the syndrome. Another large retrospective level of vigilance during this period.7-10
study reported 32% of patients with M. tuberculosis, M. Paradoxical CNS TB reactions are well described
avium complex, or Cryptococcus neoformans coinfection in HIV negative patients, and include expanding
developed IRIS after initiating ART. 3-10 Risk factors intracranial tuberculomas, tuberculous meningitis, and
identified for the development of IRIS in one cohort spinal cord lesions (vide supra).4,5 TB-associated CNS
included male sex, a shorter interval between initiating IRIS has also been reported in HIV-positive patients.
Compared to non-CNS TB-IRIS, symptoms tend to occur Clinical Features

later, usually 5–10 months after ART initiation. In general, MAC-associated IRIS typically presents with
lymphadenitis, with or without abscess formation and
Treatment suppuration. Other less common presentations include
Treatment for mycobacterial-associated IRIS depends respiratory failure secondary to acute respiratory distress
on the presentation and disease severity. Most patients syndrome (ARDS), leprosy, pyomyositis with cutaneous
present with non–life threatening presentations which abscesses, intra-abdominal disease, and involvement of
respond to the institution of appropriate antituberculous joints, skin, soft tissues, and spine.
therapy. However a range of life threatening presen Several studies have characterized the time of
tations, such as acute renal failure and acute respiratory onset of Mycobacterium-associated IRIS. In one study
distress syndrome (ARDS),7-10 are described and have of MAC lymphadenitis, the onset of a febrile illness
significant morbidity and mortality. Morbidity and was the first sign of IRIS and occurred between 6 and
mortality might also be greater in resource-limited 20 days after initiation of antiretroviral therapy 15. In
settings where limited management options exist. Since another study, the median time interval from the
the pathogenesis of the syndrome is an inflammatory start of antiretroviral therapy to the development of
one, systemic corticosteroids or nonsteroidal anti- mycobacterial lymphadenitis was 17 days (range 7-85
inflammatory drugs (NSAIDs) may alleviate symptoms. days).
In studies where therapy for IRIS was mentioned, the use
of corticosteroids was variable and anecdotally effective. Treatment
Therapies ranged from intravenous methylprednisolone As with TB-IRIS, evidence for treatment of IRIS due to
40 mg every 12 hours to prednisone 20–70 mg/day for atypical mycobacteria are scarce. Occasionally, surgical
5–12 weeks. These practices reflect the lack of evidence excision of profoundly enlarged nodes or debridement of
from controlled trials for the use of anti-inflammatory necrotic areas is anecdotally reported. However, healing
agents in IRIS. A randomized, placebo controlled trial is often poor leaving large, persistent sinuses. Needle
examining doses of prednisone 1.5 mg/kg/day for two aspiration is another option for enlarged, fluctuant and
weeks followed by 0.075 mg/kg/day for two weeks in symptomatic nodes. Otherwise, treatment is similar to
mild to moderate TB-IRIS is currently underway in South TB-IRIS (vide supra).15,16
Africa. Until data become available, it is reasonable to
administer corticosteroids for severe cases of IRIS such CYTOMEGALOVIRUS INFECTION IRIS
as tracheal compression due to lymphadenopathy, In the pre-ART era, CMV retinitis, a vision-threatening
refractory or debilitating lymphadenitis, or severe disease, carried a high annual incidence and was one of
respiratory symptoms, such as stridor and ARDS. the most significant AIDS-associated morbidities. After
Interruption of ART is rarely necessary but could be the introduction of HAART, Jacobson et al described
considered in life-threatening situations. five patients diagnosed with CMV retinitis 4-7 weeks
after ART initiation. They speculated that an HAART-
ATYPICAL MYCOBACTERIAL IRIS induced inflammatory response may be responsible for
Early observations involving atypical presentations of unmasking a subclinical infection. In addition to classical
Mycobacterium avium-intracellulare (MAC) were first CMV retinitis, ART led to new clinical manifestations of
noted with zidovudine therapy. Reports of atypical the infection, termed immune recovery vitritis (IRV) or
presentations of both Mycobacterium tuberculosis (MTB) immune recovery uveitis (IRU), in patients previously
and MAC increased in frequency with the introduction diagnosed with inactive AIDS-related CMV retinitis.
of protease inhibitors and ART. In larger cohorts, Distinct from the minimal intraocular inflammation
MAC remains the most frequently reported atypical of classic CMV retinitis, these manifestations exhibit
Mycobacterium. significant posterior segment ocular inflammation
thought to be due to the presence of residual CMV weeks), and no cases occurred before 4 weeks of therapy.
antigens or proteins which serve as the antigenic Both studies identified significant increases in CD8
stimulus for the syndrome. Clinical manifestations T cells as a risk factor for developing dermatomal zoster.20
include vision impairment and floaters17,18
Male gender, use of ART, higher CD4 cell counts, Clinical Features and Treatment
and involvement of the posterior retinal pole are factors Although complications such as encephalitis, myelitis,
associated with a reduced risk of developing IRU, cranial and peripheral nerve palsies, and acute retinal
whereas prior use of intravitreous injections of cidofovir, necrosis can occur in immune compromised HIV
large retinal lesions, and adequate immune recovery on patients, the vast majority of patients exhibit typical or
ART were associated with increased risk. atypical dermatomal involvement without dissemination
or systemic symptoms.
Clinical Features and Treatment A randomized, controlled trial demonstrated
The diagnosis of ocular manifestations of IRIS requires oral acyclovir with corticosteroids to be effective for
a high level of suspicion. In addition to signs of retinitis, dermatomal zoster in HIV-infected patients, facilitating
inflammatory symptoms include vitritis, papillitis, and healing and shortening the time of zoster-associated
macular edema, resulting in symptoms of loss of visual pain. Its use in cases of varicella zoster IRIS appears to
acuity and floaters in affected eyes. Treatment of IRIS be of clinical benefit. The combination of corticosteroids
associated CMV retinitis and IRV may involve antiCMV and acyciovir decreased healing times, improved acute
therapy with gancyclovir or valgancyclovir. However, pain, and quality of life, but did not affect the incidence or
the occurrence of IRU in patients receiving anti-CMV duration of postherpetic neuralgia.20,21 The incidence of
therapy draws its use into question. The use of systemic postherpetic neuralgia in immune competent individuals
corticosteroids has been successful, and IRV may require does not differ significantly from HIV-infected patients,
periocular corticosteroid injections. Due to its significant but increases with increasing patient age. Successful
morbidity and varying temporal presentations, clinicians symptomatic management involving opioids, tricyclic
should maintain a high level of vigilance for ocular antidepressants, gabapentin, and topical lidocaine
manifestations of CMV-associated IRIS.19 patches individually or in combination has been shown
to be beneficial and should be attempted in HIV patients
VARICELLA ZOSTER VIRUS with post-herpetic neuralgia as a complication of herpes
INFECTION IRIS zoster IRIS.
Although multidermatome zoster, once, one of the
hallmarks of AIDS, with the introduction of protease CRYPTOCOCCUS NEOFORMANS
inhibitors, increasing rates of herpes zoster were noted INFECTION IRIS
in HIVinfected patients. Two studies comparing ART and Accurate incidence of C. neoformans-associated IRIS
nonART patients reported increased incident cases of is unknown. It is infrequently reported in overall IRIS
zoster and rates estimated at 6.2–9.0 cases per 100 person cohorts, but in study of authors it constituted the 2nd most
years, three to five times higher than rates observed in common cause of IRIS.14 The majority of cryptococcal
the pre-HAART era. While another study reported no IRIS cases represent reactivation of previously treated
difference in overall incidence between HAART eras cases, suggesting either an immunological reaction
(3.2 cases per 100 person-years), the use of HAART was to incompletely treated disease or an inflammatory
associated with risk of zoster, which is reflected in large reaction to residual antigens. Although reports of
observational IRIS cohorts, where dermatomal varicella cryptococcal lymphadenitis and mediastinitis have
zoster comprises 9–40% of IRIS cases. Mean onset of been reported, most cryptococcal IRIS cases present as
disease from ART initiation was 5 weeks (range 1–17 meningitis. 80% of the cases result as a reactivation of
C. neoformans meningitis, illustrating the importance of OTHER ETIOLOGIES

maintaining a high clinical suspicion for patients at risk Other less common infectious etiologies, as well as non-
for cryptococcal IRIS, even in those previously treated. infectious etiologies, are listed in Table 1.23-27 Because
C. neoformans-induced IRIS meningitis symptoms these other infectious and noninfectious etiologies are
range in onset from seven days to ten months after rare, no recommendations exist for their management.
initiation of ART, with 20 (49%) occurring within
four weeks of therapy. In one study, patients with CONCLUSION
C. neoformans-related IRIS meningitis were compared While exact estimates of incidence are not yet available,
to typical AIDS-related C. neoformans meningitis.
IRIS in patients initiating ART has been firmly
Patients with C. neoformans-related IRIS meningitis
established as a significant problem in both high and
exhibited no difference in clinical presentation. However,
low income countries. Because of wide variation in
C. neoformans-related IRIS patients exhibited had
clinical presentation and the still increasing spectrum
higher baseline plasma HIV RNA levels and higher CSF
of symptoms and etiologies reported, diagnosis remains
cryptococcal antigen titers, opening pressures, WBC
problematic. Furthermore, no test is currently available
counts, and glucose levels. Additionally, IRIS patients
to establish IRIS. Standardized disease-specific clinical
were more likely to have ART initiated within 30 days
criteria for common infectious manifestations of the
of previously diagnosed C. neoformans meningitis.
disease should be developed to identify risk factors for
Most documented cases of C. neoformans-induced IRIS
developing pathogens capable of causing the syndrome.
meningitis have occurred in patients with CD4 counts
Until a greater understanding of the syndrome is
<100 cells/mm3.
achieved in different regions of the world, clinicians need
to remain vigilant when initiating ART and individualize
Treatment
therapy according to known treatment options for the
A recent study evaluated antifungal combination
specific infectious agent.
therapies in the treatment of C. neoformans meningitis
in HIV patients. Although significant log reductions
REFERENCES
in colony forming units were obser ved with all
1. French MA, Lenzo N, John M, Mallal SA, McKinnon EJ,
combinations, substantial numbers of patients remained James IR, Price P. Flexman JP, Tay-Kearney ML. Immune
culture positive 2 weeks after therapy. It may be important restoration disease after the treatment of immunodeficient
to delay ART until CSF sterility can be achieved with HIV-infected patients with highly active antiretroviral
effective antifungal combinations such as amphotericin therapy. HIV Med. 2000;1(2):107-l5.
B and flucytosine. However, the exact timing of ART and 2. Shelburne SA 3rd, Hamill Rj, Rodriguez-Barradas MC,
Greenberg SB, Atmar RL, Musher DW, Gathe JC Jr,
whether attaining CSF culture sterility is important in
Visnegarwala F, Trautner BW. Immune reconstitution
avoiding IRIS is unknown. This is illustrated by cases of
inflammatory syndrome: emergence of a unique syndrome
reactivation cryptococcal meningitis who had received during highly active antiretroviral therapy. Medicine
at least four weeks of antifungal therapy prior to initiation (Baltimore). 2002;81(3):213-27.
of HAART. It is reasonable to administer systemic 3. David M Murdoch, Willem DF Venter, Annelies Van Rie,
corticosteroids to alleviate unresponsive inflammatory Charles Feldman. Immune reconstitution inflammatory
effects, as anecdotal benefits have been observed in these s y n d ro m e ( I R I S ) : r ev i ew o f c o m m o n i n fe c t i o u s
manifestations and treatment options. AIDS Research and
patients. Furthermore, serial lumbar punctures may be
Therapy. 2007;49:6405-49.
required to manage persistent CSF pressure elevations
4. Teoh R, Humphries MJ, O’Mahony G. Symptomatic
in these patients. Although continuation of ART has been Intracranial tuberculoma developing during treatment of
performed safely, interruption of antiviral therapy may tuberculosis: a report of 10 patients and review of the
be necessary in severe or unresponsive cases.22 literature. QJ Med. 1987;63(241):449-60.
5. Cheng VC, Ho PL, Lee PA, Chan KS, Chan KK, Woo PC, Lau receiving highly active antiretroviral therapy. Clin Infect Dis.
SK, Yuen KY. Clinical spectrum of paradoxical deterioration 2002;35(1):E8-E13.
during antituberculosis therapy in non-HIV-infected patients. 17. Jacobson MA, Mills J. Serious cytomegalovirus disease in
Eur J Clin Microbiol Infect Dis. 2002;21(11 ):803-9. the acquired immunodeficiency syndrome (AIDS). Clinical
6. Witken et al. Characteristics of IRIS cases and matched findings, diagnosis, and treatment. Ann Intern Med.
controls in the John Hopkins Outpatient Clinic 1996-2006 1988;108(4):585-594.16(2):169-175.
J Acquire Immune Deficiency Syndrome. 2007. pp. 417-25. 18. Schrier RD. Song MK, Smith IL, Karavellas MP, Bartsch
William & Wilkins. DU, Torriani FJ, Garcia CR, Freeman WR. Intraocular viral
7. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical and immune pathogenesis of immune recovery uveitis
worsening of tuberculosis following antiretroviral therapy in patients with healed cytomegalovirus retinitis. Retina.
in patients with AIDS. Am J Respir Crit Care Med. 2006;26(2):165-9.
1998;158(I):l57-61. 19. Karavellas MP, Azen SP, Mac Donald JC, Shufelt CL,
8. Jehle AW, Khanna N, Sigle JP, Glatz-Krieger K, Battegay M, Lowder CY, Plummer Dj, Glasgow B, Torriani Fj, Freeman
Steiger J, Dickenmann M, Hirsch HH. Acute renal failure WR. Immune recovery vitritis and uveitis in AIDS: clinical
on immune reconstitution in an HIV-positive patient with predictors, sequelae, and treatment outcomes. Retina
miliary tuberculosis. Ctin Infect Dis. 2004;38(4):e32-35. 2001;21(1):1-9.
9. Bell C, Nelson M, Kaye S. A case of immune reconstitution 20. Gebo KA, Kalyani R, Moore RD. Polydefkis MJ. The incidence
rheumatoid arthritis. Int J STD AIDS. 2002;13(8):580-1. of, risk factors for, and sequelae of herpes zoster among
10. Shelburne SA, Visnegarwala F, Darcourtj, Graviss EA,
HIV patients in the highly active antiretroviral therapy era.
Giordano TP, White AC Jr., Hamill RJ. Incidence and
J.Acquire Immune Defic Syndr. 2005;40(2):169-74.
risk factors for immune reconstitution inflammatory
21. Kanazi GE, Johnson RW, Dworkin RH. Treatment of
syndrome during highly active antiretroviral therapy. AIDS.
postherpetic neuralgia: an update. Drugs. 2000;59(5):1113-
2005;19(4):399-406.
26.
11. Jevtovic DJ, Salemovic D, Ranin J, Pesic I, Zerjav S. Djurkovic-
22. Shelburne SA 3rd, Darcourt J, White AC Jr. Greenberg SB,
Djakovic O. The prevalence and risk of immune restoration
Hamill Rj, Atmar RL, Visnegarwala F. The role of immune
disease in HIV infected patients treated with highly active
reconstitution inflammatory syndrome in AIDS-related
antiretroviral therapy. HIV Med. 2005;6(2):140-3.
Cryptococcus neoformans disease in the era of highly active
12. Pakker NG, Notermans DW, de Boar RJ, Roos MT, de Wolf
antiretroviral therapy. Clin Infect Dis. 2005;40(7):1049-52.
F, Hill A, Leonard JM, Danner SA, Miedema F, Schellekens
23. Sereti I, Sarlis NJ, Arioglu E, Turner ML, Mican JM. Alopecia
PT. Biphasic kinetics of peripheral blood T cells after triple
universalis and Graves’ disease in the setting of immune
combination therapy in HIV-l infection: a composite of
redistribution and proliferation. Nat Med. 1998;4(2):208- restoration after highly active antiretroviral therapy. AIDS.
14. 2001;15(1);138-40.
13. Stone SF, Price P, Keane NM, Murray Rj, French MA. Levels 24. Mirmirani P, Maurer TA, Herndier B, McGrath M, Weinstein
of IL-6 and soluble IL-6 receptor are increased in HIV MD, Berger TG. Sarcoidosis in a patient with AIDS: a
patients with a history of immune restoration disease after manifestation of immune restoration syndrome. J Am Acad
HAART. HIV Med. 2002;3(1):21-7. Dermotol. 1999;41(2 Pt 2):285-6.
14. Vinay Rampal, et al. Immune Reconstitution Inflammatory 25. John M Flexman J, French MA. Hepatitis C virus-associated
Syndrome-Risk Factor in North India: Free Paper 69 th hepatitis following treatment of HIV-infected patients with
Annual Conference of API. 2014. pp. 20-23. Ludhiana, HIV protease inhibitors: an immune restoration disease?
Punjab, India. AIDS. 1998;12(17):2289-93.
15. Phillips P. Bonner S. Gataric N, Bai T, Wilcox P. Hogg 26. Collazos J. Mayo J, Martinez E, Blanco MS. Contrast-
R, OShaughnessy M, Montaner J. Nontuberculous enhancing progressive multifocal leukoencephalopathy as
mycobacterial immune reconstitution syndrome in HI an immune reconstitution event in AIDS patients. AIDS.
V-infected patients: spectrum of disease and long-term 1999;13(11):1426-28.
follow-up. Clin Infect Dis. 2005;41(10,):1483-97. 27. Intalapaporn P, Poovorawan Y, Suankratay C. Immune
16. Aberg JA. Chin-Hong PV, McCutchan A, Koletar SL, Currier reconstitution syndrome associated with parvovirus B
JS. Localized osteomyelitis due to Mycobacterium avium 19-induced pure red cell aplasia during highly active
complex in patients with Human Immunodeficiency Virus antiretroviral therapy. J Infect. 2005.
10
SECTION
Intensive Care Unit

Critical Care Toxicology: Update 2018 Arterial Blood Gas Analysis: Simple Steps for
Omender Singh, Deven Juneja Understanding
Ravindra Kumar Das
Hypoglycemia in ICU
Sundaram Arulrhaj, Aarathy Kannan, Manikandan R, Superbugs in ICU and the Need for Antibiotic
Vinodh Kumar A Stewardship
Biomarkers in Sepsis Pankaj Kumar
Virendra Kumar Goyal, Mohit Goyal Perioperative Management in Diabetes
Early and Empiric Antibiotics in Sepsis: Current Pramod Kumar Sinha

Controversy Hospital Acquired Infections
Trupti H Trivedi Piyush Jain
CHAPTER
114
Critical Care Toxicology: Update 2018
Omender Singh, Deven Juneja
INTRODUCTION paralytic agents. In addition, it is important to obtain

Managing a patient with suspected acute poisoning, may a urinary sample for toxicology screening before any
prove to be a difficult task in the practice of critical care sedatives or hypnotics are administered.
medicine as a high index of suspicion is warranted to Caution must be exercised in certain patients
make such a diagnosis. It may be even more challenging as some toxins like carbon monoxide may lead to
in patients who present with unexplained altered mental dyshemoglobenemias making pulse oximeter unreliable.
Supplemental oxygen should be delivered to maintain
status, seizures, cardiac dysrhythmias, and respiratory
SpO2 more than 95%. Ventilatory support in the form of
failure as the history is not forthcoming in most of
invasive or noninvasive support may be required in some
these patients. Multiple-drug ingestion, which is fairly
patients with respiratory distress.
common in poisoning patients, may further complicate
An ECG must be done and intravenous fluids should
the clinical picture. Early aggressive care during the first
be started after obtaining a good peripheral line. The
few hours of presentation may be life saving. Antidotes
“coma cocktail” of dextrose (1 Amp D50W IV), naloxone
should be used early on suspicion of a particular poison
(2 mg IV), flumazenil (0.2 mg IV), and thiamine (100
to prevent further organ dysfunction. Attempts to identify
mg IV) may be considered in patients with unknown
the causative poison should be done by obtaining a
poisoning who are unconsciousness or in coma.
focused history, detailed physical examination, and
Detailed and targeted history must be obtained from
readily available laboratory tests.
the family members and friends which must include the
past medical treatment and occupational environment.
INITIAL RESUSCITATION AND Special effort should be made to include the details
MANAGEMENT regarding the type of poison, time of exposure (acute
The initiatial resuscitation and management remains versus chronic), and administration route and the
the same, as in any other emergency condition, focusing amount exposed to. A note should also be made of use
on the airway, breathing and circulation. Airway of over-the-counter medications, vitamins, and herbal
management is of paramount importance in any preparations.
poisoning patient. Certain toxins like acid or alkali The clinical diagnosis of the type of poisoning may
ingestion, require extra precautions during airway be suggested by the clinical manifestations that may fit
management. When intubation is required, rapid into a particular toxidrome. However, it should always
sequence induction is prefered using short-acting kept in mind that the symptoms may be nonspecific
682 SECTION 10: Intensive Care Unit
like in early period of paracetamol overdose poisoning, TABLE 1: Indications for ICU admission
or the symptoms may be masked by other coexisting zz Respiratory depression or distress
conditions, like myocardial ischemia in patients with zz Need for emergency intubation
carbon monoxide poisoning. zz Seizures
The patient stabilization should take precedence zz Cardiac arrhythmias
over the detailed physical examination. Once stability zz Prolonged QRS of more than 0.12 ms
is achieved, a more comprehensive physical and zz Second or third degree atrioventricular block
systemic examination must be performed. In most of the zz Systolic BP less than 80 mm Hg
poisoning patients, alert/verbal/painful/unresponsive zz Glasgow coma scale score less than 12
scale (AVPU) may be used as a simple and rapid method zz Need for renal replacement therapy or extra-corporeal removal
of assessing consciousness. of toxins
zz Worsening metabolic acidosis
LABORATORY INVESTIGATIONS zz Pulmonary edema secondary to poisoning, including inhalation
Complete blood count, serum electrolytes, renal function injury
tests, random blood glucose, liver function test, arterial zz Tricyclic or phenothiazine with cardiologic or neurological
blood gases, chest X-ray and electrocardiograph should manifestations
be done in all patients. A pregnancy test must be zz Need for pralidoxime in patients with organophosphate toxicity
performed in all female patients of child-bearing age. zz Need for antivenom administration
The anion gap, serum osmolality, and osmolal gap zz Need for continuous infusion of naloxone
should be measured in each patient.
Specific investigations may have to be done to TABLE 2: Indications of extracorporeal toxin removal
confirm the cause of poisoning. For example, serum Hemodialysis Hemoperfusion Plasma ECMO
cholinesterase levels for organophosphorus poisoning, pheresis
serum drug levels (for digoxin, paracetamol, etc.), and Methanol Theophylline Tricyclic anti Amiodarone
oxygen saturation gap (SaO 2–SpO 2) must be done in depressants
patients with suspected carbon monoxide, cyanide, Ethylene Phenobarbital Thyroxine Beta-blocker
methemoglobinemia, and hydrogen sulfide poisoning. glycol
ICU admission may be indicated in certain patients Boric acid Phenytoin Heavy metals Calcium channel
blockers
(Table 1).
Salicylates Carbamazepine Theophylline Opioids
Lithium Paraquat Organophosphorous
DECONTAMINATION
Glutethimide Paraquat
In patients with suspected or confirmed dermal
Tricyclic
exposures, the clothing should be immediately removed
antidepressants
and the skin should be properly washed with a mild soap
and water. Eyes should be irrigated in ocular exposure to
acids or alkalis. cyanide. Also, it may not be useful if the patient presents
Gastric lavage is only of benefit in the hyperacute late, after more than 4–6 hours of ingestion.
phase of poisoning (<1 h). In addition, airway must
be secured before attempting lavage. Administer ENHANCED ELIMINATION
50-g charcoal as soon as possible and another 50 g Alkalinization of urine may be tried to improve excretion
every 4 h thereafter while indication persists. Certain of certain drugs like phenobarbital, salicylates, and
contraindications to charcoal administration exists chlorpropamide. In addition, dialysis and charcoal
which include poisoning with elemental metals like iron h e m o p e r f u s i o n s h o u l d a l s o b e c o n s i d e re d i n
and lithium, pesticides, strong acids and alkalis, and severe poisoning if the toxin is dializable (Table 2).
CHAPTER 114: Critical Care Toxicology: Update 2018 683
Plasmapheresis may also been be useful for removal of may be required as per the suspected poisoning. In
certain poisons (Table 2). Other newer modalities like addition to the general supportive measures, measures
extra corporeal membrane oxygenation (ECMO) has also to reduce absorption and enhance elimination, should
been tried in patients with acute poisoning (Table 2). be instituted immediately to improve outcomes.
Antidotes, if available, should be used early in the course.
BIBLIOGRAPHY
1. American College of Medical Toxicology. ACMT position
Intravenous Fat Emulsion
statement: interim guidance for the use of lipid resuscitation
Recently, there has been an increased interest in the use of therapy. J Med Toxicol. 2011;7:81-2.
intravenous fat emulsion (IFE) therapy in the management 2. Boyle JS, Bechtel LK, Holstege CP. Management of the
of several poisoning. It is recommended in patients critically poisoned patient. Scand J Trauma Resusc Emerg
with severe local anesthetic overdose (bupivacaine, Med. 2009;17:29.
3. Brooks DE, Levine M, O’Connor AD, French RN, Curry
mepivacaine, ropivacaine, levobupivacaine, prilocaine,
SC. Toxicology in the ICU: Part 2: specific toxins. Chest.
lignocaine, lidocaine) and is also been increasingly used 2011;140(4): 1072-85.
in several other poisoning, like beta-blockers, calcium 4. Ghannoum M, Roberts DM, Hoffman RS, Ouellet G, Roy
channel blockers, and tricyclic antidepressants, with L, Decker BS, Bouchard J. A stepwise approach for the
varied results. Even though its exact mechanism of action management of poisoning with extracorporeal treatments.
Semin Dial. 2014;27:362-70.
is unknown, it is postulated to mediate antidote activity
5. Lam SH, Majlesi N, Vilke GM. Use of intravenous fat
or act by compartmentalization of the offending drug emulsion in the emergency department for the critically ill
into a lipid phase, thereby removing it from its target poisoned patient. J Emerg Med. 2016;51(2):203-14.
receptors. The current recommended dosing states 6. Levine M, Brooks DE, Truitt CA, Wolk BJ, Boyer EW, Ruha AM.
administration of a bolus of 1.5 mL/kg, followed by an Toxicology in the ICU: Part 1: general overview and approach
intravenous infusion at the rate of 0.25 mL/kg/min. to treatment. Chest. 2011;140(3):795-806.
7. Levine M, Ruha AM, Graeme K, Brooks DE, Canning J, Curry
SC. Toxicology in the ICU: part 3: natural toxins. Chest.
CONCLUSION 2011;140(5): 1357-70.
A high index of suspicion is required for diagnosing 8. Ouellet G, Bouchard J, Ghannoum M, Decker BS. Available
extracorporeal treatments for poisoning: overview and
acute intoxication. The initial resuscitation is based on
limitations. Semin Dial. 2014;27(4):342-9.
the “ABCDE” approach. Obtaining a detailed history is 9. Singh O, Nasa P. General poisoning management. ICU
vital in diagnosing the cause of poisoning and in addition protocols: A stepwise approach. 1st edb. Chawla R, Todi, S
to the routine investigations, special investigations (Eds). Springer. 2012;68:547-52.
CHAPTER
115
Hypoglycemia in ICU
Sundaram Arulrhaj, Aarathy Kannan, Manikandan R, Vinodh Kumar A
INTRODUCTION Asymptomatic hypoglycemia

A c c o rd i n g t o A m e r i c a n D i a b e t e s A s s o c i a t i o n —— Absence of symptoms and glucose ≤70 mg/dL
Hypoglycemia is termed as a blood glucose less than 70 (3.9 mmol/L)
mg/dL. Even at higher glucose levels patients may have Probably symptomatic hypoglycemia
symptoms. —— Symptoms without documented low glucose ≥70
Hypoglycemia symptoms include sw eating, mg/dL (3.9 mmol/L)
confusion, weakness, loss of consciousness, even Pseudohypoglycemia
seizures, or death. It’s bit difficult to define a single —— Symptoms and glucose ≥70 mg/dL (3.9 mmol/L)
threshold value for hypoglycemia as the physiological
thresholds vary with age, gender and health status. And
PATHOGENESIS OF
also, recent hypoglycemic episodes will be lowering the
threshold values at which patients are symptomatic in
HYPOGLYCEMIA IN ICU
response to low blood sugar, whereas poorly controlled In patients with fulminant hepatic failure and/or overt
diabetic patients with chronic hyperglycemia may even adrenal failure during septic shock, spontaneous
experience symptoms at higher glucose levels. The episodes of severe hypoglycemia, has been recorded
awareness of hypoglycemia in hospitalized patients, is even though hypoglycemia in ICU management is
less and so healthcare provider should be alarmed by observed only in less than 1.5% patients (Fig. 1). The
a value of blood glucose 70 mg/dL (3.9 mmol/L). As strict glycemic control strategies in ICUs has been ended
this value is approximately the lower limit of normal up in, hypoglycemia, which has become a daily concern
postabsorptive plasma glucose concentration and the during the management of critically ill patients.
glycemic threshold for activation of glucose counter In critically ill patients reduced endogenous
regulatory responses. Now we have a new classification glucose production and accelerate glucose utilization,
of Hypoglycemia as developed by ADA. along with absolute or relative insulin excess, with
inadequate or interrupted nutritional support and/or
CLASSIFICATION OF HYPOGLYCEMIA insufficient provision of exogenous glucose and are the
Severe hypoglycemia fundamental causes of hypoglycemia. The occasional
—— An event requiring assistance human errors or inability to follow the algorithm also
Documented symptomatic hypoglycemia contribute to the same, in addition to other risk factors
—— Symptoms and glucose ≤70 mg/dL (3.9 mmol/L) for hypoglycemia (such as renal and/or hepatic failure,
CHAPTER 115: Hypoglycemia in ICU 685
Fig. 1: Pathophysiology of hypoglycemia
adrenal insufficiency, antibiotic treatment with a Prevalence of Hypoglycemia

quinolone).
Hypoglycemia prevalence ranges from 3% to 29% in
β - e n d o r p h i n i s i nv o l v e d i n t h e re g u l at i o n
type 2 DM patients who were on insulin therapy and has
of insulin secretion and carbohydrate metabolism
medicalor surgical issue (Fig. 2).
in hyperandrogenic, hyperinsulinemic women. 2 To
Upto 25% diabetic patients may experience
elucidate whether insulin-induced hypoglycemia
enhances the release of beta-endorphin in man, plasma hypoglycemia during hospital admission.
extracts from normal healthy individuals and patients Upto 1 in 5 diabetic patients on insulin or antidiabetic
with Graves’ disease before and after 45 minutes of agents (ADAs) have hypoglycemia related symptoms
insulin injection were subjected to gel chromatography, that required emergency department evaluation and
and the fractions obtained were measured by RIA for treatment.
betaendorphin. Basal plasma beta-endorphin levels
were less than 3–3.1 pg/mL, in four healthy subjects Recognition of Hypoglycemia
and the levels rose substantially to 47.5 +/- 12.4 pg/
Hypoglycemic symptoms (Tables 1 and 2)
mL (mean +/- SE) 45 min after insulin injection. Basal
Adrenergic
plasma beta-endorphin levels in three hyperthyroid
Neurogenic
patients (less than 3–3.8 pg/mL) did not seem to be
different from those in healthy individuals however, the Adrenergic features usually occurs prior to neur-
rise after insulin injection tended to be higher in cases of obehavioral symptoms thus act as early warning signs.
hyperthyroidism, with a peak value of 68.5 +/- 9.7 pg/mL. These symptoms are more pronounced in case of acute
Plasma beta-lipotropin and ACTH levels also increased onset hypoglycemia. Healthcare provider must be careful
in parallel with beta-endorphin in response to insulin- about adrenergic signs and symptoms like irritability,
induced hypoglycemia in both healthy individuals and diaphoresis, tachycardia, anxiety, dizziness, paleness,
hyperthyroid patients. hunger and chills.
Fig. 2: Prevalence of hypoglycemia in hospitalized patient
TABLE 1: Signs and symptoms of hypoglycemia TABLE 2: Risk factors for hypoglycemia
Early adrenergic symptoms Neuroglycopenic signs Common risk factors Less common risk factors
zz Pallor zz Confusion zz Mismatch of insulin zz Endocrine deficiencies
zz Diaphoresis zz Slurred speech timing, amount, or type for (cortisol, growth hormone, or
carbohydrate intake both), nonbeta cell tumors
zz Tachycardia zz Irrational or uncontrolled behavior
zz Oral secretagogues without zz Ingestion of large amounts of
zz Shakiness zz Extreme fatigue
appropriate carbohydrate alcohol or salicylates
zz Hunger zz Disorientation intake
zz Anxiety zz Loss of consciousness zz History of severe zz Sudden reduction of
zz Irritability zz Seizures hypoglycemia corticosteroid dose
zz Headache zz Pupillary sluggishness zz General anesthesia or zz Emesis
zz Dizziness zz Decreased response to noxious sedation that places patient
stimuli in an altered conscious
zz Reduction of oral intake zz Reduction of rate of IV
dextrose
In case of prolonged hypoglycemia, when brain zz New NPO status zz Unexpected interruption of
glucose dependence combined with low glucose stores enteral feedings or parenteral
nutrition
causes CNS dysfunction which leads to occurance of
neuroglycopenic signs and symptoms. zz Unexpected transport after zz Drug dispensing error insulin
injection of rapid- or fast-
acting
Neuroglycopenic Signs and Symptoms zz Critical illnesses (hepatic,
Headache, impaired concentration, disorientation, cardiac, and renal failure;
confusion, irritability, slurring of speech, lethargy, sepsis; and severe trauma)
altered behavior may mimic like dementia. In some
cases, patients may show focal seizures, choreoathetosis, thrombosis. Deep coma, shallow breathing, papillary
hemiplegia and patchy involvement of cerebellar dilatation, hypotonia and bradycardia occur when blood
and brainstem area, which mimic like basilar artery glucose is – 10 mg/dL, which signify the medullary phase.
Clinical Mimics
Adrenal crisis
Alcoholism
Addison disease
Anxiety disorders
Cardiogenic shock
Hypopituitarism (Panhypopituitarism)
Insulinoma
Fig. 3: Consequences of hypoglycemia
Pseudohypoglycemia
TABLE 3: Patient-related features

Complications and Consequences
Hypoglycemia can lead to significant morbidity and Patient related Others
occasional mortality, with recurrent hypoglycemia being Older age Long duration of diabetes
the most common complication. This places high risk Impaired hypoglycemia awareness Nil per oral without change in
treatment
patients at more severe hypoglycemia risk with a dose-
Severe illness disease, Food malabsorption e.g.
dependent response, with high mortality proportionally gastroenteritis celiac
with the frequency and severity of hypoglycemia (Fig. 3
Septic shock Drug dispensing error
and Tables 3 and 4).
Mechanical ventilation Drugs
Hypoglycemia affect cognitive function in adults, but
Renal failure Beta blockers
the effects are more significant in children under the age
Hepatic dysfunction Quinine
of 5 years. In a 18 year follow-up of the Diabetes Control
Malignancy Sulphonylureas
and Complications Trial (DCCT) showed transient
Severe trauma Salicylates
cognitive dysfunction but similar performances on
Sulfonamides trimethoprim
cognitive tests between patients with a known history
and without a history of severe hypoglycemia, reassuring
that there is no permanent brain damage (Fig. 4). TABLE 4: Frequent asymptomatic hypoglycemia and increased
Mostly in children, a number of case reports, have risk of arrhythmias in patients with type 2 diabetes
shown that hypoglycemia can be fatal in 4–10% of patients Nocturnal hypoglycemia

with Type 1 diabetes, prolonged or severe hypoglycemia Incident rate ratios 95% CI p-value
in the adults can cause brain injury, but most cases of of arrhythmias
fatal hypoglycemia have been attributed to ventricular Bradycardia 8.42 1.40; 51.0 0.02
arrhythmias, termed as ‘dead in bed syndrome’. Atrial ectopic 3.98 1.10; 14.40 0.04
Only NICE-SUGAR, a large multicenter trial, reported VPB 3.06 2.11; 4.44 <0.01
an overall increase in mortality with intensive insulin Complex VPB 0.79 0.22; 2.86 0.72
therapy. Also, in a retrospective analysis of diabetic Hypoglycemia may increase the risk of arrhythmias in patients with
type 2 diabetes and high cardiovascular risk
patients admitted to the general wards a correlation
of hypoglycemia with increased mortality was found,
but this association has been found true even at one multicenter randomized-controlled trials (VISEP and
year postdischarge, implying that hypoglycemia was a Glucontrol) had to be terminated early owing to high
“marker of disease burden” rather than a direct cause rates of severe hypoglycemia, but there was no evidence
of mortality. While others failed to show any significant of increased mortality.
association, several studies demonstrated a decrease A post hoc analysis of the NICE-SUGAR trial revealed
in mortality with intensive insulin control, and two the increased levels of hazard ratios after adjustment for
Fig. 4: Brain and hypoglycemia Fig. 5: The heart and hypoglycemia
baseline characteristics and postrandomization factors. Challenges for Managing Hypoglycemia in

These findings supported the fact that spontaneous the ICU Setting (Tables 5 and 6)
hypoglycemia, rather than iatrogenic hypoglycemia, Detection of hypoglycemia is difficult as patients are
is associated with increased mortality. The only trials
unable to communicate
carried out in patients with diabetes are the DIGAMI Glucose concentrations may differ according to the
trials that showed a decrease in mortality with tight
blood sampling site (venous, arterial or capillary
glycemic control at 1 and 5 years follow-up. The
blood)
DIGAMI-2 trial, but failed to show a long-term benefit
In critically ill patients, capillary blood glucose
with more aggressive insulin regimens as compared with
measured by finger stick is inaccurate
conventional therapy.
The presence of shock, use of vasopressors and upper
Many studies have been conducted to find out,
extremity edema were associated with the occurrence
whether hypoglycemia is truly a cause of mortality or
of inaccurate readings.
simply a biomarker of increased disease burden and
poor prognosis. In one study with the acute myocardial
infarction patients, it was found that, hypoglycemia
Hypoglycemia Induced Mortality
(glucose <60 mg/dL or 3.3 mmol/L) was a predictor of (Fig. 6 and Table 7)
in-hospital mortality only in patients with spontaneous Hypoglycemia induces cardiac death often quoted as
hypoglycemia, while iatrogenic hypoglycemia was not “dead in bed” syndrome
associated with increased mortality (Fig. 5). Hypoglycemia is associated with QT prolongation
and re-entrant arrhythmias
Reason for Death in Hypoglycemic Decreased baroreflex sensitivity after antecedent
Patients hypoglycemia
Information has been collected on whether death was High risk patients
—— Diabetes and and recurrent hypoglycemia
related to infection and also regarding the proximate
cause of death. By small modifications of the approach episode
—— Long standing disease and organ failure
adopted by the NICE-SUGAR trial. Five death categories
were created : a) neurologic causes (including both
traumatic and nontraumatic brain injury, with or without Hypoglycemia in Cardiac ICU
brain death), (b) cardiovascular causes (including, Hypoglycemia causes
cardiogenic shock, arrhythmia, distributive [septic] Blood coagulation abnormalities
shock, hypovolemic shock), (c) acute respiratory Inflammation
respiratory failure, (d) hepatic failure, (e) others. Endothelial dysfunction

TABLE 5: Risk factor for mortality in the ICU TABLE 6: Types of hypoglycemia in critical care
Condition Severe hypoglycemia Mortality Spontaneous hypoglycemia Iatrogenic hypoglycemia
Diabetes 3.07* 0.97
Septic shock 2.03* 1.33 Occurs in sick hospitalized zz Originates from treatment
Creatinine >3 mg/dL 1.10 1.30* patients with organ failure, zz Aggressive glycemic therapy
Mechanical ventilation 2.11* 2.43* malnutrition, or those taking (usually insulin)
predisposing medications zz Also include drug-to-drug
Tight glycemia control 1.59 0.67*
interactions
APACHE II score 1.07 1.14*
zz Patients who develop organ
Age 1.01 1.03*
failure while already taking
Severe hypoglycemia — 2.28*
(≤40 mg/dL antidiabetic agents
*Hypopyglycemia may increase the risk of arrhythmias in patients

with type 2 diabetes and high cardiovascular risk
Fig. 6: Hypoglycemia increase mortality by 2-fold in patients with acute myocardial infarction not receiving insulin
Sympathetic nervous system activation The following are the myocardial effects of hypo
glycemia:
ECG Changes in Hypoglycemia —— Ejection fraction is increased
—— Peak filling rate is increased

Prolongation of QT interval
—— EDV is increased
Tachycardia
—— Prolonged severe hypoglycemia results in
Ventricular ectopic beats
depression of myocardial function and causes LV
Changes in heart rate variability dysfunction.
ST-T changes
Atrial fibrillation Hemodynamic Changes due to
The ECG changes are primarily due to catecholamines Hypoglycemia
and hypokalemia which is the probable mechanism Hemodynamic changes are primarily due to epinephrine
for “Dead in bed syndrome”. Systolic BP is increased
Diastolic BP is decreased
Myocardial Effects due to Hypoglycemia Pulse pressure is increased
Myocardial effects are mediated by insulin and Increase in central aortic pressure
epinephrine Heart rate is increased

TABLE 7: Intensive glycemic control studies showing rates of hypoglycemia and mortality
Study (Reference) Characteristics Definition of hypoglycemia Rate of Mortality impact
N (% diabetes) hypoglycemia
Surgical ICU (30) Glucose goal Glucose 5% vs 0.78% ↓
N = 1,548 (13%) 80–110 mg/dL vs usual care (≤215 mg/dL) <40 mg/dL arterial blood 43% ICU p = 0.01
34% Hospital p = 0.01
Medical ICU (38) Glucose goal Glucose 18.7% vs 3.1% ↓
N = 1,200 (16.9%) 80–110 mg/dL vs usual care (≤200 mg/dL) <40 mg/dL arterial blood 9.5% p = 0.009 (overall)
↑
(In first 3 days)
Pediatric ICU (39) Normoglycemia vs conventional therapy Glucose 24.9% vs 1.4% ↓
N = 700 (0.9%) (≤214 mg/dL) <40 mg/dL (or <30 mg/dL for 3% p = 0.038
neonates) arterial blood
VISEP (41) Glucose goal Glucose <40 mg/dL (method 17% vs 4.1% ↔
N = 537 (30.4%) 80–110 mg/dL vs conventional not documented) Study terminated early
(≤200 mg/dL)
Glucontrol (42) Glucose goal Glucose 8.7% vs 2.7% ↔
N = 1,101 (18.8%) 80–110 mg/dL vs conventional <40 mg/dL (method variable) Study terminated early
(140–180 mg/dL)
Nice-sugar (40) Glucose goal Glucose 6.8% vs 0.5% ↑
N = 6,104 (20%) 81–108 mg/dL vs conventional <40 mg/dL (method of testing 2.6% p = 0.-2
(≤180 mg/dL) variable) At day 90
↔
At day 28
Digami (43) Intravenous insulin and glocose for 24 Glucose 15% vs 0% ↓
N = 620 (100%) hours followed by basal-bolus insulin vs <54 mg/dL (method not 28% p = 0.011
standard therapy reported) At 5 years
Digami 2 (44%) Two arms with intravenous insulin Glucose 12.7% in ↔
N = 1,253 (100%) and glucose for 24 hours (one more <54 mg/dL (method not intensive Between the 3 arms
aggressive) followed by basal-bolus reported) therapy vs 9.6%
insulin vs standard therapy vs 1.0%
ACUTE CORONARY SYNDROME

Vascular endothelial growth factor, plasminogen
activator inhibitor, vascular adhesion molecules,
interleukin-6 and platelet activation marker
levels shows increments in situation of moderate
hypoglycemia.
In T2 DM patients with coronary artery disease,
hypoglycemic episodes are asssocited with depressed
heart rate variability. Fig. 7: Hypoglycemia treatment procedure
Treatment (Fig. 7 and Table 8) Interrupt insulin pump infusion till blood glucose
If patient who is on subcutaneous insulin pump becomes become >60 mg/dL. If unable to interrupt infusion
hypoglycemic, then: pump infusion and patient shows alteration in level
TABLE 8: Treatment
BG less than 70 mg/dL and patient unconscious or uncooperative or NPO
Immediate action/treatment Repeat Follow-up
*Staff to remain with patient Repeat BG and retreat q15 min If patient NOT NPO or when able to swallow, feed
DO NOT WAIT FOR LAB CONFIRMATION until BG >70 mg/dL without patient carbohydrate to avoid recurrent hypoglycemia.
OF BG BEFORE TREATING symptoms or BG >80 mg/dL. zz If more than 1 hour until next meal/snack, also give
zz If IV access: Give 50 mL (25 gm) D50 IVP over Glucagon should only be 15 grams of carbohydrate*:
2–5 minutes repeated x 1 —— 3 graham crackers OR
zz If no IV access AND glucose <60 mg/dL: Give Add order to check BG once —— 6 saltine crackers OR
1 mg Glucagon SC x 1 and start IV access every 2 hours. —— 8 oz skim milk.
STAT. Patient must be turned on their side zz If more than 2 hours until next meal/snack.
to prevent aspiration. Note: Glucagon may zz Also add protein:
be ineffective in patients with inadequate —— ½ sandwich OR

glycogen stores such as children or newly
—— 3 graham crackers with one TBSP peanut butter
diagnosed adults
IF NPO OR CONTINUES TO BE UNCONSCIOUS/
UNCOOPERATIVE:
zz IF IV ACCESS: Verify IV fluids contain 5% dextrose.
Recheck BG in 1 hour.
zz IF NO IV ACCESS: Obtain MD orders for IV fluids with
dextrose. Check BG in 1 hour. Then follow treatment

per IV access.
Notify treating person for glucose management ASAP, and
certainly PRIOR to administering the next insulin or oral
diabetes agent for medication and glucose monitoring
orders.
BG less than 45 mg/dL and patient conscious or cooperative and able to swallow
Staff to remain with patient Repeat BG and retreat q15 min zz If more than 1 hour until next meal/snack, also give
DO NOT WAIT FOR LAB CONFIRMATION OF BG until BG >70 mg/dL without 15 gm of carbohydrate*:
BEFORE TREATING symptoms or BG >80 mg/dL. *3 graham crackers OR
Give 30 gm carbohydrate: Add order to check BG once *6 saltine crackers OR
zz 8 oz juice or regular pop OR ever 2 hours *8 oz skim milk
zz 2 TBSP jelly or sugar OR zz If more than 2 hours until next meal/snack. Also
zz 6 glucose tablets OR give 15 gm carbohydrate with protein:

zz 2 tubes Dextrose gel *½ sandwich OR
*3 graham crackers with one TBSP peanut butter
Notify treating person for glucose management ASAP and
certainly PRIOR to administering the next insulin or oral
diabetes agent for medication and glucose monitoring
orders
BG 45–59 mg/dL and patient conscious, cooperative, and able to swallow
*Staff to remain with patient Repeat BG and retreat q15 min zz If more than 1 hour until next meal/snack, also give
DO NOT WAIT FOR LAB CONFIRMATION BEFORE until BG >70 mg/dL without 15 gms of carbohydrate*:
TREATING symptoms or BG >80 mg/dL. *3 graham crackers OR
Give 20 gm carbohydrate: Add order to check BG once *6 saltine crackers OR
zz 6 oz juice or regular pop OR every 2 hours *8 oz skim milk.
zz 1 ½ TBSP of jelly or sugar OR zz If more than 2 hours until next meal/snack. Also add
zz 4 glucose tablets OR protein:

zz 1 ½ tubes Dextrose gel *½ sandwich OR
Notify treating person ASAP and certainly PRIOR to
administering the next insulin or oral diabetes agent and
glucose monitoring orders
Contd...
Contd...
BG 60–100 mg/dL and patient symptomatic and is conscious, cooperative and able to swallow
Give 15 gm carbohydrate: Repeat BG and retreat q15 min zz If more than 1 hour until next meal/snack, also give
zz 4 oz juice or regular pop OR until BG >100 OR symptoms 15 gm of carbohydrate*:
zz 3 glucose tablets OR resolved *3 graham crackers OR
zz 1 TBSP jelly or sugar OR Add order to check BG once *6 saltine crackers OR
zz 1 tube Dextrose gel
every 2 hours *8 oz skim milk
zz If more than 2 hours until next meal/snack. Also add
protein:
*½ sandwich OR
Notify treating person ASAP and certainly PRIOR to
administering the next insulin or oral diabetes agent for
medication and glucose monitoring orders
BG 60–70 mg/dL and patient has no symptoms of hypoglycemia and can take orally
No treatment required if the patient is going to Repeat BG and retreat q15 min zz If more than 1 hour until next meal/snack, also give
take meal with in 30 min until BG >100 OR symptoms 15 gms of carbohydrate*:
If meal takes more than 30 min, give 15 gm resolved *3 graham crackers OR
carbohydrate: Add order to check BG once *6 saltine crackers OR
zz 4 oz juice or regular pop OR every 2 hours *8 oz skim milk
zz 1 TBSP jelly or sugar OR zz If more than 2 hours until next meal/snack. Also add
zz 3 glucose tablets OR protein:

zz 1 tube Dextrose gel *½ sandwich OR
BG 70 mg/dL and patient has no symptoms
NO TREATMENT REQUIRED
of consciousness then stop insulin pumping by Standardize Insulin Therapy to Reduce

pulling out infusion site. Errors
Glucose gel is recommended for patients who is on Single insulin infusion concentration
fluid restrictions and renal restrictions. Single insulin infusion protocol
Ask the patient to avoid orange juice, soft drinks, Guidelines for transitions—IV to SC
cheese, milk and peanut butter in case of renal Guidelines for special situations
restriction. —— Enteral nutrition
Ask patient to take 120 mL of juice with 2 table spoon —— Parenteral nutrition
thickener in case of level one pured diet. —— Patient transportation and other handoffs
Ask patient to take only glucose gel if he/she is taking —— Hypoglycemia—BG <70 mg/dL
acarbose and develop hypoglycemia. Sucrose has no

use in this situation. Prevention
We have to keep balance between hyperglycemia and
How to Avoid Hypoglycemia in hypoglycemia, and that is the key for providing optimum
care for diabetic patients. We can prevent or decrease
Noncritical Patients
hypoglycemic episodes by the following:
Use OHA drugs with caution
Don’t use sliding – scale insulin alone as a marker Recognizing the Precipitating Factors
If patient is on insulin before admission then change That may include finding out delay in the timing of
insulin dose after discharge. meals or adjusting dosage of oral hypoglycemic drugs
or insulin, wrong dosages administered; correct timing advantage of increasing dosing flexibility when caloric
of the drugs, especially insulin; and also the presence intake is erratic.
of comorbidities, such as pituitary insufficiency, renal
insufficiency, adrenal insufficiency, and which increases Monitoring of Glucose Levels
the risk for hypoglycemia. Self-management by diabetic Bedside capillary blood glucose monitoring must be
patients who are well controlled as outpatients and who performed for at least four times daily (i.e. and before
possess the ability of managing the insulin regimen in the meals and at bedtime for patients who are taking food).
hospital, like those who wear an insulin pumps or those An early morning glucose check at 3:00 am can also be
who use multiple daily injections of glargine, aspart or used in patients with fasting hyperglycemia. An increased
lispro, can be a means to decrease hypoglycemia. glucose level at that time will indicate insufficient
nighttime dose of insulin, but a low glucose level at that
Prescheduled Insulin Therapy time will indicate an early peak in the evening insulin or
Even though endocrinologists used to warn against its insufficient food intake at night time.
use for decades, the regular and rapidly acting analog
Medical Nutritional Therapy
insulin sliding scale, without basal insulin replacement
It is very important to have a consistent carbohydrate
is a common method to control hyperglycemia in the
diet to appropriately match the insulin dosage or the
hospital. Because of concern for hypoglycemia, usually
secretagogue activity to food for optimum glucose level
no basal insulin is given and prandial insulin will be
control and prevent hypoglycemia. All the three meals
given only if the premeal blood glucose level is elevated.
should therefore follow a consistent carbohydrate
If insulin is not given before a meal, the blood glucose
approach and that will emphasize the importance of a
level will rise substantially and it will remain elevated
mixed meal.
even at the time of the next meal. Then, if a large dose
of regular or aspart or lispro insulin is given, which Applying the Systems
could cause hypoglycemia, especially if administered at The recent ADA technical review have discussed the
nighttime without a meal. use of protocols for scheduled and corrected dose
insulin, which might reduce the reliance on sliding
Inpatient Use of Oral Hypoglycemic Agents scale management for maintaining the glycemic control
Oral drugs should not be used by ill patients who are in the hospital. A team or multidisciplinary approach
not able to maintain adequate caloric intake or who will be necessary to establish hospital pathways and to
are on NPO status. Because Secretagogues can cause implement intravenous insulin infusions for the majority
hypoglycemia as side effects, alpha glucosidase inhibitors of patients who are having prolonged NPO status outside
will be ineffective without carbohydrate intake and the critical care units.
metformin will increase the risk in renal compromised
or in heart failure patients. Thiazolidinediones must be Practice Points
discontinued Class III or Class IV heart disease patients, The relationship between mortality and glycemic
although the side effects of TZDs may last several weeks. control demonstrates a U- shaped or J–shaped curve
A common mistake in such population of patients with increased risk of death at both ends.
is the discontinuation of oral drugs in the absence of Spontaneous hypoglycemia is associated with
other alternative methods for diabetes control. These more mortality when compared to iatrogenic
patients should recieve a subcutaneous or IV insulin hypoglycemia. It may imply that hypoglycemia may
regimen during hospitalization. Glycemic control with not be a true cause of mortality rather it may be a
insulin in these circumstances is safer and has the added biomarker for poor prognosis.
Current guidelines suggest to maintain blood glucose The occurrence of hypoglycemia in critically ill
values in the range of 140–180 mg/dL (7.8–10 mmol/L) patients, weather spontaneous or due to insulin infusion
for most patients. Glucose levels <100 mg/dL (5.6 is associated with poor prognosis and higher mortality.
mmol/L) should be avoided, and treatment needs to This is especially high in cases of severe hypoglycemia.
be revised when levels are < 70 mg/dL (3.9 mmol/L) Increased incidence of severe hypoglycemia is
Particularly in critically ill and elderly patients associated with intensive insulin therapy in order to
hypoglycemia unawareness is common as often they achieve normoglycemia. Due to the dreadful effects of
have low glucose values without any symptoms. Due hypoglycemia and its consequences, hypoglycemia is
to this, it is better to treat patients with glucose levels
the limiting factor for tightly controlling sugar levels in
<70 mg/dL with or without hypoglycemic symptoms.
critically ill.
In healthy and stable patients intensive glycemic
control may be appropriate where as for elderly and
critically ill patients less intensive control seems BIBLIOGRAPHY
appropriate. 1. Bates DW. Unexpected hypoglycemia in a critically ill
Risk factors for hypoglycemia include aggressive patient. Annals of Internal Medicine. 2002:137(N 2);110-7.
glycemic control, recent hospitalization, older 2. Egi M, Bellomo R, Stachowski E, et al. Hypoglycemia
age, terminal illness, renal failure, mechanical and outcome in critically Ill patients. Mayo Clin Proc.
2010;85(3):217-24.
ventilation, shock, malignancy, other comorbidities,
3. Hulkower RD, Pollack RM, Zonszein J. Understanding
hy p o a l b u m i n e m i a a n d p re v i o u s h i s t o r y o f
hypoglycemia in hospitalized patients. Diabetes Manag
hypoglycemia.
(Lond). 2014;4(2):165-76.
4. Hypoglycemia and risk of death in critically Ill patients.
CONCLUSION The NICE-SUGAR Study Investigators. N Engl J Med.
In critically ill patients diagnosing hypoglycemia is a 2012;367:1108-18.
challenge. Beside we cannot rely upon glucose analyzer 5. Lacherade JC, Jacqueminet S, Preiser JC. An overview of
at low ranges of glucose, and neurological signs related to hypoglycemia in the critically IllJ Diabetes Sci Technol. 2009;
hypoglycemia may be masked. 3(6):1242-9.
CHAPTER
116
Biomarkers in Sepsis
Virendra Kumar Goyal, Mohit Goyal
INTRODUCTION Cytokines like TNF, interleukins, etc. and their

The immune response triggered by the systemic receptors
Clotting factors
inflammation caused by various microbial viz. bacterial,
Markers of vascular endothelial damage
viral and fungal infections is called sepsis. The phase
of a so called “hyper-inflammatory” response gives During the hyperinflammatory phase, there is release
way to an immune suppressed phase in which multiple of proinflammatory cytokines and chemokines; proteins
organ dysfunctions may occur and the patient becomes such as C-reactive protein and procalcitonin which are
susceptible to other infections. This is the phase where synthesized in response to infection and inflammation;
nosocomial or hospital acquired infections start. The and markers of neutrophil and monocyte activation.
grave and sometimes irreversible complications that may Targeting the immune suppressed phased with novel
occur in sepsis warrant a timely and accurate diagnosis. approaches is important in reducing the mortality rate
Time and accuracy are of equal essence as they help associated with severe sepsis.
in making treatment choices, deciding the level of Systemic inflammatory response syndrome (SIRS) is
monitoring required and formulating the prognosis. a close differential of sepsis and has to be kept in mind to
Biomarkers with acceptable sensitivity and specificity avoid diagnostic pitfalls. SIRS is the physiologic response
can prove invaluable towards reducing sepsis related to sepsis, burns, injuries and other inflammatory
morbidity and mortality and thus search for these has conditions like pancreatitis. Diagnostic criteria for SIRS
assumed paramount importance. Biomarkers may not be are given in Table 2.
diagnostic in isolation but combined with clinical picture
and other parameters they allow early intervention.
TABLE 1: Applications of biomarkers
The various applications of biomarkers are listed in
To diagnose or rule out sepsis To assess response and predict
Table 1.
outcome
The various stages of sepsis are characterized by
To distinguish localized and To distinguish bacterial, viral
surge in levels of various markers. They can be broadly systemic infections and others infections
classified into: To decide and provide early To differentiate between gram
Acute phase reactants like ESR, CRP, Pracalcitonin, intervention positive and negative infections
Ferritin and others As a guide to the choice of
HLA and CD cell markers therapy
TABLE 2: Diagnostic criteria for SIRS TABLE 3: Characteristics of a “perfect” biomarker for sepsis
zz Temperature dysregulation: > zz Tachycardia: heart rate >90 zz High sensitivity and specificity
38ºC or <36ºC bpm zz Appearance or surge in its levels should precede the clinical
zz Tachypnea: respiratory rate zz TLC i.e. white blood cells signs and symptoms
> 20/min, or pCO2 < 32 mm dysregulation: > 12000/mm3 zz Should be easily detectable (in terms of equipment required)
Hg or the patient requires or < 4000/mm3 or > 10% and affordable
mechanical ventilation bands
zz Should be biologically plausible
SIRS is diagnosed when >2 of these criteria are met.
These diagnostic challenges and the urgent need

to cut down on the morbidity and mortality explain
the increasing interest and debate regarding the use of
biomarkers for the diagnosis of sepsis.
Sepsis is basically a systemic inflammatory response
syndrome secondary to infection, either confirmed
or a strong suspicion and altered variables: general,
inflammatory, hemodynamic; organ dysfunction and/
or tissue perfusion. Tissue hypoperfusion of acute
dysfunction of at least one organ or hypotension or
abnormal serum lactate level or oliguria are features
which give a “severe” label to the sepsis. Septic shock
is sepsis-induced hypotension, despite adequate fluid
resuscitation, and which requires support of vasopressor
agents.
These issues have fueled the search for a reliable
marker. Many potential biomarkers have been
investigated, only Lactate, C-reactive protein (CRP) and Fig. 1: An example of receiver operator characteristic (ROC) curves
procalcitonin (PCT) are currently used on a routine basis. A perfect biomarker has an AUC of 1, whereas a nondiscriminating
marker has an area of 0.5
While no single marker may prove to be the “master Source: The figure was first published in: Kofoed K, Andersen O,
key”, a combination of markers could improve diagnosis, Kronborg G, el al. Use of plasma C-reactive protein, procalcitonin,
prognosis and treatment efficacy. The characteristics a neutrophils, macrophage migration inhibitory factor, soluble
urokinase-type plasminogen activator receptor, and soluble triggering
desired (as yet hypothetical) “perfect” sepsis biomarker receptor expressed on myeloid cells-1 in combination to diagnose
are given in Table 3. infections: a prospective study. Crit Care. 2007;11:R38.
Receiver-operator characteristic (ROC) curves are
tools for comparing diagnostic tests and it is important to This example shows ROC curves comparing soluble
talk of them when discussing biomarkers in sepsis. With urokinase-type plasminogen activator receptor (suPAR),
specificity of the x-axis and sensitivity on y-axis the graph soluble triggering receptor expressed on myeloid cells
is plotted and shape of the curve and the area under it (sTREM)-1, macrophage migration inhibitory factor
(AUC) provide the estimates of the discriminative power (MIF), neutrophil count, procalcitonin (PCT), C-reactive
the particular test. The closer the curve is located to the protein (CRP), and the combined three-marker and six-
upper left-hand corner and the larger the AUC and the marker tests for detection of bacterial versus nonbacterial
better the marker is at discriminating between septic and causes of systemic inflammation. The six-marker has
nonseptic patients. A perfect biomarker has an AUC of 1, the highest power of discrimination (ROC-AUC 0.88)
whereas a nondiscriminating marker has an area of 0.5 or whereas suPAR in comparison is as good as the toss of a
less. Figure 1 gives an example of an ROC curve. coin (ROC-AUC 0.50).
CHAPTER 116: Biomarkers in Sepsis 697
TABLE 4: Examples of biomarkers in sepsis therapy and most estimation assays are cost effective as
zz Acute phase protein zz Coagulation well. It has a short half-life of 19 hours.
—— CRP —— Activated partial thromboplastin
—— Procalcitonin
—— Pentraxin 3 (PTX3)
time (aPTT) waveform analysis
—— Protein C receptor
Procalcitonin
—— Lipopolysaccharide —— Thrombomodulin Procalcitonin (PCT) is a precursor of the peptide
binding protein calcitonin. It is almost universally expressed as part of
(LBP) the inflammatory response to a various insults discussed
zz Cytokines and zz Endothelial damage earlier in the chapter. Although studies investigating
chemokines —— Heparin binding protein
—— IL-1RA, IL-1b, IL-2, —— E-selectin

the use of PCT and CRP have found their diagnostic
IL-6, MCP-1 —— Neopterin performance similar but CRP may be raised because of
—— TNF-a, TNFR1/2 —— ICAM-1, VCAM-1
other coexisting medical conditions in the patient. With
—— HMGBP1 —— Angiopoietin -1 and -2
—— Syndecan -1 and -2
regard to diagnosing bacteremia in particular, PCT have
shown excellent diagnostic ability; so, PCT is superior to
zz Cell surface markers zz Vasodilation
—— Soluble CD14 —— Copeptin (AVP precursor) CRP in diagnosing systemic infections. Judicious use of
(presepsin) PCT can help optimize the duration of antibiotic therapy
—— Neutrophil CD64
and help find the earliest time for discontinuation of the
index (CD64in)
—— mHLA-DR
same.
(monocyte HLA-DR
levels) Triggering Receptor Expressed on
—— CD-163
Myeloid Cells 1
zz Receptor markers zz Cell damage
—— VEGF —— MicroRNA
Triggering receptor expressed on myeloid (TREM)
—— Soluble VEGF- —— Microparticles belong to the superfamily of immunoglobulins by
receptor 1 (sFLT) zz Cell repair
structure and are cell-surface receptors by function.
—— Soluble urokinase —— Procollagen III amino
plasminogen propeptide
TREM-1 is expressed mainly on macrophages and
activator (suPAR) neutrophils, and has been identified as an amplifier of
—— sTREM-1 the immune response that strongly enhances leukocyte
—— RAGE (soluble
activation in the presence of microbial products. Levels
receptor for
advanced glycation of TREM-1 at the cell surface are up-regulated in the
end products) presence of bacteria or fungi; however, nonmicrobial
stimuli (e.g. urate crystals) have also been shown to
The list of proposed sepsis biomarkers is rather long enhance the expression of TREM-1.
(more than 170). Some examples are listed in Table 4. A In addition to the membrane-bound form, a soluble
few of them are discussed below. TREM-1 variant (sTREM-1) has been detected in several
body fluids. Findings suggest that proteolysis of the
C-REACTIVE PROTEIN membrane-anchored TREM-1 is the source of sTREM-1.
C-reactive protein (CRP) is an acute-phase protein Elevated sTREM-1 is found in fluids from patients
synthesized in hepatocytes and alveolar macrophages. with microbial infections, as well in patients with
IL-6 and some other cytokines trigger the production of noninfectious conditions, such as inflammatory bowel
C-reactive protein. Interestingly, this protein has pro- as disease and chronic obstructive pulmonary disease, and
well as anti-inflammatory effects. Serum CRP enthuses in patients undergoing cardiac surgery.
all clinicians and intensivists as its levels in the blood The latter results suggest that sTREM-1 can be
rise rather sharply, it goes down rapidly after response to released by a broad spectrum of inflammatory stimuli.
The first promising result of the use of sTREM-1 in of the innate immune system and guide management
plasma to diagnose sepsis in ICU patients indicated decisions in a patient with sepsis.
that sTREM-1 might be that perfect diagnostic sepsis
biomarker. BIOMARKER COMBINATIONS
Diagnostic accuracy of sTREM-1 has been most Sepsis can have varied etiology, may be caused by
extensively investigated is pneumonia and sepsis. innumerable pathogens, can have varied pathogenic
The measurement of sTREM-1 in BAL fluid might mechanisms and can involve any organ or major organ
be practicable in an ICU setting, particularly bacterial system; thus no single marker is expected to have very
infections. high sensitivity and specificity for its detection.
Therefore, as we discussed earlier, the search for a
Cytokines single “master key” might be futile but an appropriate,
After the initial host-microbial pathogen interaction, research backed combination of markers could improve
there is activation of all humoral and cellular factions diagnosis, prognosis and treatment efficacy. The right
of the innate immune response. For a comprehensive combination of biomarkers could be the right crack of
response humoral as well as cellular components have the cryptic “sepsis code”.
A combination of the three best-performing markers
roles.
i.e. CRP, PCT and neutrophil count is frequently used
The good age old proinflammatory cytokines
in practice and the ideal as of today would be to use the
produced by mononuclear cells hold ground when
six markers as discussed in the ROC curve. Future bears
it comes to detecting sepsis as well. These include
the possibility of multimarker panels that will add to the
interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α,
diagnostic accuracy and risk assessment in sepsis.
and other uncommonly used ones like IL-12, IL-15 and
macrophage migration inhibitory factor (MIF). CONCLUSION
The rise in levels of the proinflammatory molecules
Accurate and timely diagnosis of infection and
is only a part of the developing immunological response.
monitoring of response are the most important for
Anti-inflammatory modulators, such as IL-1 receptor improvement of patient outcome. For the same there is
antagonist, IL-10 and soluble TNF-α receptors I and need for a biomarker for sepsis that is reliable, can be
II also play important roles. Severe sepsis is more of quickly estimated and is cost effective.
a dysregulation of the immune system rather than a Current evidence suggests that CRP still remains
black and white rise in “pro-” or “anti-” inflammatory an important sensitive marker of inflammation and
substances. infection, and when combined with PCT, the specificity
Being central is the process of sepsis, cytokines are also increases significantly.
important sepsis biomarkers. Single measurement
of most cytokines has proven to be insufficient for STATEMENT OF UNMET NEED
distinguishing between infected and noninfected STREM-1 is the best among the studied markers and still
patients. Studies have suggested an encouraging role is only as accurate as the toss of a coin. Studies into the
IL-6 as a biomarker especially in neonates. An ROC-AUC mechanism of the innate immune response to infections
of 0.75 has been reported for distinguishing SIRS from have laid down the possibilities for various biomarkers.
sepsis. More such in-depth studies are needed to find such
Based on the present knowledge of biomarkers in markers and then their role in diagnosis and predicting
sepsis while levels of single cytokines may not have great prognosis shall need to be validated with further studies.
value but real-time monitoring of multiple cytokines and A perfect biomarker has an AUC of 1, whereas a non-
receptors may help determine the level of dysregulation discriminating marker has an area of 0.5.
CHAPTER 116: Biomarkers in Sepsis 699
BIBLIOGRAPHY and validation for successful biomarker measurement.

1. Adib-Conquy M, Monchi M, Goulenok C, Laurent I, Thuong Pharmaceutical Research. 2006;23(2):312-28.
M, Cavaillon J, et al. Increased plasma levels of soluble 6. Martinez F, Curtis J. Procalcitonin-guided antibiotic therapy
triggering receptor expressed on myeloid cells 1 and in COPD exacerbations. Chest. 2007;131(1):1-2.
procalcitonin after cardiac surgery and cardiac arrest 7. Martins P, Colo Brunialti M, Fernandes M, Martos L, Gomes
without infection. Shock. 2007;28(4):406-10. N, Rigato O, et al. Bacterial recognition and induced cell
2. Anwaruddin S, Askari A, Topol E. Redefining risk in acute activation in sepsis. Endocrine, Metabolic and Immune
coronary syndromes using molecular medicine. Journal of Disorders-Drug Targets. 2006;6(2):183-91.
the American College of Cardiology. 2007;49(3):279-89. 8. Oda S, Hirasawa H, Shiga H, Nakanishi K, Matsuda K,
3. Gaini S, Koldkjaer OG, Pedersen C, et al. Procalcitonin, Nakamua M. Sequential measurement of IL-6 blood levels
lipopolysaccharide-binding protein, interleukin-6 and in patients with systemic inflammatory response syndrome
C-reactive protein in community-acquired infections and (SIRS)/sepsis. Cytokine. 2005;29(4):169-75.
sepsis: a prospective study. Crit Care. 2006;10:R53.
9. Schenk M, Bouchon A, Seibold F, Mueller C. TREM-1–
4. Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen
expressing intestinal macrophages crucially amplify chronic
J, Eugen-Olsen J, et al. Use of plasma C-reactive protein,
inflammation in experimental colitis and inflammatory
procalcitonin, neutrophils, macrophage migration inhibitory
factor, soluble urokinase-type plasminogen activator bowel diseases. Journal of Clinical Investigation.
receptor, and soluble triggering receptor expressed on 2007;117(10):3097-106.
myeloid cells-1 in combination to diagnose infections: a 10. Wagner J, Williams S, Webster C. Biomarkers and surrogate
prospective study. Critical Care. 2007;11(2):R38. end points for fit-for-purpose development and regulatory
5. Lee J, Devanarayan V, Barrett Y, Weiner R, Allinson J, evaluation of new drugs. Clinical Pharmacology &
Fountain S, et al. Fit-for-purpose method development Therapeutics. 2007;81(1):104-7.
CHAPTER
117
Early and Empiric Antibiotics in Sepsis:
Current Controversy
Trupti H Trivedi
INTRODUCTION TABLE 1: Recommendations regarding antibiotic therapy for

treatment of severe sepsis and septic shock by Survival Sepsis
Sepsis is a clinical syndrome characterized by systemic Campaign (SSC)
inflammation secondary to infection. Severity of sepsis Blood cultures before antibiotic therapy
can range from sepsis, severe sepsis to septic shock. Imaging studies performed promptly to confirm a potential source
Mortality of this disorder is estimated to 10% in absence of infection
of shock and more than 40% in septic shock. Successful Administration of broad-spectrum antimicrobials therapy within 1
treatment of sepsis includes supportive treatment and hour of the recognition of septic shock and severe sepsis without
septic shock as the goal of therapy
control of the underlying infection, in critical time
Reassessment of antimicrobial therapy daily for de-escalation, when
frame. Delayed and ineffective antimicrobial therapy appropriate
leads to uncontrolled infection and irreversible shock, Infection source control with attention to the balance of risks and
characterized by refractory hypotension, lactic acidosis benefits of the chosen method within 12 hours of diagnosis
and multiorgan dysfunction syndrome (MODS) with Source: Adapted from Survival Sepsis Guidelines 2016 Critical Care
Medicine. 2017;45(3):486-552.
mortality exceeding 50%. Key recommendations of
survival sepsis guidelines include administration of
Time of Administration of First
effective antimicrobial therapy, covering potential
pathogens within 1 hour of diagnosis of septic shock and
Antibiotic Dose
Recent surviving sepsis campaign (SSC) guideline
severe sepsis as a goal, in addition to other strategies
recommends administration of effective, broad-
related to control of infection (Table 1). As exact
spectrum intravenous antimicrobials within one hour
identification of etiology is not possible within an hour,
of diagnosis of septic shock and severe sepsis. This
majority of patients receive empiric antibiotic therapy
recommendation is based on observational studies that
after identification of suspected source. The controversies report poor outcomes with delayed (beyond one hour),
related to this are-timing of administration of first dose inadequately dosed, or inappropriate (in vitro resistance
of antibiotic, use of combination vs monotherapy, of pathogen to antibiotic documented subsequently)
de-escalation, duration and dose of therapy. These antimicrobial therapy. Studies done recently focusing
controversies are described in this chapter followed on the impact of timing of antibiotic administration have
by sitewise choice of regimen, reasons for failure of been inconsistent. In a recent meta-analysis of patients
treatment and ancillary therapies beyond antibiotics. with severe sepsis and septic shock, administration of
CHAPTER 117: Early and Empiric Antibiotics in Sepsis: Current Controversy 701
antibiotics within 3 hours of Emergency Department identify the causative organisms and make de-escalation
(ED) triage or within 1 hour of recognition of severe possible. In a review of 493 studies it was observed that
sepsis/septic shock did not result in any mortality that there was lack of sufficient evidence to conclude
benefit. While exact time beyond which initiation of if de-escalation was safe and effective in adult patients
antibiotic will prove detrimental is not known, it is with sepsis.
unlikely that administration of first dose of antibiotic will
have major impact on patient’s outcome without other Duration of Therapy and Dosing
supportive therapies. Hence appropriate cultures should There is a risk of relapse of infection with inadequate
be sent prior to antibiotic dose and supportive therapies eradication due to shorter course of therapy. At the same
initiated simultaneously. time prolonged course of antibiotics is associated with
increased chances of toxicity, higher cost and selection
Selection of Appropriate Antibiotic: of multidrug resistant (MDR) pathogens. Decision about
Monotherapy vs Combination Therapy duration of antibiotics should be individualized based on
severity of illness, presence of persistent septic focus, site
Though there is mortality benefit in administration of
of infection and presence of MDR pathogens. Infections
appropriate and adequate antibiotic initially in patients
due to Staphylococcus aureus and Pseudomonas
with sepsis, combination therapy as initial empiric
aeruginosa are often associated with treatment failure
choice has remained controversial. While there are
early relapse, metastatic complications and may warrant
advantages like-broader coverage and antibacterial
longer duration of treatment (14–21 days) against usual
synergy, potential disadvantages are super-infection,
guidelines of 7–10 days. In addition to clinical response,
increased chances of resistance and toxicity in addition
biomarkers like procalcitonin (PCT) can assist in
to increased cost. Combination therapy does increase the
determining duration of antibiotic therapy. PRORATA
likelihood of appropriate therapy more so in presence of
trial, which was a large trial done in 621 ICU patients
multidrug resistant (MDR) pathogens. Gram-negative
with severe sepsis and septic shock, measurement of
coverage typically involves a beta-lactam antibiotic in
PCT concentrations helped in shortening duration of
combination with fluoroquinolone or aminoglycoside.
antibiotic therapy without causing harm.
Quinolones have more lung penetration and less renal
Hydrophilic antibiotics like beta-lactam, glyco
toxicity as compared to aminoglycosides, but evidence peptides, lipopeptides and aminoglycosides are
demonstrates trend towards increased survival with distributed in extra-cellular space and have renal
aminoglycoside-containing regimens. However routine clearance. These drugs usually need a loading dose
use of combination therapy for treatment of Gram- and dose adjustment in setting of hypoalbuminemia
negative infections is not recommended. Combination (higher dose required), renal failure (lower dose) and
therapy should be reserved for patients with very severe dialysis. Lipophilic antibiotics like fluoroquinolones,
illness, septic shock, having risk factor for resistant macrolides, tetracyclines, lincosamides and glycylcyclins
infection, nosocomial infections, neutropenia, severe have intracellular penetration and hepatic clearance.
respiratory infection and sepsis due to unknown source. They do not need loading dose and dose adjustment
is needed in setting of severe hepatic failure only. Also
De-escalation with certain drugs having time-dependent killing (beta-
While one is justified in starting combination in certain lactam and glycopeptides) continuous intravenous
situations, every effort must be made to change to infusions are more effective as they achieve higher
narrow spectrum antibiotic coverage once culture blood concentrations exceeding minimum inhibitory
reports are available, as a part of “antibiotic stewardship” concentration (MIC) of pathogen by prolong infusion.
program and optimize the use of antibiotics. However, in For patients with ventilator associated pneumonia (VAP)
practice only in 20–30% cases subsequent culture reports aerosolized delivery of antibiotics through nebulizer
can achieve higher MIC of drug at lesser risk of systemic infection. Potential for infection with resistant organism
toxicity and resistance. But size of droplet generated for is judged by patient’s risk factors like comorbid illness
delivery should be ideally between 1 µm and 3 µm as (DM/CKD/HIV/immune-suppressive therapy), prior
larger droplets are trapped in circuit and smaller one antibiotic exposure, hospitalization and presence of
are expelled during expiration. However meta-analysis indwelling devices. However diagnosis can only be
of use of colistimethate sodium this used as adjunct confirmed by isolating causative organism from blood
in treatment of VAP have revealed conflicting results or appropriate fluid by culture. This takes several days
with more clinical and microbiological response but no for results and also if patient is already on antibiotics
mortality benefit. chances of positivity of culture report are bleak. There
are more rapid methods like – polymerase chain reaction
Selection of Regimen for Empirical (PCR) and mass spectrometry to identify causative
Antibiotic Therapy organisms. But, these are not routinely available and
Antibiotics remain the standard therapy for patients with when available are expensive. Gram stains and data from
sepsis since long. MONARCS trial, done in 2004, on over local hospital infection control committee often help in
2500 patients of sepsis demonstrated significant decrease choosing the correct empirical regimen. Hence, most
in crude mortality in patients receiving adequate of the times physicians have to administer antibiotics
antibiotic therapy. Selection of regimen should begin empirically, while awaiting laboratory confirmation.
with detailed clinical assessment to identify the site Table 2 gives the recommendation for selection of
of infection. Routine laboratory investigations and empirical regimen to cover most likely pathogens,
imaging are usually sufficient to identify source of according to probable site of infection. But therapy
TABLE 2: Regimen for empirical selection of antibiotics in severe sepsis and septic shock
Suspected source of infection Special situation Antimicrobials of choice
Urinary tract infection No risk for MDR pathogen Ceftriaxone 1
Or
Levofloxacin
Risk for MDR pathogen Cefaperazone and sulbactam
Prior history/ antibiotics Or
Indwelling catheter/stent Piperacillin tazobactum
+/ – Amikacin/ Gentamycin
Postoperative setting/Nosocomial +Vancomycin
Community acquired pneumonia No risk of Pseudomonas Ceftriaxone
Plus azithromycin or levofloxacin
Risk for Pseudomonas Cefepime
structural lung disease, steroid Or
therapy, malnutrition Piperacilllin tazobactum
Plus
Azithromycin
+/-
Aminoglycoside/tobramycin
Intra-abdominal sepsis Piperacillin tazobactum
Or
Cefepime
+Metronidazole
+/ – Aminoglycoside
Contd...
CHAPTER 117: Early and Empiric Antibiotics in Sepsis: Current Controversy 703
Contd...
Suspected source of infection Special situation Antimicrobials of choice

Emphysematous ckolecystitis/ Plus vancomycin
pyelonephritis
Skin and soft tissue infection (SSTI) MRSA not suspected Oxacillin
MRSA suspected Vancomycin
Necrotizing fasciitis Vancomycin
+
Piperacillin tazobactum
+/-
Clindamycin
Unknown Source Piperacillin Tazobatam/Cefepime
Suspected catheter related blood +
stream infection CR-BSI Vancomycin
+/-
Antifungal
should be individualized considering above factors. with severe sepsis and septic shock. Toxin-neutralizing
Invasive fungal infections are considered as possibility antibodies for Clostridium, fecal flora reconstitution by
in neutropenic patients, major abdominal surgery, fecal transplant, monoclonal antibodies for Pseudomonas
patients on parenteral nutrition, transplant recipients and Staph. aureus are some emerging adjuvant therapies.
and on chemotherapy. Once empirical therapy is Targeting bacterial pore-forming toxins (PFT) with
initiated, response is assessed periodically by clinical liposomes to reduce their virulence is one innovative
and laboratory parameters. Whenever possible after therapy under investigation.
stabilizing patient, source control should be achieved
like drainage of abscess, debridement and removal SUMMARY
of infected device. De-escalation to narrow spectrum In spite of standard recommendations and availability
antibiotics is recommended once culture reports are of guidelines for early and empiric antibiotic therapy
available. in sepsis, there are controversy at each step—regarding
In absence of clinical response, patient should diagnosis, timing, selection of antibiotic, mode of
be reassessed for alternative diagnosis as several administration, dose and duration of antibiotic. As sepsis
noninfective conditions mimic sepsis. In addition to is a complex pathophysiological syndrome, multiple
delayed initiation of antibiotics, persistent septic focus, interventions are needed to have favorable outcome in
uncontrolled DM, antimicrobial resistance and super
these patients. Physicians must follow the prevailing
added fungal infection are common causes for failure of
recommendations as most are based on good evidence
response to therapy. One must also consider that target
but treatment has to be individualized depending on
site penetration of antibiotics is hampered in patients of
severity of illness, patient’s comorbid conditions and
shock due to microvascular hypoperfusion.
prevailing degree of antimicrobial resistance.
FUTURE THERAPY
BIBLIOGRAPHY
With limited number of new antibiotics in pipeline 1. Liang, Stephen Y, Kumar A. Empiric antimicrobial
and presence of multiple factors resulting in failure of therapy in severe sepsis and septic shock: optimizing
antibiotic therapy, there is a need to focus on therapies pathogen clearance. Curr Infect Dis Rep. 2015;17(7):493.
other than antibiotics to reduce mortality in patients doi:10.1007/s11908-015-0493-6
2. MacArthur RD, Miller M, Albertson T, Panacek E, Johnson 5. Venkatesh, Srinivas & Chauhan, Lakhbir & Gadpayle,
D, Teoh L, Barchuk W. Adequacy of early empiric antibiotic Adesh & S. Jain, T & Wattal, Chand & Aneja, Satinder &
treatment and survival in severe sepsis: Experience Ghafur, Abdul & Puri, Manju & Sinha, Ajit & Singh, Varinder
from the MONARCS Trial, Clinical Infectious Diseases. & Baveja, Usha & Dutta, Renu & Gaind, Rajni & Sardana,
2004;38(2):284-8.
Raman & Manchanda, Vikas & Kotwani, Anita & Hans,
3. Michael B, et al. The early antibiotic therapy in septic
Charoo & Chandelia, Sudha& Jain, Piyush & Jain, Sarika.
patients-milestone or sticking point? Critical Care. 2014;
(2016). National Treatment Guidelines for Antimicrobial Use
18:671.
4. Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The in Infectious Diseases.
impact of timing of antibiotics on outcomes in severe sepsis 6. Vincent JL, Bassetti M, François B, Karam G, Chastre J,
and septic shock: A systematic review and meta-analysis. Torres A, et al. Advances in antibiotic therapy in the critically
critical care medicine. 2015;43(9):1907-15. ill. Crit Care. 2016;133:10.1186/s13054-016-1285-6.
CHAPTER
118
Arterial Blood Gas Analysis: Simple
Steps for Understanding
Ravindra Kumar Das
INTRODUCTION recommended. Bubbles if any, should be expelled out.

For diagnosis blood should be drawn prior to therapy.
Arterial blood gas (ABG) is widely measured in hospitals
Background of patient’s history and provisional
and it is gold standard of ICU. So direct measurement
clinical diagnosis are recorded. In the next five minutes
of pH, PaO2, PaCo2 and electrolytes is precisely done.
analysis of ABG measurement is done.
Analyzed report of these measurements helps in
establishing the diagnosis of different diseases having
the effect on gas, electrolyte and acid base status; helps METHOD OF ANALYSIS
guide treatment plan; sometimes it has prognostic value ABG Analysis is Done in Five Headings
and is important monitor in critically ill patients. But 1. Accuracy of ABG.
till date no textbook or literatures have written easy and 2. Gas analysis.
complete method of ABG analysis. So the critically ill 3. Electrolyte analysis.
patient is devoid of expected benefit of ABG worldwide. 4. Acid-base analysis.
Thorough understandings of blood gas are mandatory 5. Complete diagnosis.
for the physician and recognition of mixed disorders is
the demand of the alert physician. Accuracy of ABG
Purpose of knowing the accuracy of ABG is important
COLLECTION OF BLOOD for accurate result of analysis. But the hurdle has not
SAMPLES AND TRANSPORTATION been resolved till date because HCO3- is not measured
by any ABG machine. Till the direct measurement of
Arterial blood is taken according to the protocol in
HCO3- comes in force, we have overcome this hurdle by
heparnized syringe and the collected blood with folded
taking in consideration of the following two steps which
needle of the syringe is transported to the ABG lab in
has been proved satisfactory in my other work on ABG.
shortest possible time. If any delay in transporting the
Accuracy is judged either by BE and derived HCO3- or by
sample it must be kept in icepack and measurement must
the relation between pH and H+.
be taken within half an hour. ABG measurement is taken
from the machine available. I measured from “cobas b Step 1: If the difference between measured HCO3- and
121 of Roche”. Temperature correction is generally not derived HCO 3- satisfies to ± 2–3 mmol/L, the ABG is
considered accurate. For all clinical purpose Van Slyke Gas Analysis
Equation according to the Zander is the best choice for Purpose of gas analysis should be to establish the relation
derivation of BE and can be obtained with high accuracy. between PaO2 and SpO2, severity of hypoxemia (mild,
The equation involves pH, PaCo2, cHb and SpO2. From moderate and severe), cause of hypoxemia (decreased
the BE thus obtained, measured HCO 3- is derived as FiO2, ventilation defect, Ventilation–Perfusion mismatch,
follows: shunt and diffusion defect across the alveolar wall),
Derived BE = Measured HCO3- - Normal value of type of respiratory failure (Type 1 and type 2 respiratory
HCO3- failure) and to know arterial oxygen content (CaO2).
= Measured HCO3- -24 For gas analysis we proceed in the following steps:
So, Measured HCO3- = BE +24.
Step 1: We look for SpO 2 (oxygen saturation). SpO 2
Derived HCO3- is achieved by clinically applicable
reflects how much of the oxygen carrying capacity by
Handerson Equation and from total CO2 on electrolyte
hemoglobin is utilized.
panel.
In my other observation 18% of ABG were found Step 2: We look for PaO 2 (partial pressure of oxygen
inaccurate with this method while they were found in arterial blood). It is an indicator of adequacy of
accurate by the second method. oxygenation of blood by the lung.
Step 2: pH and H+ relation (Table 1) also satisfies the Step 3: The relation between PaO2 and SpO2. It is decided
accuracy of ABG. In the patient whose ABG sample is by Figure 1 and Table 2.
inaccurate by the above method, the relation between H+ For ready reference of relation between PaO 2 and
and pH is decided. If they match, in that condition also SpO2 we can take help of the Table 2.
the ABG is accurate. Step 4: We calculate PAO 2 (alveolar oxygen content).
H+ can be derived either by the Handersan equation PAO2 is a derived value and is calculated as:
H = 24 × PaCO2/HCO3-
+
or by H+ = 83- two digits of pH after decimal if the pH PAO2 = FiO2 (PB-PH2O) – PaCO2/R
falls in range of 7.10–7.60. = 150 – 1.25 × PaCO2
Where FiO2 (oxygen fraction in inspired air) = 0.21. PB
(barometric pressure) = 760 mm of Hg at sea level, PH2O
TABLE 1: Relation between pH value and corresponding H +
concentration (water vapor pressure) = 47 mm of Hg. PaCO2 (partial
pressure of carbon dioxide). R (respiratory quotient)
pH [H+] mmol/L pH [H+] mmol/L
6.70 200 7.40 40
=0.8.
6.75 178 7.45 35 Normal value of PAO2 is 96–98 mm of Hg.
6.80 158 7.50 32 Step 5: P(A-a) O2 gradient (mm of Hg) = PAO2-PaO2. Other
6.85 141 7.55 28 simple way to decide the value is age/4+4. Normally, it is
6.90 126 7.60 25 <15 mm of Hg. It may be as high as 30 mm of Hg in elderly.
6.95 112 7.65 22
If this value is increased it indicates parenchymal lung
7.00 100 7.70 20
disease. The value of P(A-a) gradient in type 2 respiratory
7.05 89 7.75 18
failure helps to determine whether the patient has
7.10 79 7.80 16
associated lung disease or just reduced respiratory effort.
7.15 71 7.85 14
7.20 63 7.90 13 Step 6: We look for PaCO2 (partial pressure of carbon
7.25 56 7.95 11 dioxide). PaCO 2 is an indicator of the efficacy of
7.30 50 8.0 10 ventilation. Normal value is 36–45 mm of Hg. But for the
7.35 45 purpose of ABG analysis, it is taken as 40 mm of Hg. More
CHAPTER 118: Arterial Blood Gas Analysis: Simple Steps for Understanding 707
Fig. 1: Graphic relation of PaO2 and SpO2
TABLE 2: Relation between PaO2 and SpO2 In an adult of 72 kg the normal value of CaO2 is 200 mL
PaO2 Corresponding SpO2 Interpretation O2/L of blood. O2 dissolved in plasma = 3 mL/L of blood
(mm of Hg) (%) When the cardiac output is low, we should calculate
80–100 95–100 Normal oxygen delivery (DO2).
60–80 90–94 Mild hypoxemia
DO2 = Cardiac output (CO) × arterial oxygen content
40–60 75–89 Moderate hypoxemia
(CaO2) and then evaluate tissue diffusion.
<40 <75 Severe hypoxemia
Electrolyte Analysis
than 49 mm of Hg is considered as due to hypoventilation
Purpose of electrolyte analysis is to provide the complete
and not due to compensatory effect.
picture of acid-base derangement. Sometimes, it adds
Step 7: Type of respiratory failure is decided. It is defined
key insight in difficult diagnosis. It helps in management.
as Type1 respiratory failure- when there is moderate
Some calculated parameters help in modern way of acid-
hypoxemia (PaO 2 <60 mm of Hg) in the absence of
base analysis.
hypercapnea and Type 2 respiratory failure when there is
Modern blood gas analyzers offer the option of
hypercapnea (PaCo2 > 49 mm of Hg). Type 2 respiratory
measuring electrolytes using part of the ABG sample.
failure may be associated with hypoxemia.
In general, sodium largely reflects reciprocal change
Step 8: Causes of hypoxemia is determined from the in body water content, chloride generally change in
value of PaCo2, P(A-a)O2 and the knowledge of response parallel with plasma Na+. Chloride is low in metabolic
to supplemental O2 by the Flow chart 1. alkalosis and high in some form of metabolic acidosis.
Step 9: We calculate P/F i.e. PaO2/FiO2. It is known as Potassium may reflect potassium shift in and out of
hypoxemia index. It is the measure of gas exchange. P/F cells related to H+ ion. Each decrease in blood pH of
<300, indicates the development of acute lung injury 0.10, the plasma potassium should rise by 0.6 mmol/L.
(ALI). In the absence of pneumonia and heart failure, This relation is not invariable. Other than the pH, low
progressive diffuse pulmonary infiltration in X-ray chest level of potassium generally means excessive losses
and P/F <200, suggest the acute respiratory distress (gastrointestinal or renal). High level usually means renal
syndrome (ARDS). dysfunction. In critically ill patient free calcium should
Step 10: Calculate the arterial oxygen content (CaO2), be assessed with acid-base disturbances.
particularly when there is anaemia and/or hypoxemia. Step 1: We calculate osmolality.
CaO2 = Hb(gm/L) ×1.34×SpO2/100+0.003×PaO2 Osmolality =
Flow chart 1: Algorithm for decision of cause of hypoxemia
Plasma glucose imbalance or abnormal water handling. So hyponatremia

(mg/dL) BUN (mg/dL) usually reflect excess water and less commonly there is
2 × Na (mEq/L) + +
18 2.8
sodium deficiency. Serum osmolality and volume status
Blood urea (mg/dL) are essential to determine the etiology.
Where BUN =
2.14 Hypernatermia is defined as serum concentration
Normal value of osmolality is 285–300 mosm/kg of >150 mmol/L. In general, hypernatermia reflect
Step 2: We calculate blood volume restricted water intake.
Where there is no anemia or polycythemia, the blood Step 4: Potassium level. Normal value is 3.5–5.0 mmol/L.
volume can roughly be calculated from hematocrit (Hct) Hypokalemia is defined as K + concentration <3.5
value. mmol/L. Hyperkalemia is defined as K+ concentration
Hct = RCC volume >5.0 mmol/L. K+ level >7 mmol/L is significant and can
Whole blood volume be dangerous.
(RCC volume + Plasma volume)
Step 5: Calcium level. Normal value of ionized calcium
RCC volume 2L
So, whole blood volume = = 1.15-1.33 mmol/L.
Hct Hct (%)
Hypocalcemia is defined as Ca ++ concentration
In a normal individual blood volume is 5L and Hct <1.15 mmol/L. Alkalosis decrease the free calcium by
40%, So RCC = 2L. enhancing the binding of calcium. Hypercalcemia is
Step 3: Sodium level. Its normal value is 135–150 mmol/L. defined as Ca++ concentration >1.33 mmol/L. In general
Hyponatremia is defined as serum concentration of kidney do not contribute to hypercalcemia, rather it
<135 mmol/L. Most cases of hyponatremia reflect water defends against the development of hypercalcemia.
Step 6: Chloride level. Normal value of chloride 98–107 When delta gap is added with measured HCO3–, the
mmol/L. sum value should satisfy the normal range of HCO3– i.e.
Its value is low in metabolic alkalosis. It is high in 22–26 mmol/L. If this value is greater than 26 mmol/L it
some form of metabolic acidosis. Value of chloride indicates the additional presence of metabolic alkalosis
generally changes in parallel with plasma Na+. and reduction to less than 22 indicates nonanion gap
metabolic acidosis.
Step 7: Anion Gap (AG). AG is calculated as
AG = [(Na+)+(K+)] – [(Cl–) + (HCO3–)] mmol/L. Step 9: Gap-gap ratio.
+ Gap-gap ratio is calculated in high AG acidosis
Concentration of K must be taken in AG calculation
by anion gap excess (Measured AG-12)/HCO 3– deficit
in the critically ill patients. Normal value of AG is 12 ± 4
(24-measured HCO3–).
(i.e. 8–16) mmol/L. For all purpose of measurement of
If the ratio is <1 means coexistence of non AG
delta gap and gap-gap ratio we consider normal anion
metabolic acidosis or treatment with N/S.
gap as 12 mmol/L.
If the ratio is >1 means coexistence of metabolic
AG increases most often due to increase of
alkalosis or when NaHCO3 is added.
unmeasured anions and less commonly due to decrease
in unmeasured cations. Major unmeasured cations Step 10: Base excess (BE).
are calcium, magnesium and gamma globulin. Major Base excess is defined as the fully ionized acid which
unmeasured anions are negatively charged plasma could be required to return the patient blood pH 7.4
proteins (albumin), sulphate, phosphate, lactate when CO2 has been adjusted to 40 mm of Hg.
and other organic anions. Albumin is the principal BE is determined by Van Slyke equation according to
unmeasured anion and principal determinant of the Zander is
the anion gap. Decreased AG is usually caused by BE = (1 – 0.014.cHb) . [(1.45.cHb + 7.7)
hypoalbuminemia and severe hemodilution. Since the (pH-7.4) – 24.8 + CHCO3–].
hypoalbuminemia is present in as much as 90% of the It is calculated by machine.
ICU patients, the following formula for the “Corrected Otherwise, BE = HCO3– (measured)-24 (Normal value
AG” (AGc) has been proposed to include the contribution of HCO3–).
of albumin. Normally, BE is zero. Positive value indicates
AGc = AG + 2.5 [4.5 – (albumin in gm/dL)] metabolic alkalosis and negative value indicates
metabolic acidosis. BE of ± 5 mmol/L or greater requires
AG should always be calculated for two reasons.
explanation. BE is true reflection of nonrespiratory
1. AG is useful to decide the cause of metabolic acidosis.
component of AB balance.
2. AG ≥20 mmol/L supports a primary metabolic acid–
base disturbance regardless of the pH or serum HCO3–.
Cause of metabolic acidosis has been grouped as
Acid Base Analysis
If a patient has PaCo2 36–45 mm of Hg, HCO3– 22–26
high, normal and low anion gap metabolic acidosis.
mmol/L, pH 7.36–7.44, BE < ± 5 mmol/L and AG <20 then
In a patient all three can be present simultaneously
there is no acid base disorder and thus no need of further
and there can be simultaneous presence of metabolic
analysis for acid base.
alkalosis. To segregate these four, we take the help of
The purpose of acid-base analysis is to identify
Delta Gap, ∆Gap + HCO3–, Gap-Gap ratio and BE of the
the primary disorder, evaluate the compensatory
patient.
response and to decide the disorder as simple or mixed.
Step 8: Delta gap. If mixed, decide the respiratory acidosis or alkalosis
Delta Gap = Patient’s AG – Normal value of AG with metabolic alkalosis and/or metabolic acidosis. If
= Patient’s AG – 12. metabolic acidosis, decide high, non or low anion gap.
Use the “gaps” to evaluate high anion gap metabolic Step 6: Compensatory change of acid-base disturbance is
acidosis for associated nonanion gap metabolic acidosis predicted as indicated in Table 3.
and/or metabolic alkalosis. To conclude we proceed The plasma HCO3– concentration rarely exceeds 45
systematically in the following steps. mmol/L as a result of compensation for respiratory
acidosis. Plasma HCO3– concentration rarely falls below
Step 1: We look for pH and H+ simultaneously and decide
12–15 mmol/L as a result of compensatory respiratory
academia/alkalemia. H+ is derived as stated in accuracy
alkalosis.
of ABG. Normal value of pH as 7.4 and H+ as 40 mmol/L
for all calculation of ABG. A normal pH can be normal, Step 7: In high anion gap metabolic acidosis and/or
compensated or mixed defect. mixed disorder, we take help of Delta Gap + HCO3– and
Gap–Gap ratio to know about associated nonanion gap
Step 2: See HCO 3–. Its normal value is 24 mmol/L for
metabolic acidosis and/or metabolic alkalosis. In mixed
analysis of ABG. It is >24 mmol/L in metabolic alkalosis.
disorder, respiratory acidosis and respiratory alkalosis do
It is <24 mmol/L in metabolic acidosis.
not coexist.
Step 3: See the direction of movement of H+ and HCO3–. If
Step 8: We thus decide the acid-base disturbance and try
they move in the opposite direction–primary metabolic
to search the cause of it in the particular patient.
cause. If they move in the same direction–primary
respiratory cause.
Complete Diagnosis of ABG
Step 4: See PaCO2. This part includes diagnosis of gas analysis, electrolyte
Step 5: See the direction of movement of PaCO2 and analysis and acid-base analysis together. Then etiology
HCO3–. If they move in the same direction–simple cause. is searched and corelated with provisional diagnosis
If they move in the opposite direction–mixed disorder. If and history of the patient. Management is planned
one value is normal–simple cause. accordingly. In critically ill patients, it is also an important
Other ways to know about mixed disorder are: monitor.
–
Know the expected value of PaCO or HCO
2 3 from
Table 3. If expected value and actual value match– CASE HISTORY/
mixed disorder unlikely. If expected and actual value PROVISIONAL DIAGNOSIS
differ–mixed disorder likely. For easy understanding of the method I have taken ABG
In respiratory cause if BE >±5 it is mixed disorder. of five patients admitted in emergency department.
In respiratory cause with AG>20 is also mixed Those are:
disorder.
TABLE 3: Compensatory change in different acid base disorders
Predicted compensation
Metabolic acidosis PaCO2 fall in mm of Hg = 1.2 × HCO3 fall in mmol/L
Metabolic alkalosis PaCO2 rise in mm of Hg = 0.6 × HCO3 rise in mmol/L
Respiratory acidosis Acute HCO3– rise in mmol/L = 0.1 × PaCO2 rise in mm of Hg

Chronic HCO3- rise in mmol/L = 0.35 PaCO2 rise in mm of Hg.
Respiratory alkalosis Acute HCO3– fall in mmol/L = 0.2 × PaCO2 fall in mm of Hg

Chronic HCO3– fall in mmol/L = 0.5 × PaCO2 fall in mm of Hg.
Case 1 Was not taking insulin from last 5 days. Parameters were
A 17 yrs/HM presented in ED with the c/o altered pulse 120/minute, BP 100/60 mm of Hg, RR 32/m SpO2 94%,
sensorium on 19.06.17 and had history of type 1 DM. febrile, diagnosed clinically as a case of diabetic ketoacidosis.
Accuracy of ABG
– –
BE Measured HCO 3 Derived HCO 3 Difference Accurate/not accurate pH H+ Matched/not matched
–16.7 7.3 7.7 -0.4 Accurate 7.286 51.8 Matched
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 mm PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg Hg mm Hg mm Hg mL/L of blood diagnosis
97.1 110.6 128.4 17.8 16.6 526.7 140.50 Hyperventilation Diabetic ketoacidosis
Electrolyte analysis
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/Gap D Gap + HCO3– BE Conclusion
mmol/L mol/L mmol/L mmol/L mOsm/kg Hb(g/ L mmol/L mmol/L mmol/L ratio mmol/L mmol/L
dL)
131.8 1.31 0.484 109.7 263.6 37/10.8 5.41 15.6 - 3.6 3.6/16.7 11.1 –16.7 Hypokalemia
<1 Hypocalcemia
Low osmalality
Normal anion
metabolic acidosis
Acid base analysis

+ –
pH H HCO PaCO2 3 Direction of Primary Direction of Cause Expected Associate Conclusion Complete
mmol/L mmol/L mm of movement cause movement compensatory cause diagnosis
Hg HCO3–/H+ of HCO3–/PaCo2 change in
HCO3–/PaCo2
7.286 51.8 7.7 16.6 Opposite Metabolic Same Simple PaCo2 20.44 Respiratory Non AG Normal AG
PaCo2 value 16.6 alkalosis Metabolic Metabolic Acidosis
Acidosis with Respiratory
Respiratory Alkalosis with
Alkalosis Hypokalemia/
Hypocalcaemia with
hyperventilation
Case 2 year Ganja smoking for 15 yrs, and was working as a cook
A 50 yrs/HM admitted in ED on 02.07.17 with c/o for 10 yrs, diagnosed as a case of pneumonia. Parameters
Breathlessness for 7 days and Fever for 10 days. Had past were Pulse 110/m, BP 110/70 mm of Hg, RR 38/m, SpO2
history of alcohol intake for 10 yrs, Toddy drinking for 1 70%, temp febrile ECG-P-Pulmonale.
Accuracy of ABG
– –
8.6 32.6 35.9 –3.3 Accurate 7.360 43.7 Matched
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg mm Hg mm Hg mm Hg mL/L of blood diagnosis
90 60 72.3 12.3 65 285.7 130.25 Type 2 RF with hypoxemia Pneumonia
due to hypoventilation
and ALI
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/gap D GAP + HCO3– BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb(g/dL) L mol/L mmol/L mmol/L ratio mmol/L mmol/L
112.8 3.62 0.199 80 228.2 49.3/10.8 4.05 0.4 — –11.6 24.3 8.6 Hyponatrimia
Hypocalcemia
Low osmalality
Hypovolemia
Acid base analysis

+ –
pH H HCO PaCO2 Direction of
3 Primary Direction of Cause Expected Associate Conclusion Complete
mmol/L Mmol/L mm of Hg movement cause movement compensatory cause diagnosis
HCO3–/H+ of change in
HCO3–/PaCo2 HCO3–/aCo2
7.36 43.7 35.9 65 Same Respiratory Same Simple HCO3 (Acute 26.5) Metabolic Respiratory Respiratory acidosis and
chronic 32.7 Alkalosis Acidosis with metabolic alkalosis.
HCO 3– value 35.9 Metabolic Type 2 RF with
Alkalosis hypoxemia due to
hypoventilation and
ALI with hyponatremia/
hypocalcemia,
hypoosmolality
and hypovolemia
Case 3 chronic kidney disease for which he was on medication.

A 50 yrs male presented in ED with the c/o decreased He was a diagnosed case of CKD with obstructive
urine output for last 2 months, painful micturation 2 uropathy. Parameters were Pulse 100/m, BP-120/90, RR
months, and backache 2months. He had past history of 22/m, SpO2 98.6% and afebrile.
Accuracy of ABG
BE Measured HCO3– Derived HCO3– Difference Accurate/not accurate pH H+ Matched/not matched
1.8 25.8 22 3.8 Accurate 7.60 25.1 Matched
Gas analysis
99.4 134.2 134.2 0 23 639 159.8 Unnecessary use of O2 CKD
+ + ++ –
Na K Ca Cl Osmality Hct (%)/ Volume AG AGc D Gap Gap/gap DGap + HCO3– BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb (g/dL) L mmol/L mmol/L mmol/L ratio mmol/L mmol/L
121.9 3.92 0.567 96.1 245.3 42.2/12 4.74 7.7 — 4.3 — 26.3 1.8 Hyponatremia
Hypocalcemia
Low osmalality
Metabolic alklosis
Acid base analysis

+ –
pH H HCO 3 PaCO2 Direction of Primary Direction of Cause Expected Associate Conclusion Complete
mmol/L mmol/L mm of Hg movement cause movement compensatory cause diagnosis
HCO3–/H+ of HCO3/PaCo2 change in
HCO3/PaCO2
7.6 25.1 22 23 Same Respiratory Same Simple HCO3 15.5 Metabolic Respiratory Respiratory Alkalosis
Value 22 Alkalosis Alkalosis and and metabolic
metabolic alkalosis with
alkalosis Hyponatremia and
hypocalcemia
Case 4 treatment outside (betnesol, asthalin tab) diagnosed as

A 60 yrs male presented in ED with the c/o shortness of a case of acute exacerbation of COPD. Parameters were
breath for last 2 months, decreased urine output for 18 pulse 110/m, BP 110/70 mm of Hg, RR 24/m, SpO2 99%
hours and he was reformed ganza smoker and was taking afebrile.
Accuracy of ABG
– –
-04 23.6 21.9 1.7 Accurate 7.436 32.6 Matched
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 mm PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg Hg mm Hg mm Hg mL/L of blood diagnosis
99 123.1 123.1 0 29.6 586.4 183.0 mmol/L Unnecessary use of O2 COPD
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/ D Gap + BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb(g/dL) L mmol/L mmol/L mmol/L Gap Ratio HCO3– mmol/L
mmol/L
130.7 2.8% 0.546 106.6 261.5 43.3/13 4.6 5 – –7 –7/2.1<1 14.9 –0.4 Hypocalcemia
Hyponatremia
Metabolic Acidosis
Acid base analysis

+ –
pH H HCO PaCO2 3Direction of Primary Direction of Cause Expected Associate Conclusion Complete
HCO3–/H+ of HCO3–/ change in HCO3–/
PaCO2 PaCo2
7.437 32.6 21.9 29.6 Same Respiratory Same Simple HCO3– 18.8 Metabolic Respiratory Respiratory Alkalosis
acidosis Alkalosis and and NAG
normal AG Metabolic acidosis.
metabolic Hypocalcemia,
acidosis Hyponatremia
Case 5 edema+, absent breath sound in the base, doll’s head sign
A 58 yrs male presented in ED in unconscious state for 1 present diagnosed as a case of hepatic encephalopathy
day, distension of abdomen 1 month, B/L pedal edema with volume overload. Pulse-100/m BP-110/m RR-24/m
20 days. Past history of T2 DM/CLD, O/E jvp+, Ascites+, temp-980 F, SpO2 90%.
Accuracy of ABG
– –
-13 11 10.9 0.1 Accurate 7.457 35 Matched
Gas analysis
88.1 66.1 128.5 62.4 15.7 314.9 6.6 Type 1 RF with shunt/ Hepatic
alveolar filling defect encephalopathy
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/ D Gap+ BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb(g/dL) L mmol/L mmol/L mmol/L Gap ratio HCO3– mmol/L
mmol/L
119.1 5.30 0.599 97.2 240 23.2/5.6 - 16.3 20.05 8.05 8.05/ 18.95 -13 Hyponatremia
13.1<1 Hypocalcemia
Hyperkalemia
Low osmalality
High AG and
Normal AG
Metabolic acidosis
Acid base analysis

+ –
pH H HCO PaCO2
3 Direction of Primary Direction of Cause Expected Associate Conclusion Complete
HCO3–/H+ of HCO3–/ change in
PaCO2 HCO3–/PaCO2
7.457 35 10.9 15.7 Same Respiratory Same Simple HCO3– 11.5 Metabolic Respiratory Respiratory Alkalosis
acidosis Alkalosis and with high AG and NAG
metabolic metabolic acidosis
acidosis with hyponatremia,
hypocalcemia and
hyperkalemia
CONCLUSION tables, graphs and algorithm for reference during

From my obser vation I concluded that if ABG interpretation in the early stage.
interpretation is done by this suggested step-wise If ABG machine is provided in peripheral hospitals
in India and worldwide after a short training of ABG
method, it becomes so simple that it can be analysed
interpretation to the doctors working there, there will be
even by nursing staff within 5 minutes. Analyzed value
improvement in diagnosis, management, referral and
of ABG helps the clinician in diagnosis. ABG also direct
death rate of the patients.
the change in management and helps in monitoring of
This simplification of ABG interpretation will open
the patient in ICU. Analyzed ABG has power to reduce the scope of new research in the field of medicine,
the mortality rate particularly in the patients of mixed pediatrics, gynecology and emergency department.
disorder. This method of ABG interpretation must be added in
all textbooks of Medicine, ICU and Anesthesia.
My Opinion In course of time this method of ABG analysis
ABG analysis must always be done according to the will be known as “rkdas Indian 2017 method of ABG
Proforma and the beginner should keep ready all the interpretation”.
BIBLIOGRAPHY 6. Marino PL, Marino’s The ICU Book, 4th edition, Wolters
1. Brenner and Rector. The Kidney 9th edition, Elsevier Kluwer Health, 2014. pp. 587-98.
Saunders. 2012. pp. 604-37. 7. Rao SM, Nagendranath V. Arterial blood gas monitoring,
2. Coombs M. Making sense of arterial blood gases. Nursing Indian J Anaeth. 2002;46(4):289-97.
Times. 2001;97(27):36. 8. Sood P, Paul G, Puri S. Interpretation of arterial blood gas.
3. Dubin A, Menises MM, Masevicius FD, et al. Comparison Indian Journal of Critical Care Medicine. 2010;14(2):57-64.
of three different methods of evaluation of metabolic acid- 9. Thomas D, DuBose, Jr. Harrison’s Principles of Internal
base disorders. Crit Care Med. 2007;35:1264. Medicine, 19th edition, McGraw Hill Education. 2015. pp.
4. Electrolyte analysis using ABG samples, 2007, Uploaded 315-24.
online in http://www.r tmagazine.com/2007/02/ 10. Wiliams AJ. ABC of oxygen: Assessing and interpreting
electrolyte-analysis-using-abg-samples/. arterial blood gasses and acid-base balance. BMJ. 1998;
5. Field MJ, Burnett L, Sullivan DR, Stewart P. Davidson’s 317:1213-6 Periodical.
Principles and Practice of Medicine, 21st Edition, Churchill
Livingstone Elsevier. 2010. pp. 442-6.
CHAPTER
119
Superbugs in ICU and the Need
for Antibiotic Stewardship
Pankaj Kumar
INTRODUCTION Bacteria produce enzymes which alter the structure

Antibiotics are the cornerstone of modern medicine for or cause lysis of antibiotic. These beta-lactamases are
infections and have saved innumerable lives. They have important determinants of antibiotic resistance. They
brought a major turnabout in the world of medicine. affect the beta-lactam (BL) ring of antibiotics and
Ever-increasing resistance to antibiotics has been degrade penicillins, cephalosporins, carbapenems
reported since 1940s when the bacterial penicillinase and monolactams. More complex beta-lactamases
was first found. Antibiotic use has been associated with have emerged in an effort to combat resistance. They
alarming rise in resistance and has become a public can propagate resistance by horizontal gene transfer.
health concern because of significant cause of mortality. Beta-lactamases can be either early beta-lactamase
which hydrolyze only penicillins. Broad-spectrum
Definition ones hydrolyze modified penicillins, and narrow
Antibiotic resistance is said to be present when microbes spectrum cephalosporins. The extended spectrum
continue to grow in presence of a drug which should beta-lactamases (ESBL) affect third and fourth
either limit its growth or should be lethal to them. generation cephalosporins and monobactams,
but BL inhibitors (BLI) can inhibit them. AmpC
Effects affect cephamycins and cephalosporins and are not
Presence of resistance has resulted in use of more and inhibited by BLI. Carbapenemases (KPC, NDM, OXA-
more antibiotics with increasingly higher doses, with 48) affect carbapenems and are not inhibited by BLI.
higher mortality, morbidity besides also escalating the Target modification: This is responsible for resistance
cost of treatment. to flouroquinolones, aminoglycosides, macrolides,
This is a problem with worldwide implications vancomycin, etc. Naturally occurring enzymes
and has the potential to undo all the progress made by methyl transferase, a natural defense of the organism,
medicine. If an urgent action is not taken, there is real has been found in pathogenic bacteria. These
threat of being pushed to “pre-antibiotic era”. plasmid mediated enzymes can cause resistance to
aminoglycosides, lincosamides, oxazolidinones, and
Mechanisms of Resistance streptogramin A.
One or more of following may result in antibiotic Multidrug efflux pumps: This could be due to
resistance: altered porin channels through which drug enters
CHAPTER 119: Superbugs in ICU and the Need for Antibiotic Stewardship 717
the bacterial cell. Alternately, efflux pumps could Some Important Nosocomial
be activated and cause efflux of antibiotic from Pathogens Seen in ICU
the bacterial cell. These mechanisms can cause
There are several organisms which are extremely difficult
resistance to fluoroquinolones, macrolides, and
to treat due to their resistance profiles and are the new
aminoglycosides.
superbugs in intensive care unit. These include ESKAPE
Production of biofilms: These are collection of one or
pathogens namely Enterococcus faecium, Staphylococcus
more species of bacteria enmeshed in extracellular
aureus, Klebsiella pneumonia, Acinetobacter Baumaanii,
matrix. All foreign bodies whether endotracheal
Pseudomonas aeruginosa, and Enterobacter species,
tubes or catheters could acquire a biofilm. Antibiotics
which account for majority of the nosocomial infections
may not be able to penetrate biofilms. So eventhough
and consequent increased morbidity and mortality of
bacteria may be sensitive to antibiotics, the immune
hospitalized patients.
cells and antibiotics are unable to penetrate deeper
In India, Gram-negative organisms are responsible
and hence cannot kill them.
for majority of the nososcomial infections. They possess
Large inoculums: Antibiotics may be rendered
multiple mechanisms for antibiotic resistance. E. coli
ineffective, if large number of bacteria infect a
and Klebsiella are most common and produce ESBL.
patient. They may produce increased quantity of
Porin channel loss and multidrug efflux pumps may also
hydrolyzing enzymes.
be present. Klebsiella is further equipped with Plasmid-
Genetic Transmission of Bacterial Resistance mediated carbapenemases such as KPC and NDM
The resistance could develop as a result of mutations make Klebsiella resistant. Acinetobacter Baumaanii,
( vertical transmission dependent) or may be due to Pseudomonas aeruginosa, and Enterobacter species too
mobile genetic elements (horizontal transmission). are less amenable to antibiotics because of thick cell wall.
These may then be passed on to bacteria of same species The resistance is further compounded, if plasmids too
as well as other species. Plasmids are one of the most are acquired.
important causes of development of antibiotic resistance. Polymyxins are being used again due to emergence
These are extrachromosomal genetic materials, capable of resistance but Serratia, Proteus and Providencia are
of multiplying in bacterial cytoplasm independent of inherently resistant to these. Tigecycline has no activity
bacterial DNA. Their resistance genes (r-genes) are against Pseudomonas, Proteus and Providencia. It is
easily exchanged or transferred between plasmids and bacteriostatic and not much effective in bloodstream and
chromosomes. Integrons are bigger DNA sequences urinary infections.
which are packed with gene cassettes. Each cassette Gram-positive organisms are more permeable
then has small recognition site with a r-gene attached to antibiotics. However, Enterococcus is inherently
to it. These integrons are distributed in environment resistant to certain antibiotics such as penicillin and
and are not mobile, but crucial for transfer of r-genes. aminoglycosides. Enterococcus faecium is also emerging
Transposons are DNA sequences which are associated as resistant organism because of resistance to BL
with the genome of a bacterial cell and are also called antibiotics and vancomycin due to B-lactamases and Van
as “jumping genes”. Plasmids can integrate a transposon A mutations especially in bloodstream infections and
and pass it on to other plasmids or to the chromosome of endocarditis. A virulent organism, Staphylococcus aureus
the bacteria. causes necrotizing infections. Methicillin-resistant
Genetic material could be transferred between Staphylococcus aureus (MRSA) is one of the most
bacteria by either conjugation, transduction or dangerous organisms associated with resistant infections
transformation. and have been reported from community as well.
Antibiotic Resistance Threat in India Using alternates to antibiotics: Though several alternatives
Several factors have contributed to widespread resistance are being explored, none have reached the stage of being
in India: marketed and accepted as standard therapy. Inhibitors
Excessive indiscriminate use of antibiotics: Antibiotics
of quorum sensing, antibodies, phage therapy, Lysins,
are increasingly being prescribed over the counter agents to target type IIa topoisomerases, antimicrobial
and used for even viral or non infective conditions. peptides or lipopeptides, efflux pump inhibitors are
Prolonged duration of intake, sometimes in being evaluated for possible future use.
suboptimal dosage or usage as part of multiple
antibiotic regime has further compounded the
Antimicrobial Stewardship Program
problem. A robust antimicrobial stewardship program must
Quality of antibiotic: With no quality checks in place,
be in place in every hospital to ensure judicial use
the spurious drugs are also available. of antibiotics. It should include timely and optimal
Indiscriminate use in agriculture, poultry and
selection of antibiotic with optimal dose and duration for
meat industry too has lead to antibiotic resistance the best clinical outcome for the treatment or prevention
developing in mass population. of infection with minimum possible toxicity to the patient
and minimum impact on resistance and other ecological
How to Tackle this Problem? adverse effects. Centres for Disease Control has defined
the core elements of an antimicrobial stewardship
There is an urgent need to control this looming threat
program as follows:
about antibiotics and it needs commitment from all
quarters of society. Clinicians, microbiologists, hospital Committed leadership: Dedicating necessary human,
administrators, pharmacologists, drug manufacturers, financial, information technology resources.
policy makers, government and drug controllers need to
Accountability: Appointing a single leader ( ideally a
come together to overcome this menace.
physician) responsible for program outcomes.
Judicial use of antibiotics: In view of absence of new
Drug expertise: Appointing a single pharmacist leader
antibiotics and molecules, there is no way except
responsible to improve antibiotic use.
to prolong life of current antibiotics. Guidelines for
antibiotic use need to be strictly adhered to for achieving Action: systemic evaluation of ongoing treatment need,
this goal. Right patient, right drug, right dose for correct after a set period of initial treatment.
duration and appropriate e-escalation are few cardinal Tracking: Monitoring antibiotic prescribing and
principles. resistance patterns.
Newer Interventions Reporting: Regular reporting information on antibiotic

use and resistance to doctors and staff.
Role of microbiology laboratory: A rapid method of
diagnosis of infections to cut the need to start empirical Education: educating physicians about resistance and
antibiotics is extremely desirable but sadly elusive. optimal prescribing.
Biomarkers like C-reactive proteins and procalcitonin are Stewardship programs and enforcement varies
of limited value. Recent automated systems for culture significantly at different institutes. There is a need
are helpful for early reports. Molecular diagnostics such to develop and implement uniform criteria and
as polymerase chain reaction, matrix-assisted laser requirements for prevention and control of infections.
desorption, mass spectroscopy and next generation The need of the hour is to implement corrective measures
sequencing have potential to revolutionize diagnostics, early and effectively to reduce healthcare-associated
but are currently very expensive. infections.
CHAPTER 119: Superbugs in ICU and the Need for Antibiotic Stewardship 719
BIBLIOGRAPHY 2. Hollenback BL, Rice LB. Intrinsic and acquired resistance

1. Harris PNA, Tambyah PA, Paterson DL. Beta-lactam mechanisms in enterococci. Virulence. 2012;3:421-569.
and beta lactamase inhibitor combinations in the 3. Nathwani D. Antimicrobial Stewrdship In: mayhall GC (Ed).
treatment of extended spectrum beta lactamse producing Hospital epidemiology and infection control. 4th edn.
enterobactereiaceae: time for a reappraisal in the era of few Philadelphia: Lippincott, Williams and Wilkins; 2012.
antibiotic options? Lancet Infect Dis. 2015;475-85. 4. Santajit S, Indrawattana N. Mechanisms of antimicrobial
resistance in ESKAPE pathogens. Biomed Res Int. 2016;
2016:2475067
CHAPTER
120
Perioperative Management in Diabetes
Pramod Kumar Sinha
INTRODUCTION and nearly two fold rise in incidence of myocardial

Diabetes is one of the most common metabolic disorder, infarction and acute kidney injury.
globally 422 million adults were suffering in 2014
according to latest 2016 data from WHO and its prevalence FACTORS CAUSING
is increasing rapidly. 65.1 million–8.56% affected in ADVERSE OUTCOME
India, expected to rise to 87 million by 2030. Patient with Failure to detect patients with diabetes or hyper
diabetes are more likely to require hospital admission for glycemia: Slightly more than a third of diabetics
conditions other than diabetes and 25% needs surgical undergoing surgery remain undetected or untreated
intervention. In fact, 10–15% of the surgical patients before operative procedure or admission to the
are found to suffer diabetes or hyperglycemia and they intensive coronary unit. Clinician must keep vigiant
have higher complication rates and longer hospital stay to properly detect diabetics, glucose intolerance,
resulting in up to 50% greater perioperative mortality rate insulin resistance, and associated pathology of
than nondiabetic population. Study have clearly revealed diabetes.
that high preoperative and perioperative blood sugar and Associated hypo- and hyperglycemia: The 2013
glycated hemoglobin-HbA1c are associated with higher NIDS reported that nearly 22% percent of patients
risk of adverse surgical outcomes and better control of surgical ward suffered hypoglycemic episode
reduces the risk. Thus, management of diabetes remains accounting for increased mortality. Recognizing the
a vital element in surgical workup however many a times neurological features of hypoglycemia while a patient
diabetes in perioperative situation is managed in an ad- is under general anesthesia or when given sedatives/
hoc fashion or sometimes becomes a forgotten element analgesics postsurgery is difficult, potentially leaving
in perioperative package. the hypoglycemic situation undetected for a critical
period of time culminating many a times in a bad
RISKS OF POOR outcome. DKA sometimes occurs on surgical wards
DIABETIC CONTROL and can result in postsurgery death however careful
Frisch A et al. in one study showed that poor perioperative vigilance could prevent the sad happening.
diabetic/hyperglycaemic control leads to almost—2–3 Multiple comorbidities including microvascular and
fold increase in the incidence of postoperative infection macrovascular complications, and hypertension.
(respiratory, urinary tract and surgical wound infection) Postsurgery myocardial ischemia shows increased
CHAPTER 120: Perioperative Management in Diabetes 721
incidence among diabetic patients undergoing The surgical trauma leads to higher production of
cardiac or noncardiac surgery. Patients having cardiac stress hormones, the amount of which parallels the
and/or kidney disease are at greater risk of fluid severity of operation or any postsurgery complications.
overload. Presence of autonomic neuropathy causes It also inhibits anabolic hormone especially insulin.
higher risk of postoperative postural hypotension, In patients without DM this can cause transient
cardiac arrhythmia and delayed gastric emptying. hyperglycemia, but in the diabetic patients, insulin
Postural hypotension may precipitate AKI in those production is already marginalized so the metabolic
with kidney disease. Neuropathy affects nearly changes causes marked catabolic state requiring careful
30–50% of people placing them at increased risk attention. Many of the anesthetic drugs also have
of heel ulceration and delayed wound healing, variable effect on glycemic control so needs proper
specially if PVD is also present. Current evidence consideration.
suggests that many a times high risk patients are
not identified before surgery with a failure to ensure PRINCIPLES AND TARGET OF
proper perioperative interventions.
PERIOPERATIVE MANAGEMENT
Increased perioperative infection: Hyperglycemia
To optimize the diabetic management especially
impairs leukocytic activity including impaired
targeting HbA1c <8.5% (69 mmol/mol) prior to
chemotaxis and phagocytic function thereby
surgery and identification with optimization of
increasing infection which accounts for 65% of
comorbidities. So postpone elective surgery if
postoperative complications and nearly 25% of
possible when glycemic control is poor (HbA1c
perioperative deaths in patients with diabetes
mellitus. >8.5%).
Er ro r s i n i n su l i n p re s c r i p t i o n a n d c o mpl e x
To maintain electrolyte level within normal range and
polypharmacy: Patients having diabetes many optimize intraoperative kidney and cardiovascular
a times require or are already on multiple drug function, to use appropriate anesthetic agent, IV
regimens with high probability for mistakes. Many a fluids, analgesics and minimally invasive techniques
times drugs are omitted in error or judicially stopped to lessen postsurgery pain and gut dysfunction
and never started, sometimes drugs are continued thereby facilitating early return to normal diet.
inappropriately. Insulin being one of the top listed Plan for rapid mobilization and discharge with early
high alert medicine needs proper and careful use, it return to usual diabetic management and normal
could be life saver but with probability of becoming activities.
life threatening if proper care not taken. To maintain CBG target of 6–10 mmol/L (upto
Absence of institutional guidelines for perioperative 12 mmol/L acceptable), presently lower limit of
care of diabetes and untrained staff in this regard. 8 mmol/L is considered better during perioperative
period.
METABOLIC RESPONSE TO SURGERY Hypoglycemia (<6 mmol/L) must be avoided,
AND ANESTHESIA AND THE EFFECT patient must be made sensitive of the hypoglycemic
OF DIABETES symptoms.
Surgery frequently requires starvation period and
also causes trauma to the system. Starvation leads to PREOPERATIVE MEASURES
a catabolic state which can be managed in diabetics Patient should ideally be optimized at the primary
by insulin and glucose infusion -180 g/day, however level and then should be sent to surgery outdoor with
if starvation period is short e.g. only one meal missed, important data like type and duration of diabetes,
patient can be managed without insulin infusion. comorbidities and complications present with their
present status, treatment patient is taking and his BMI, needs longer starvation period, emergency operation or
blood pressure, current blood glucose and HBA1c level. when glycemic level is keeping outside the target range.
Once surgery is decided, arrangement for preoperative Patient with diabetes should be prioritized on the
assessments needs to be made soon possible to optimize surgery list and be kept 1st in the morning so as to cause
the patient. Patient should be admitted on the day of least disturbance to the normal dietary routine
operation Diabetes specific preadmission needs to be
avoided.
INTRAOPERATIVE MANAGEMENT
Preoperative assessment aims for current blood The day case surgery and patient with diabetes on
only dietary therapy could be managed by proper
glucose parameters with HbA1c, blood urea and serum
manipulation of the patients normal medication and the
electrolytes and ECG for all patients with diabetes
diet.
and specific investigation as required for present and/
Use of variable rate intravenous insulin infusion
or expected comorbidities beside general routine
(VRIII) are preferred-in those who needs longer period of
investigation. If HbA1c >8.5% and/or comorbidities are
starvation; patients having type 1 diabetes and have not
found not to be optimized, elective surgery if feasible
received background insulin; those with poorly managed
should be delayed.
DM (HbA1c >8.5%) and nearly all patients with diabetes
Planning admission—It is advised to ensure norm-
requiring emergency surgery. Its use however needs
oglycemia (CBG: 6–10 mmol/L) before admission and
experienced staff (Table 3).
the patient is also asked for adjustment of existing therapy
Conventional glucose-insulin-potassium (GIK)
during perioperative period as per the requirement that infusion may be used in these situation. This provides
is whether patient is fit for day case surgery needing a safe substrate with coadministered insulin and is well
short starvation period or needs IV glucose/insulin supported by evidence.
consideration. (Tables 1 and 2).
Patient fit for day case surgery are those who requires MEASURES DURING SURGERY
short starvation period (less than 12 hrs) missing only Before induction of anaesthesia, CBG (capillary blood
one meal and is well controlled (HbA1c <8.5%). Patients glucose) should be checked and there after regularly-
needs inpatient surgery who are not well controlled, hourly or more frequently-during the procedure. If CBG
TABLE 1: Perioperative adjustment of insulin–An overview

Usual routine insulin Measures to be Measures to be taken on day of surgery
schedule of the patient taken on day Morning surgery Afternoon surgery If needs VRIII
before surgery
Once evening dose daily Cut the dose zz Measure blood glucose on admission 80% of usual
by 20% dose should be
Once morning dose daily Cut the dose by zz Lessen the dose by 20% continued
20% zz Measure blood glucose on admission
Two daily injections Usual dose zz Half of the usual morning dose should be given Needs to be
continued zz Measure blood glucose on admission stopped until
zz Keep the evening dose unchanged patient starts
Two daily Usual dose zz Half of the total dose of morning insulin should be given as eating and
Separate injections continued intermediate insulin in the morning drinking normally
of short acting and zz Measure blood glucose on admission
intermediate acting zz Keep the evening dose unchanged
Daily 3, 4 or 5 doses Usual dose Basal bolus regimen: zz Give usual morning
continued zz Leave morning and lunch time dose dose
zz Cut the basal by 20% if taken in the morning zz Drop the lunch dose
CHAPTER 120: Perioperative Management in Diabetes 723
TABLE 2: Perioperative adjustment of noninsulin medicine: An overview

Tablets being taken by the Measures to be taken Day of surgery
patient before day of admission Morning surgery Afternoon surgery If needs VRIII
Acarbose Leave morning dose Morning dose
and if NBM given if eating
Meglitinides
Sulphonylureas Leave morning dose Leave both morning zz Stop all the drugs except
and evening dose GLP1 once VRII commenced
Metformin Usual dose continued If taken once or twice daily – take as normal
zz Do not restart until patients
(If eGFR >60/mL/min/1.73 m2) If taken thrice daily, omit lunch time dose begins eating and drinking
normally
Pioglitazone Usual schedule maintained
DPP4 inhibitor Usual schedule maintained
GLP1 analogue Usual schedule maintained
SGLT-2 inhibitor Drop on the day of surgery
In accordance with recent guidelines
TABLE 3: Use of variable rate intravenous insulin infusion (VRIII)

Glucose (mmol/L) Insulin rates (mL/hr) 1 mL = 1 unit
Standard rate (begin on standard rate Reduced rate (for use in patients who Increased rate (for use in patients who
unless indicated) are insulin sensitive) are insulin resistant)
If basal insulin not If basal insulin If no basal If basal insulin If no basal If basal insulin
used continued insulin continued insulin continued
<4 0.5 mL/hr 0 mL/hr and 0.2 mL/hr 0 mL/hr and 100 cc 0.5 mL/hr 0 mL/hr and 100 cc IV
and 100 cc IV 20% 100 cc IV and 100 cc IV IV 20% glucose and 100 cc IV 20% glucose
glucose 20% glucose 20% glucose 20% glucose
4.1–6 0.5 mL/hr 0 mL/hr and 50 cc 0.2 mL/hr 0 mL/hr and 50 cc IV 0.5 mL/hr 0 mL/hr and 50 cc IV
and 50 cc IV 20% IV 20% glucose and 50 cc IV 20% glucose and 50 cc IV 20% glucose
glucose 20% glucose 20% glucose
6.1–8 1 0.5 2
8.1–12 2 1 4
12.1–16 4 2 6
16.1–20 5 3 7
20.1–24 6 4 8
>24.1 8 6 10
>24.1 Check whether insulin is running or not and whether measurement of blood sugar is correct or not
exceeds 12 mmol/L and is not on insulin, DKA should But then if someone with type 1 diabetes is on insulin
be looked for and managed as medical emergency if infusion, it must not be stopped unless subcutaneous
present. Otherwise increased blood glucose should be insulin has been given. Management of hyperglycemia
lowered by giving additional subcutaneous insulin or in a patients with type 1 diabetes-SC rapid acting insulin
by using a VRIII if two subcutaneous (SC) insulin fails analogue up to a maximum of 6 IU should be given,
to work or by changing the rate of VRIII if already in assuming that 3 mmol/L of CBG will drop with 1 IU. A
use. However, VRIII should not be used unnecessarily. second dose should be planned only after 2 hrs.
Management of hyperglycemia in a patient with type POSTOPERATIVE MANAGEMENT

2 diabetes–SC rapid-acting insulin analogue 0.1 IU/kg up Postoperative hyperglycemia (CBG >12 mmol/L) is
to a maximum of 6 IU should be given, 2nd dose planned managed in similar fashion by subcutaneous rapid
only after 2 hours. A VRII OR GKI should be planned if acting insulin and hypoglycemia by 20% glucose IV. Once
the patient continues to be hyperglycemic. the patient recovers and is able to eat and drink, return
Treatment of intraoperative hypoglycemia requires to normal preoperative medication planned with careful
intravenous 20% glucose, amounts depends upon attention–the change to subcutaneous insulin from
severity of hypoglycemia. insulin-glucose infusion should take place when the next
meal related dose is expected e.g. with lunch or breakfast
Care of Fluid and Substrate and 30–60 minutes overlap time must be given
For patients on VRIII, 5% glucose in saline, 0.45%
premixed with either potassium chloride 0.15% (20
CONCLUSION
Perioperative morbidity and mortality is very high in
mmol/L) or 0.3 (40 mmol/L) depending on the presence
diabetics as compared to nondiabetics so meticulous
of hypokalemia is a good choice and infused at a rate of
management required, regular monitoring of CBG
83–125 cc/hr by a separate volumetric pump with insulin
remains the most important element. Diabetes should
from syringe pump though one IV cannula.
be optimized to keep HbA1c <8.5% and also the
For patients on GKI infusion, 500 cc 10% glucose and
comorbidities especially cardiac and renal should be
0.15% KCL is used with insulin as per need-5 units if CBG
optimized before elective operation. Perioperatively
level <6 mmol/L, 10 units if CBG 6–10 mmol/L; 15 units
CBG level around 6–12 mmol/L is acceptable but level
if CBG 10–20 mmol/L; 20 units if CBG is > 20mmol/L’–all
7.4–11 mmol/L (140–200 mg/cc) is better.
at the rate of 100–125 cc/hr and with additional 0.9%
saline through another cannula if hyponatremia present. BIBLIOGRAPHY
To optimize intravascular volume status Ringer lactate 1. JBDS–IP–relevant topics revised up to 2016 are available
remains a good choice. online.
CHAPTER
121
Hospital Acquired Infections
Piyush Jain
INTRODUCTION TABLE 1: CDC criteria for nosocomial pneumonia
Hospital acquired infections (HAI) or nosocomial Pneumonia must meet one of the criteria (only in patients >12
months of age)
infections are defined as infections which are not present
zz Rales or dullness to percussion on chest examination and one of
at the time of hospital admission and develop after 48
the following:
hours of admission or even after discharge from hospital. —— new onset of purulent sputum or change in character of
The incidence of HAI has increased considerably over sputum;

—— organism isolated from blood culture;
recent years. They add to the huge cost of hospitalization
—— isolation of pathogen from specimen obtained by
and also increase hospital stay leading to loss of work
transtracheal aspirate, bronchial brushing or biopsy.
hours. Nosocomial infections are commonly exogenous, zz Chest radiographic examination shows new or progressive
the source being any part of the hospital ecosystem, infiltrate, consolidation, cavitation or pleural effusion and any of
including people, objects, food, water, and air in the the following:
—— new onset of purulent sputum or change in character of
hospital.
sputum;
The common nosocomial infections are: —— organism isolated from blood culture;
Hospital acquired pneumonia (HAP) —— isolation of pathogen from specimen obtained by
Catheter associated urinary tract infection (CAUTI) transtracheal aspirate, bronchial brushing or biopsy;
—— isolation of virus or detection of viral antigen in respiratory
Catheter related blood stream infection (CRBSI)
secretions;
Nosocomial surgical site and soft tissue infection
—— diagnostic single antibody titer (IgM) or four-fold increase in
(SSI). paired serum samples (IgG) for pathogen.

Around 10–30% patients in India have nosocomial
infections compared to 5–15% in most developed agents which are absent or incubating at the time of
nations. CA-UTI is the most common infection around hospital admission; that is, conditions that develop after
28% followed by HAP. But the HAP/VAP has highest 48 h of hospital admission (Table 1).
mortality rate. HAP has been further classified as:
Nosocomial pneumonias that develops in patients
NOSOCOMIAL PNEUMONIA admitted in wards

Hospital acquired pneumonia (HAP) is defined as an That develops in patients admitted in intensive care
inflammation of the lung parenchyma due to infectious unit (ICU) (ICU HAP).
If HAP occurs in initial 96 h of hospital admission it TABLE 2: Treatment for ventilator associated pneumonia (VAP)
is called ‘early-onset’ and termed ‘late-onset’ if it occurs Gram-positive Gram-negative Gram-negative
after 96 h of hospital admission. antibiotics with antibiotics with antibiotics with
Ventilator associated pneumonia (VAP) is a type MRSA activity antipseudomonal antipseudomonal
activity: β-lactam– activity: Non-β-lactam–
of HAP, diagnosed in patients who are on mechanical based agents based agents
ventilation at the time of infection. About 86% of all
Vancomycin 15 Piperacillin– Fluoroquinolones
ICU HAP are ventilator associated pneumonia. The mg/kg IV q8–12h tazobactam 4.5 g Ciprofloxacin 400 mg
American Thoracic Society criteria for the diagnosis of IV q6h IV q8h
VAP are pneumonia in a patient mechanically ventilated Levofloxacin 750 mg
IV q24h
for greater than 48 h with at least two of the following
OR OR OR
criteria:
Fever Linezolid 600 mg Cefepime 2 g IV q8h Aminoglycosides
IV q12h Ceftazidime 2 g IV zz Amikacin 15–20 mg/
Leukocytosis or leukopenia
q8h kg IV q24h
Purulent tracheal secretions. zz Gentamicin 5–7 mg/
In addition, one or more of the following criteria must kg IV q24h

also be met: OR OR
New or persistent infiltrates on chest radiographs Imipenem 500 mg IV Polymyxins,
The same microorganism isolated from pleural fluid q6hd Meropenem 1 Colistin 5 mg/kg IV × 1
g IV q8h (loading dose) followed
and tracheal secretions
by 2.5 mg × (1.5 × CrCl
Or radiographic cavitation or histopathological
+ 30) IV q12h
demonstration of pneumonia and positive cultures Polymyxin B 2.5–3.0
obtained from bronchoalveolar lavage (BAL) (greater mg/kg/d divided in 2
daily IV doses
than 104 CFU/mL).
OR
DIAGNOSIS Aztreonam 2 g IV
q8h
Bi o ma rk e r s s u c h a s s e r u m p ro c a l c i t o n i n a n d
bronchoalveolar fluid level of soluble triggering receptor
expressed on myeloid cells (STREM-1) have been found studies as MDR or late onset pathogens are also present
to be useful in diagnosing nosocomial pneumonias. in the culture of early onset group of HAP/VAP.
However, the recent IDSA guidelines for treatment of
VAP recommend use of clinical criteria alone rather than TREATMENT
biomarker (serum PCT or STREM-1) plus clinical criteria Treatment of HAP/VAP should be based on the common
for decision on initiation of antibiotics. organisms isolated and the resistance pattern observed
in the ICU and wards at the individual hospital and
CAUSATIVE ORGANISMS local antibiogram and antibiotic guidelines should be
Methicillin-sensitive Staphylococcus aureus (MSSA), S. generated.
pneumoniae, and Haemophilus spp. as early-onset Emperical treatment of clinical suspected VAP/HAP
pathogens and P. aeruginosa, MRSA (methicillin- should include coverage for S. aureus (MRSA is quite
resistant Staphylococcus aureus), Enterobacter spp., prevalent), Pseudomonas aeruginosa, and other gram
Acinetobacter spp., and S. maltophilia as late-onset negative bacilli (Table 2).
pathogens. It is recommended to use two antipseudomonal
But this distinction of early onset and late onset HAP antibiotics from different classes for treatment of
on the basis of microbes has been challenged in recent suspected VAP/HAP in high risk patients for MDR such
CHAPTER 121: Hospital Acquired Infections 727
as patients on prior antibiotics, septic shock, ARDS, >4 catheterization and it depends on the indication for
days of hospitalization or on dialysis. catheterization such as:
Empirical therapy in nonventilated HAP patients 1. Surgery, 2. Urine output measurement, 3. Urine
without high risk factors includes vancomycin (or retention and 4. Urinary incontinence.
linezolid) plus any one of piperacillin-tazobactem/ Most bacteriuria in short-term catheterization is
fluroquinolones/carbapenems/ceftazidime or cefepime. of single organism most commonly Escherichia coli.
In case of high risk of mortality or MDR pathogens Others include Pseudomonas aeruginosa, Klebsiella
aminoglycosides should be added to above regimen. pneumoniae, Proteus mirabilis, Staphylo co ccus
epidermidis, enterococci, and Candida species.
PREVENTIVE MEASURES Long-term catheterization is associated with
General aseptic techniques polymicrobial bacteriuria with common uropathogens
Application of general infection control measures such as E. coli, Klebsiella and others organisms like
Judicious antibiotic use Providencia stuartii.
Semirecumbent patient positioning
Oral endotracheal tube
DIAGNOSIS
Oral gastric tube CAUTI in patients with indwelling urethral, suprapubic,
Aseptic tracheal suctioning-closed circuit suctioning or intermittent catheterization is defined by the presence
Avoiding unplanned extubation of symptoms or signs compatible with UTI with no other
identified source of infection along with >10 3 colony
Less frequent ventilator tube changing.
forming units (cfu)/mL of 1 bacterial species in a single
catheter urine specimen or in a midstream voided urine
NOSOCOMIAL URINARY TRACT
specimen from a patient whose urethral, suprapubic, or
INFECTIONS
condom catheter has been removed within the previous
The most common hospital acquired infection is
48 h.
nosocomial urinary tract infection (UTI) and is generally C A-ASB (Catheter associated-asymptomatic
associated with urinary tract catheterization. bacteuria) is defined by the presence of >105 cfu/mL of 1
bacterial species in a single catheter urine specimen in a
Pathogenesis patient without symptoms compatible with UTI.
Insertion of a catheter may carry urethral organisms Signs and symptoms suggestive of CAUTI include
into the bladder. fever (it may be new onset or worsening of pre-existing
The drainage tube of the urine collecting bag may be
fever), chills and rigors, altered sensorium, generalized
contaminated with bacteria that can ascend the bag weakness; flank pain; tenderness over renal angle;
and catheter. hematuria; pelvic discomfort. In patients where catheters
Even in a closed system, the bacteria can enter the
have been removed, symptoms include dysuria, frequent
bladder directly through the space present between urination and suprapubic pain or tenderness.
the external catheter and the mucosal wall of urethra In the catheterized patient, pyuria is not diagnostic of
and this is the most common route for bacterial entry. CAUTI and the presence or degree of pyuria should not
A biofilm is formed over the drainage bags, catheter be used to differentiate CA-ASB from CAUTI.
and even uroepithelium which provide a favorable
microenvironment for growth of bacteria. TREATMENT
The most important risk factor for the development Unnecessary catheterization should be avoided.
of catheter-associated bacteriuria is the duration of All efforts should be made to reduce inappropriate
urinary catheter insertion and minimize the duration of A short term catheter (<14 days) is commonly
catheterization. colonized along the external surface of catheter from a
Screening and treatment for CA-ASB is not re skin microbe, therefore, the roll-plate culture method
commended in general, except in pregnant women and is highly sensitive. Whereas in long-term catheters
patients who undergo urologic procedures. (>14 days) the bloodstream infection occurs due to the
Treatment for CAUTI is with broad spectrum intraluminal spread of microbes from the catheter hub.
antibiotics such as piperacillin-tazobactam with or A definitive diagnosis of CRBSI is made when there
without aminoglycosides or as per the culture reports is a positive percutaneous blood culture along with
and resistance pattern. Seven days of antibiotic treatment concordant microbial growth from the tip of catheter or
is recommended for patients who shows good response catheter-drawn blood cultures.
to antibiotics, and in others treatment should continue
for 10–14 days. TREATMENT
The empirical treatment is with vancomycin (linezolid
CATHETER RELATED BLOOD STREAM in proven cases but not suspects) and coverage for
INFECTION gram negative bacilli with either of a fourth-generation
The use of intravascular devices and catheters have cephalosporin, carbapenem, or β-lactam/β-lactamase
increased considerably over recent times for therapeutic combination, with or without an aminoglycoside.
and monitoring patients such as peripheral arterial line, In patients with neutropenia or severe sepsis CRBSI
central venous catheters, pulmonary arterial catheters. should be empirically treated with combination antibiotic
The risk of bloodstream infections due to catheters covering gram negative bacilli such as Pseudomonas
depends on the type of intravascular device, the site of aeruginosa.
insertion, intended use for the catheter, the duration, on In certain high risk patients, suspected to have
how frequently the catheter is accessed, the preventive candidemia, antifungal such as echinocandin or
measures followed and the patients characteristics. The flucanazole should be added empirically. These includes
most infections occurs either from the site of catheter patients on total parenteral nutrition, hematologic
insertion or hub of catheter, or both. malignancy, on broad-spectrum antibiotics for long
I n n o n c u f f e d p e rc u t a n e o u s c a t h e t e r s, t h e duration, recipients of bone marrow or solid-organ
commonly associated microbes are: coagulase-negative transplant, femoral catheterization, or colonization of
staphylococci, S. aureus, Candida species, and enteric Candida species at multiple sites.
gram-negative bacilli. Removal of long term catheters should be considered
For surgically implanted catheters and peripherally in patients with CRBSI associated with : severe
inserted CVCs, they are coagulase-negative staphylococci,
sepsis; endocarditis; suppurative thrombophlebitis;
enteric gram-negative bacilli, S. aureus, and P. aeruginosa.
bloodstream infection persisting even after >72 h of
culture sensitive antimicrobial therapy; or infections
DIAGNOSIS
with S. aureus, P. aeruginosa, fungi, or mycobacteria.
Fever is a common presentation. Patient should be
Short-term catheters should be removed in patients
examined for any signs of local inflammation or pus
discharge around the catheter insertion site. with infections due to gram-negative bacilli, S. aureus,
The suspicion for catheter related blood stream enterococci, fungi, or mycobacteria.
infection (CRBSI) is high if no other source of infection
is identified, and the blood cultures are positive for NOSOCOMIAL SURGICAL SITE AND
organisms commonly associated with CRBSI, as SOFT TISSUE INFECTION
mentioned above. If within 24 hrs of catheter removal, SSI can be superficial involving only skin and
the symptoms improve, it is suggestive of CRBSI. subcutaneous tissue, or deep SSIs involving fascia and
CHAPTER 121: Hospital Acquired Infections 729
muscle with or without superficial extension. Superficial piperacillin/tazobactam, fluoroquinolone (ciprofloxacin,

SSIs occur within 30 days of a surgical operative incision. levofloxacin) or cefepime is indicated.
Deep SSIs usually occur within one month if no implant/
prosthesis used or within 1 year in presence of implant. CONCLUSION
These are diagnosed by purulent discharge, presence of HAI can be prevented to a large extent by observing
signs of local inflammation and culture of organism from standard safety precautions and maintain asepsis. Also
the site. the judicious use of antibiotic can help in decreasing
The majority of SSIs are caused by skin commensals, the drug resistance and early discharge of patient.
usually S. aureus and coagulase-negative staphylococci Monitoring and surveillance for nosocomial infections is
(CoNS). The resistant organisms such as methicillin- required to control the morbidity and mortality with HAI.
resistant S. aureus (MRSA) or Gram negative organisms,
Klebsiella spp., Enterobacter spp, Pseudomonas spp, etc. BIBLIOGRAPHY
are seen in patients with high risk. 1. Dasgupta S, Das S, Chawan NS, Hazra A. Nosocomial
infections in the intensive care unit: Incidence, risk factors,
Factors responsible for wound infection include:
outcome and associated pathogens in a public tertiary
type of surgery, anesthesia, wound drains, extent of teaching hospital of Eastern India. Indian Jrnl Critic Care
tissue damage, blood loss, preoperative preparation, Med. 2015;19(1):14-20.
postoperative care and host factors such as age, 2. Hooton TM, Bradley SF, Cardenas D, et al. Diagnosis,
immunity, co-morbid illness, nutrition, etc. prevention, and treatment of catheter-associated urinary
tract infection in adults: 2009 International Clinical Practice
Guidelines IDSA Clin Infect Dis. 2010;50(5):625-63.
MANAGEMENT 3. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney
Management includes wound debridement and pus D, Palmer LB, et al. Management of adults with hospital-
culture from the site. The source of infection should be acquired and ventilator-associated pneumonia: 2016
Clinical Practice Guidelines. Clin Infect Dis. 2016;63:575-
searched.
82.
If the SSI is superficial and without systemic sepsis, 4. Ramasubramanian V, Iyer V, Sewlikar S, Desai A.
the use of antibiotic is not necessary. Otherwise the Epidemiology of healthcare acquired infection–An Indian
antibiotic choice is determined by culture sensitivity and perspective on surgical site infection and catheter related
resistance pattern and the site of surgery. blood stream infection. Indian Jrnl Basic Applied Med
Research. 2014;3(4):46-63.
For gram positive organism, a glycopeptide 5. Rotstein C, Evans G, Born A, et al. Clinical practise
(teicoplanin or vancomycin) or linezolid and if Gram- guidelines for HAP/VAP in adults. Can J Infect Dis Med
negative, a broad-spectrum agent such as a carbapenem, Microbiol. 2008;19(1):19-30.
SECTION
11
Toxicology
Clinical Approach to Patient of Coma Management of Snake Bite in India
Geeta Kampani, Umashankar US, Munish Prabhakar Shibendu Ghosh, Prabuddha Mukhopadhyay
Common Poisoning and Management
Saurabh Srivastava
CHAPTER
122
Clinical Approach to Patient of Coma
Geeta Kampani, Umashankar US, Munish Prabhakar
INTRODUCTION ETIOLOGY AND PATHOGENESIS

Coma is one of the most challenging and interesting Consciousness is a function of the reticular activating
subjects in all of clinical medicine. It is characterized system (RAS) and its connections with the cerebral
by altered arousal and is an acute life threatening cortex. Any lesion involving the RAS or its cortical
emergency. Immediate and prompt intervention is connections can alter the level of consciousness
required for preservation of brain function. (Table 1). These may be
Various states of alertness help in localizing the lesion Lesion in the upper mid brain causing damage to the
in a case of coma. RAS.

Coma: By definition is a state from which the patient Massive lesion involving both the cerebral hemi
cannot be aroused. spheres.

Stupor: Is a state of relative arousability as compared Metabolic derangements, drugs, toxins, effecting the
to coma in which the patient can be aroused by RAS and cerebral cortex.
vigorous stimuli.
Akinetic mutism: Represents fully awake patient ASSESSMENT OF COMA
capable of thinking but has no motor functions or Assessment comprises of detailed history, general
speech. This is due lesions in the medial thalamic physical examination and neurological assessment.
nuclei, frontal lobes or massive hydrocephalus.
Abulia: Is similar to akinetic mutism but a milder HISTORY
form in which patient has decreased ability to The course of events and progress of neurological
initiate activity. The lesion is in frontal lobe and its lesion in time and space.
connections. History of preceding symptoms of fever, raised
Catatonia: Is a disorder seen in psychotic and intracranial tension, seizures.
schizophrenic patients. The patient looks like akinetic Medication and drug abuse.
mutism but evidence of focal neurological damage in Associated co-morbid illness.
the form of extensor plantar, hypertonia is absent.
The locked-in state: There is no speech or motor GENERAL PHYSICAL EXAMINATION
activity of the limbs. The only movement is lid Fever: Suggestive of anticholinergic overdose, heat
elevation and vertical eye movements. This is as a stroke, bacterial/viral meningitis, sepsis, neuroleptic
result of hemorrhage in ventral pontine region. malignant syndrome.
734 SECTION 11: Toxicology
TABLE 1: Etiology of coma TABLE 2: Glasgow Coma Scale

zz Causes with normal imaging studies and no focal neurological S. no. Eye opening (E) Verbal response (V) Motor response (M)
deficit 1 None None None
—— Intoxications: alcohol, sedatives
—— Metabolic disturbances: anoxia, dyselectrolytemia, diabetic 2 To pain Incomprehensible Extension

ketoacidosis, hypoglycemia, uremia, hepatic coma, etc. 3 To command Inappropriate words Flexion
—— Severe systemic infections
4 Spontaneous Confused speech Withdraws to pain
—— Shock
—— Post seizure states, status epilepticus 5 Oriented Localizes pain

—— Hypertensive encephalopathy, eclampsia
6 Follows commands
—— Severe hyperthermia, hypothermia
—— Concussion
Causes with meningeal irritation and CSF abnormality, imaging

NEUROLOGIC EXAMINATION
zz
shows no mass lesion

—— Subarachnoid hemorrhage Loss of movements on one side of the body or abducted
—— Acute bacterial meningitis
—— Viral encephalitis
upper or lower limb is suggestive of hemiplegia.
—— Miscellaneous: Fat/cholesterol embolism, carcinomatous Occasional twitching movements of the limb may be
meningitis, etc. suggestive of underlying seizure activity. Myoclonic
zz Causes with abnormal imaging with or without CSF abnormality jerking is seen commonly in patients with anoxic/
—— Cerebrovascular accident
—— Brain abscess
ischemic encephalopathy and other toxic or metabolic
—— Intracranial space occupying lesion with surrounding edema disorders.
—— Massive bilateral cerebral injury Abnormal posturing as:
—— Metabolic causes as described above associated with
—— Decorticate posture: In which the patient lies with
previously coexisting focal brain damage
—— Miscellaneous: Sagittal sinus thrombosis, viral encephalitis, flexion at elbows and wrist with supination of the
vasculitis, thrombotic thrombocytopenic purpura, etc. arm suggestive of bilateral midbrain lesion
—— Decerebrate posture: Characterized by extension
Hypothermia: Toxicity of barbiturate/sedative/ of the elbows and wrist with pronation either
phenothia-zine, peripheral circulatory failure, spontaneously or on noxious stimuli indicating
hypothyroidism. Hypothermia itself causes coma damage to the motor tracts in the mid brain or
when the temperature is <31°C caudal diencephalon.
Tachypnea: Seen in systemic acidosis, sepsis and
brain stem lesions. Level of Arousal
Hypertension : Hypertensive encephalopathy, The Glasgow Coma Scale (GCS) (Table 2) was initially
intracranial bleed, head injury devised for patients with head injury but it is now used as
Hypotension: Seen in acute coronary syndrome, bedside tool to assess the level of consciousness in all the
sepsis, myxoedema coma, Addisonian crisis, cases of coma irrespective of cause.
barbiturate poisoning, and alcohol intoxication. The GCS has certain limitations:
Cutaneous petechiae: As in bleeding diathesis leading —— Mild impairment of consciousness may not be
to intracerebral bleed, meningococcemia. captured by GCS.

Discoloration of skin: Reddish in carbon monoxide, —— GCS cannot be obtained in intubated patients,
cyanosis in CO2 narcosis. sedated patients, patients with dominant

The fundus examination for papilloedema, other hemisphere lesions and aphasia.
hypertensive changes and subarachnoid hemo —— Correlates poorly with outcome and neuro
rrhage. imaging findings.

CHAPTER 122: Clinical Approach to Patient of Coma 735
BRAINSTEM REFLEXES Ocular bobbing: No horizontal eye movements seen.

These are important to localize the site of lesion in coma. Only rapid vertical downward movement with slow
Includes upward return. Occurs in bilateral brainstem lesion.
Size of pupil, reaction to light (direct and consensual)
Ocular dipping: Slow downward movement of
Eye movements (voluntary and involuntary) eyeballs with fast upward return and normal
Corneal responses horizontal movements, could be due to diffuse
Respiratory pattern. cortical hypoxic damage.
The brainstem reflexes especially the pupillary Oculocephalic reflexes (Doll’s eye movement): These
reaction and eye movements are preserved in coma due are elicited by turning the head from side to side.
to bilateral cerebral hemispheric lesion however absence The eyes turn in the direction opposite to the head
of brainstem reflexes does not necessarily point to a movement. Doll’s eye movements are not seen in an
brainstem lesion because hemisphere mass lesion can awake patient. Their presence is indicative of integrity
lead to secondary brainstem damage. of the oculomotor nuclei and their interconnecting
tracts.
Thermal or “caloric” test: Oculocephalic reflex can
Pupillary Reactions also be elicited by stimulation of the vestibular
Unilateral enlargement of the pupil with poor apparatus.
response to light indicates third nerve damage and
can be false localizing sign. Corneal Reflex
Bilaterally dilated and fixed pupil not reacting to light Presence of the corneal reflex indicates the integrity
indicate severe midbrain damage. of connection between the fifth (afferent) and seventh
Bilateral small reactive pupils are suggestive of (efferent) cranial nerves.
metabolic encephalopathy, thalamic bleed and
lesion involving both cerebral hemispheres. RESPIRATORY PATTERNS
Small pinpoint reactive pupils are characteristic Che yne-Stokes respiration: Characterized by
of narcotic/barbiturate poisoning and pontine alternating apnea and hyperapnea. Seen in cases with
hemorrhage. a bilateral lesion of cerebral hemispheric.
Bilateral fixed dilated pupil with no response to light Hyperventilation (Kussmaul’s breathing): Seen in
and loss of vertical and adduction movements carries ponto-mesencephalic lesions, sepsis, metabolic
a poor prognosis suggesting a lesion in the brainstem. acidosis and psychiatric disease.
Apneustic breathing: Occurs in pontine lesions and is
Ocular Movements characterized by a long pause after inspiration.
Presence of spontaneous eye movements rules out Ataxic breathing: Indicates brainstem damage and is
midbrain/brainstem lesion. irregular in both rate and volume.
Conjugate horizontal deviation of the eyes to one side
is due to the lesion in the pons on the contralateral INVESTIGATIONS
side or ipsilateral cortical lesions. ‘The eyes look Complete hemogram
towards a cortical lesion and away from a brainstem Metabolic profile: RBS, KFT, LFT, serum NH3, ABG,
lesion.’ serum electrolytes, calcium.
Epileptic activity is also associated with deviation of Radiological investigations: CT, MRI useful in
eyes to one side. detecting hemorrhage, tumor, or hydrocephalus.
Downward and medial deviation of the eyeballs is MRI is highly sensitive in acute ischemic stroke,
typical of thalamic bleed. cerebral venous sinus thrombosis, brain edema, brain
tumor, inflammatory processes, cerebral abscess and dolls eye movement, GCS less than 5 are poor prognostic
diffuse axonal injury. indicators.
EEG: Useful in nonconvulsive seizures, herpes virus
encephalitis, prion (Creutzfeldt-Jakob) disease and to BIBLIOGRAPHY
assess severity of metabolic encephalopathy. 1. Di Perri, Thibaut A, et al. Measuring consciousness in coma
and related states. World J Radiol. 2014;6:589-97.
CSF in the diagnosis of meningitis and encephalitis.
2. Huff JS, Stevens RD, et al. Emergency neurological life
Toxicological analysis in cases of poisoning and when support: approach to the patient with coma. Neurocrit Care.
diagnosis is obscure. 2012;17(Suppl 1):S54-9.
3. Kasper DL, Hauser SL, Jameson JL, et al. Harrison’s
PROGNOSIS Principles of Internal Medicine. 19th edition, McGraw-Hill.
This depends on the cause and severity of coma. Comas 2015. pp. 1171-7.
due to metabolic causes are usually reversible unless 4. Oliveira deAmorim RL, Nagumo MM, et al. Current clinical
approach to patients with disorders of consciousness. Rev
associated with hypoxic brain damage. A significant
Assoc Med Bras. 2016;62(4):377-84.
degree of recovery occurs after 48 hours of coma. In
5. Plum F, Posner JB, Saper CB, Schiff ND. Plum and Posner’s
coma due to structural lesions, nature of the lesion Diagnosis of stupor and coma, fourth edition, Oxford. 2007.
and rapidity with which it is corrected are important pp. 309-27.
determinants of prognosis. Absence of pupillary reflex, 6. Young GB. Coma. Ann NY Acad Sci. 2009;1157:32-47.
CHAPTER
123
Common Poisoning and Management
Saurabh Srivastava
INTRODUCTION CLINICAL FEATURES OF INTOXICATION

Poisoning is major problem worldwide more so in The fatal dose of aluminium phosphide (unexposed
developing countries like India. Rapid urbanization is the pellet) is 150–500 mg. The signs and symptoms depend
major contributor for the same. In India, pesticides and on the route of entry, dose and time duration from the
insecticides are the common agents used in poisonings. exposure of the poison.
Suicidal as well as homicidal poisonings are common
in India. Kerosene poisoning is common poisoning in Inhalational Exposure
children. Exact incidence of the poisonings is not known, Airway irritation and breathlessness are the common
however some common poisonings in clinical practice presentation. Other features of the poisoning include
will be discussed. nausea, diarrhea, vomiting, jaundice, dizziness,
headache, ataxia, numbness and paresthesia.
ALUMINIUM PHOSPHIDE POISONING In severe cases, patient can develop cardiac failure,
(CELPHOS POISONING) cardiac arrhythmias, acute respiratory distress syndrome
(ARDS), convulsion and coma.
Aluminium phosphide is a solid fumigant pesticide. In
India, it is marketed as tablets of celphos and quickphos
Exposure by Ingestion
and used to preserve grains as a pesticide. It is available
as 3 g tablets or powder and is one of the main causes of Mild Poisoning
suicidal poisoning in north India. Patients present with nausea, vomiting, diarrhea,
headache, abdominal discomfort and tachycardia.
MECHANISM OF TOXICITY
Moderate to Severe Poisoning
Phosphine gas, a cytotoxic compound, is implicated in
There are signs and symptoms of the systemic
the toxicity of aluminium phosphide and causes injury
involvement, later on disseminated intravascular
due to free radical generation. Inhibition of cytochrome
coagulation may also occur.
c oxidase leads to cellular hypoxia and there is formation
of highly reactive hydroxyl radicals. Lipid peroxidation is Cardiovascular : Myocardial damage, peripheral
also responsible for cellular injury. Activity of superoxide vasodilatation and fluid loss lead to profound and
dismutase is increased while that of catalase is decreased. refractory hypotension. Congestive heart failure
and myocarditis can also occur. ST-T wave changes, monitoring to manage shock. Refractory hypotension
ventricular arrhythmias and conduction blocks can may require low-dose dopamine (4–6 Hg/kg/min)
occur in case of severe myocardial injury and steroids. Sodium bicarbonate is given to correct
metabolic acidosis.
Respiratory: Cough, dyspnea, cyanosis and pulmonary
edema are common presenting complaints, however ORGANOPHOSPHATE POISONING
in severe cases patient can have respiratory failure and
Organophosphates (OP) are commonly used
ARDS.
as insecticides (agricultural domestic and industrial),
Neurological: Consciousness is maintained till the late medications, and nerve gas. OPs are one of the most
stage, but headache, altered sensorium, convulsion and common causes of poisoning worldwide, as suicidal
coma can also occur. poison. Intentional or unintentional contamination of
food sources is the common cause of organophosphate
Other features: Patients can have severe metabolic
exposure. Commonly used compounds are malathion,
acidosis, disseminated intravascular coagulation,
parathion, etc. Absorption of poison is possible by all
intravascular hemolysis and acute adrenocortical
routes—respiratory, eyes, skin and gastrointestinal.
insufficiency.
Carbamates include carbaryl, carbofuran and propoxur,
etc.
Diagnosis
The diagnosis is based on history, clinical features, and
MECHANISM OF TOXICITY
foul garlic smell; however gastric aspirate or breath, silver
Acetylcholinesterase (AChE) enzyme is inhibited by
nitrate impregnated paper test is done, for confirming
organophosphates. AChE hydrolyzes acetylcholine,
the diagnosis.
leading to excess of acetylcholine at sympathetic and
parasympathetic synaptic junctions. Excess acetylcholine
Management
at synaptic junction, results in initial stimulation of
The deleterious effects of poison are due to phosphine, so
neurotransmission followed by paralysis.
the management is directed to sustain life till phosphine
is excreted. CLINICAL FEATURES
In early presentation, gastric lavage is done to Clinical presentation of organophosphate poisoning can
reduce absorption of phosphine, using potassium be divided into three broad categories:
permanganate in 1:10000 dilutions. Activated charcoal
is also useful. Phosphine excretion is through breath 1. Muscarinic Effects
and urine so adequate ventilation and renal perfusion is Cardiovascular: Hypotension, Bradycardia
maintained. Respiratory: Rhinorrhea, bronchorrhea, broncho
There is no antidote to reduce the deleterious effects spasm, respiratory distress
of phosphine on various organs. Magnesium sulphate Gastrointestinal: Nausea, vomiting, abdominal pain,
has been used to reduce these effects, but with variable diarrhea and increased salivary secretions (Hyper
results. One gram of magnesium sulphate is given salivation)
intravenously, followed by 1 g every hour for the next Ocular: Miosis and blurred vision.
two hours, thereafter 1.0–1.5 g is given every 4–6 hourly Glands: Diaphoresis and increased lacrimation
for around 3–5 days. Other regimen is 1 gm of MgSO4/ Genitourinary: Incontinence.
intravenously followed by 1 gm every 4–6 hours, with
magnesium levels within safe limits (3–3.6 mEq.). 2. Nicotinic Effects
Two-three litres of saline is infused over the first Common nicotinic effects include weakness, muscle
3–6 hours, preferably under central venous pressure fasciculations, cramps and diaphragmatic failure.
CHAPTER 123: Common Poisoning and Management 739
Hypertension, mydriasis and tachycardia are autonomic MANAGEMENT

effects of organophosphates. Decontamination of the gut and skin (if cutaneous
exposure has occurred) is the most important aspect of
3. CNS Effects management. The clothes should be removed to prevent
CNS effects include restlessness, anxiety, ataxia, tremors, further absorption through skin. Activated charcoal and
seizures, and coma. gastric lavage is used for decontamination of gut.
ECG findings commonly include nonspecific ST-T
wave changes and low voltage complexes. Uncommonly,
Specific Antidote
ventricular extrasystoles, polymorphic ventricular
Atropine: 2–5 mg atropine is given intravenously in
tachycardia, AV dissociation and torsade de pointes can
adults and 0.04–0.08 mg/kg in children. Atropine in
occur. Table 1 summarizes the features of mild, moderate
same dose is given every 5–10 minutes till the patient
and severe poisoning.
shows signs of atropinization (drying of mouth,
Organophosphate poisoning is characterized by
pulmonary secretions and clearing of crepitations).
three neurological syndromes:
Dose and frequency of atropine is reduced later,
Acute cholinergic crisis: It occurs due to accumulation however signs of atropinization are maintained.
of acetylcholine at nerve endings leading to initial Continuous infusion at the rate of 0.02–0.1 mg/kg/
stimulation and eventually exhaustion of cholinergic hour can also be given as maintenance and is to be
synapses. The features are similar as described above. continued for 2–5 days.
Pralidoxime: Regeneration of cholinesterase
Intermediate syndrome: It is due to the prolonged action of
enzyme at all sites is done by pralidoxime. It is given
acetylcholine on nicotinic receptors and is characterized
intravenously in doses of 1–2 g (30 mg/kg) over 15–20
by weakness of bulbar, ocular, neck, respiratory and
minutes, followed by continuous infusion of 8–10
proximal limb muscles. Sensory functions are normal.
mg/kg/hr until clinical recovery.
Full recovery is usually evident in 4–18 days.
Delayed polyneuropathy: It is common with compounds CORROSIVE POISONING
having weak anticholinesterase activity. The symptoms
Acids and alkalis are the two primary types of agents
start with paresthesias and calf pain. Weakness appears
most often responsible for caustic exposures. These
in distal limb muscles causing foot drop later on small
account for a large number of accidental and intentional
muscles of hands and truncal muscles are also involved.
poisonings.
Patient usually has gait ataxia with absent tendon
reflexes. Cranial nerves and autonomic nervous system
are not involved.
MECHANISM OF INJURY
Alkali ingestion causes liquefaction necrosis and acid
TABLE 1: Features of mild, moderate and severe organophosphate ingestion causes coagulation necrosis. Fibrosis and
poisoning cicatrization can be caused by both acid and alkali.
Mild Moderate Severe
Walks and talks Cannot walk Unconscious
Headache, dizzy Soft voice Muscle twitching,
CLINICAL PRESENTATION
dyspnea Gastrointestinal
Nausea, vomitting, Fasciculations, Flaccid paralysis,
abdominal pain anxiety, restlessness bronchorrhea Common presentation is pain of mouth, throat, chest
Sweating, salivation, Miosis Convulsions, and abdomen, excessive salivation, dysphagia, and
rhinorrhea respiratory failure odynophagia. Hematemesis and perforation can also
AChE – 1.6–4 u/L AChE – 0.8–2 u/L AChE – <0.8 u/L occur.
Respiratory System reactivates vitamin K and interferes with the normal

Patient presents with cough, dyspnea, broncho synthesis of coagulation proteins (factors II, VII, IX, and
constriction and sometimes with pulmonary edema and X) in the liver; thus, adequate amounts are not available
chemical pneumonitis. to convert prothrombin into thrombin. Commonly used
agents are bromadiolone, brodifacoum, etc. Ingestion of
Eyes and Skin small amount does not cause significant abnormality but
Pain, burn, erythema and vesicle formation at the site of larger amount may lead to prolongation of prothrombin
exposure. time and bleeding. Management include administration
of vitamin K and fresh frozen plasma.
MANAGEMENT
KEROSENE OIL
Protection of Airway Kerosene oil ingestion is the most common accidental
Hemodynamic correction by replacement with poisoning due to its extensive use in cooking and lighting.
crystalloid fluids is to be done.
Decontamination: Nasogastric tube insertion for CLINICAL FEATURES OF INTOXICATION
decontamination is contraindicated. Emetics should not Ingestion of kerosene produces burning sensation in the
be given as they increase the risk of mucosal injury and mouth immediately followed by nausea and vomiting.
subsequent perforation. Cough, tachypnea, breathlessness, bronchospasm,
Management depends on the time of presentation to and atelectasis occurs due to chemical pneumonitis
the hospital: following aspiration. Hypoxia and acidosis leads to CNS
Early admission: (Presentation within 48–72 hours of involvement. In severe cases, there can be intravascular
ingestion): upper GI endoscopy should be performed hemolysis due to damage to red cell membrane.
between 12 hours and 24 hours of ingestion. Gastrostomy Pneumonitis, perihilar densities, pleural effusion,
is indicated if severe lesions are seen on endoscopy. atelectasis, and rarely, cysts or pneumatoceles are
radiographic findings seen in kerosene poisoning.
Delayed admission: (Presentation from 72 hours to three
weeks of ingestion): no endoscopy is indicated. If there is
MANAGEMENT
severe dysphagia, gastrostomy can be done.
Gastric lavage is to be avoided to reduce the risk of
Late admission: (More than three weeks of ingestion): aspiration. Activated charcoal is not effective. Ventilatory
requires endoscopy and dilatation of stricture. support may be required for patients having respiratory
distress.
RODENTICIDES
Zinc phosphide, and anticoagulants are commonly used BENZODIAZEPINES
rodenticides. Therapeutic index and margin of safety of
benzodiazepines is very wide so fatality is rare. Mortality
ZINC PHOSPHIDE occurs in patients having underlying chronic obstructive
Zinc phosphide releases phosphine gas in the stomach. lung disease or use of alcohol.
The clinical features are similar to aluminium phosphide
but the onset is slower. Symptomatic and supportive CLINICAL FEATURES OF INTOXICATION
management is given, similar to aluminium phosphide. CNS depression is commonly seen in benzodiazepine
poisoning. Patients are mainly drowsy, ataxic and sleepy
ANTICOAGULANTS from which they can be aroused. Overdose is generally
Vitamin K epoxide reductase enzyme is inhibited by produces prolonged sleep, without serious depression of
anticoagulant rodenticides. The enzyme normally respiratory and cardiovascular function.
CHAPTER 123: Common Poisoning and Management 741
MANAGEMENT Psychiatric Association. Am J Psychiatry. 2006;163(8

Suppl):5-82.
Only supportive care is required in most patients.
3. Mehrpour O, Jafarzadeh M, Abdollahi M. A systematic
Flumazenil is the specific antagonist of benzodiazepeine review of aluminium phosphide poisoning. Arh Hig Rada
but is not required in most cases. Flumazenil is indicated Toksikol. 2012;63(1):61-73.
mainly in patients having respiratory depression or 4. Naik RRR, Vadivelan M. Corrosive poisoning. Indian Journal
in those cases, likely to develop complications due to of Clinical Practice. 2012;(23):131-4.
prolonged coma. It is given in dose of 0.1–0.2 mg IV over 5. Peter JV, Sudarsan TI, Moran JL. Clinical features of
30–60 seconds, and is repeated every 1–2 minutes to a organophosphate poisoning: A review of dif ferent
classification systems and approaches. Indian J Crit Care
total of 1–2 mg. Resedation can occur due to its short
Med. 2014;18(11):735-45.
half-life, and in such cases, flumazenil can be given as an 6. Singh S, Sharma N. Neurological syndromes following
infusion at a rate of 0.3–1 mg/hour for 3–6 hours. organophosphate poisoning. Neurol India. 2000;48:308-
13.
BIBLIOGRAPHY 7. Spahr JE, Maul JS, Rodgers GM. Superwarfarin poisoning:
1. Bajpai SR. Aluminium phosphide poisoning: Management and a report of two cases and review of the literature. Am J
prevention. J Indian Acad Forensic Med. 2010;32(4):352-54. Hematol. 2007;82(7):656-60.
2. Kleber HD, Weiss RD, Anton RF, et al. Treatment of patients 8. Tormoehlen LM, Tekulve KJ, Nañagas KA. Hydrocarbon
with substance use disorders, Second Edition. American toxicity: A review. Clin Toxicol (Phila). 2014;52(5):479-89.
CHAPTER
124
Management of Snake Bite in India
Shibendu Ghosh, Prabuddha Mukhopadhyay
INTRODUCTION
India is a country known to the western population as
a country of snake charmers and snakes over centuries,
despite generation after generations some families in our
country who play with snakes (snake charmers) we fail to
protect the community from snake bite which requires
at least education of the common people, how to protect
themselves from snake bite as well as what to do after the
bite has occurred.
The estimated death in India is an underestimate
because of lack of proper registration of snake bite. The
real number of death in our country probably much
higher. The persons or population at risk of snake bite in
Fig. 1: Complicated and uncomplicated snake bite cases. Complicated
our country is around 50 million people which may occur
cases are more who comes late and reaches about 100% who comes
any time in the life (Fig. 1). 3 days after
The infrastructure of the medical profession in India
is maldistributed in such a manner to protect this poor to establish a single protocol for both first-aid and
rural population against the snake bite. Scientifically and treatment which contained evidence based procedures
ethically we, the doctors cannot treat the patients of snake and was relevant to the Indian context. In July 2006, a
bite properly. Moreover, ignorance of the people around National Snake Bite Conference was convened, including
the snake bite victims, the misbelieves about snake Indian and International experts. Moreover publications
bite and ignorance of the medical profession also play issued by the WHO Regional Office for South-East Asia,
a large part to care this patients in a proper way. There written and edited by David A Warrell in the year 2015
are large number of conflicting protocols for dealing and enduring efforts of the scientist and doctors working
with first aid and treatment. In 2004, WHO established a indifferent regions of India is the back bone of these
snake bite Treatment Group, whose role was to develop update. We have treated about 10000 cases of snake
recommendations to reduce mortality according to bite patients in Medical College Hospitals, Kolkata,
international norms. A primary recommendation was Tarakeswer Rural Hospitals and Seba Nursing Home,
CHAPTER 124: Management of Snake Bite in India 743
Tarakeswar, Hooghly, West Bengal, SRI Hospitals, Betai, GH = Get to Hospital immediately. Traditional
Nadia, West Bengal since 1987. remedies have NO PROVEN benefit in treating snake
Early treatment definitely reduces complications that bite.
can be proved by a study done in South India presented T = Tell the Doctor of any systemic symptoms that
as below. manifest on the way of hospital.

Do not waste time for doing the first aid management.
First Aid Treatment Protocol This method will get the victim to the hospital quickly,
Primary importance is the need to recommend the most without recourse to traditional medical approaches
effective first aid for victims, to enable them to reach the which can dangerously delay effective treatment (Sharma
nearest medical facility in the best possible condition. et al. 2004), and will supply the doctor with the best
Much of the first aid currently carried out is ineffective possible information on arrival.
and dangerous (Simpson, 2006). Indian research has The snake, if killed should be carefully taken to the
agreed on the following recommended method having hospital for identification by the doctor. No time should
viewed and considered the available research and be wasted in attempting to kill or capture the snake. This
concluded that other methods are not appropriate for the solely wastes time and can lead to other victims.
conditions in India.
Traditional Methods to be Discarded
Recommended Method for India Tourniquets: Tourniquet use is contraindicated in India
-
Recommended first-aid methods emphasise reassurance, Risk of ischemia and loss of the limb (Warren, 1999).
application of a pressure-pad over the bite wound, Increased risk of necrosis with 4/5 of the medically
immobilization of the bitten limb and transport of the significant snakes of India. (Fairly, 1929) (Pugh et al,
patient to a place where they can receive medical care 1987) OA/Auell, 1995)
without delay. Increased risk of massive neurotoxic blockade when
The first aid being currently recommended is based tourniquet is released (Watt, 1988).
around the mnemonic. Risk of embolism if used in viper bites. Procoagulant
“CARRY NO R.I.G.H.T.” It consists of the following: enzymes will cause clotting in distal blood. In addition,
CARRY = Do not allow victim to walk even for a short the effect of the venom in causing vasodilatation
distance; just carry him in any form, specially when bite presents the danger of massive hypotension and
is at leg. neuroparalysis when the tourniquet is released.
No-Tourniquate They do not work! (Tun Pe 1987) (Khin-Ohn Lwin
No-Electrotherapy 1984)! Venom was not slowed by the tourniquet

No–Cutting in several experimental studies, as well as in field
No-Pressure immobilization conditions. Often this is because they are tied on
Nitric oxide donor (Nitrogesic ointment/Nitrate the lower limb or are incorrectly tied (Watt, 2003)
Spray) (Amaral, 1998) (Nishioka, 2000).
R = Reassure the patient. 70% of all snake bites are They give patients a false sense of security, which
from nonvenomous species. Only 50% of bites by encourages them to delay their journey to hospital.
venomous species actually envenomate the patient Diagnosis of the species of snake responsible for
I = Immobilize in the same way as a fractured limb. the bite is important for optimal clinical management.
Use bandages or cloth to hold the splints, not to block This may be achieved through expert identification
the blood supply or apply pressure. Do not apply any of the dead snake or a (mobile-phone) image of it, or
compression in the form of tight ligatures, they do not by inference from the resulting “clinical syndrome”
work and can be dangerous! of envenoming. It is recommended that syndromic
approaches and algorithms for diagnosing the species chance to move away. If collecting grass that has
responsible for snake bites be developed in different previously been cut and placed in a pile, disturb the
parts of India. grass with the stick before picking the grass up.
Keep checking the ground ahead when cutting crops
SNAKE BITE PREVENTION AND like Millet, which are often harvested at head height
OCCUPATIONAL RISK and concentration is fixed away from the ground.
The normal perception is that rural agricultural workers Pay close attention to the leaves and sticks on the
are most at risk and the bites occur first thing in the ground when wood collecting.
morning and last thing at night. However, this is of very Keep animal feed and rubbish away from your house.
little practical use to rural workers in preventing snake They attract rats and snakes will follow.
bite since it ignores the fact that often snake bites cluster Try to avoid sleeping on the ground.
around certain biomechanical activities, in certain Keep plants away from your doors and windows.
geographic areas, at certain times of the day. Snakes like cover and plants help them climb up and
Grass-cutting remains a major situational source of into windows.
bites.
In rubber and coconut plantations clearing the DIAGNOSIS PHASE
base of the tree to place manure causes significant Symptoms (Figs 2 to 11)
numbers of bites.
General
Harvesting high growing crops like Millet which
There are a great many myths surrounding snake
require attention focused away from the ground.
Rubber tapping in the early hours 03:00–06:00.
symptoms. Table 1 below summarizes the evidence-
Vegetable harvesting/fruit picking.
based situation. Hemostatic abnormalities are prima
facie evidence of a Viper bite. Cobras and Kraits do not
Tea and coffee plantation workers face the risk of
cause generally hemostatic disturbances.
terrestrial vipers when picking or tending bushes.
Saw Scaled Vipers do not cause renal failure whereas
Clearing weeds exposes workers to the same danger
Russell’s Viper and Hump-nosed Pitviper do.
as their grass-cutting colleagues.
Russell’s Viper can also manifest neurotoxic
Walking at night without a torch barefooted or
symptoms in a wide area of India. But in our study none
wearing sandals accounts for a significant number of
of the Russell’s Viper bite presented with neurotoxic
bites.
feature.
Bathing in ponds, streams and rivers, in the evening.
It should not be assumed that because the victim

GENERAL SIGNS AND SYMPTOMS OF
is bitten in water that the species is nonvenomous.
Cobras and other venomous species are good
VIPERINE ENVENOMATION
swimmers and may enter the water to hunt.
Swelling and local pain.
Walking along the edge of waterways.
Tender enlargement of local lymph nodes as large
molecular weight Viper venom molecules enter the
system via the lymphatics.
PREVENTATIVE MEASURES Bleeding from the gingival sulci and other orifices
Walk at night with sturdy footwear and a torch and epistaxis
use the torch! When walking, walk with a heavy step Vomiting (Kalantri SP et al. 2006).
as snakes can detect vibration and will move away! Acute abdominal tenderness which may suggest
Carry a stick when grass cutting or picking fruit or gastro-intestinal or retroperitoneal bleeding.
vegetables or clearing the base of trees. Use the Hypotension resulting from hypovolemia or direct
stick to move the grass or leaves first. Give the snake vasodilatation.
A B
Fig. 2A and B: Two types of krait. (A) Narrow band throughout the body. Very dangerous, No ASV available, Can kill a person silently;
(B) Wide band starts from the nake sparing the tail, less toxic to humen
Fig. 3: Daboia Russelii (Russel Viper), most important hematotoxic Fig. 4: Nonpoisonus snake, mixes with the green leaves (Laudaga)
snake in India, but ASV is available in India
Fig. 5: Very beautiful to see, known in the mythology for killing Fig. 6: Type krait. Usually very timid but dangerous if bite named
lakhinder the husband of Behula named Kalnagini, very little toxic Sankhamuthi. Maintain the environment and ecology by eating
to human snakes
Fig. 7: Narrow band throughout the body. Very dangerous, no ASV Fig. 8: King Kobra (Naja naja) very lethal snake, neurotoxic, can kill
available, can kill a person silently an elephant within seconds
Fig. 9: Naja kautia, neurotoxic, ASV available in India Fig. 10: Naja kautia, neurotoxic, ASV available in India
TABLE 1: Summary of evidence-based situation for diagnosis phase

Feature Cobra Kraits Russells Saw Humped
Viper Scaled Nose
Viper Viper
Local pain/tissue Yes No Yes Yes Yes
damage
Ptosis, Yes Yes No* No No
neurological sign
Hemostatic No May Yes Yes Yes
abnormality occur
Renal No No Yes No Yes
complication
Response to Yes +/- No No No
neostigmine
Response to ASV Yes Yes Yes Yes No
In addition some of the Krait bite (Sochoureki) does not respond to
Fig. 11: Different type of Naja kautia, neurotoxic, ASV available in India ASV of Indian origin.
Low back pain, indicative of a early renal failure the length of time it can take for symptoms to manifest.
or retroperitoneal bleeding, although this must be Often this can take between 6 hours and 12 hours. Late
carefully investigated as many rural workers involved onset envenoming is a well documented occurrence (Ho
in picking activities complain of back pain generally. et al, 1986) (Warren et al. 1977) (Reitz,1989).
The skin and mucous membranes may show evidence This is also particularly pertinent at the start of the
of petechiae, purpura ecchymosis. rainy season when snares generally give birth to their
The passing of reddish or dark-brown urine or young. Juvenile snakes, 8–10 inches long, tend to bite the
declining or no urine output. victim lower down on the foot in the hard tissue area, and
Lateralizing neurological symptoms and asymmetri thus any signs of envenomation can take much longer to
cal pupils may be indicative of intracranial bleeding.
appear.
Muscle pain indicating rhabdomyolysis.
Parotid sw elling, conjunctival e dema, sub-
DIAGNOSIS PHASE: INVESTIGATIONS

conjunctival hemorrhage.
20 Minute Whole Blood Clotting Test
General Signs and Symptoms of Elapid (20 WBCT)
Envenomation Considered the most reliable test of coagulation and
Swelling and local pain (Cobra), may be asymptomatic should be carried out at the bedside by treating physician.
in case of Krait (Figs 2A and B) patient often could It can also be carried out in the most basic settings. It is
not recognize the bite significantly superior to the ‘capillary tube’ method
Local necrosis and/or blistering (Cobra). of establishing clotting capability and is the preferred
Descending paralysis, initially of muscles innervated
method of choice in snake bite.
by the cranial nerves, commencing with ptosis,
A few mililiter of fresh venous blood is placed in
diplopia, or ophthalmoplegia. (The patient complains
a new, clean and dry, glass vessel and left at ambient
of difficulty in focusing and the eyelids feel heavy.
temperature for 20 minutes. The vessel ideally should be
There may be some involvement of the senses of taste
a small glass test tube. The use of plastic bottles, tubes or
and smell but these need further research).
syringes will give false, readings and should not be used.
Paralysis of jaw and tongue may lead to upper airway
obstruction and aspiration of pooled secretions The glass vessel should be left undisturbed for 20
because of the patient’s inability to swallow numbness minutes and then gently tilted, not shaken. If the blood is
around the lips and mouth, progressing to pooling of still liquid then the patient has incoagulable blood. The
secretions, bulbar paralysis and respiratory failure. must not be washed with detergent as this will inhibit
Hypoxia due to inadequate ventilation can cause the contact element of the clotting mechanism. The test
cyanosis, altered sensoriun and coma. This is a life should be carried out every. 30 minutes from admission
threatening situation and needs urgent intervention. for three hours and then hourly after that. If incoagulable
Paradoxical respiration, as a result of the intercostal blood is discovered, the 6 hourly cycle is then be adopted
muscles becoming paralyzed is a frequent sign. to test for the requirement for repeat doses of ASV.
Stomach pain which may suggest submucosal
hemorrhages in the stomach (Kularatne 2002) (Krait). MANAGEMENT OF SNAKE BITE
Krait bites often present in the early morning with IN GENERAL
paralysis that can be mistaken for a stroke (Figs 2A
and B). Pain
Snake bite can often cause severe pain at the bite site; this
LATE-ONSET ENVENOMING can be treated with pain killers such as paracetamol.
The patient should be kept under close observation for at Aspirin should not be used due to its adverse impact on
feat 24 hours. Many species, particularly the Krait and the coagulation. Do not use nonsteroidal anti-inflammatory
Hump-nosed pitviper (Joseph et al, 2006) are known for drugs (NSAIDs) as they can cause bleeding. This can
be particularly dangerous in a patient already having may be questionable. These species should be detected
coagulopathy. first and special measures to be taken for these bites.
If available, mild opiates such as Tramadol, 50 mg can
be used orally for relief of severe pain. In cases of severe ASV ADMINISTRATION CRITERIA
pain at a tertiary center, Tramadol can be given IV. ASV (hyperimmune immunoglobulin), a lifesaving,
WHO-recognized, essential medicine, is the only effective
HANDLING TOURNIQUETS antidote for envenoming. However, they are scarce, costly
Care must be taken when removing tight tourniquets commodity and should only be administered when there
which most of the time used. Sudden removal can lead are definite signs of envenomation. Unbound, free
to a massive surge of venom leading to neurological flowing venom, can only be neutralized when it is in
paralysis, hypotension due to vasodilatation, etc. the bloodstream or tissue fluid. In addition, antisnake
Before removal of the tourniquet, test for the presence venom carries risks of anaphylactic reactions and should
of a pulse distal to the tourniquet. If the pulse is not therefore be used unnecessarily. The doctor should
absent ensure a doctor is present before removal. be prepared for such reactions. It is recommended that
Be prepared to handle the complications such as antivenom should be used in all patients with signs
sudden respiratory distress or hypotension. If the of systemic and/or severe local envenoming in whom
tourniquet has occluded the distal pulse, then a blood the benefits of treatment are judged to exceed the risks
pressure cuff can be applied to reduce the pressure of antivenom reactions. It should not be used in the
slowly. absence of evidence of envenoming
ONLY if a patient develops one or more of the
Antisnake Venom (Figs 3 to 6) following signs/symptoms will ASV be administered.
After assessing patient whenever decision is taken for
giving antisnake venom (ASV), start ASV whatever Systemic Envenoming
dose is available in hand, do not wait for full dose to be Evidence of coagulopathy: Primarily detected
available. by 20WBCT or visible spontaneous systemic
In India polyvalent ASV is only available, it is effective bleeding, gums, etc. Further laboratory tests for
against all the four common species; Russell’s viper thrombocytopenia, fibrinogen abnormalities, PCV,
(Fig. 3) (Daboia russelii), Common Cobra (Raja naja) peripheral, smear, etc. provide confirmation, but
(Fig. 8), Common Krait (Bungarus caeruleus) and Saw 20WBCT is paramount importance.
Scaled viper (Echis carinatus). There are no currently Evidence of neurotoxicity: Ptosis, external ophthal-
available monovalent ASVs primarily because there are moplegia, muscle paralysis, inability to lift the head,
no objective means of identifying the snake species, in etc.
the absence of the dead snake. And unavailability of The above two methods of establishing systemic
ELISA method to detect species specific envenomation envenomation are the primary determinants. They
for these reason it would be impossible for the physician are simple to carry out, involving bedside tests
to determine which type of monovalent ASV to employ in or identification of visible neurological signs and
treating the patient. symptoms. In the Indian context and in the vast
There are known species such as the hump-nosed majority of cases, one of these two categories will be
pitviper (Hypnale hypnale) where polyvalent ASV is the sole determinant of whether ASV is administered
known to be ineffective. In addition, there are regionally to a patient.
specific species such as Sochurek’s Saw Scaled Viper Cardiovascular abnormalities: Hypotension, shock,
(Echis carinatus sochureki) in Rajasthan, and Kalach in cardiac arrhythmia, abnormal ECG.
West Bengal where the effectiveness of polyvalent ASV Persistent and severe vomiting or abdominal pain.
Severe Current Local Envenoming Two regimen are normally recommended:

100 mg of hydrocortisone and Hl antihistamine
Severe current, local swelling involving more than
half of the bitten limb (in the absence of a tourniquet). (10 mg chlorpheniramine maleate IV or 25 mg
In the case of severe swelling after bites on the digits promethazine HCI IN1) 5 minutes before ASV
(toes and especially fingers) after a bite from a known administration.
necrotic species. ( Th e do s e fo r ch ildre n is 0.1–0.3 mg/ kg of
Rapid extension of swelling (for example, beyond antihistamine IV and 2 mg/kg of hydrocortisone IV.
the waist or ankle within a few hours of bites on the Antihistamine should be used with caution in pediatric
hands or feet). Swelling a number of hours old is not patients
grounds for giving ASV. The conclusion in respect of prophylactic regimens to
Purely local swelling, even if accompanied by bite prevent anaphylactic reactions, is that there is no evidence
mark from an apparently venomous snake, is not from good quality randomized clinical trials to support
grounds for administering ASV. their routine use. If they are used then the decision must
rest on other grounds. But the regime have got an added
Note: If a tourniquet or tourniquets have been applied
advantage of decreasing the nonanaphylactic reaction
these themselves can cause swelling, once they have
such as febrile, allergic reaction, etc.
been removed for 1 hour and the swelling continues,
then it is unlikely to be as a result of the tourniquet and If the victim has a known sensitivity to ASV,
ASV may be applicable. premedication with hydrocortisone and antihistamine
may be advisable, in order to prevent severe reactions.
PREVENTION OF ASV REACTIONS: Adrenalin should not be used as premedication, when
it will be required it should be given IV route without
PROPHYLACTIC REGIMES
wasting time.
There is no statistical, trial evidence of sufficient
statistical power to show that prophylactic regimes
are effective in the prevention of ASV reactions in
ASV Administration
India. Of the three published studies on the efficacy of Total required dose will be between 10 vials and 30 vials
prophylactic regimens for prevention of reactions to ASV, usually, as each vial neutralizes 6 mg of Russells Viper
one (Wen Fan et al) showed no benefit and the other venom. Not all victims will require 10 vials as some may
two (Prernawardenha et al, 1999) (Gawarammana et al, be injected with less than 63 mg. However, starting with
2003) showed modest benefit. However, because these 10 vials ensures that there is sufficient neutralizing power
studies were underpowered to detect the true outcome to neutralize the average amount of venom injected and
effect, larger clinical trials are needed to conclude that during the next 12 hours to neutralize any remaining
the prophylactic treatment is beneficial. Recent trial in free flowing venom, even in the large study from south
Sri Lanka using low dose adrenalin (0.25 mL) on good India, the amount of ASV exceeded 50 vials in some
number of patient showed benefit but a proper study patients. So decision of the treating physician is of utmost
to be undertaken in India before making it a routine importance, because the guidelines may not be useful for
procedure as a prophylactic manner. Moreover, Indian all patients.
population are at high risk for premature atherosclerosis There is no evidence that shows that low dose
and coronary artery disease. Any adverse effect before strategies (Paul et al, 2004) (Srimanarayana et al,
ASV may be detrimental as a social issue also. However, 2004) (Agraval et al 2005) have any validity in India.
putting the adrenalin via three way cannula or by These studies have serious methodological flaws: the
puncturing the latex tube may be undertaken and to be randomization is not proper, the allocation sequence
injected in emergency. Prophylactic regime should be was not concealed, the evaluators were not blinded
reserved for children and young adult. to the outcome; there was no a prior sample size
estimation, and the studies were underpowered to detect

the principle outcome.
No ASV Test Dose Must be Administered

Test doses have been shown to have no predictive value
in detecting anaphylactic or late serum reactions and
should not be used (Warren et al 1999). These reactions
are not IgE mediated but complement activated. They
may also pre-sensitize the patient and thereby create
greater risk. Fig. 12: Novel method of assessing the respiratory muscle for
neurotoxic poisoning, sanke bite
ASV is Recommended to be Administered
in the following Initial Dose reported when spontaneous abortion of the fetus has
Neurotoxic/Antihemostatic 10 Vials (Fig. 12): been reported although this is not the outcome in the
N.B. Children and pregnant women receive the same majority of cases. It is not clear if venom can pass the
ASV dosage as adults. The ASV is targeted at neutralizing placental barrier.
the venom. Snakes inject the same amount of venom into Pregnant women are treated in exactly the same
adults and children. way as other victims. The same dosage of ASV is given.
The victim should be referred to a gynaecologist for
ASV can be administered in two ways: assessment of any impact on the fetus.
Infusion: liquid or reconstituted ASV in isotonic
saline or glucose, may be started without any diluent ASV Reactions

fluid in volume overload patients. Anaphylaxis can be rapid onset and can deteriorate into
All ASV to be administered over 1 hour at constant a life-threatening emergency very rapidly. Prophylactic
speed. Local administration of ASV, near the bite site, subcutaneous adrenaline has proved effective in reducing
has been proven to be ineffective, painful and raises the the frequency and severity of early antivenom reactions
intra compartmental pressure, particularly in the digits, and its routine use is, therefore, recommended unless the
it should not be used. risk of reactions associated with a particular antivenom is
low. But in our opinion, adrenaline should be deferred
ASV Dosage in Victims Requiring till signs of reactions appear in unknown patient profile.
Life Saving Surgery But, adrenaline should always be immediately available
In very rare cases, symptoms may develop which indicate bedside.
that life saving surgery is required in order to save the The patient should be monitored closely (Peshin et al,
victim. viz. intracranial bleed. 1997) and at the first sign of any of the following:
Before surgery can take place, coagulation must Urticaria, itching, fever, chills, nausea, vomiting,
be restored in the victim in order to avoid catastrophic diarrhea, abdominal cramps, tachycardia, hypotension,
bleeding. In such cases, a higher initial dose of ASV is bronchospasm and angioedema.
justified (upto 25 vials) solely on the basis on guaranteeing ASV to be discontinued
a restoration of coagulation after 6 hours. 0.5 mg of 1:1000 adrenaline will be given IV
Children are given 0.01 mg/kg body weight of adre-
Snake Bite in Pregnancy naline IV.

There is little definitive data published on the effects In elderly noradrenaline and nitroglycerin infusion
of snake bite during pregnancy. There have been cases when hypotension is corrected can be given to avoid
adrenalin induced arrhythmia which is common in Length of time upward gaze can be maintained
elderly. FEV 1 or FVC (If available)
If after 10–15 minutes the patient’s condition has not Water column measurement. (Length of water
improved or is worsening. column that can be held with blowing through tubes).
A second dose of 0.5 mg of adrenalin 1:1000 IV is For example, if single breath count or inter incisor
given. This can be repeated for a third and final distance is selected the breath count or distance between
occasion but in the vast majority of reactions, 2 doses the upper and lower incisors, and more objective
of adrenaline will be sufficient. waterlevel measurement that much patient can blow
If there is hypotension or hemodynamic instability, are measured and recorded. Every 10 minutes the
IV fluids should be given. measurement is repeated. The average blood plasma
Once the patient has recovered, the ASV can be time for neostigmine is 20 minutes, so by T+ 30 minutes
restarted slowly for 10–15 minutes, keeping the patient any improvement should be visible by an improvement
under close observation. Then the normal drip rate in the measure.
should be resumed.
Adrenaline should be given iv in case of anaphylactic RECOVERY PHASE
reaction, because If an adequate dose of appropriate antivenom has been
1. Faster action administered, the following responses may be seen:
2. Predictable availability Spontaneous systemic bleeding such as gum bleeding
3. Intramascular hematoma in patient with coagulo usually stops within 15–30 minutes.
pathy can be avoided. Blood coagulability is usually restored in 6 hours.
Late Serum sickness reactions can be easily treated Principal test is 20WBCT.
with an oral steroid such as prednisolone, adults 5 mg 6 Postsynaptic neurotoxic envenoming such as the
hourly, pediatric dose 0.7 mg/kg/day. Oral antihistaminic Cobra may begin to improve as early as 30 minutes
provide additional symptomatic relief. after antivenom, but can take several hours.
Presynaptic neurotoxic envenoming such as the
NEUROTOXIC ENVENOMATION Krait usually takes a considerable time to improve

Neostigmine is an anticholinesterase that prolongs the reflecting the need for the body to generate new
life of acetylcholine and can therefore reverse respiratory acetylcholine emitters.
failure and neurotoxic symptoms. It is particularly Active hemolysis and rhabdomyolysis may cease
effective for post synaptic neurotoxins such as those of within a few hours and the urine returns to its normal
the Cobra (Watt et al, 1986). color.
In the case of neurotoxic envenomation where In patients who were in shock, blood pressure may
edrophonium is not available neostigmine test can increase after 30 minutes.

bed one. The neostigmine dose is 0.04 mg/kg IV and
atropine/glycopyrolate may be given by continuous Repeat Doses: Antihemostatic
infusion. In case of antihemostatic envenomation, the ASV strategy
The patient should be closely observed for l hour to will be based around a six hour time period. When the
determine if the neostigmine is effective. initial blood test reveals a coagulation abnormality, the
The following measures are useful objective methods initial ASV amount will be given over 1 hour.
to assess this: No additional ASV will be given until the next clotting
Single breath count test is carried out. This is due to the inability of the liver to
Uncovered area of iris measured in mm replace clotting factors in under 6 hours.
Inter incisor distance (Measured distance between After 6 hours a further coagulation test should be
the upper and lower incisors) performed and a further dose should be administered
in the event of continued coagulation defect and in that what should the clinician do after say, 30 vials have been
case ASV to be given over 1 hour CT tests and repeat administered and the coagulation abnormality persists?
doses of ASV should continue on a 6 hourly pattern until It has been established that envenomation by the
coagulation is restored or unless a species is identified as Hump-nosed Pitviper (Hypnale hypnale) does not
one against which polyvalent ASV is not effective. respond to normal ASV. This may be a cause as, in the
The repeat dose should be 5–10 vials of ASV i.e. half case of Hypnale, coagulopathy can continue for upto
to one full dose of the original amount. The most logical 3 weeks.
approach is to administer the same dose again, as was
administered initially. Some Indian doctors however, Surgical Intervention
argue that since the amount of unbound venom is Whilst there is undoubtedly a place for a surgical
declining, due to its continued binding to tissue, and due debridement of necrotic tissue, the use of fasciotomy is
to the wish to conserve scarce supplies of ASV, there may highly questionable. The appearance of (Joseph, 2003):
be a case for administering a smaller second dose. In the Pain on passive stretching
absence of good trial evidence to determine the objective Pain out of proportion
position, a range of vials in the second dose has been Pulselessness
adopted. Pallor
Parasthesia
Recurrent Envenomation Paralysis
When coagulation has been restored no further ASV With significant swelling in the limb, can lead to the
should be administered, unless a proven recurrence of a conclusion that the intracompartmental pressure is
coagulation abnormality is established. If patient comes above 40 mm of mercury and thus requires a fasciotomy.
with features of coagulopathy ASV to be administered Fasciotomy is required if the intracompartmental
(10 vials). There is no need to give prophylactic ASV pressure is sufficiently high to cause blood vessels
to prevent recurrence (Srimannarayana et al, 2004). to collapse and lead to ischemia. Nowadays, we are
Recurrence has been a mainly US phenomenon, due to using multiple puncture technique using large bore
the short half-life of Crofab ASV. needle. Fasciotomy does not remove or reduce any
Indian ASV is a F(ab)2, product and has a half- envenomation. It is recommended that fasciotomy
life of over 90 hours and therefore is not required in a should never be carried out in snake bite patients unless
prophylactic dose to prevent re-envenomation. But if
or until hemostatic abnormalities have been corrected,
the patient comes even after few days reinstitute ASV
clinical features of an intracompartmental syndrome are
therapy, because sometime absorption of snake venom
present and a consistently raised intracompartmental
depot under skin is erratic. If there is no improvement
pressure has been confirmed by direct measurement.
from the beginning of the whole blood clotting time,
T h e re i s l i t t l e o b j e c t i v e e v i d e n c e t h a t t h e
rather it goes on increasing then we are dealing with
intracompartmental pressure due to snake bite in India,
the snake bites which are not amenable to our usual
ever reaches the prescribed limit for a fasciotomy. Very
polyvalent ASV.
limited trial data has tended to confirm this.
What is important is that the intracompartmental
ANTIHEMOSTATIC MAXIMUM ASV
pressure should be measured objectively using saline
DOSAGE GUIDANCE manometers or newer specialised equipment such as
Repeat Dose: Hematotoxic the Stryker Intracompartmental Pressure Monitoring
The normal guidelines are to administer ASV every 6 Equipment.Visual impression is a highly unreliable guide
hours until coagulation has been restored. However, to estimating intracompartmental pressure.
The limb can be raised in the initial stages to see if Mechanical ventilation to be avoided as far as possible, as
swelling is reduced. However, this is controversial as because most of the death in ventilated snake bite patient
there is no trial evidence to support its effectiveness. is ventilator associated pneumonia. Early initiation and
early weaning from ventilator is the strategy, noninvasive
Renal Failure in Snake Bite ventilator with a patent upper air way is better option.
The acute renal failure which occurs due to snake bite
are multifactorial 1) Severe and persistent hypotension Heparin and Botropase
leading to acute tubular necrosis, 2) Hb and other No role
cellular parts of RBC and others (myoglobin and
rhabdomylysis) 3 part of DIC 4) vasculitis 5) acute Snake Bite Management in Primary/Community/
diffuse intersticial nephritis) extra capillary proliferative Dispensary Health Care Centers
glomerulonephritis. A key objective of this protocol is to enable doctors
Most of the patients of acute tubular necrosis in Primary Care Institutions to treat snake bite with
recovers by few weeks, with the help of occational need confidence. Evidence suggests that even when equipped
of hemodialysis, but who develops cortical necrosis with antisnake venom, primary care doctors lack the
confidence to treat snake bite due to the absence of
requires reanal replacement therapy on along term
a protocol tailored to their needs and outlining how
basis. It is the hyoperkalemia rather than elevated urea,
they should proceed within their context and setting
creatinine requires dialysis. The hyperkalemia of snake
(Simpson, 2007).
bite AKI is a hypermetabolic hyperkalemia, which may
kill the patient within few minutes and calcium gluconate
Patient Arrival and Assessment
and glucose insulin is mostly ineffective.
Patient should be placed under observation for 24
Early urgent adequate treatment with ASV can
hours.
reverse the whole process of deterioration of renal
The snake, if brought, should be carefully examined
function which is far from our expectation in our country.
and compared to the snake identification material.
Renal failure is a common complication of Russell’s Pain management should be considered.
Viper and Hump-nosed Pit viper bites (Tin-Nu-Swe et 20WBCT in clean, new, dry, glass test tubes should be
a1,1993) Joseph et al, 2006). The contributory factors are carried out every 30 minutes for the first 3 hours and
intravascular hemolysis, DIC, direct nephrotoxicity and then hourly after that. Attention should be paid for
hypotension (Chugh et a1, 1975) and rhabdomyolysis. any visible neurological symptoms.
Renal damage can develop very early in cases of 20 WBCT must be done in glass tube never in plastic
Russell’s Viper bite and even when the patient arrives tube, should be done at bed side, sample must not be
at hospital soon after the bite, the damage may already sent to laboratory.
have been done. Studies have shown that even when ASV Severe, current, local swelling should be identified.
is administered within 1–2 hours after the bite, it was If no symptoms develop after 24 hours the patient can
incapable of preventing ARF (Myint-Iewin et al, 1985). be discharged with a TT.
Neurological Manifestation in Snake Bite Envenomation; Hematotoxic

Neurological manifestation of snake bite pose an If the patient has evidence of hemotoxic envenomation,
important problem for transportation from the site of determined by 20WBCT, then 8–10 vials of ASV are
bite to the hospital. A well designed study from PGI administered over 1 hour.
Chandigarh shows that just putting an airway tube and Adrenaline to be kept ready in two syringes of 0.5 mg
an AMBU bag decrease the morbidity to a great extent. 1:1000 for IV administration is indicated if symptoms of
any adverse reaction appears, it is better to keep ready Referral Criteria

the adrenalin through a three way cannula. The primary consideration, in the case of neurotoxic
If symptoms do appear, ASV is temporarily suspended bites, is respiratory failure. Capacity of neck lifting is
while the reaction is dealt with and then ASV restarted. good predictor of requirement of ventilator support.
Refer such patient to the center equipped with invasive
Referral Criteria ventilation.
Once the ASV is finished and the adverse reaction
dealt with the patient should be automatically referred Conditions and Equipment Accompanying
to a higher center with facilities for blood analysis to Neurotoxic Referral
determine any systemic bleeding or renal impairment. The primary consideration is to be equipped to provide
The 6-hour rule ensures that a six hour window is respiration support to the victim.
now available in which to transport the patient. Transfer the patient with a face mask, resuscitation
bag and a person, other than the driver of the vehicle,
Envenomation; Neurotoxic who is trained of how to use these devices. If respiration
If the patient shows signs of neurotoxic envenomation fails then the victim must be given artificial respiration
8–10 vials are administered over 1 hour. until arrival at the institution.
Adrenaline is made ready in two syringes of Greater success can be achieved with two additional
0.5 mg 1:1000 for IV administration if symptoms of any approaches, prior to dispatch.
adverse reaction appear. If symptoms do appear, ASV is In the conscious patient, two nasopharyngeal tubes
temporarily suspended while the reaction is dealt with (NP) should be inserted before referral. These will
and then recommenced. enable effective resuscitation with the resuscitation bag
A neostigmine (edrophonium if available) test is by not allowing the tongue to fall back and block the
administered using 1.5–2.0 mg of neostigmine IM plus airway, without triggering the gagging reflex. Improvised
0.6 mg of atropine IV. An objective measure such as single nasopharyngeal tubes can be made by cutting down size
breath count or indegeniously made device from oxygen 5 endotracheal tubes to the required length i.e. from
moistening bottle used as water level marker of blowing the tragus to the nostril. If necessary allow the patients
capacity of patient is used to assess the improvement or relative alongwith an AMBU bag after proper description
lack of improvement given by the neostigmine over 1 of how to use it.
hour. If there is no improvement in the objective measure NP tubes should be prepared and kept with the snake
the neostigmine is stopped. If there is improvement bite kit in the PHC. This is preferable as the patient may
0.5 mg neostigmine is given IM every 30 minutes with well be unable to perform a neck lift but still remain
atropine until recovery. Usually this recovery is very conscious and breathing. The danger will be that
rapid. IV neostigmine a preffered method nowadays respiratory failure will occur after the patient has left the
along with glycopyrolate PHC and before arriving at the eventual institution. In
If after 1 hour from the end of the first dose of ASV, that case, the patient will be pre-prepared for the use of a
the patient’s symptoms have worsened i.e. paralysis has resuscitation bag by the use of NP tubes.
descended further, a second full dose of ASV is given over In the unconscious patient, a Laryngeal Mask Airway
1 hour. ASV is then completed for this patient. or preferably a Laryngeal Tube Airway should be
If after 2 hours the patient has not shown worsening inserted before referral which will enable more effective
symptoms, but has not improved, a second dose of ASS is ventilatory support to be provided with a resuscitation
given over 1 hour. Again, ASV is now completed for this bag until the patient reaches an institution with the
patient. facility of mechanical ventilation.
BIBLIOGRAPHY 6. Paul V, Pratibha S, Earail KAPJ, Fracis S, Lewis F. High-dose

1. Bawaskar HS. Snake venoms and antivenoms: Critical anti-snake venom versus low-dose anti snake venom in the
supply issues. JAPI. 2011;52:11-3. treatment of poisonous snake bites-a critical study. JAPI. Vol
2. Guidelines for the clinical management of snake bites in 52 January, 2004.
south-east asia region. David A Warrell, WHO, 2005. 7. Simpson ID. Management of Snakebite-The National, API
3. Guideline for management of snake bite in south east Asia WB branch, update in Medicine, 2006. pp. 88-93.
countries, David Warrd. 8. Srimannaryan J, Dutta TK, Sahai A, Badrinath S. Rational
4. Indian National snake bite Protocol 2008. use of anti-snake venom (ASV): Trial of various regimens in
5. Nar vencar K. Correlation between timing of ASV hemotoxic snake envenomation. JAPI. 2004;52:788-92.
administration and complication in snake bite, JAPI. Vol 54.
2006.
SECTION
12
Hematology/Oncology
Stem Cell Therapy in Various Diseases: Idiopathic CD4 Lymphocytopenia
Dawn of a New Era Bhupendra Gupta, Harpreet Singh
Hepatocellular Carcinoma: Surveillance,
Basics of Hematopoietic Stem Cell Transplant: Diagnosis and Management
Autologous and Allogeneic Kirti Shetty
Punit L Jain
Approach to a Patient with Polycythemia
Clinical Approach to Patient with Purpuric Spot Mathew Thomas
Immunotherapy: A New Weapon in Cancer
Thrombocytosis: Clinical Approach Treatment
Sudhir Mehta, Laxmi Kant Goyal, Vineet Talwar, Venkata Pradeep Babu K
Shaurya Mehta, Gunja Jain
Metronomic Chemotherapy in Metastatic
Macrophage Activation Syndrome Malignancies: A New Concept
Tarun Kumar Dutta, Tony Kadavanu, Ankur Bahl
Arunkumar Ramachandrappa
Hemotransfusion Therapy: Boon or Bane?
Anil Kumar Gupta
CHAPTER
125
Stem Cell Therapy in Various
Diseases: Dawn of a New Era
Today, in the 21st century, we still do not have proper TABLE 1: Classes of stem cells1,2
treatments for many diseases like Parkinsons, Alzheimers, Stem cells classes Features
multiple sclerosis, cardiomyopathies, etc. Some light of Totipotent cells Only zygote can form an entire organism
hope for the treatment of these incurable diseases are: Pluripotent cells It can differentiate into any tissue type except
the stem cells. The stem cell therapies even at the initial placental tissue e.g. embryonic stem (ES) cells
stages have an extraordinary potential to revolutionize Multipotent cells Can form many cell lineages but not all e.g.
the medical care.1 hematopoeitic stem (HS) cells
Oligopotent cells They are more restricted in forming the cell
(progenitor or lineages e.g. neural stem cells
STEM CELL precursor cells)
A cell can be called a stem cell if it fulfils two requirements:
unique ability to produce same daughter cells i.e. self-
(allogeneic stem cells). HSCT is the gold standard as all
renewal and to differentiate into specialized cell types
other stem cell transplantation therapies are measured
(Tables 1 and 2).2
against it.3
METHODS FOR STEM CELLS Sources

TRANSPLANTATION Peripheral blood stem cells
Undifferentiated stem cells are injected into the target Bone marrow stem cells
organ directly or intravenously. Cord blood stem cells.
Stem cells can be differentiated ex vivo before
injection into the target organ. Indications3
Endogenous stem cell populations are stimulated Inherited metabolic disorders
with the help of injected growth factors. Inherited immune disorders
Inherited red blood cell disorders
HEMATOPOIETIC STEM CELL Marrow failure states
TRANSPLANTATION (HSCT) —— Autoimmune diseases (experimental)
It involves the intravenous infusion of patient’s own cells —— Malignant/premalignant diseases
(autologous stem cells) or cells of some other person Myelodysplastic syndromes.

760 SECTION 12: Hematology/Oncology
TABLE 2: Types of stem cells with their source1,2 Engraftment phase: Several weeks; management of
Types of stem cells Source GVHD and prevention of viral infections like CMV are
Embryonic stem Blastocysts or immune-surgically isolated the biggest challenges in this phase. For engraftment, a
cells inner cell mass from blastocysts dose of 1 × 108 marrow mononuclear cells per kilogram
Hematopoietic They are CD34+ cells. in autologous and 2 × 108 marrow mononuclear cells per
stem cells Plerixafor (chemokine receptor 4 (CXCR4)
kilogram in allogenic marrow transplants is required.
inhibitor) is used in conjunction with G-CSF
to mobilize HS cells to peripheral blood for Postengraftment period: Months to years.
collection
Induced Formed from the conversion of terminally
pluripotent stem differentiated cells into ES-like cells by over
HSCT-Peripheral Blood Stem Cell
cells (iPSC) expressing four transcription factors. It is associated with rapid engraftment, decreased
Advantage–genetically identical to those of leukemia relapse rates because of higher GVL effect,
the patient and have less ethical constraints as
ESCs. Disadvantage–more prone to mutations
better overall survival, but increased chronic GVHD.
Umbilical cord Contains two classes of stem cells; HSC and
blood stem cells MSC. Volume of cord blood obtained is less Uses of Stem Cell Therapy
and therefore, these cells are sufficient to
transplant an individual of <40 kg only IHD and cardiomyocyte regeneration: For successful
Mesenchymal Bone marrow, muscle, peripheral blood and myocardial repair, stem cell therapy are delivered either
stem cells (MSC) umbilical cord blood systemically or locally so that functional cardiomyocytes
Adipose stem cells Fat that couple mechanically and electrically with the
recipient myocardium are produced after survival,
Autologous HSCT engraftment and differentiation.4
Advantage: Immunosuppression is not needed. Diabetes: ES and iPS cells can be differentiated into
Disadvantage: not used for correction of immuno- insulin producing cells but these cells have a low content
deficiencies. of insulin and a high rate of apoptosis.5 Clinical trials are
going on in both type 1 and type 2 diabetes.
Allogeneic HSCT Neurological diseases:
Spinal cord injury (SCI): Both ES cells and MSCs can
The most important factor in this type of transplantation
is the degree of HLA match between the donor and the facilitate remyelination of nerve cells. It was the first
recipient because the risk of graft versus host disease disorder targeted for the clinical use of ES cells.6
Stroke, Parkinson’s disease, Huntington’s chorea,
(GVHD) is less in matched transplants. Because of the
graft-versus-leukemia (GVL) effect, lower relapse rate Amyotrophic lateral sclerosis, Alzheimer’s disease,
are associated with allogeneic transplants than are multiple sclerosis and muscular dystrophies.
autologous transplants. Hence, more the GVHD, more Liver: The available evidence suggests that transplanted
the GVL effect and lower the relapse rate. HSCs and MSCs can generate hepatocyte-like cells in the
liver only at a very low frequency, but there are beneficial
5 Phases of HSCT consequences presumably related to indirect paracrine
Conditioning: 7–10 days to deliver chemotherapy, effects.
radiation, or both.
Tissue repair: Regenerative responses by migrating
Stem cell infusion. into a tissue and differentiating into specific cell types
Neutropenic phase: 2–4 weeks; supportive care and are observed with the help of stem cells. So stem cell
empirical antibiotic therapy are needed for this phase as therapies to promote replacement of cells in damaged
immune system is affected in this phase. organs are being evaluated.
CHAPTER 125: Stem Cell Therapy in Various Diseases: Dawn of a New Era 761
HIV/AIDS: Cellular chemokine receptor, the most Risks

common CCR5 and CXCR4 mediates viral entry in to Active proliferation of stem cells may lead to
CD4+ cells. One patient has discontinued ART following accumulation of chromosomal abnormalities and
transplantation of allogeneic BMT from a donor lacking mutations.
the CCR5 cell surface protein.7 So, an approach is being In immunosuppressed animals, injected ES cells can
investigated to treat HIV-1/AIDS through transplantation form teratomas.
of gene-modified (HIV-1-resistant) autologous Potential important risks of colonization of nontarget
hematopoietic stem and progenitor cells (GM-HSPC). tissues, stimulation of cancer and transmission of
Drug testing: Stem cells could allow testing of new drugs infections.
using human cell line which could speed up new drug Giving stem cell therapy indiscriminately as a magical
development. treatment to cure disease states by multiple centres
worldwide has led to many disasters.
Other organs: Skin, hair loss, endometrium, bone, kidney,
corneal injury, lung, vascular endothelium, smooth and
Recent Advances
striated muscle; clinical trials in these and other organs
Prochymal approved in Canada in 2012 for the
are ongoing.
management of acute GVHD in children unresponsive
Important Trials in Stem Cell Therapy to steroids. It is an allogenic stem therapy. MSCs
are derived from a single donar and then purified,
Significant improvement in global left ventricular
cultured and packaged, with up to 10,000 doses.8
function ejection fraction (EF) from a baseline with
Five HS cell products have been approved by
acute myocardial infarction (AMI) patients has
FDA for the treatment of primary and secondary
been observed in the trial conducted by Li ZQ et
immunodeficiency states derived from umbilical
al.4 by using autologous peripheral blood stem cell
transplantation through intracoronary route. cord blood.
Significant decrease in the insulin dose requirement
In 2014, Holoclar has been approved as a treatment
along with an improvement in the stimulated for people with severe limbal stem cell deficiency due
C-peptide levels in T2DM was seen in a trial by to burns in the eye.
Bhansali A et al.5 by using autologous bone marrow-
Defibrotide (FDA-2014) is a mixture of single-stranded
derived stem cell transplantation. oligonucleotides that is purified from the intestinal
MMSCs (autologous bone marrow mesenchymal mucosa of pigs. It is used to treat veno-occlusive
stem cells) transplantation was shown to improve disease of the liver of people having had a bone
neurological function in patients with complete and marrow transplant.9
chronic cervical SCI by Dai G et al.6 August 3, 2017: FDA has approved IBRUTINIB, a
bruton’s tyrosine kinase inhibitor for use in patients
Ethical Issues who develop life threatening chronic GVHD after
Widespread controversy for human ES cells as it HSCT. 10
causes destruction of the blastocyst.
Philosophical, moral, or religious objections lead to SCOPE OF STEM CELL
opposition to the use of human ES cells in research. THERAPY IN INDIA
Abortion politics and human cloning also raises According to the National guidelines for stem cell therapy
ethical issues. which are prepared by the Department of Biotechnology
Treatments based on transplant of stored umbilical and the Indian Council of Medical Research (ICMR):
cord blood have been marketed which is a big stem cells cannot be offered as ‘therapy’ to the patients.
controversial issue. After approval from the Drugs Controller General of
India (DGI), they can be used only in “clinical trials. The transplantation: Clinical and ethical considerations. Stem
only approved therapy is use of HS cells for treating blood Cells International. 2017;7:2017.
4. Zhan-quan L, Ming Z, Yuan-zhe J, Wei-wei Z, Ying L, Li-jie
disorders. India is a hub for medical tourism for people
C, et al. The clinical study of autologous peripheral blood
worldwide because treatment here costs only 25 % of
stem cell transplantation by intracoronory infusion in
what it costs in Western countries with no waiting period. patients with acute myocardial infarction (AMI). Int J Cardiol.
The top picks are: 2007;115(1):52-6.
Life cell (Chennai and Gurugram) 5. Bhansali A, Asokumar P, Walia R, Bhansali S, Gupta V, Jain
Baby cell (Lonavala, Mumbai) A, et al. Efficacy and safety of autologous bone marrow-
Cord life (Kolkata)
derived stem cell transplantation in patients with type 2
diabetes mellitus: a randomized placebo-controlled study.
Cell transplantation. 2014;15:23(9):1075-85.
SUMMARY 6. Dai G, Liu X, Zhang Z, Yang Z, Dai Y, Xu R. Transplantation
Stem cells show great promise for regenerative of autologous bone marrow mesenchymal stem cells in
medicine. the treatment of complete and chronic cervical spinal cord
Ethical concerns need to be taken into account. injury. Brain research. 2013;1533:73-9.
Proper guidelines are needed to ensure appropriate 7. Barmania F, Pepper MS. CC chemokine receptor type five
(CCR5): An emerging target for the control of HIV infection.
conduct of the research.
Appl Transl Genom. 2013;2:3-16.
Much research needed before definitive therapies are 8. Leventhal A, Chen G, Negro A, Boehm M. The benefits and
realized. risks of stem cell technology. Oral Dis. 2012;18(3):217-22.
9. Al Jefri AH, Abujazar H, Al-Ahmari A, Al Rawas A, Al
REFERENCES Zahrani Z, Alhejazi A, et al. Veno-occlusive disease/
1. Buzhor E, Leshansky L, Blumenthal J, Barash H, Warshawsky sinusoidal obstruction syndrome after haematopoietic
D, Mazor Y, et al. Cell-based therapy approaches: the stem cell transplantation: Middle East/North Africa regional
hope for incurable diseases. Regenerative medicine. consensus on prevention, diagnosis and management.
2014;9(5):649-72. Bone marrow transplantation. Bone Marrow Transplant.
2. Mahla RS. Stem cells applications in regenerative medicine 2017;52(4):588-91.
and disease therapeutics. International Journal of Cell 10. Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y,
Biology. 2016;19:2016. Kaffenberger B, et al. Ibrutinib treatment ameliorates
3. Riezzo I, Pascale N, La Russa R, Liso A, Salerno M, Turillazzi murine chronic graft-versus-host disease. J Clin Invest.
E. Donor selection for allogenic hemopoietic stem cell 2014;124(11):4867-76.
CHAPTER
126
Basics of Hematopoietic Stem Cell
Transplant: Autologous and Allogeneic
Punit L Jain
INTRODUCTION TABLE 1: Common indications of autologous and allogeneic HSCT
Hematopoietic stem cell transplant (HSCT) is a Autologous HSCT

procedure that involves replacing or repopulating the zz Plasma cell dyscrasias:
entire hematopoietic system (HS) using one’s own —— Multiple myeloma
—— Amyloidosis
hematopoietic stem cells (HSCs), or of a matched
HLA identical stem cell donor. These infused HSCs zz Non-Hodgkins lymphoma:
—— Peripheral T-cell lymphomas
are multipotent and carry the ability to self-renew and
—— Relapsed B-cell lymphomas
differentiate into multilineage hematopoietic elements
zz Relapsed/Refractory Hodgkins lymphoma
(HE), giving rise to a new donor derived HS in the recipient.
Dr E Donnall Thomas, a 1990 Nobel laureate conducted zz Solid tumors:
—— Germ cell tumors
the first such successful allogeneic HSCT in a patient —— Neuroblastomas
with a refractory leukemia. Since then, more than a —— Medulloblastomas
million HSCTs have been reported by the Worldwide Allogeneic HSCT

Network for Blood and Marrow Transplantation Group
zz Benign disorders
(WBMT), with more than 50,000 HSCTs being conducted
—— Severe aplastic anemia (SAA)
annually worldwide. India recorded its first HSCT in 1983
at Tata Memorial Hospital (TMH), Mumbai. Since then —— Congenital marrow failure syndromes
approximately 10,000 HSCTs have been reported from —— Thalassemia major
our country, being actively recorded in the Indian stem —— Sickle cell anemia
cell transplant registry (ISCTR). —— Subacute combined immunodeficiency syndromes (SCID)
Wiskott-Aldrich syndrome (WAS)
PRINCIPLES OF HSCT
——
zz Malignant disorders
Autologous HSCT —— Acute myeloid leukemia (AML)
Indications —— Acute lymphoblastic leukemia (ALL)
Common indications have been listed in Table 1.
zz Inherited metabolic disorders
Steps:
—— Osteopetrosis
—— Stem cell mobilization : An HSCT recipient
( au t o l o g o u s a n d a l l o g e n e i c) u n d e rg o e s —— Adrenoleukodystrophy
a pretransplant workup to assess his organ —— Engraftment : An absolute neutrophil count

functions, using scoring systems like HSCT— (ANC) more than 500/cm mm on first of
comorbidity index (HCT-CI). HCT-CI helps the 3 consecutive days and an unsupported
predict the nontransplant related mortality after platelet count reaching 20,000/cm mm on
transplantation. Once deemed fit, stem cell first of 7 consecutive days, marks engraftment.
mobilization from the bone marrow (BM) into An autologous HSCT does not require any
peripheral blood (PB) begins with a 4 day course immunosuppressive therapy post-transplant,
of injection granulocyte-colony stimulating due to lack of any graft versus tumor (GVT) effect.
factor (G-CSF or GCSF), given subcutaneously —— Supportive management: The high-risk of oppor-
(SC) at a dose of 10 µg/kg/day in two divided tunistic infections especially during the phase of
doses. It is believed that G-CSF helps in breaking neutropenia requires strict neutropenic care and
free the micro-environmental bonds that bind guidelines to be followed by the treating team.
these HSCs to their niche in the BM. Plerixafor, a
reversible antagonist of CXCR4-SDF-1 interaction Allogenic HSCT
is a more powerful stem cell mobilizer. It is Common indications of an allogeneic HSCT are listed
especially helpful in patients with extensive prior in Table 1. The process of an allogeneic HSCT is more
chemotherapy and potential poor mobilizers. complex and begins with identifying a donor through
An apheresis machine positively selects out the characterizing his histocompatibility antigens (HLA).
Donor search: An ideal donor should be a full match
HSCs based on their specific gravity. Stem cells
with the recipients HLA for HLA-A, – B, – C, – DR,
are identified through their surface antigen—
– DB and – DQ. Since each patient has 30% chance
CD34 and a minimum CD34 dose of 2 x 106 cells/ of finding an identical match in his siblings, many
kg in the PB stem cell harvest (PBSC) is essential do not find a suitable donor within his family. In
for an optimum engraftment. Post-harvest, HSCs such situations, an alternative donor could be a
can even be cryopreserved for long-term storage. matched unrelated donor (MUD) obtained through
—— Pretransplant conditioning: This involves myelo independent SC donor registries, notably the NMDP,
ablative doses of chemotherapy (± radiotherapy) DKMS, DATRI and MDRI. Another alternative is a
to eradicate the remaining tumor cells, and create haploidentical donor who is matched at atleast 4 of
the 8 antigens at HLA-A, – B, – C and – DRB1, with
space in recipient’s BM for the new stem cells
only one mismatch per locus. Any of the patient’s
to settle in. Common regimens include BEAM
parents, or siblings can be a haploidentical donor.
(carmustine, etoposide, cytosine arabinoside Several factors are considered during the selection of
and melphalan) for lymphomas, and high dose a donor like his age (younger donor preferred), HLA
melphalan in multiple myeloma. parity, CMV serology (higher mortality in CMV (-)
—— Stem cell infusion and rescue: The next step recipients whose donor is CMV (+), ABO blood group
involves reinfusion of harvested stem cells under compatibility (same blood group preferred) and sex
controlled conditions. If cryopreserved stem cells (male gender has better outcomes).
Donor source: This SC source could be from the
are used, then adequate thawing in a water bath
is needed before infusion. Recipients stromal cell PB, BM or the cord blood (CB), with merits and
limitations of each.
derived factor (SDF)-1, a chemokine serves as a
—— PBSC: PBSC collection is an outpatient procedure
chemoattractant for the infused CD34 (+) SCs.
with lower morbidity for the donor. PBSC T-cell
In combination with the adhesion molecules, dose is higher, helping in a faster engraftment and
it arrests the newly infused stem cells through early T-cell reconstitution. Other characteristics
its CXCR4 progenitors, expediting its homing in include a higher incidence of graft vs host disease
their niche. (GVHD), requirement of cytokine support for
CHAPTER 126: Basics of Hematopoietic Stem Cell Transplant: Autologous and Allogeneic 765
HSC mobilization and a special catheter for its —— Reduced toxicity myeloablative conditioning
collection. (RTC): RTC involves chemotherapeutic drugs
—— BM: This collection is an intraoperative procedure,
with similar potency and reduced toxicity as a
requiring general anesthesia, and thus a higher standard MAC regimens. Common regimens
morbidity for the donor. It does not require are intravenous fludarabine and busulfan/
any special catheter or any cytokine support.
treosulphan.
Other features include a longer neutropenia and
Po s t- t ra n s p l a n t i m m u n o s u p p re ss i o n ( P T I ) :
delayed engraftment, due to the lower number of
T cells in BM. Cyclosporine and methotrexate are the most
—— Cord blood: This is a painless collection as it is commonly used drugs as PTI. More recently, post-
collected from the umbilical cord, causing no transplant cyclophosphamide is being commonly
morbidity to the donor. Engraftment and immune used, especially in haploidentical transplants.
reconstitution is slower due to a lower amount Supportive care: Allogeneic HSCT have a longer
of SC dose in each collection. The incidence of duration of neutropenia, requiring extensive
GVHD is lower due to the increased tolerance of support and care till engraftment as well as immune
the HLA disparity in recipient with CB. recovery is complete. Strict isolation and use of HEPA
Choosing the right conditioning regimen: (high efficiency particulate air) filters offers better
These include: protection from infections in the peritransplant
—— Myeloablative conditioning (MAC): MAC involves
period.
doses of chemotherapy that cause an irreversible Engraftment and chimerism: Once the HSCT recipient
and fatal pancytopenia, unless accompanied achieves engraftment, chimerism analysis helps
by SC rescue. Common regimens include detect the percentage of donor-derived cells in the
cyclophosphamide/total body irradiation (Cy/ recipient. This is done through PCR amplification
TBI) and cyclophosphamide/busulfan (Bu/ of highly repetitive short tandem repeat (STR)
Cy). High MAC dose attempts to eradicate the sequences, followed by capillary electrophoresis.
defective or tumor cells and thus can be very Fluorescent in situ hybridization (FISH) studies
toxic. These are reserved for younger patients (< can also help in assessing the chimerism, if donor-
45 years). recipient are of separate gender. An incomplete
—— Reduced intensity conditioning (RIC): RIC
chimerism would necessitate immunomodulation or
involves chemotherapy with at least 30% reduced and use of donor lymphocyte infusion (DLI).
doses in the alkylating agents or TBI, but still Complications in an allogeneic HSCTL:
requires a SC rescue. Common regimens are —— Early complications: Nausea, vomiting, painful
fludarabine/melphalan (Flu/Mel) or fludarabine mucositis, diarrhea are early common complica-

with reduced doses of TBI (Flu/TBI). tions. Others include hemorrhagic cystitis with
—— Nonmyeloablative conditioning (NMA): NMA cyclophosphamide and busulfan induced veno-
involves doses of chemotherapy that causes occlusive disease (VOD).
cytopenia that is minimal and reversible. It —— Late complications:
does not actually need a SC rescue. A common GVHD: This is due to an interplay between
regimen is fludarabine-cyclophosphamide (Flu/ the alloreactive donor T cells and host

Cy). These regimens are less toxic, enabling microenvironment. A classic acute GVHD
HSCT in frail and elderly patients, especially with would present within the first 100 days with
some organ dysfunction. These regimens bank any of the features listed in the Table 2. Acute
on the GVT effect for the long-term control of GVHD presenting after 100 days post-HCT is
disease. classified as a persistent, recurrent late onset
TABLE 2: Glucksberg criteria for organ grading in acute GVHD BIBLIOGRAPHY

classification
1. Bendall L J, Bradstock KF. G-CSF: From granulopoietic
Organ Skin Liver Gastrointestinal
stimulant to bone marrow stem cell mobilizing agent.
Parameters Degree of rash Total Bilirubin Diarrhea in mL/day Cytokine Growth Factor Rev. 2014;25(4):355-67.
in mg/dL
2. Chandy M. Stem cell transplantation in India. Bone Marrow
1+ < 25% body 2–3 500–1000
Transplant. 2008;42(Suppl 1):S81-4.
surface area
3. Edward A Copelan, et al. Hematopoietic stem-cell
2+ 25–50% 3.1–6 1000–1500
transplantation. N Engl J Med. 2006;354:1813-26.
3+ Generalized 6.1–15 >1500 < 2000
erythroderma 4. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-Host
4+ Bullae/ >15 > 2000 or pain/ Disease. Lancet. 2009;373(9674):1550-61.
desquamation melena or ileus 5. Gyurkocza B, Brenda M Sandmaier. Conditioning regimens
for hematopoietic cell transplantation: one size does not fit
all. Blood. 2014;124(3):344-53.
GVHD. A chronic GVHD can affect any organ, 6. Howard CA, Fernandez-Vina MA, Appelbaum FR, Confer
severely impairing the overall quality of life. A DL, Devine SM, Horowitz MM, et al. Recommendations for
classic chronic GVHD may present at any time Donor HLA assessment and matching for allogeneic stem
cell transplantation: consensus opinion of the blood and
post-HSCT, but with its defined diagnostic
marrow transplant clinical trials network (BMT CTN) Biol
and distinctive features and absence of any
Blood Marrow Transplant. 2015;21(1):4-7.
signs of an acute GVHD. An overlap syndrome 7. Kekre N, Antin JH. Hematopoietic stem cell transplantation
has features of both acute and chronic GVHD, donor sources in the 21st century: choosing the ideal donor
and could present at any time post-HCT. when a perfect match does not exist. Blood. 2014;124(3):
Appropriate immunomodulation can control 334-43.
8. Khan F, Agarwal A, Agrawal S. Significance of chimerism in
GVHD and maintain its beneficial effects,
hematopoietic stem cell transplantation: new variations on
especially in malignancies.
an old theme. Bone Marrow Transplantation. 2004;34:1-
Secondary long-term effects: These include 12.
endocrinopathies, poor growth in children, 9. Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford
osteoporosis, secondary malignancies and S, Marks DI, et al. Indications for autologous and allogeneic
psychosocial symptoms. Regular screening hematopoietic cell transplantation: Guidelines from the
American Society for Blood and Marrow Transplantation.
clinics ensures early detection and timely
Biol Blood Marrow Transplant. 2015;21(11):1863-9.
interventions.
10. Sharma SK, Choudhary D, Gupta N, Dhamija M, Khandelwal
Vaccination: Once off immunosuppression, V, Kharya G, et al. Cost of hematopoietic stem cell
the HSCT recipient receives vaccination with transplantation in India. Mediterr J Hematol Infect Dis.
inactivated vaccines and later live vaccines 2014;6(1):e2014046.
like MMR (measles, mumps and rubella) to
boost his immune system, thereby completing
his/her transformation.
CHAPTER
127
Clinical Approach to Patient
with Purpuric Spot
INTRODUCTION Strength of blood vessels and its surrounding tissues

Purpura is defined as the leakage of red blood cells from The transmural pressure gradient
the vasculature into the skin and/or mucus membrane. Purpuras have been traditionally classified as:
Nonpalpable
Purpuras do not blanch on pressure. This is in sharp
Palpable (probably because of extravascular fibrin
contrast to those erythematous or violet-colored lesions
that are due to local vasodilatation and do blanch on deposition).
pressure. Lesions ≥2 mm are called purpura, <2 mm are Inflammation leads to increased capillary per
petechiae and confluent purpuras >1 cm in diameter are meability and extravasation of plasma proteins which
called echymoses.1 includes fibrinogen along with other coagulation factors.
Purpuric lesions along with petechiae and echymoses This further triggers the cascade of cytokine activation
are traditionally grouped under the umbrella term of in symphony with coagulation as cells starts expressing
“The Purpuras”. tissue factors.
Differentiation from Erythema and Telangiectasia
Blood remains confined in the vasculature CAUSES OF NONPALPABLE PURPURA2
Blanching on pressure-Diascopy Cutaneous disorders
Partial blanching may be seen with purpura but a —— Trauma
non-blanching component will always remain. —— Solar purpura
—— Steroid purpura
Color —— Senile purpura
Superficial–Red Systemic disorders

Deep-Purple —— ITP
Color may change over time from purple to brown to —— Abnormal platelet function in renal and hepatic
orange/green. disorders
—— Thrombocytosis in myeloproliferative disorders
PATHOPHYSIOLOGY —— Clotting factor abnormality
Extravasation of red cells depend upon integrity of blood —— Ehler Danlos syndrome
vessels, which in turn depends upon: —— Scurvy
Competence of hemostatic mechanisms —— Amyloidosis

—— DIC
—— Thrombotic Thrombocytopenic purpura
—— Monoclonal cryoglobulinemia
—— Warfarin necrosis
—— Embolic–Cholesterol, Fat, Tumor emboli, Emboli
from Atrial myxoma
CAUSES OF PALPABLE PURPURA

Vasculitis
—— Leukocytoclastic vasculitis
—— Henoch–Schönlein purpura
—— Urticarial vasculitis
—— Polyarteritis nodosa
Infectious emboli Fig. 1: Petechiae

—— Meningococcemia
—— Gonococcemia intermittent colicky pain lower abdomen with bloody

—— Ecthyma gangrenosum and mucus diarrhea with reddish rashes in both legs,
buttocks and lower abdomen for last 3 weeks (Fig. 1).
CLINICAL APPROACH TO No history of menorrhagia or gum bleeding. There is
PURPURIC SPOTS no past history of similar illness. There is no suggestive
A thorough history and physical examination plays a family history.
pivotal role in arriving at a diagnosis, and often it’s all that On clinical examination: Afebrile, Pulse–88/min,
is necessary. BP–120/76 mm Hg, Respiration–18/min. Anemia–nil

Important history and physical examination include:3 Skin rash: Red, palpable, blanching purpuric spots in
Any bleeding or thrombotic disorder history/family both legs, buttocks and lower abdomen (Figs 2 and 3).
history must be taken. Certain drugs may interfere Respiratory system and CVS exam: Within normal
with platelet function and coagulation (e.g. Aspirin, limits

Warfarin) and any use of these drugs must be G I s y s t e m e x a m i n a t i o n : Up p e r G I- n o r m a l ,
documented in drug history. abdomen–soft with tenderness in hypogastrium and

Deranged coagulation profile may be seen in certain
left iliac fossa; no organomegaly.
medical conditions (e.g. acute/chronic liver disease) Lab orator y investig ation : Hb–11.8 gm, RBC
History of viral hemorrhagic fever (e.g. Dengue

morphology–normal, Platelet–2,45,000/c.mm, WBC-
hemorrhagic fever) in the community 6800/c.mm, CRP–16, Prothrombin time–within
Tourniquet test for capillary fragility (Hess capillary
normal limit (Flow chart 1)
fragility test) Urine R/E–RBC: Few, RBC cast +. Stool–Occult blood
Complete hemogram including platelet count along +, No ova, Parasite or Cyst.

with differential count, coagulation profile (PT, APTT,
CT, BT) are helpful in assessment of platelet function and
evaluation of coagulation status.
DIAGNOSIS: HENOCH–SCHÖNLEIN
PURPURA
CASE STUDIES Case 2
Case 1 A 26-year-old man was admitted through the emergency
A 21-year-old, unmarried female presented to the medical with chief complains of headache, high fever, stiffness
outpatient department with history of polyarthralgia, around neck and lower extremity rash. The patient was
CHAPTER 127: Clinical Approach to Patient with Purpuric Spot 769
A B
Figs 2A and B: Palpable purpura in legs and lower abdomen
—— Vitals: Temp: 103 ºF, Heart rate: 132, BP: 82/42,

Respiratory rate: 26, Oxygen saturation 95% on
room air. Neck rigidity ++
DIAGNOSIS: PURPURA FULMINANS

Laboratory Evaluation3
CBC with platelets
ESR
ANA by Hep-2 (a positive test may suggest the
presence of connective tissue disease)
ANCA (Wegner’s granulomatosis, Churg-Strauss
disease, microscopic polyangiitis and drug induced
vasculitis)
Fig. 3: Petechieal rashes and Echymoses over both legs Complement (∇ mixed cryoglobinemia and lupus)
Urine analysis
apparently well 4 days ago when he developed fever Test for cryoglobins, viral serology (HBV and HCV
along with vomiting. serology), ASO titer, streptococcal throat swab culture
Surgical history: Splenectomy 18 months ago
and occult blood in stool
following a RTA Skin biopsy.
Medications: Nil
No history of any allergies

MANAGEMENT OF SOME COMMON
Immunization history: Received childhood immu
CAUSES OF PURPURA
nization only
Family history: Nothing significant college student, ITP
unmarried, lives in a sharing dorm Corticosteroid remains the drug of choice for initial
Drinks during weekends (2–3 drinks/night) management of acute ITP. Oral prednisolone, IV
On clinical examination: methylprednisolone or high dose dexamethasone
may be used.4
Flow chart 1: Clinical profile
IVIG has been the drug of second choice for many Leukocytoclastic Vasculitis
years. For cutaneous predominant leukocytoclastic Vasculitis
Rituximab is a third line therapy. (LCV), colchicine or dapsone is used.
Platelet transfusion may be required to control For systemic involvement, corticosteroids, immuno-
clinically significant bleeding. suppressive drugs (e.g. Cyclophosphamide) and
If >6 months medical management fails to bring Rituximab can be used.
platelet count >30,000/mL, splenectomy may be
considered. Henoch–Schönlein Purpura
For pain management, NSAIDs or Paracetamol may
TTP be used, but with caution in patients with renal
The treatment of choice is plasma exchange with fresh failure. Corticosteroids with or without azathioprine,
frozen plasma.5 cyclophosphamide and high dose IVIG have been used.6
CHAPTER 127: Clinical Approach to Patient with Purpuric Spot 771
CONCLUSION REFERENCES
Purpura denotes red or purple lesion on the skin or 1. Schneiderman PI. The vascular purpuras. In: Ernest Beutler,
mucous membrane resulting from leakage of RBC’s Marshall A. Lichtman. Williams Hematology. 6th Edition.
New York: McGRAW Hill. 2001. pp. 1603-13.
from the blood vessels. Purpura can be classified as
2. Korman NJ. Macular, papular, vesiculobullous and pustular
palpable or nonpalpable. Purpuras usually do not diseases. In: Lee Goldman, Andrew I. Schafer. Goldman-Cecil
blanch on pressure, even if they do, a nonblanching Medicine. 25th Edition. New York: Elsevier. 2016;2:2673-5.
component will always remain. Thrombocytopenia, 3. Leung AKC, Chan KW. Evaluating the child with purpura.
hypercoagulable or hypocoagulable states, endothelial American Family Physician. 2001;1:64(3):419-29. Available
dysfunction and extravascular factor may contribute to from: http://www.aafp.org/afp/2001/0801/p419.html
4. Sandler SG, Tutuncuoglu SO. Immune thrombocytopenic
the development of purpuras. Various life-threatening
purpura–current management practices. Expert Opin
conditions like meningococcemia may present with Pharmacother. 2004;5(12):2515-27. Available from:
petechiae or purpura. The presence of purpura in https://www.ncbi.nlm.nih.gov/pubmed/15571469
a patient with sepsis should raise concern for DIC. 5. Scully M, Hunt BJ, Benhamin S, Liesner R, Rose P, Peyvandi
Palpable purpuras result from underlying vascular F, et al. Guidelines on the diagnosis and management of
inflammation (vasculitis). Palpable purpura is a classic thrombotic thrombocytopenic purpura and other thrombotic
microangiopathies. Br J Haematol. 2012;158(3):323-35.
clinical presentation of leukocytoclastic vasculitis. An
6. Faedda R, Pirisi M, Satta A, Bosincu L, Bar toli E.
early recognition by meticulous clinical assessment with Regression of Henoch-Schölein disease with intensive
supporting laboratory investigation is most necessary. immunosuppressive treatment. Clin Pharmacol treatment.
Prompt treatment approach depending upon the cause Clin Pharmacol Ther. 1996;60(5):576-81. Available from:
is most rewarding. https://www.ncbi.nlm.nih.gov/pubmed/8941031.
CHAPTER
128
Thrombocytosis: Clinical Approach
Sudhir Mehta, Laxmi Kant Goyal, Shaurya Mehta, Gunja Jain
INTRODUCTION proliferation. Thus, whenever platelet count decreases,

Thrombocytosis is defined as elevated platelet count raised plasma free TPO promotes platelet production;
above the reference range for healthy individuals of similarly when platelet count rise, reduced level of free
particular age, sex and race. The term thrombocytosis is TPO slow platelet production. By this check, the total
used when platelet count is above 450 × 109/L.1 number of platelets/megakaryocytes) regulates platelet
The usually thrombocytosis is reactive/secondary production and platelets remains in a stable state.4
and less commonly primary (clonal disorder). The In inflammatory/neoplastic diseases, interleukin-6
primary cause of thrombocytosis requires complete increases as an acute phase response. This IL-6 up-
evaluation and treatment. re g u l at e s h e p at i c t h ro m b o p o i e t i n m R NA a n d
This review will outline the causes, pathophysiology, promotes TPO synthesis. Thus, in reactive/secondary
clinical features and management of thrombocytosis. thrombocytosis, plasma TPO levels becomes high which
leads to thrombocytosis.5
REGULATION OF THROMBOPOIESIS In primary/clonal thrombocytosis, TPO levels
Thrombopoietin (TPO, a glycoprotein, encoded by are high or inappropriately normal due to different
THPO gene located on chromosome 3q27) has a key role mechanisms which involve abnormal regulation of
in megakaryocyte production. Various cytokines (i.e. c-MPL receptor–mediated uptake of constitutively
interleukins, IL-6 and IL-11) play an add-on role.2 TPO is formed thrombopoietin. In essential thrombocythemia
synthesized mainly in liver and in small amount in kidney (ET), inappropriate high plasma free TPO occurs due to
and bone marrow. TPO prevents apoptosis, induces a clonal defect in megakaryocytic expression of c-MPL
mobilization of stem cells and stimulates megakaryocyte leading to defective binding of thrombopoietin.6
differentiation.3 Receptors for thrombopoietin (c-MPL In myeloproliferative neoplasm (except ET), reduced
receptors) are located on megakaryocytes and their number of thrombopoietin receptors on megakaryocytes
progeny. TPO in plasma act in two ways; it bind with leads to reduced TPO binding and thrombopoiesis
c-MPL on the circulating platelets and the free form usually does not increase.
of TPO stimulate megakaryocyte proliferation. The In ET, these platelet progenitors are also markedly
c-MPL receptor recruits and directly associates with hypersensitive to the action of the TPO leading to
cytoplasmic JAK2 to activate a wide array of downstream increased megakaryocytic proliferation and platelet
signalling pathways, promoting cellular survival and production.7
CHAPTER 128: Thrombocytosis: Clinical Approach 773
TABLE 1: Causes of thrombocytosis*

Spurious Secondary/reactive Primary/clonal
Microspherocytes Infection Essential thrombocythemia (ET)
Cryoglobulinemia Inflammation: Connective tissue disease Polycythemia vera
Neoplastic cell fragments Tissue damage Primary myelofibrosis
Schistocytes Acute blood loss Myelodysplasia with 5q del
Bacteria Hyposplenism Refractory anemia with ringed sideroblasts associated
with marked thrombocytosis (RARS-T)
Postoperative Chronic myeloid leukemia (CML)
Iron deficiency Chronic myelomonocytic leukemia
Malignancy Atypical CML
Hemolysis MDS/MPN-U
“Rebound”/recovery from POEMS syndrome
thrombocytopenia
Drug effect: Vincristine, all-trans retinoic Hereditary thrombocytosis: THPO, MPL or GSN gene
acid, cytokines, growth factors mutation
*Adapted with modification from Jonathan S Bleeker and William J Hogan et al.1
TABLE 2 : Differences between reactive and clonal thrombocytosis@

Secondary/reactive Primary/clonal
Underlying systemic disease Yes No
ESR, CRP Raised Normal
Digital or cerebrovascular ischemia No Characteristic
Large vessel thrombosis-arterial or venous No Increased risk
Bleeding No Increased risk
Splenomegaly No Yes, in 40%
Peripheral blood smear Giant platelet Normal platelet
Platelet function Normal May be abnormal
Bone marrow megakaryocytes Morphologically normal Giant, dysplastic forms, platelet debris
Molecular analysis Not required Specific to the cause
@ Adapted with modification from Andrew I Schafer, MD 13
CAUSES OF THROMBOCYTOSIS Peripheral blood smear examination and manual

The thrombocytosis can be due to spurious, reactive, platelet counting are simple techniques to rule out
or clonal causes (Tables 1 and 2).1 The most common spurious thrombocytosis.1
cause of thrombocytosis is reactive in nature. Reactive Thrombocytosis
It occurs as a response to infection, inflammation or
Spurious Thrombocytosis malignancy. The most important step in evaluation of
It occurs when automated cell counters counts thrombocytosis is to rule out reactive causes. Detailed
nonplatelet structures in blood as platelets i.e. history and clinical examination are pivotal to exclude
cryoglobulin crystals, trashes of circulating leukemic reactive thrombocytosis. Inflammatory markers
cells, bacteria, fragmented or very small red blood cells (C-reactive protein, ESR, Ferritin, IL-6) are significantly
and microvesicles as after massive burn.1 raised in reactive thrombocytosis.1,8
Flow chart 1: Approach to thrombocytosis
Abbreviations: CML, chronic myeloid leukemia; PMF, primary myelofibrosis; ET, essential thrombocytosis; MPN, myeloproloferative neoplasms
Source: Adapted with modification from Jonathan S Bleeker and William J Hogan et al. 1
Thrombocytosis can also occur as a rebound effect The myelodysplastic disorders related w ith
following drug or alcohol associated thrombocytopenia.9 thrombocytosis are the 5q-syndrome and refractory
If thrombocytosis occurs in iron deficiency state, one anemia with ring sideroblasts (RARS).
should suspect overt/occult blood loss. In CML, dysregulated clonal expansion of all cells
However, presence of a cause for reactive thrombo lines along the granulocytic maturation pathway occurs
cytosis does not exclude a concomitant clonal process with characteristic “Philadelphia chromosome” and
in case of persistent thrombocytosis as both may coexist. resultant BCR-ABL fusion protein. About half of the cases
of CML have thrombocytosis (Flow chart 1).10
JAK2V617F is an acquired point mutation, found in
Clonal Thrombocytosis
PV (95%), ET (40–60%) and PMF.1,11
Myeloproliferative neoplasms (MPNs) are characterized Other mutations in the JAK2 gene are also detected in
by a clonal expansion of particular lineage of mature PV in absence of V617F mutation.1 Mutations in the MPL
and/or maturing myeloid cells that arise from a common gene are found in PMF (5–7%), ET (1–4%) and not in PV.12
hematopoietic stem cell. The most common causes of MPL mutations are also found with JAK2V617F.12
clonal thrombocytosis are essential thrombocythemia TET2 mutations are found in myeloid disorders,
(ET), chronic myeloid leukemia (CML), polycythemia including PhMPNs (13%) and are more common in
vera (PV) and primary myelofibrosis (PMF). geriatric patients.1
PV is diagnosed on the basis of increased red cell In ET, recurrent spontaneous abortion and fetal
mass, low/normal serum erythropoietin and a clonal growth retardation occurs in 50% cases and are caused
marker (i.e. JAK2 mutation). 1 Thrombocytosis (50%) by multiple placental infarctions due to platelet
can be the only hematologic finding in PV, as the thrombosis.1,13
expected erythrocytosis can be concealed due to volume Though uncommon, bleeding can occur in clonal
expansion or with concomitant iron deficiency.1 thrombocytosis and is attributed to platelet function
PMF is diagnosed in view of peculiar bone marrow abnormalities along with acquired von Willebrand’s
findings including reticulin fibrosis along with syndrome resulting from increased absorption of large
megakaryocytic proliferation. Thrombocytosis (30%) is vWF multimers by the elevated circulating platelets.1
also found but the grading of thrombocytosis decreases
with disease progresses and mostly thrombocytopenia DIFFERENTIAL DIAGNOSIS
occurs due to splenomegaly.1 Clinical history and physical examination are important
Diagnosis of ET is essentially a diagnosis of exclusion. in differentiating reactive and clonal thrombocytosis.
The presence of an infective or inflammatory condition,
CLINICAL FEATURES hemolysis, blood loss or recent surgery or trauma points
Thromb o c ytosis is ass o ciate d w ith vas omotor to a reactive thrombocytosis. Conversely, vasomotor
s y m p t o m s ( h e a d a c h e, v i s u a l s y m p t o m s, l i g ht
symptoms, pruritus, splenomegaly and acral erythema
headedness, atypical chest pain, acral dysesthesia,
favor clonal thrombocytosis. Spurious thrombocytosis
erythromelalgia), bleeding (“platelet type” bleeding
can be excluded with the help of peripheral blood film
involving spontaneous hemorrhage at superficial sites
and manual platelet counting.
i.e. the skin or mucous membranes) or thrombotic
Rais e d er ythro c yte s e dimentation rate and
complications. 13 These symptoms does not correlate
C-reactive protein (acute phase reactant) favor reactive
with degree of thrombocytosis and are common in clonal
thrombocytosis.1,13 Giant megakaryocytes are feature of
thrombocytosis.1,13 The qualitatively normal interaction
MPN and hyposplenism.
between platelets and vessel wall may be the reason of
In peripheral blood film, leukocytosis with toxic
absence of these symptoms in reactive thrombocytosis.13
granules and Döhle bodies are seen in infection and
The major causes of morbidity and mortality in MPNs
chronic neutrophilic leukemia, 14 and hypochromia
are bleeding and thrombosis.13
with microcytosis suggests iron deficiency, Howell Jolly
Digital microvascular ischemia with palpable
peripheral pulses is characteristic of ET.13 Erythromelalgia bodies suggests hyposplenism and macrocytosis with
is also common in ET, characterized by intense burning dysplastic forms/platelet debris (platelet drifts) suggests
and/or throbbing pain with a patchy distribution in clonal neoplasm.13 A leukoerythroblastic blood film and
hands and feet with warmth, duskiness and mottled teardrop poikilocytes suggests primary myelofibrosis.
erythema of the involved areas.13 Thrombocytosis with a dimorphic blood film and
Neurologic complications are due to cerebrovascular Pappenheimer bodies is typical of refractory anemia with
ischemia (platelet-mediated) and present with ring sideroblasts and thrombocytosis.1,13
nonspecific symptoms such as chronic headache or Bone marrow aspiration-biopsy, cytogenetic and
dizziness or focal neurologic signs.13 molecular analysis are used when clinical features and
Venous thrombosis is more common in MPNs than blood smear remain inconclusive.
arterial thrombosis and may manifest as deep vein On bone marrow aspiration biopsy, large hyper
thrombosis, pulmonary embolism, intra-abdominal lobulated megakaryocytes are found in ET, normal in
thrombotic complications such as hepatic-vein reactive thrombocytosis, pleomorphic in PV, pleomorphic
thrombosis (Budd–Chiari syndrome) and portal-vein with dysplastic changes in PMF and smaller size in CML.
thrombosis.13 Reticulin fibrosis is characteristic of PMF.
On molecular analysis, BCR-ABL is found in CML, side effects which include fluid retention, palpitation,
JAK2 mutation in PV (almost 100%) and mutation of JAK2 arrhythmias, heart failure, and headache. So caution
(almost 50%) or MPL in ET or PMF. is required in aged patients or heart disease. The side
In the 5q-syndrome, macroc ytic anemia, effects of anagrelide decrease over time, but progressive
thrombocytosis and hypolobulated megakaryocytes are anemia develops in many patients.13
found. Interferon alfa is an effective, nonmutagenic agent
and is drug of choice in pregnancy as hydroxyurea is
TREATMENT teratogenic and anagrelide crosses the placenta.1,13
Secondary/reactive thrombocytosis is a self limited Hematopoietic stem cell transplantation can be
process and thrombocytosis reverts to normal when considered for selected young patients with advanced
the underlying cause resolves. In persistent reactive complicated clonal thrombocytosis.
thrombocytosis, occult cancer should be looked into and Aspirin is highly effective for vasomotor symptoms
a thorough search should be conducted. and as an adjunctive drug in ET if patient have recurrent
In clonal thrombocytosis, specific platelet lowering thrombotic complications, digital or cerebrovascular
therapy is required because these patients are at high risk ischemia. In PV, low-dose aspirin (100 mg per day) can
for thrombosis/bleeding. The risk of arterial thrombosis prevent thrombotic complications without increase in
the risk of major bleed.13
is more in ET than PV.15 The high risk patients include
PV patient requires therapeutic phlebotomy for
those with history of thrombosis or bleeding, leukocytosis
maintaining a hematocrit below 45% in men and below
(9.4 × 109/L), associated cardiovascular risk factors, or
42% in women.1 Hydroxyurea is needed in addition to
above 60-year-old.1,16
phlebotomy in high risk patients. Low dose aspirin is
Patients with ET with active cerebrovascular/digital
used in all cases of PV to reduce thrombosis. Interferon
ischemia should be treated urgently and aggressively
alfa is therapy of choice in pregnancy. JAK2 inhibitor
with platelet-lowering agents.
(Ruxolitinib) is used when hydroxyurea is ineffective/
Plateletpheresis is reserved for acute cerebrovascular
intolerant.1,13
complications, digital ischemia or active bleeding when
rapid depletion in the platelet count and symptomatic
Carry Home Message
relief are required.1
Reactive/secondary thrombocytosis is more common
Platelet reducing (cytoreductive) therapy is required
than clonal thrombocytosis.
in clonal thrombocytosis. Agents commonly used are Reactive thromboc ytosis resolves when the
hydroxyurea, anagrelide and interferon alfa.
underlying cause is identified and treated.
Hydroxyurea, a nonalkylating agent, is the platelet- The clonal thrombocytosis are associated with
lowering agent of choice because of its ease of use. It is thrombotic and bleeding complications.
given in dosage of 500 mg–2 gm/day and the common These patients require prophylactic platelet-
side effects include hyperpigmentation, rash, cytopenias cytoreductive therapy along with aspirin.
and skin ulceration. The only concern is its leukemogenic
potential, especially after prolonged use, in combination REFERENCES
with other drugs, or in cases of ET with 17p-deletion.13 1. Bleeker JS, Hogan WJ. Thrombocytosis: Diagnostic
Anagrelide is the alternative first-line platelet lowering evaluation, thrombotic risk stratification, and risk-based
therapy in patient of clonal thrombocytosis. Anagrelide is management strategies. Thrombosis. 2011;16:536062.
Article ID 2011;doi:10.1155/2011/536062.
nonleukemogenic and is drug of choice in young patients
2. Kaushansky K. Regulation of megakaryopoiesis. In:
of ET as they need therapy for platelet-count over long Loscalzo J, Schafer AI, eds. Thrombosis and hemorrhage.
period of time. However, it is intolerant in about 30 % 3rd ed. Philadelphia: Lippincott Williams and Wilkins. 2003.
patients due to its vasodilatory and positive inotropic pp. 120-39.
3. Hitchcock IS, Kaushansky K. Thrombopoietin from 10. Savage DG, Szydlo RM, Goldman JM. Clinical features at
beginning to end. Br J Haematol. 2014;165:259-68. diagnosis in 430 patients with chronic myeloid leukaemia
4. Wolber EM, Fandrey J, Frackowski U, Jelkmann W. Hepatic seen at a referral centre over a 16-year period. British
thrombopoietin mRNA is increased in acute inflammation. Journal of Haematolog. 1997;969(1):111-6.
Thromb Haemost. 2001;86:1421-4. 11. Kralovics R, Passamonti, Buser AS, et al. A gain-offunction
5. Kaser A, Brandacher G, Steurer W, et al. Interleukin-6 mutation of JAK2 in myeloproliferative disorders. NEJM.
stimulates thrombopoiesis through thrombopoietin: role in 2005;352(17):1779-90.
inflammatory thrombocytosis. Blood. 2001;98:2720-5. 12. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in
6. Teofili L, Pierconti F, Di Febo A, et al. The expression pattern
myeloproliferative disorders: analysis of the PT-1 cohort.
of cmpl in megakaryocytes correlates with thrombotic risk in
Blood. 2008;112(1):141-9.
essential thrombocythemia. Blood. 2002;100:714-7.
13. Schafer AI. Thrombocytosis. N Engl J Med. 2004;350:1211-
7. Axelrad AA, Eskinazi D, Correa PN, Amato D. Hypersensitivity
19.
of circulating progenitor cells to megakaryocyte growth
14. Bain BJ, Ahmad S. Chronic neutrophilic leukaemia and
and development factor (PEG-rHu MGDF) in essential
thrombocythemia. Blood. 2000;96:3310-21. plasma cell-related neutrophilic leukaemoid reactions. Br J
8. Tefferi A, Ho TC, Ahmann GJ, Katzmann JA, Greipp PR. Haematol. 2015;171(3):400-10.
Plasma interleukin-6 and C-reactive protein levels in 15. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and
reactive versus clonal thrombocytosis. American Journal of neoplastic risk in a large cohort of patients with polycythemia
Medicine. 1994;97(4):374-7. vera. Journal of Clinical Oncology. 2005;23(10):2224-32.
9. Haselager EM, Vreeken J. Rebound thrombocytosis after 16. Carobbio A, Antonioli E, Guglielmelli P, et al. Leukocytosis and
alcohol abuse: a possible factor in the pathogenesis of risk stratification assessment in essential thrombocythemia.
thromboembolic disease. Lancet. 1977;1:774. Journal of Clinical Oncology. 2008;26:2732-6.
CHAPTER
129
Macrophage Activation Syndrome
Tarun Kumar Dutta, Tony Kadavanu, Arunkumar Ramachandrappa
INTRODUCTION been described by Ramachandran B et al. The authors

Described first by Hadchouel et al. in 1985, and later studied retrospectively 33 children who were diagnosed
coined in 1993 by the same group, macrophage activation to have HLH during a 2-year-period. In this cohort of
syndrome (MAS) represents a potentially life threatening, patients, 58% were male. The median age at diagnosis
hyper-inflammatory complication of rheumatologic of HLH ranged from 50 days to 14 years (median 33
disorders. Often considered a type of hemophagocytic months). The overall mortality was 24%.
lymphohistiocytosis (HLH), it is most commonly seen
with systemic juvenile immuno arthritis (sJIA) and adult ETIOPATHOGENESIS AND TRIGGERS
onset Still’s disease. There is an excessive activation of While the precise etiology of MAS is unknown, it is often
macrophages and T cells. This activation in turn results considered to be due to abnormal immune regulation
in excessive cytokine production and hemophagocytosis leading to an exaggerated inflammatory response
leading to an overwhelming, and potentially fatal, (Fig. 1). The various triggers are described in Table 1.
inflammatory response involving multiple organ systems.
It mainly affects children, though there are reports of CLINICAL FEATURES
adult onset as well. The evolution of clinical features is often rapid which
may cause patients to become acutely, significantly
EPIDEMIOLOGY unwell. The onset is usually with sudden occurrence of
Since there are no well-established diagnostic criteria for nonremitting high fever, liver enlargement, splenomegaly
MAS, the epidemiology is unclear. In the context of sJIA, and generalized lymphadenopathy. Common to all forms
the largest population based study demonstrated that of MAS and familial hemophagocytic lymphohistiocytosis
MAS occured more frequently in girls, with a female-to- (fHLH) is fever, typically high and sustained in nature.
male ratio of 6:4. This is in contrast to sJIA which has an However, since biologic agents are now frequently used
equal male to female ratio. The median age at onset of to treat rheumatologic disorders that can result in MAS,
sJIA was 5.3 years, the median time interval between the even fever is not an absolute finding in all cases of MAS.
onset of sJIA and MAS was 4 months. In 22.2% patients, The other clinical findings are summarized in Table 2.
MAS and sJIA were diagnosed simultaneously with a Mortality risk is higher in those with renal dysfunction.
mortality rate of 8.1%. Renal, pulmonary, and cardiac involvement may develop
A large case series of hemophagocytic syndromes, in very sick patients, who then progress to develop
including MAS, seen in tertiary care hospitals in India has multiorgan failure.
CHAPTER 129: Macrophage Activation Syndrome 779
Fig. 1: Pathogenesis of macrophage activation syndrome (MAS)
TABLE 1: Triggers for MAS TABLE 2: Clinical features of MAS

Rheumatologic SLE, sJIA, Kawasaki disease, polyarticular JIA, CNS Encephalopathy, lethargy, irritability, disorientation,
juvenile dermatomyositis, antiphospholipid headache, cranial nerve palsies, ataxia, seizures, or
syndrome, mixed connective tissue disease coma
Infection Viral infections [Epstein-Barr virus (EBV), Bleeding Hemorrhagic, disseminated intravascular coagulation
cytomegalovirus , hepatits A/B/C and herpes diasthesis (DIC) like syndrome causing skin rashes ranging from
viruses] mild petechiae to purpura and extensive ecchymoses
Bacterial infections [Staphylococcus, Salmonella, Bleeding from other sites (e.g. respiratory and
gastrointestinal tract)
Legionella, Mycoplasma and Ehrlichia]
Fungal infections [Histoplasma and Respiratory Pulmonary infiltrates, acute respiratory distress
Cryptococcus] syndrome
Tuberculosis Renal Renal dysfunction
Parasitic infections [Leishmania and
Toxoplasma]
due to inflammation and not due to bone marrow
Oncologic T-cell leukemia/lymphoma, Hodgkin and non-
Hodgkin lymphoma suppression since aspirates from the bone marrow
Solid tumors, such as hepatocellular carcinoma in patients with MAS often show increased cellularity
and lung cancer and normal megakaryocytes.
Hemophagocytic syndrome is also a recognized
complication following hematopoietic stem cell
Ferritin: The laboratory finding most suggestive
transplantation used to treat severe JIA of MAS is a markedly elevated serum ferritin level
(often >10,000). This is thought to be due to excessive
erythrophagocytosis with the resultant free iron
LABORATORY FEATURES being sequestered. Proinflammatory cytokines such
Hematologic: One of the earliest events to occur as, IL-1 and IL-6 which are increased in MAS can
is a decrease in two of the three blood cell lines also upregulate ferritin expression (Flow chart 1).
(leukocytes, erythrocytes and platelets) with In the absence of pre-existing liver disease, a highly
thrombocytopenia generally occurring first. This elevated serum ferritin, combined with elevated liver
decrease in cell counts is as a result of increased enzymes, in a febrile hospitalized patient is both
cell destruction by phagocytosis and consumption highly sensitive and specific for the diagnosis of MAS.
Flow chart 1: Pathogenetics of MAS. Genetic mutations lead to a sequence of events that ultimately lead to cytokine storm and MAS
Raised liver enzymes: Aspartate aminotransferase the presence of hypofibrinogenemia and liver
[AST] and lactate dehydrogenase [LDH]. dysfunction.
Ominous trends: A falling ESR with either an increasing
Hypertriglyceridemia C-reactive protein or a rising serum follistatin-like
Markers of coagulopathy such as elevated D-dimers protein 1 have been found to be associated with bad
and hypofibrinogenemia prognosis.
Elevated markers of inflammation e.g. C-reactive Hemophagocytosis: Hemophagocytosis in bone
protein, soluble IL-2 receptor alpha chain [sCD25] marrow though helpful to confirm the diagnosis of
Paradoxical ESR : Er ythrocyte sedimentation HLH, is often absent, especially in the early stages.
rate (ESR), the common marker of nonspecific One study found hemophagocytosis in only 60.7%
inflammation, may be relatively low because of of patients with MAS in their initial bone marrow
examination. Serial bone marrow biopsies may be Currently, only specialized immunology or research
required to demonstrate hemophagocytosis in the laboratories can measure NK cell function and soluble
negative cases. However, this is not essential for a interleukin 2 receptor α chain (sIL-2Ra, CD25) which
diagnosis of MAS to be made. are required by the HLH 2004 criteria.
A critically ill child with coagulopathy should not
DIAGNOSTIC CRITERIA be made to undergo bone marrow biopsy just to detect
Since MAS is considered clinically similar to HLH, hemophagocytosis.
some recommend the use of the HLH-2004 (Table 3) The above tests, thus, may not be available in time
diagnostic guidelines, which were developed mainly to which can cause a delay in initiation of appropriate
diagnose homozygous genetic disorders leading to fHLH. treatment which may be detrimental to the patient.
Consensus-derived classification criteria for MAS in
Limitations of 2004 HLH Criteria sJIA have recently been published to help distinguish
active sJIA from MAS (Table 3). The platelet count and
Absolute drop: Owing to the inflammatory nature of sJIA,
fibrinogen levels do overlap with the normal range.
it would be more useful to consider a relative drop in
However, it is these levels when present in a child with
white blood cell count, platelets or fibrinogen instead of
significant systemic inflammation that should raise
the absolute decrease which is required by the HLH-2004
suspicion of MAS.
criteria to make an early diagnosis.
Ferritin levels: The diagnosis of HLH requires a ferritin FURTHER APPROACH
level of above 500 ng/mL. This low threshold may not Once diagnosed, the underlying cause should be looked
discriminate MAS from a flare of sJIA since many patients into by searching for genetic mutations using flow
with active sJIA, have ferritin levels above that level even cytometry. Specific mutations should then be confirmed
in the absence of MAS. In the acute phase of MAS, ferritin using molecular genetic analysis. Viruses such as EBV,
levels may have values >5000 ng/mL. CMV, adenovirus, parvovirus B19, human herpes virus
6, HSV, human herpes virus 6 and varicella zoster virus
TABLE 3: MAS diagnostic criteria should be screened using PCR . If a bone marrow biopsy
is performed, a sample should also be sent for PCR
Revised 2004 diagnostic criteria 2016 criteria of MAS in sJIA
for HLH
looking for leishmania infection.
Either: A febrile patient or suspected
zz Molecular genetic sJIA with: DIFFERENTIAL DIAGNOSIS
confirmation zz Ferritin >684 µg/L and
Several conditions can closely mimic MAS (Table 4).
or zz Any two of the following:
Five of the following: 9

—— Platelets ≤181x10 /L However, an early diagnosis is paramount to timely
zz Fever —— AST >48 IU/L selection of appropriate therapeutic interventions.
zz Splenomegaly —— Triglycerides >156 mg/dL
zz At least two of the following: —— Fibrinogen ≤3.6 g/L
—— HB <90 g/L MANAGEMENT

9
—— Platelets <100 x 10 /L
9
Central to the management of MAS is its early recognition,
—— Neutrophils <1 x 10 /L
zz Either of:
which requires increased awareness of the condition
—— Fasting triglycerides ≥265 amongst the medical community, followed by prompt
mg/dL treatment.
or
—— Fibrinogen ≤1.5 g/L
Steroids: High-dose intravenous (IV) methylprednisolone
zz Ferritin ≥500 µg/L
zz Tissue hemophagocytosis (30 mg/kg, maximum 1000 mg, daily for 3 d) followed by
zz Decreased NK cell function oral prednisolone 2–3 mg/kg/d in divided doses are
zz sIL–2R ≥ 2400 U/mL
usually part of the initial treatment regimen.
TABLE 4: Differential diagnosis

Conventional sJIA flair An absence of arthritis and serositis, a hemorrhagic rather than maculopapular rash and a sudden drop in ESR
are highly suggestive of MAS
Juvenile SLE Hyperferritinemia is a key discriminator between a SLE flare and SLE-induced MAS
FHLH/virus associate Onset at a very young age, positive family history, and more profound cytopenias are clues to differentiate FHLH
HLH (VA-HLH) from MAS
Neutrophil count and CRP were significantly higher in patients with MAS
Soluble CD25 level <79,000 U/l indicated MAS
Thrombotic Microangiopathic anemia with the finding of fragmented red blood cells in the peripheral blood smears, is not
thrombocytopenic typically seen in MAS
purpura (TTP)
Infections Intracellular bacterial infections and zoonotic diseases frequently presenting with hepatosplenomegaly and
leukopenia, such as Brucella, Rickettsia spp, and visceral leishmaniasis, bear a close resemblance to MAS
It is also important to consider epidemics caused by hemorrhagic fever viruses (e.g. dengue, Crimean-Congo,
and possibly Ebola) as causes of potentially treatable MAS
Cyclosporin: Cyclosporin (2–7 mg/kg/d IV) is often used MAS occuring in patients while taking these drugs have
as a second line agent in steroid ineffective cases. Several also emerged.
case series have found it to be effective under these
Anakinra: It is a recombinant, nonglycosylated form of
circumstances.
human IL-1Ra. It blocks the biologic activity of both IL-
IVIg: Intravenous immunoglobulin (IVIg, 2 g/kg in a 1α and IL-1β by competitively inhibiting their binding
single dose) can be considered, when it is difficult to to IL-1R. It is now widely used for the treatment of sJIA
exclude sepsis. and, occasionally, MAS. The consensus is that anakinra,
particularly at higher doses, might be effective at least in
Etoposide: Etoposide may be considered as part of the
some patients with sJIA-associated MAS.
HLH-2004 treatment protocol. It is metabolized by
the liver and excreted by the kidneys. Severe MAS can Rituximab: A monoclonal antibody against CD20,
impair both these organs thus leading to toxicity. It can rituximab has been found to be effective in cases of MAS
have side effects such as bone marrow suppression and caused by Ebstein Barr virus.
overwhelming sepsis which may be reduced by using
Tocilizumab: It is a monoclonal antibody against the
lower doses of etoposide.
IL-6 receptor. It has been found to be effective in the
ATG: Patients with MAS who have renal or hepatic treatment of sJIA in several trials.
involvement, antithymocyte globulin (ATG) can be used
Future therapies: The targets in pathways that trigger the
as an alternative to etoposide. Generally it is tolerated
cytokine storm (Flow chart 1) are INF ϒ and IL-18 and
well, however it is known to cause infusion reactions
trials of drugs which block them are ongoing.
especially in the context of hematopoietic stem cell
transplantation.
CONCLUSION
MAS is a potentially life threatening complication
BIOLOGICALS
of rheumatologic conditions in children. Important
In the past decade, biologic agents have been given to
clinical features include fever, lymphadenopathy,
treat steroid- and cyclosporin-refractory MAS.
h epato spleno me ga ly, c yto p e nias a nd extreme
Tumor necrosis factor inhibitors: These drugs have shown hyperferritinemia. It is crucial to recognize and treat
efficacy in some cases. Unfortunately some reports of it early. Consensus criteria for diagnosis of MAS in
the context of sJIA will help with this process. Initial BIBLIOGRAPHY
treatment revolves around supportive care and high- 1. Bracaglia C, Prencipe G, Benedetti FD. Macrophage
dose corticosteroids with addition of cyclosporin activation syndrome. Pediatric Rheumatology. 2017;15:5
for unresponsive cases. Etoposide or ATG have also 2. Cron RQ, Davi S, Minoia F, Ravelli A. Clinical features and
correct diagnosis of macrophage activation syndrome.
been used, in refractory cases. Anakinra however is
Expert Rev Clin Immunol. 2015;11:1043-53.
increasingly being reported as the next step after steroids
3. Sen ES, Steward CG, Ramanan AV. Diagnosing haemo
and cyclosporin. phagocytic syndrome. Arch Dis Child. 2017;102:279-84.
CHAPTER
130
Hemotransfusion Therapy: Boon or Bane?
Anil Kumar Gupta
INTRODUCTION with thrombocytopenia, granulocytes for severe

Modern blood transfusion or hemotherapy started leukopenic patients as in fulminating septicemia or
during world war II following massive requirement after chemotherapy; plasma provides clotting factors,
of blood for war victims and saved many lives; but essential for normal coagulation. The hemotherapy is
not without transfusion reactions. Hemotransfusion- an integral part of modern medical care; thus it will be
reduced morbidity and mortality; however the world better to have an overview of important components of
also witnessed increased incidence of transfusion- hemotherapy.
a s s o c i a t e d h e p a t i t i s a n d re a c t i o n s f o l l o w i n g
transfusion. Components and availability of coagulation Hemothearpy with Whole Blood
factors improved the precision and effectiveness Whole blood is most common and frequently used
of hemotherapy, however new emerging pathogens such product in hemotherapy to raise the oxygen carrying
as HIV posed a serious threat for safe hemotransfusion. capacity. One unit of whole blood should raise
Screening assays for various infectious diseases and hemoglobin (Hb) by 1–1.5 g/dL in an adult. The rise of
other surrogative markers in blood have started to reduce Hb should be evaluated 24–48 hours after transfusion to
the transfusion such as transmitted infections (TTI). allow adjustment of transfused volume.
Nevertheless, other transfusion hazards e.g. human Whole blood has limited indication as in acute
error results in wrong blood transfusions and hemolytic hemorrhage or exchange transfusion with simultaneous
reactions, immunologic reactions such as transfusion- need of RBCs and plasma. It is contraindicated in
related acute lung injury (TRALI), transfusion-associated chronic anemia for fear of pulmonary edema and heart
graft-versus-host disease (TA-GVHD); are concern for failure because of volume overload. Whole blood, as
safe hemotransfusion.1 traditionally thought, is not an ideal for hemotherapy.
Platelets, coagulation proteins and granulocytes are
HEMOTHERAPY: A PRECIOUS lost or become nonviable during storage, thus become
TOOL FOR HUMANS ineffective.
Hemotherapy is a life-saving measure when correctly
administered, it relieves morbidity and reduces Red Blood Cells
mortality. Whole blood may be used to replace volume Red blood cells (RBCs) are ideal in patients with chronic
and blood cells lost during hemorrhage; red cells are anemia to raise oxygen-carrying capacity. Normally,
essential for oxygen delivery; platelets in patients about 25% oxygen is extracted from RBCs at tissue
CHAPTER 130: Hemotransfusion Therapy: Boon or Bane? 785
level, however with increased demand, extraction of Additional dosage may be required, if prothrombin time
oxygen can go upto 50%. No more oxygen is extracted is > 1.5 times of normal or INR is > 2.0. Factor VII, VIII, IX
with further increased demand, and compensatory have their half life < 24–48 hrs, thus necessitate daily FFP
hemodynamics sets in patients including trachycardia transfusion till coagulation return normal.
(>100/min), tachypnea (>30/min ), dizziness, weakness, FFP should not be used as volume expanders due to
angina and decreased mental response. RBCs are risk of TTI, allergic reaction and TRALI. FFP should be
contraindicated for treatment of nutritional anemia ABO compatible and Rh-typing is not required.
(iron, folic acid, vitamin B12 deficiency); not to be given as
tonic to enhance the general well being, promote wound HEMOTHERAPY, INHERENT RISKS
healing or infection;2 due to inherent risk of TTI. One unit Hemothearpy although saves lives but not without risks
of RBCs should raise a Hb. By 1–1.5 g/dL in an adult, but and complications. Each component of hemotransfusion
increment appears more rapidly than the whole blood. is a potential source of inherent risks, thus required
a judicious management of hemotherapy. Various
Platelets concerns are:
Platelets are frequently used in thrombocytopenia,
due to increased destruction (e.g. DIC) or decreased Risks with RBCs
thrombopoiesis (e.g. chemotherapy). Platelets are Hemolytic transfusion reactions (HTR): HTR are mostly
prepared from a unit of blood is called random donor due to ABO incompatible RBCs or plasma. They can
platelets (RDP), while from apheresis machine is called be of immediate HTR or delayed HTR usually 3–7 days
single donor platelets (SDP). after transfusion. Immediate HTR shows fever, chills,
A unit of RDP should raise platelets by 5–10000/ chest pain, back pain, hypotension, abdominal pain and
µL; and SDP should raise by 20–60000/µL in an adult hemoglobinuria, shock, anemia, oliguria, DIC. Delayed
from initial count.Platelets increment may be less with HTR, are less severe,occur when a sensitized patient
splenomegaly, high fever, septicemia, DIC, hemorrahge (either through pregnancy or previous hemotransfusion)
and platelet antibodies. Platelets count done between 10 receives incompatible RBCs. Patients show slow fall of
min and 60 min of transfusion, are less likely affected by Hb, fatigue, and jaundice often go unnoticed.3
above variables. If HTR occurs, transfusion should be stopped, vitals,
Platelets of same ABO group as that of patients renal output maintained through infusion and vasoctive
is selected for transfusion. ABO incompatible plate drugs should be given.
lets may be given in emergency but show lesser
increment after transfusion. Rh immunoglobulins are Risks with Leukocytes
given prophylactically with transfusion of platelets Febrile nonhemolytic transfusion recation (FNHTR):
contaminated with Rh positive RBCs in women of Hemotransfusion may initiate a severe febrile
reproductive age group. A vial of Rh immunoglobulin reaction, due to leukocytes present in the blood.
containing 300 µg is sufficient for 3 SDP or 30 RDP.2 Leukodepleted reduced products minimize this
FNHTR.
Fresh Frozen Plasma Transfusion-related acute lung injury (TRALI): TRALI
Plasma is separated from RBCs and frozen within 6 hours is now the most frequent cause of reaction with high
of collection; is fresh frozen plasma (FFP), contains all fatality due to leukocyte antibody in donor plasma.
coagulation factors, used to treat multiple or single factor Antibodies directed against leukocytes are formed
deficiency to stop or prevent bleeding. in donor plasma as a result of the sensitization with
Dose of FFP is 10–15 mL/kg of body weight; usually past pregnancies or hemotransfusion. Patients have
4–6 units of FFP are required to correct coagulopathy. dyspnea, hypotension, fever and rigors soon after the
reaction followed by pulmonary edema and hypoxia. induced) reaction. Patient may be over-transfused
The administration of oxygen with respiratory resulting in hypervolemia, develops dyspnea,
support, is vital in the acute stage of TRALI. cyanosis, cough, frothy blood-tinged sputum. It may
Transfusion-associated graft versus host disease be fatal, if not treated promptly; transfusion should be
(TvGVHD): TA-GVHD occurs when transfusion stopped and administer diuretics.
is from first or second degree donors in a poorly
developed or immunocompromised patients, e.g. Bacterial Contamination Risk
lymphoma,bone marrow suppression, fetus with Bacterial contamination of blood may follow rapid
intrauterine transfusion, newborn with exchange onset and death. Bacteria can get entry in a blood from
transfusion. T-lymphocytes present in transfused the skin during phlebotomy. Platelets rather than RBCs
blood, engraft in the recipient, proliferate at the are more prone for bacterial contamination due to its
cost of native cell population and is invariably storage temperature of 22–24°C. patients may have chills,
fatal. TA-GVHD occurs 1–6 weeks after transfusion. headache, vomiting, muscular pain, diarrhea, high fever,
Patients may have diarrhea, abdominal pain, nausea hypotension and shock within 30 min. The transfusion
and vomiting, jaundice and skin rash. No definite should be stopped, infuse broad spectrum antibiotics
treatment is available, therefore prevention is the and maintain vitals.
only way. Leukoreduced components reduces
occurence but not eliminated totally. Irradiating Transfusion-transmitted Infections
blood components is ideal to prevent TA-GVHD In India, all blood donations are subjected for mandatory
tests for HIV, HBV, HCV, syphilis and malaria that make
Risks with Plasma hemotherapy safe.
Allergic reactions: Most commonly noted reaction in Hepatitis: Strengthening of surrogate markers in the
wards; is due to sensitization with plasma proteins wake of the AIDS epidemic and screening for HCV,
and occurs in about 1% of transfusion. It is mediated incidence for hepatitis has come down (i).
through IgE; antigen antibody complex is attached on H I V : I n c i d e n c e d e c r e a s e d m a r k e d l y f o r
mast cell, histamine is released, produces vascular HIV transmission after screening for HIV. HIV
dilatation and increased vascular permeability. is still possible from a donation during window
Reaction occurs within 30 minutes of transfusion phase,although newer generation kit, incorporation
and cause urticaria, pruritis, hives and weals. Fever is of p24 antigen and NAT testing has reduced the risk
usually not present. Edema of the face, lips or mouth considerably
results in respiratory distress. Treatment is to stop Syphilis: Treponema pallidum, causative agent of
transfusion immediately and administer a suitable syphilis, cannot survive at 4°C if blood is stored 48–72
antihistaminic. hrs, thus incidence of transmission is nil.
Anaphylactic reactions: Antibodies to IgA appear to Malaria: Malaria can be acquired by receiving blood
be a cause, developed in patients sensitized through from asymptomatic donor, and is the most common
past pregnancies or hemotransfusion. They are of complication of hemotransfusion. Plasmodium can
immediate hypersensitivity type, vary from mild survive at storage temperature of 4°C for a week.
urticaria to severe anaphylactic shock, can be fatal, Incorporation of sensitive tests with higher sensitivity
if immediate intervention is not done. Transfusion for malaria has reduced the transmission.
should be stopped immediately; and adrenalin Emergent infections: Dengue fever virus, West Nile
administered. Corticosteroid may also be helpful. virus (WNV), Trypanosoma cruzi (Chaga’s disease),
TACO: Transfusion-associated circulatory overload Babesia sp (babesiosis), human herpes virus-8 (KS
(TACO) is an example of iatrogenic (physician- virus), variant Creutzfeld-Jakob disease (vCJD), ZIKA
CHAPTER 130: Hemotransfusion Therapy: Boon or Bane? 787
virus etc are newly emergent infections, and pose SUMMARY

threats to safe hemotransfusion. No blood transfusion is ideal or 100% safe. Tremendous
progress has been made in recent times for safer
Biochemical Risks hemotransfusion. However at times, it is not possible
Heterogeneous group of hemotherapy causing reactions: to add new and lengthy test protocols to each and every
Citrate toxicity: Citrate is present as preservative.
emerging threat. Unknown pathogens in future may
Citrate toxicity occurs, if large volume of blood is make hemotherapy more challenging; which hopes to
transfused with impaired liver functions. Citrate be addressed with due course of time for the benefit of
chelate calcium and causes hypocalcemia; however, mankind.
the replacement of calcium to treat hypocalcemia
should be carefully monitored to avoid overdose. REFERENCES
Potassium toxicity: Extracellular efflux of potassium 1. Alter HJ, Klein HG. The hazards of blood transfusion in
occurs during storage and may result in hyperkalemia historical perspecyive. Blood. 2008;112:2617-26.
with impaired renal function; and precipitates cardiac 2. Harmening DM. Modern blood banking and transfusion
practices. 6th edn. Philadelphia; FA Devis company. 2005.
arrest. These patients will require hemotransfusion
pp. 336-58.
with RBCs rather whole blood.
3. Pineda AA, Brzica SM, Taswell HF. Hemolytic transfusion
Iron overload: Iron overload is chronic complication
reaction: recent experience in a large blood bank. Mayo Clin
in chronically transfused patients, as in thalassemics. Proc. 1978;53:378-90.
Iron gets accumulated around internal organs and
may become life-threatening. Iron-chelating agents
are available to prevent this complication.
CHAPTER
131
Idiopathic CD4 Lymphocytopenia
Bhupendra Gupta, Harpreet Singh
INTRODUCTION a maturation or differentiation problem. Early aging of

Idiopathic CD4+ T cell lymphocytopenia (ICL) is CD4+T cells, low CD8+ T cells and surface expression
suspected when a patient presents with opportunistic defects of the CXCR4 may occur. Low B-cells, low NK
infections similar to a HIV infected individual but cells, and the T cell receptor transduction pathway
repeated testing yields a negative HIV status and abnormalities were also seen in some reports.
no other causes of immunodeficiency. It was first Few specific genetic mutations have been discovered
described in 1992 by CDC in the US.1 Patients with ICL in a small number of patients of ICL.
may also present with malignancies, or autoimmune
disorders.2 Most of the cases reported from India involve CLINICAL MANIFESTATIONS
cryptococcal or Pneumocystis infection in such patients. Patients with idiopathic CD4+ T cell lymphocytopenia
(ICL) are usually symptomatic, although upto 20%
PATHOGENESIS maybe asymptomatic.5,6 Large studies done in 1992 and
Idiopathic CD4+ T cell lymphocytopenia (ICL) is a case reviews in 2013 describe the frequency of various
heterogenous group of disorders with a common manifestations mentioned.
denominator of low CD4 cell count, hence similarity to Common presentations in symptomatic individuals
HIV led to a search for infective etiology.3 Prevalence include-opportunistic infections, malignancies, and/
of ICL is more among intravenous drug users and or autoimmune disorders.7 Allergic conditions are also
hemophiliacs, retroviral screening of blood donors sometimes seen.
yielded negative results. No definite infectious agent Clinical manifestations in ICL occur usually when the
could be isolated. absolute CD4 cell count drops below 200 cells/mm3.
The increased activation and turnover of CD4+ cells
in patients with ICL, as well as accelerated CD4 + cell INFECTIONS
apoptosis may be responsible for cytopenia.4 Apoptosis Infections common in ICL are common pathogens,
may be associated with enhanced expression of Fas and such as human papilloma virus (HPV) and varicella
Fas ligand. This occurs inspite of a preserved thymic zoster virus, and opportunistic organisms, especially
function. Cryptococcus and mycobacteria.5 These infections occur
The alpha/beta and gamma/delta T cell repertoires usually as a consequence of CD4 lymphopenia although
of ICL patients are highly restricted4 possibly indicating Tuberculosis itself might cause lymphopenia.
CHAPTER 131: Idiopathic CD4 Lymphocytopenia 789
Malignancies associated with ICL Autoimmune disorders in ICL EVALUATION

Non-Hodgkin lymphomas Sjögren’s syndrome (most Due to absence of any consensus criteria, a basic approach
Leptomeningeal lymphomas8 common) can be used as described:
Intravascular cerebral lymphomas Sarcoidosis
Complete blood cell count and differential –
EBV-related lymphoproliferative Idiopathic thrombocytopenic
disease and Burkitt lymphomas purpura commonly demonstrate lymphopenia.
Kaposi sarcoma Autoimmune hemolytic CD4+ T counts by flowcytometry - should be below
Vulvar carcinoma anemia
Systemic lupus 300 cells/mm3 or less than 20% of total lymphocytes
erythematosus5 on several occasions separated by time.
Antiphospholipid antibody
Delayed type hypersensitivity (DTH) testing, typically
syndrome5
Polyarteritis/vasculitis with candida and tetanus toxoid antigens. Degree
Thyroiditis of lymphopenia determines the response to DTH
Psoriasis
Behçet’s-like syndrome testing.
Measurement of serum immunoglobulins (IgG, IgA,
Cryptococcus: Cryptococcal meningitis is the most and IgM)4 – Immunoglobulin levels may be normal
common presenting opportunistic infection in most or slightly low. Lymphocyte proliferation Assays-
series published.5 Involvement of bone (osteomyelitis), proliferation may be depressed or normal.
Measurement of serum specific antibodies to
skin, and musculoskeletal systems, and may occur before
disseminated infections. vaccines 4- Results are usually normal if the only
detectable defect is CD4 lymphopenia.
Human papilloma virus: Persistent genital infection with
HIV-1, HIV-2, tuberculosis, hepatitis B and C, and
HPV is a common infection in patients. Types 2, 3, and 18
several other viruses-EBV, CMV, HHV-6, RSV, HTLV-
cause various clinical manifestations, including chronic
1 and 2, need to be excluded which can also cause
pruritic papules, skin warts, anogenital dysplasia, and
lymphopenia sometimes transient.
Bowen’s disease.
Other possible tests—These might help depending on
Mycobacterial infections: Patients with ICL may suffer historical/epidemiological clues:
from mycobacterial infections, including tuberculosis Peripheral blood mononuclear cells (PBMCs)
and nontuberculous mycobacterial infections. cultures for unidentified pathogens.

To differentiate tuberculosis as the cause or effect of Disseminated fungal infections—Evaluation may
the disease is challenging. Under such circumstances, include blood cultures, serum cryptococcal antigen,
the diagnosis of ICL cannot technically be made until the galactomannan testing for Aspergillus, and image
tuberculosis infection has been treated; at which point, guided biopsies depending on clinical scenarios.
lymphocytopenia should be reassessed. Serologic assays for measles virus and human
Varicella-zoster virus: Varicella-zoster virus, some papilloma virus (HPV).
times affecting multiple dermatomes simultaneously can
be seen. DIAGNOSIS
Candida: Chronic mucocutaneous candidiasis is also Idiopathic CD4 lymphocytopenia (ICL) is a diagnosis
seen in almost 8% of total infections.5 of exclusion. CD4+ T cell counts below 300 cells/mm3
Children may rarely present with recurrent bacterial or less than 20% of total lymphocytes on at least two
infections. separate analyses. The testing should be atleast one to
Pneumocystisjiroveci, Aspergillosis, EBV, CMV, Toxo three months (usually six weeks) apart. Immunological
plasmosis, Histoplasmosis, JC virus, Nocardia and many abnormalities or predisposing infections that cause
other unusual pathogens are known to occur with ICL. lymphopenia should be absent.
The clinical presentation includes differentials PROGNOSIS

like HIV, sarcoidosis, immunosuppressive states like It depends on the degree and duration of immuno
neoplasia and postchemotherapy status. However, an suppression along with severity of infections. Transient
isolated low but stable CD4 unlike HIV, points to ICL. lymphopenia can occur in a small subset whereas
OKT 4 epitope deficiency is supected when profoundly stabilization of CD4 at a lower set point is commonly
low CD4 counts occur in absence of infections. seen. This is unlike HIV where the CD4 continues to fall
in absence of ART. Associated low CD8 and low NK cell
TREATMENT counts portend a bad prognosis.
In the absence of any standard treatment, it is the
management of associated conditions and the prompt REFERENCES
treatment of infections which is the major focus. 1. Smith DK, Neal JJ, Holmberg SD. Unexplained opportunistic
Infections (such as mycobacteria) further deplete the infections and CD4+ T-lymphocytopenia without HIV
CD4 cell pool, and treatment may improve the degree of infection. An investigation of cases in the United States.
The Centers for Disease Control Idiopathic CD4+
CD4 specific lymphopenia.
T-lymphocytopenia Task Force. N Engl J Med. 1993;328:373.
Prophylaxis against infections—Antimicrobial
2. Ahmad DS, Esmadi M, Steinmann WC. Idiopathic CD4
prophylaxis for opportunistic infections is suggested Lymphocytopenia: Spectrum of opportunistic infections,
when CD4+ T cell counts fall below 200 cells/mm 3, malignancies, and autoimmune diseases. Avicenna J Med.
using the protocols similar to HIV infected patients. 2013;3:37.
Measurement of CD4 counts twice yearly would be 3. Núñez MJ, de Lis JM, Rodríguez JR, et al. Disseminated
encephalic cryptococcosis as a form of presentation
appropriate in most cases. Patients who present with an
of idiopathic T-CD4 lymphocytopenia. Rev Neurol.
opportunistic infection should be appropriately treated
1999;28:390.
and then started on secondary prophylaxis for that 4. Nielsen-Saines Karin. Idiopathic CD4+ lymphocytopenia
particular organism especially in case of recurrences. In: UpToDate, Feldweg Anna (Ed), UpToDate, Waltham, MA,
Need for prophylaxis can be reconsidered if CD4 counts 2013.
improve on therapy. 5. Zonios DI, Falloon J, Bennett JE, et al. Idiopathic CD4+
lymphocytopenia: natural history and prognostic factors.
Immunoglobulin replacement should be considered
Blood. 2008;112:287.
for children with recurrent serious bacterial infections as
6. Régent A, Autran B, Carcelain G, et al. Idiopathic CD4
a presenting symptom. lymphocytopenia: clinical and immunologic characteristics
and follow-up of 40 patients. Medicine (Baltimore).
OTHER TREATMENT MODALITIES 2014;93:61.
IL-2—The most widely used treatment of ICL is IL-2.9 7. Gholamin M, Bazi A, Abbaszadegan MR. Idiopathic lympho
cytopenia. Curr Opin Hematol. 2015;22:46.
IL-2 should only be considered in individuals with
8. Busse PJ, Cunningham-Rundles C. Primar y lepto
recalcitrant disease and profoundly low CD4 cell counts. meningeal lymphoma in a patient with concomitant
IL-2 will increase CD4 counts in most patients, although CD4+ lymphocytopenia. Ann Allergy Asthma Immunol.
it may not improve their function. 2002;88:339.
IL-2 therapy has significant side effects and should 9. Cunningham-Rundles C, Murray HW, Smith JP. Treatment
be administered with informed consent, as part of a of idiopathic CD4 T lymphocytopenia with IL-2. Clin Exp
Immunol. 1999;116:322.
comprehensive investigational protocol.
10. Cervera C, Fernández-Avilés F, de la Calle-Martin O, et al.
Hematopoietic cell transplantation 4— Allogeneic Non-myeloablative hematopoietic stem cell transplantation
bone marrow transplantation has been used to treat a in the treatment of severe idiopathic CD4+ lymphocytopenia.
small number of patients with severe manifestations Eur J Haematol. 2011;87:87
of ICL. Only in recurrent infections not prevented
with prophylaxis, or in patients who could not tolerate
prophylaxis should this be considered.10
CHAPTER
132
Hepatocellular Carcinoma: Surveillance,
Diagnosis and Management
Kirti Shetty
BACKGROUND are those with cirrhosis of any etiology as well as

noncirrhotic HBV.
Hepatocellular carcinoma (HCC) currently represents
the second leading cause of cancer related death
worldwide. Its incidence has shown an alarming increase TESTS
over the past two decades. Of the 782,000 new HCC cases Hepatic nodules within a liver which is cirrhotic can be
in 2012, approximately 83% occurred in East and South detected by ultrasound (US), computerized tomography
Asia as well as sub Saharan Africa. (CT), and magnetic resonance imaging (MRI).
HCC incidence varies widely by geographic region Of these, US is the only modality endorsed by all
and is dependent on differing prevalence of various risk societies for surveillance.
factors such as hepatitis B (HBV)/C (HCV) and non-
alcoholic steatohepatitis (NASH). It is recognized that the Ultrasound
most crucial premalignant state for HCC is cirrhosis of This is the imaging modality of choice given its cost-
the liver, regardless of etiology, which underlies 80–90% effectiveness and availability even in low resource
of all HCC. By recognizing risk factors for HCC, identified settings. Overall, ultrasound has good performance
high-risk groups may undergo systematic surveillance, characteristics, with sensitivity and specificity of 94%
which has been shown to improve the early detection and 90% respectively reported on a recent meta-
and outcome of HCC. analysis. However, small HCC nodules may be difficult
to distinguish from benign regenerative nodules. The
SURVEILLANCE STRATEGY performance characteristics of HCC depends on operator
experience, and its utility is limited in obese patients.
Surveillance is defined as the repeated application of a Contrast enhanced ultrasound (CEUS) has been reported
screening test to a population under study. The essential to help distinguish regenerative nodules from HCC.
components of an effective surveillance program are the
identification of a target population and the delineation
of an ideal surveillance test.
Serum Biomarkers
Serum α-fetoprotein (AFP) is the most commonly
utilized tumor marker for HCC. However, its adequacy as
TARGET POPULATION a screening tool has been questioned, since it is normal
In general, surveillance is believed to be cost effective in up to 35% of cases of early HCC and may be elevated
if the expected HCC risk exceeds 1.5% per year. The in situations characterized by hepatic inflammation or
populations targeted by most surveillance programs regeneration. AFP levels in combination with ultrasound
TABLE 1: Regional guidelines on HCC surveillance These differences in diagnostic criteria are
Society Region Target groups Test Interval attributable to regional variations in HCC prevalence
KLCSG-NCC Asia Cirrhosis/HBV/HCV US+AFP N/A as well as management options. Western guidelines
APASL Asia Cirrhosis/HBV/HCV US+AFP 6 Mo
are optimized for maximum specificity (not sensitivity)
to dovetail with policy regarding liver transplantation
JSH Asia Cirrhosis/HBV/HCV US+AFP+ 3–12 Mo
DCP+ADP-L3 allocation. Other imaging options include: Contrast-
EASL Europe Cirrhosis/HBV US 6 Mo enhanced ultrasonography (CEUS) and/or tissue-
Carriers/HCV F3 specific MRI contrast media, proposed by certain
AASLD USA Cirrhosis/HBV US 6 Mo societies such as Asia Pacific Association for the Study
Carriers of Liver (APASL) and JSH, as well as rising AFP proposed
Abbreviations: KLCSG-NCC, Korean Liver Cancer Study Group – National by the 2014 Korean Liver Cancer Study Group–National
Cancer Center; JSH, Japanese Society of Hepatology; APASL, Asia Pacific
Cancer Center (KLCSG-NCC) guidelines
Association for the Study of Liver; EASL, European Association for the Study
of Liver; AASLD, American Association for the Study of Liver Diseases.
TISSUE DIAGNOSIS
can provide additional detection only in 6–8% of cases HCC is the only major cancer which does not require
not visualized by US. This has led to certain Western a mass biopsy. Liver biopsy is recommended only if
guidelines dispensing with the recommendation for imaging does not demonstrate characteristic features of
AFP, citing a lack of cost effectiveness. In contrast, Asian HCC as described above.
guidelines recommend US and AFP in combination.
Furthermore, a recent Japanese Society of Hepatology STAGING
(JSH) guideline advocates the combined use of tumor Staging of HCC is crucial for defining treatment strategy.
markers (AFP >200 ng/mL), AFP-L3 (lens culinaris
The Barcelona-Clinic Liver Cancer (BCLC) staging
agglutinin) >15%), or descarboxyprothrombin (DCP)
system is widely utilized in the West to guide decision
>40 mU/mL) for the diagnosis of HCC. The comparative
making regarding treatment and prognosis. This system
efficacy of these differing strategies in HCC surveillance
not only incorporates tumor burden and extension,
is unclear, and will depend on geographic and clinical
but also hepatic functional reserve and performance
variables.
status. These factors have been shown in cohort studies
Table 1 summarizes the guidelines proposed by
and randomized controlled trials to have prognostic
major international societies.
significance. However, the BCLC system has several
drawbacks and some Asian societies such as the KLCSG-
DIAGNOSIS NCC have chosen to adopt the modified International
Noninvasive Diagnosis Union for Cancer Control (UICC) to stage HCC. It is
HCC diagnosis is based on characteristic imaging important to note that a global consensus on the ideal
patterns noted on four-phase multidetector computed staging system is lacking.
tomography (MDCT) or contrast-enhanced dynamic
MRI. These diagnostic criteria include arterial phase TREATMENT
hypervascularity and venous or delayed phase washout. Approach to HCC management shows a geographic
Western guidelines utilize these criteria to allow variation. Although BCLC staging has been adopted in
noninvasive diagnosis only for nodules >1 cm in cirrhosis most Western centers to determine treatment options,
whereas Asian guidelines allow imaging diagnosis of its basic principles are the source of controversy for
subcentimeter nodules based on typical appearance of many Asia-Pacific experts. Asian guidelines recommend
HCC in those who have either cirrhosis or chronic liver locoregional therapy and surgical resection for more
diseases. advanced tumors than do BCLC guidelines.
CHAPTER 132: Hepatocellular Carcinoma: Surveillance, Diagnosis and Management 793
Flow chart 1: Approach to HCC management based on APASL guidelines
Abbreviations: HCC, Hepatocellular carcinoma; TACE, Transarterial chemoembolization

Source: Modified from Ref. 1
Flow chart 1 illustrates an algorithmic approach to to intrahepatic tumor burden upto 3 lesions, as long as
HCC management based on APASL guidelines. there is no macrovascular invasion and liver function is
well preserved. LR has been found to be most beneficial
SURGICAL THERAPIES FOR HCC for single tumors in patients without cirrhosis, conferring
postresection 5-year survival rates of 41–74%. For
Liver Resection (LR) vs Liver cirrhotics with local lesions and good liver function
Transplantation (LT) (Child-Pugh A), the choice of a resection versus LT is a
The decision regarding surgical treatment for HCC subject of discussion. Western guidelines recommend LT
depends on tumor burden and nature of underlying as the first approach since recurrence occurs following
liver disease. In general, LR is the first line therapy for resection in a significant number of cases (approximately
those with limited tumour burden and no cirrhosis. LT 50% and 70% at 3 and 5 years respectively). Organ
is reserved for those with decompensated cirrhosis and/ allocation policies in the West prioritize tumours which
or multiple lesions. In the West, resection is limited to satisfy Milan criteria (solitary tumor <5 cm or up to 3
those with solitary tumor and no portal hypertension. In tumors ≤3 cm each without evidence of vascular invasion
contrast, Asian guidelines expand resection indications or extrahepatic spread).
Locoregional Therapies lasting 6 months or longer and 55% had responses

The choice of locoregional therapies (LRT) depends on lasting 12 months or longer. In comparison, sorafenib
tumour burden and location. Ablative therapies such and second-line regorafenib are associated with ORR of
as radiofrequency ablation (RFA), and more recently, only 2–3% and ~7%, respectively. Additionally, median
microwave ablation may be utilized in those with a overall survival with sorafenib is under 11 months.
solitary tumor or up to 3 tumors ≤3 cm each and good Based on these encouraging results, the US Food and
hepatic function. Transarterial therapies may be used Drug Administration granted expedited approval to
either as a bridge to LT or as primary treatment in Nivolumab for the treatment of advanced HCC on
those tumors too advanced for either resection or LT. September 22, 2017.
These therapies include conventional transarterial
chemoembolization (TACE), drug eluting beads TACE CONCLUSION
(DEB-TACE) or transarterial radioembolization (TARE). HCC is a complex disorder that occurs against a
External Beam Radiation Therapy (EBRT) is an evolving background of cirrhosis. Developing a global consensus
option that is being increasingly utilized. to treat this condition is complicated by regional
variations in epidemiology, tumor biology, resources and
treatment options. Development of treatment guidelines
Systemic Therapies
and practice patterns will require physicians and policy
Sorafenib, a multikinase inhibitor, was approved in 2007
makers to be mindful of these considerations.
for the treatment of patients with unresectable HCC by
both European and US agencies. The efficacy of sorafenib
in advanced HCC was demonstrated in the landmark
BIBLIOGRAPHY
1. Chen BB, Murakami T, Shih TT, Sakamoto M, Matsui O,
SHARP trial, which showed an overall decrease in Choi BI, et al. Novel imaging diagnosis for hepatocellular
mortality of 31%, with a median survival of 10.7 months carcinoma: Consensus from the 5th Asia-Pacific Primary
for the sorafenib group versus 7.9 months for placebo Liver Cancer Expert Meeting (APPLE 2014). Liver Cancer.
2015;4(4):215-27.
group. Regorafenib, which has been recently approved
2. Ho MC, Hasegawa K, Chen XP, Nagano H, Lee YJ, Chau GY,
in the US, is a novel multikinase inhibitor with more et al. Surgery for intermediate and advanced hepatocellular
potent inhibitory activities against multiple angiogenic carcinoma: A consensus report from the 5th Asia-Pacific
pathways as compared to sorafenib. In a phase III Primary Liver Cancer Expert Meeting (APPLE 2014). Liver
Cancer. 2016;5(4):245-56.
double-blind study (RESORCE trial) of patients who had
3. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia
progressed on sorafenib, it was found to significantly J, et al. Asia-pacific clinical practice guidelines on the
reduce the risks of death or disease progression (HR 0.46; management of hepatocellular carcinoma: a 2017 update.
95% CI 0.37–0.56; p < 0.001). Hepatol Int. 2017;11(4):317-70.
4. Renzulli M, Golfieri R; Bologna Liver Oncology Group
An exciting new frontier in HCC treatment is
(BLOG). Proposal of a new diagnostic algorithm for
the development of immunotherapy. Nivolumab, a hepatocellular carcinoma based on the Japanese guidelines
human immunoglobulin G4 monoclonal antibody but adapted to the Western world for patients under
that disrupts the immune check point interaction surveillance for chronic liver disease. J Gastroenterol
Hepatol. 2016;31(1):69-80.
between programmed cell death protein-1 (PD-1)
5. Wang CH, Wey KC, Mo LR, Chang KK, Lin RC, Kuo JJ. Current
and programmed death-ligand 1 (PD-L1), is currently trends and recent advances in diagnosis, therapy, and
undergoing evaluation in CHECKMATE-040 (NCT prevention of hepatocellular carcinoma. Asian Pac J Cancer
01658878), a global multicenter, open-label trial Prev. 2015;16(9):3595-604.
6. Yu SJ. A concise review of updated guidelines regarding
conducted in patients with HCC and Child-Pugh A
the management of hepatocellular carcinoma around the
cirrhosis who progressed on or were intolerant to world: 2010-2016. Clin Mol Hepatol. 2016;22(1):7-17.
sorafenib. In an interim analysis of 154 patients, the 7. Zhao C, Nguyen MH. Hepatocellular carcinoma screening
confirmed overall response rate to nivolumab was 14.3% and surveillance: Practice guidelines and real-life practice. J
Clin Gastroenterol. 2016;50(2):120-33.
(95% CI: 9.2, 20.8), with 3 complete responses and 19
8. Zhu RX, Seto WK, Lai CL, Yuen MF. Epidemiology of
partial responses. Response duration ranged from 3.2 hepatocellular carcinoma in the asia-pacific region. Gut
to 38.2+ months; 91% of responders had responses Liver. 2016;23;10(3):332-9.
CHAPTER
133
Approach to a Patient with Polycythemia
Mathew Thomas
INTRODUCTION, DEFINITIONS AND TABLE 1: Main classification of polycythemia
CLASSIFICATION zz Polycythemia
—— Relative polycythemia (isolated decrease in plasma volume)
In polycythemia, there is an increased concentration —— Absolute polycythemia (increase in RCM)
of hemoglobin in the circulating blood along with —— Combined polycythemia
—— Idiopathic erythrocytosis
an increase in the number of red blood cells and the
hematocrit (PCV) (Table 1). zz Absolute polycythemia
—— Primary e.g. polycythemia vera
—— Secondary e.g. chronic lung disease, congenital cyanotic
Relative Polycythemia heart disease

Relative polycythemia is an apparent increase in the
hemoglobin, RBC and the hematocrit due to an isolated usually erythropoietin (Epo). Most of the conditions
decrease in the plasma volume. The classical condition in producing secondary polycythemia are due to
India is acute dengue fever with capillary leak syndrome. hypoxia which produce more Epo-(Epo sensitive
We have seen hemoglobin going up to 20 or 21 gm/dL in hypoxia). It can also result from Epo secreting tumors.
Dengue fever and once the plasma volume is restored by
fluid resuscitation, the parameters return to normal. In Combined Polycythemia
such situations, there is no increase in the red cell mass In this situation, there is an increased RCM together
(RCM). with reduced plasma volume. This type of combined
polycythemia occurs among the smokers (smoker’s
Absolute Polycythemia polycythemia).
There is an increase in the Red Cell Mass in absolute
polycythemia. These patients with absolute polycythemia Idiopathic Erythrocytosis
are further classified into primary and secondary types. This is used to categorize subjects with primary
There is an inherited or acquired mutation in primary polycythemia who do not fulfil the usual criteria for the
polycythemia leading to an abnormality in the RBC diagnosis of PV.
progenitors. This includes polycythemia vera (PV)
and rare familial variants (e.g. activating mutations of MECHANISMS
the erythropoietin receptor, Chuvash polycythemia). Kidney synthesizes 90% of the Epo in human. This is
Secondary polycythemia is due to a factor in the in response to a hypoxic signal. The hypoxic signal to
circulation stimulating erythropoiesis which is the kidney cells producing Epo, may be the result of
reduction in hemoglobin (HGB) concentration as in TABLE 2: Major causes of polycythemia

anemia, reduced hemoglobin saturation as in hypoxemia, zz Primary polycythemia
—— Polycythemia vera (JAK 2 mutation)
decreased oxygen released from hemoglobin as in high
—— Activating mutations of the Epo receptor
oxygen affinity hemoglobinopathies or reduced oxygen —— Chuvash polycythemia (VHL gene mutation)
delivery to the kidney as in vascular occlusion. zz B and C are called primary familial polycythemia
As the result of increased oxygen delivery, there is a Secondary polycythemia

zz Hypoxia secondary to
negative feedback inhibition mechanism, down regu —— Chronic pulmonary disease
lating the Epo production. This happens in polycythemia —— Right to left cardiac shunts
—— Sleep apnea
vera an Epo independent erythrocytosis resulting in low
—— Massive obesity
serum concentrations. In Epo dependent erythropoiesis —— High altitude
(e.g. hypoxia or Epo producing tumors) which is found —— Red cell defects (e.g. congenital methemoglobinemia, carbon
monoxide poisoning including heavy smoking)

occurs in secondary erythrocytosis, a normal or high zz Epo producing tumors
serum Epo concentrations is found. —— Renal cell carcinoma
—— Hepatocellular carcinoma
—— Cerebellar hemangioblastoma
MAJOR CAUSES OF POLYCYTHEMIA —— Pheochromocytoma
It is seen from this table that secondary polycythemia —— Uterine fibroids
—— Other tumors e.g. cushing syndrome

is much more common than primary polycythemia
zz Epo producing renal lesions e.g. hydronephrosis, renal artery
(Table 2). There is a subset of patients with polycythemia stenosis, distal tubular acidosis
zz Following renal transplantation
(idiopathic polycythemia) who cannot be categorized
zz Miscellaneous causes
into primary or secondary and they should have a regular
—— Use of androgen or anabolic steroids
follow up for a long period of time to understand the —— Diuretics by reducing plasma volume
nature and progression of the disease. —— Blood doping in athletes (autologous blood transfusion)
—— Self-injection of Epo
—— Poems syndrome
INITIAL EVALUATION OF PATIENTS —— Idiopathic polycythemia (failure to categorize patients)
WITH POLYCYTHEMIA
History and physical examination Medications and lifestyle (androgens, anabolic
Complete blood count (CBC) with differential count steroids, self-injection of Epo, etc.)
and the red cell indices History of smoking and possibly diet with high iron
Pulse oximetry and/or arterial oxygen saturation at content

rest and after exercise Chronic carbon monoxide poisoning in workers of
Urine analysis underground parking and taxi drivers in congested

Liver function test environment
Chest X-ray History of working or living in high altitude.
Ultrasound of the abdomen. Increase in the blood viscosity account for most
of the symptoms of polycythemia. They include chest
History and abdominal pain, fatigue, headache, myalgia and
Some of the following points in the history may be helpful: weakness, blurred vision or transient loss of vision,
History of respiratory or cardiac illness and details paresthesia and slow mentation. Polycythemia vera
of previously diagnosed respiratory and cardiac may have specific symptoms like pruritis after a bath,
diseases, history of renal transplantation, prior stroke erythromelalgia symptoms of gout, arterial or venous
or venous thrombosis thrombosis, hemorrhage and early satiety due to
Family history of polycythemia splenomegaly.
CHAPTER 133: Approach to a Patient with Polycythemia 797
PHYSICAL EXAMINATION Polycythemia producing functional endocrine tumors

General physical examination may show polycythemia, may produce laboratory findings of hyperglycemia
cyanosis, clubbing of the fingers and toes, increased and electrolyte imbalance (hypokalemia).
respiratory rate and working of the accessory muscles In hepatocellular carcinoma, LFT may be deranged.
of respiration. Plethoric face, dilated lingual and retinal Pulse oximetry may not be sensitive enough to
veins or areas of painful erythema may be more specific detect the presence of carbon monoxide. So, a more
in polycythemia vera. Clinical features of Cushing’s sensitive test like direct blood testing via co-oximetry
syndrome and pheochromocytoma should be examined. should be performed in patients where CO poisoning
Pulse oximetry for arterial oxygen saturation is very or congenital methemoglobinemia is suspected.
useful especially after minimum exertion. The chest X-ray findings may be very helpful in
finding out the cause of polycythemia as in AV fistula,
SYSTEMIC EXAMINATION COPD and pulmonary artery hypertension.
Respiratory and cardiovascular systems should be
examined for diseases producing secondary polycythemia FURTHER DIAGNOSTIC APPROACH
e.g. chronic lung diseases, cyanotic congenital heart Polycythemia is present (2016 WHO classification)
diseases, arteriovenous fistula. Gastrointestinal system when hematocrit HCT or hemoglobin HGB is
should be examined for hepatosplenomegaly which may elevated; HCT more than 48% in women or more than
indicate polycythemia vera or Epo secreting hepatoma. 49% in men; HGB more than 16.0 gm/dL in women or
more than 16.5 gm/dL in men.
LABORATORY INVESTIGATIONS The class of polycythemia e.g. relative, absolute,
Polycythemia is confirmed and documented when the primary, secondary is determined by blood volume
HCT (hematocrit, PCV) is more than 48% in women and studies if available, otherwise history physical
more than 49% in males or HGB (hemoglobin) is more examination and simple laboratory testing can lead
than 16.0 gm/dL in women and more than 16.5 gm/dL us to suspect its cause.
in males. RBC count should be the least often considered Pulse oximetry after mild exertion on during sleep
investigation of the three tests to suggest polycythemia. can determine the presence of hypoxia. Serum Epo is
This is because the RBC count may be elevated in helpful in determining if the polycythemia is primary
patients with thalassemia minor but at the same time or secondary.
have a reduced HGB and HCT due to the presence of If any cause of secondary polycythemia is suspected
an increased number of small (microcytes), poorly by the initial evaluation full investigations for that
hemoglobinized (hypochromic) red cells. cause should be carried out e.g. ECHO cardiogram if
The following points regarding CBC and initial congenital cyanotic heart disease is suspected.
investigations should be kept in mind.
2.5% of normal persons may have HGB above the FURTHER EVALUATION
levels of polycythemia documentation. So, sex and One of the most important points during the evaluation
age adjusted normal reference interval should be of polycythemia is to repeat the CBC. In clinical studies,
applied before considering polycythemia in such it was found that a good number of patients who showed
situations. polycythemia in the initial evaluation showed normal
Polycythemia vera should be strongly considered values when CBC was repeated.
when there is an elevated white cell count and Carbon monoxide poisoning is a possibility if the
platelets. patient is exposed to tobacco smoke, fire wood and

In Epo secreting renal cell carcinoma, microscopic kitchen smoke as in India, engine exhaust or other
hematuria may be the only pointer for an initial sources of this gas. A blood carboxyhemoglobin
diagnosis. (COHGB) is the investigation of choice. COHGB
values more than 5% strongly suggest polycythemia Bone marrow aspiration and biopsy is usually not
secondary CO excess. necessary for most of the patients during the workup of
When hypoxia is suspected, screening with pulse PV but may be useful if a PV related complication like
oximetry should be done. If this is not available, myelofibrosis, myelodysplasia or myeloid leukemia is
arterial oxygen saturation (ABG) should be measured suspected.
during rest, after mild exertion on during sleep.
DIAGNOSIS OF POLYCYTHEMIA VERA
Direct measurement of arterial hemoglobin oxygen
Polycythemia vera is one of the four classic
saturation should be investigation when the cause
myeloproliferative neoplasms (MPN). The other three
polycythemia is not clear and especially when
are essential thrombocythemia, primary myelofibrosis
arterial oxygen tension (pO2) is normal. A low arterial
and chronic myeloid leukemia.
hemoglobin saturation in the presence of normal
The 2016 WHO criteria for diagnosing PV are:
arterial oxygen saturation is a pointer for the presence
of high concentrations of carboxyhemoglobin or
methemoglobin. This can be confirmed by co-
Major Criteria
oximetry. A family history of polycythemia suggests
Increased hemoglobin HGB level (more than 16.5
the presence of high oxygen affinity hemoglobin. This gm/dL in males or more than 16 gm/dL in females),
is confirmed by showing a left shifted hemoglobin hematocrit HCT (more than 49% in males and more
oxygen dissociation curve. than 48% in females) or other tests of increased
blood volume. Hypercellularity for age with trilineage
Blood volume studies if available should be ordered to growth (panmyelosis) on bone marrow biopsy. Biopsy
determine if the polycythemia is due to an elevation should show prominent erythroid, granulocytic and
in the red cell mass (RCM), a reduction in plasma megakaryocytic proliferation with pleomorphic
volume or both. But this investigation is not readily mature megakaryocytes.
available. However, a venous HCT significantly more Exon 14 JAK2 V617F or JAK2 exon 12 mutation
than 56 to 60% in men and 50–55% in women is
(Figs 1 and 2).
almost always associated with an absolute increase
in RCM.
Minor Criterion
In all other situations, one should proceed for the test Serum Epo level below the reference range for normal PV
which will measure the serum erythropoietin (Epo) is diagnosed if all three major criteria are present. It may
concentration. In India, this is an important test for be diagnosed also if first two major criteria together with
economic reasons and a low serum erythropoietin the minor criterion are present. If there is a persistent
(Epo) level in patients with polycythemia can be absolute erythrocytosis (hemoglobin more than 18.5 gm/
taken as a strong specific evidence for polycythemia dL or hematocrit more than 55.5% in men, hemoglobin
vera (PV). It may be seen in other rare situations more than 16.5 gm/dL or hematocrit more than 49.5%
also e.g. congenital erythrocytosis. Polycythemia in women) bone marrow biopsy is not necessary for
associated with increased serum Epo is unlikely diagnosis provided that the third major criterion and the
to be PV and secondary polycythemia should be minor criterion are present.
considered as the working diagnosis.
JAK2 mutation testing is essential if the diagnosis of TREATMENT OF POLYCYTHEMIA VERA
PV is being considered as virtually all patients will For patients below 60 years of age and without any
have a mutation in either 12 or 14th exon of this gene. history of prior thrombosis, phlebotomy (350–500
But in India we do not see this and some patients with mL) once or twice weekly to keep the HCT below
a clinical diagnosis of PV do not have JAK2 mutation. 45% is the treatment of choice. If there were no
CHAPTER 133: Approach to a Patient with Polycythemia 799
Fig. 1: Normal JAK2 signaling leading to normal proliferation of RBC
Fig. 2: Excess JAK2 signaling due to JAK2 mutation and increased proliferation of RBC
contraindications, all the patients with PV should be 55–60% may result in relief of the symptoms. If the
given aspirin in a dose of 75 mg per day. levels are reduced less than that 55% they are likely
For patients at higher risk of thrombosis (above 60 to exacerbate symptoms of the underlying hypoxic
years of age and prior thrombosis) treatment with condition.
phlebotomy and aspirin should be supplemented
with the use of a myelosuppressive agent. The best SUMMARY
recommended is hydroxy urea in the doses of 15–20 Polycythemia refers to a laboratory finding of increase in
milligrams per kilogram per day. Dose adjustments the concentration of hemoglobin in the peripheral blood
should be made only once a week since the effect of this along with an increase in the number of red cells and
drug is seen only by 3–5 days. Iron supplementation the hematocrit PCV. It is divided into absolute (increase
should not be given as this drug acts by creating an in the red cell mass RCM) and relative (an isolated
iron deficiency state. It is reasonable to use interferon decrease in the plasma volume). Absolute polycythemia
alpha 2a, another cyto reducing agent, in intractable is further divided into primary (no detectable causes)
pruritis, in high risk women of childbearing potential and secondary (secondary to many diseases). Secondary
including pregnancy and in patients refractory to all polycythemia is much more common. The classical
other medications. Supportive treatment includes example of absolute polycythemia is polycythemia vera
allopurinol for symptomatic hyperuricemia and (PV) which is one of the four classic myeloproliferative
second line drugs like busulfan in hydroxy urea neoplasms (MPN). Common examples of secondary
resistant cases. The new drug ruxolitinib (JAK2 polycythemia are chronic lung diseases, left to right cardiac
inhibitor) should be used only in patients having shunts, AV fistula, erythropoietin producing tumors,
post PV myelofibrosis with hydroxy urea refractory living in high altitude and chronic carbon monoxide
symptomatic splenomegaly or severe constitutional poisoning including smoking. The various causes of
symptoms. secondary polycythemia and primary polycythemia are
differentiated by a careful history, physical examination
MANAGEMENT OF SECONDARY and laboratory investigations. Serum erythropoietin
POLYCYTHEMIA levels are increased in secondary polycythemia. A
The most important aspect of the management will low serum erythropoietin is characteristic of PV. JAK 2
be treatment or removal of the underlying cause e.g. mutation is virtually found in all cases of PV. Revised
surgical removal of an Epo secreting tumor, means of 2016 WHO classification criteria help us to diagnose
stopping carbon monoxide exposure, surgical closure PV. Treatment of PV consists of careful combination of
of large arteriovenous shunt, stopping drugs like phlebotomy, aspirin, cytoreducing drugs and newer
testosterone or anabolic steroids. drugs targeting JAK2 mutation. Secondary polycythemia
Limited phlebotomy—When there are symptoms is treated by removing/ treating the causes and by limited
and increased blood volume and viscosity limited phlebotomy. Newer drugs targeting JAK2 mutations are
phlebotomy is appropriate e.g. patients with expected in the future.
secondary polycythemia due to various conditions
of hypoxia have increased blood volume and/or BIBLIOGRAPHY
viscosity. This may produce symptoms like fatigue, 1. The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia.
headache, blurred vision, transient loss of vision,
2. Uptodate: Sections on approach to polycythemia and
paresthesia and slow mentation. These symptoms polycythemia.
occur when the HCT rises to 65%. Careful phlebotomy 3. Wintrobe’s clinical hematology: Chapters on Erythrocytosis
to reduce their HCT into the range of approximately and polycythemia vera.
CHAPTER
134
Immunotherapy: A New Weapon
in Cancer Treatment
Vineet Talwar, Venkata Pradeep Babu K
INTRODUCTION Interleukin-2 and Interferon–Gamma or cell based

The introduction of immunotherapy has opened a new therapies such as use of vaccinations and the introduction
vista in medical oncology. Immunotherapy constitutes a of oncolytic viruses for initiation of systemic immunity
wide variety of therapies including anticancer vaccines, against cancer. The second and most useful strategy is
oncolytic viruses, adoptive T cell therapies and inhibition to counteract the inhibitory mechanisms. The various
of checkpoint pathways of immune mediation. In this mechanisms used by tumor to counter the immune
review, we have tried to define the strategic pathways of system are recruiting T regulatory cells, releasing
immunotherapy, approved therapies and other immune immunosuppressive cytokines, downregulation of major
therapies in pipeline. histocompatibility complex and expression of inhibitory
Immune system has two main subdivisions: Innate ligands i.e. checkpoints. Out of all these mechanisms,
immunity and adaptive immunity. checkpoint inhibition is most important. The latter
Innate immunity originates from germ line, acts in strategy includes approved antibodies against immune
nonspecific manner, and is first line of defense with no checkpoint molecules mainly CTLA-4 (Cytotoxic T
immunological memory that acts on antigen almost lymphocyte associated protien, PD1 (Programmed
instantaneously. Adaptive immunity derives from Death-1 receptor) and PDL-1 (Programmed Death-1
multiple clonal progenitor cells, recognizes each antigen Ligand), while many other inhibitory molecules yet to be
with high specificity, forms immunological memory deciphered.
but takes time to respond. Innate immunity consists
of physical barriers like respiratory epithelium, gastric ONCOLYTIC VIRUSES IN
mucosa, white blood cells, complement system and IMMUNOTHERAPY
chemical barriers like hydrochloric acid in stomach. Oncolytic viruses are a novel technology of employing
Adaptive immunity in turn is subdivided into two arms of genetically modified viruses to kill cancer cells specifically
cell mediated immunity consisting of CD4 and CD8 cells without affecting normal cells. The effect of these viruses
(including helper T cells, regulatory T cells and memory occurs in two ways. The first effect is tumor specific
cells) and humoral mediated immunity consisting of infection of viruses and intratumoral replication, lysis
antibodies produced from B cells. and tumor debulking. The second effect is production of
Based on the mechanism of action, immunotherapies specific cytokines from the infected tumoral tissue and
can be broadly divided into two categories. The first release of intratumoral antigens resulting in induction of
strategy is to boost already existing immunity by using sustained T cell immune response.
Some of the pathogenic viruses such as herpes ADOPTIVE CELL THERAPY (ACT)
simplex virus and vaccinia virus are genetically Tumors create immunosuppressive environmental by
engineered to become nonpathogenic. Currently, the secreting cytokines which recruits T regulatory cells (T
most advanced oncolytic virus agent approved by FDA regs) and Myeloid Derived Suppressor Cells (MDSCs) in
is Talimogene laherparepvec (T-VEC), for the treatment its own microenvironment. The Adoptive T cell transfer
of advanced melanoma. T-VEC is first and only approved technique attempts to reverse the functional impairment
oncolytic virus till now in oncology, indicated for the local of tumor specific T cells that reside within the tumor
treatment of unresectable cutaneous, subcutaneous, often referred to as Tumor Infiltrating Lymphocytes
and nodal lesions in patients with melanoma recurrent (TILs). These T cells are isolated from peripheral blood,
after initial surgery. It is however contraindicated in draining lymph nodes or resected tumor tissue, and
immunocompromised patients and in pregnancy. grown and cultured ex vivo, replicated in sufficiently
large numbers and then reinfused along with cytokine
cocktail.
VACCINES IN IMMUNOTHERAPY
Improvement in genetic engineering techniques has
Vaccination against the cancer neoantigens is one of the
explored two strategies to broaden the use of TILs. The
earliest attempts for the immunotherapy in oncology,
first strategy is engineered expression of alpha and beta
with the basic understanding that all of us harbor CD8+
chains of T cell receptor with antigen specificity. This
and CD4+ T cells capable of recognizing tumor antigens. is accessible to any patient whose tumor expresses the
The main difference between prophylactic and tumor HLA peptide complex and expresses the target antigen
vaccines is that, active immunity is required for the former, that can be recognized by TCR. The second strategy is
whereas the tumor vaccines requires the breakage of development of Chimeric antigen receptors (CARs),
immune tolerance induced by tumor. For this to happen, which virtually can recognize any specific antigen that
Dendritic cells must be targeted with high quantities of is expressed on cell surface, omitting the need for MHC
antigens, expanded, activated with appropriate agents. expression and antigen processing in the target tumor
The most crucial step in the development of successful cell. These strategies are being actively evaluated in B cell
cancer vaccine is identification of antigens specific to malignancies, melanoma, synovial sarcoma and several
tumors and exposing them at a specific peptide length to other cancers.
Dendritic cells for stimulation.
Sipuleucel-T, a dendritic cell vaccine, cultured with IMMUNE CHECK POINT BLOCKADE
a fusion protein consisting of prostatic acid phosphatase The multitude of somatic gene mutations confers
potential antigenicity to human cancers, but this immune
linked to the dendritic cell growth and differentiation
response is inhibited by cell mediated and cytokine
factor GM-CSF (granulocyte macrophage colony-
mediated responses by tumor as already described in
stimulating factor), showed approximately 4-month
previous session. One of the very important mechanism
improvement in median survival, which led to US-FDA
is induction of tolerance among tumor specific T cells by
approval in 2010 for the treatment of asymptomatic or
expression of inhibitory ligands that binds the inhibitory
minimally symptomatic metastatic castrate resistant receptors that are naturally present over T cells. Some
(hormone refractory) prostate cancer. Despite this of the inhibitory ligands are CTLA-4, PDL-1, BTLA,
increase in survival, Sipuleucel-T have failed to show VISTA and LAG-3. This inhibition of T cells also occurs
meaningful decreases in tumor volumes in randomized naturally to control total amount of immune response
clinical trials. Moreover, this therapy is available in only and it is referred to as checkpoint. The most exciting part
few centers across the globe, as it is a very cumbersome of immunotherapy was ensued with the success of this
technique. checkpoint inhibitors causing “Checkpoint blockade”
CHAPTER 134: Immunotherapy: A New Weapon in Cancer Treatment 803
Table 1: Immunotherapy directed at PD1, PD-L1 and CTLA-4

Name of immunotherapy Type of immunotherapy Indication Approved year
Pembrozulimab Anti PD-1 antibody NSCLC, SCCHN, melanoma 2014
Nivolumab Anti PD-1 antibody NSCLC, bladder cancer, RCC, SCCHN, melanoma, 2014
Hodgkin’s lymphoma
Atezolizmab Anti-PDL1 antibody NSCLC, bladder cancer 2016
Ipilimumab Anti-CTLA4 antibody Melanoma 2011
Sipileucel-T Dendritic cell vaccine Prostate cancer 2010
Talimogene Genetically modified oncolytic Unresectable cutaneous, subcutaneous, and nodal lesions 2015
Laherparepvec (T-VEC) viral therapy in melanoma recurrent after surgery
Avelumumab PDL-1 antibody Metastatic merkel cell ca 2017
Durvalumab PDL-1 antibody Metastatic urothelial cancer 2017
Source: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm
to trigger antitumor immune response and it strikes Currently, immunotherapy directed at PD1, PD-L1
in a new era in the treatment approach to advanced and CTLA-4 has shown activity in several immunogenic
cancers. Because this is the most important part of the cancers such as melanoma, lung cancer, head and
immunotherapy let us discuss these mechanisms and neck cancer, renal cell carcinoma and bladder cancer
drugs more clearly. which are shown in Table 1. Several trials targeting
As a part of normal physiological response, when new pathways like IDO (Indoleamine Dioxygenase) are
tumor sheds antigens or expresses on the cell surface, underway.
these are recognized, digested into smaller epitopes and So, to summarize the treatment modalities in
presented by antigen presenting cells to CD4 and CD8 oncology has taken enormous shift with time, where
cells. For this process to occur and immune response to once it was entirely dependent on surgical modality, then
develop, two positive signals are required through two radiotherapy followed by chemotherapy and finally now
receptors on T cell. The first interaction is between T in an exciting era of immunotherapy. These tailor-made
cell receptor and MHC on APC. The second interaction immunotherapies are associated with less morbidities,
is between CD28 on T cell and either activating ligans acts in more specific manner as described above. In
B7 on APC or inactivating ligand which can be either cancer underneath, what might seem like overwhelming
CTLA-4 or PDL-1 which leads to abortion of immune diversity is a deep genetic unity and this immunotherapy
response. This inhibitory response is used to prevent tries to exploit that concept. As old proverb runs, there
autoimmune response in lymphoid organs. The same are mountains beyond mountains, we have hope beyond
inhibitory ligands may also be expressed by several what at present is possible, that is to convert cancer into a
tumors escaping from the natural immune response. chronic disease like diabetes and hypertension.
The most common and well-studied inhibitory pathway
in tumors is programmed death receptor and ligand BIBLIOGRAPHY
interactions between tumor cells and T cells. This 1. Aguiar PN Jr, De Mello RA, Hall P, Tadokoro H, Lima
interaction which is normally used by cells lining of Lopes G. PD-L1 expression as a predictive biomarker in
advanced non-small-cell lung cancer: updated survival
epithelium and white blood cells for self-tolerance by
data. Immunotherapy. 2017;9(6):499-506.
inhibition of T cell proliferation and cytokine secretion 2. Arasanz H, Gato-Cañas M, Zuazo M, Ibañez-Vea M, Breckpot
and attracting more T regulatory cells, is exploited by K, Kochan G, Escors D. PD1 signal transduction pathways in
tumor microenvironment for its survival. T cells. Oncotarget. 2017;19.
3. De Maeseneer DJ, Delafontaine B, Rottey S. Checkpoint 7. Lehman JM, Gwin ME, Massion PP. Immunotherapy and
inhibition: new treatment options in urologic cancer. Acta targeted therapy for small cell lung cancer: There is hope.
Clin Belg. 2017;72(1):24-8. Curr Oncol Rep. 2017;19(7):49.
4. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The 8. Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A, Zhang G. A mini-review
future of cancer treatment: immunomodulation, CARs for cancer immunotherapy: Molecular understanding of
and combination immunotherapy. Nat Rev Clin Oncol. PD-1/PD-L1 pathway and amp; Translational Blockade of
2016;13(6):394. Immune Checkpoints. Int J Mol Sci. 2016;17(7):18.
5. Kohrt HE, Tumeh PC, Benson D, Bhardwaj N, Brody J, 9. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine
Formenti S, et al. Cancer Immunotherapy Trials Network 2,3-dioxygenase pathway in cancer. J Immunother Cancer.
(CITN). Immunodynamics: a cancer immunotherapy trials 2015;15:3-51.
network review of immune monitoring in immuno-oncology 10. Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD.
clinical trials. J Immunother Cancer. 2016;15:4-15. Combination immunotherapy: a road map. J Immunotherapy
6. Kourie HR, Awada G, Awada A. The second wave of immune Cancer. 2017;21:5-16.
checkpoint inhibitor tsunami: advance, challenges and
perspectives. Immunotherapy. 2017;9(8):647-57.
CHAPTER
135
Metronomic Chemotherapy in
Metastatic Malignancies: A New Concept
Ankur Bahl
INTRODUCTION METRONOMIC CHEMOTHERAPY

The cure rate in adult malignancies has dramatically VERSUS CONVENTIONAL
increased form less than 30% 4–5 decades ago to as high CHEMOTHERAPY
as 50-60% presently. Over the past four decades mortality Conventional cytotoxic drugs are designed for use at
rates in patients with various malignancies have also maximum tolerated dose (MTD) to treat cancer directly
shown significant declining trends. Despite intensive by inhibiting or killing rapidly dividing tumor cells and are
research and addition of targeted chemotherapy in usually administered at defined intervals as determined
the existing armamentarium of chemotherapy, many by the recovery of bone marrow.1 In the past two decades,
cancers still cannot be cured with current treatments. progress in our understanding of the molecular basis of
In progressive cancers after multiple lines of tumor cells has highlighted the limits of conventional
chemotherapy have failed, further treatment with schedules of cytotoxic agents. First, most solid neoplasm
chemotherapy imposes many side effects that limit is the result of multiple genetic abnormalities and
dosing and hamper the efficacy of anticancer treatment. may contain heterogeneous subpopulations of cells
At this crucial junction of progressive disease and limited with different cell kinetics, angiogenic, invasive, and
options of chemotherapy, declining further treatment for metastatic properties.2 Therefore, tumor responses to
the patient usually gives the patient and their caretakers a chemotherapeutic regimen may differ, even between
a feeling of being abandoned. Saying yes to an alternative patients with the same histology. Secondly, after varying
way of administering chemotherapy drugs may prevent periods of sensitivity, tumor cells develop resistance to
impending doom and provides a ray of hope. cytotoxic agents that cause DNA damage or disrupt DNA
Low dose chemotherapy administered continuously replication, a phenomenon related to their genomic
with an antiangiogenic potential is referred to as instability. Thirdly, conventional chemotherapy is, in
metronomic chemotherapy and is an option for a vast general, more effective against the primary tumor than
majority of patients suffering from multiply relapsed or against metastasis. Metastasis is the leading cause of
refractory cancer. This review will address the basis of cancer-related death. Most cytotoxic agents, even if given
metronomic chemotherapy and the data on the same in in combined schedules at MTD, achieve only palliation
malignancies. in patients with advanced cancer.
The word metronomic is derived from word ACTIVATION OF IMMUNITY

“metronome”, a musical instrument that produces Convincing evidence from the literature indicates
regular, metrical ticks (beats, clicks) — settable in beats that both innate and the adaptive immune systems
per minute. These ticks represent a fixed, regular make a crucial contribution to the antitumor effects of
aural pulse. Metronomic chemotherapy is the frequent conventional chemotherapy based cancer treatments.
administration of chemotherapy drugs at doses below Despite causing neutropenia and lymphocytopenia,
the MTD and with no prolonged drug-free break. It certain cytotoxic chemotherapy drugs (anthracyclins,
thus achieves a sustained low blood level of the drug taxanes and alkylating agents) have immunostimulatory
without significant toxic side effects. It is administered properties. Among them, the effect on regulatory T cells
with the aim of achieving cancer control by targeting (Treg) appears to be relevant in the context of metronomic
angiogenesis. Thus metronomic chemotherapy differs chemotherapy. T reg are CD4+ CD25+ lymphocytes,
from standard cytotoxic chemotherapy in terms of enriched in FoxP3, glucocorticoid-induced TNF receptor
frequency of the dose, pharmacokinetics, target, intent of and cytotoxic T-lymphocyte-associated antigen-4 that
treatment and host toxicity. can inhibit antigen-specific immune response both
in a cytokine dependent and cell contact-dependent
ANGIOGENESIS–CHEMOTHERAPY manner. 5 T reg can thus inhibit antitumor immune
MODEL response by suppressing the activity of both tumor-
In 1971, Dr. Judah Folkman proposed the tumor specific (CD8+ cytotoxic T lymphocytes and CD4+
a n g i o g e n e s i s hy p o t h e s i s — “ In t h e a b s e n c e o f T helper cells) and tumor nonspecific effector cells
vascularization, solid tumors remain dormant and 2–3 (natural killer [NK] and NK T cells). Increased number
mm 3 in size, with size being limited by the ability of of Treg cells is associated with tumor progression and lack
oxygen and nutrients to diffuse into the tumor.”3 Like of response. Many studies (preclinical and clinical) have
normal endothelial cells, tumor endothelial cells are documented the role of low dose cyclophosphamide
also thought to be genetically stable. They proliferate in reducing the number of T reg cells, suppressing the
under the stimulus of known growth factors like vascular function of the Treg cells and increasing both lymphocyte
endothelial growth factor (VEGF). Proliferation and proliferation and memory T cells.
migration of endothelial cells are inhibited by naturally Besides the activity of low dose chemotherapy on
occurring angiogenesis inhibitors like endostatin, Treg cells and subsequent activation of NK cell antitumor
angiostatin and thrombospondin-1. Till date around 40 activity, this therapy also has immunostimulatory effect
antiangiogenic agents are under clinical trials.4 Besides by inducing dendritic cell maturation.
direct cell kill, conventional chemotherapy drugs also act
by altering tumor blood supply via inhibition of tumor RATIONAL OF VARIOUS DRUGS USED
angiogenesis, a process by which tumors induce their IN METRONOMIC CHEMOTHERAPY
own blood supply. However, long gaps in conventional Metronomic chemotherapy regimen is usually
cytotoxic chemotherapy results in regrowth of the a combination of various drugs of different class
endothelial cells and further angiogenesis. Endothelial having antiangiogenic, immunostimulatory as well as
cells of the tumor vessels are more vulnerable to low dose apoptotic properties. Continuous administration of
continuous chemotherapy as compared to endothelial low dose of a surprisingly wide range of drugs (such
cells of normal (mature) vessels. Additionally, continuous as Cyclophosphamide, Methotrexate, Etoposide,
low-dose chemotherapy enhances the antiangiogenic Vinblastine and Paclitaxel6 is cytotoxic to both circulating
and proapoptotic effects of some cytotoxic agents, in endothelial cells and circulating endothelial progenitor
both dividing tumor cells and endothelial cells. cells but has no effect on nonendothelial cells and
CHAPTER 135: Metronomic Chemotherapy in Metastatic Malignancies: A New Concept 807
leukocytes. Because of their relative genetic stability, in adult patients. Patil et al. from India demonstrated
endothelial cells are inherently less susceptible to the clinical benefit rate of 66.67% with an estimated
development of drug resistance than are tumor cells. Even median progression free survival of 5.2 months by
when maximally tolerated doses of chemotherapy drugs using metronomic chemotherapy for palliation in
are no longer effective, significant inhibition of tumor advanced oral cancer.9
growth and sparing of normal tissue can sometimes be
achieved by simply changing to a metronomic dosing TOXICITY OF METRONOMIC
regimen. CHEMOTHERAPY
Cyclo-oxygenase 2 (COX 2) inhibitors also show Metronomic chemotherapy appears to be safe and
antitumor activity, caused partly by inhibition of convenient based on various clinical trials done in adult
angiogenesis. These compounds, being orally active, are as well as pediatric patients. Metronomic chemotherapy
suitable for long-term administration and cause only also may be a cost effective/cost-saving treatment option
moderate side-effects. Preliminary preclinical studies as demonstrated in various trials. High-grade toxic
have shown that the antitumor activity of some cytotoxic effects are rare. The most common toxic effects noted
agents is potentiated when combined with COX2 in trials so far includes grade 1 nausea and/or vomiting,
inhibitors. Celecoxib (COX-2 inhibitor) treatment of cells grade 1 and 2 anemia, neutropenia, leukopenia and
in culture has been shown to result in cell cycle arrest.7 lymphopenia as well as low-grade fatigue. However, data
Thalidomide, an immunomodulator is known to have are still limited and definitive conclusions cannot be
powerful antiangiogenic activity. It has well established drawn regarding the tolerance of these combinations.
anticancer activity against multiple myeloma and Overall, metronomic chemotherapy is associated with
Kaposi sarcoma and various other tumors. Thalidomide minimal toxicity and can provide significant clinical
increases the degradation of the mRNA of a number of benefit and improve the quality of life of patients with
peptide-signaling molecules such as fibroblast growth advanced and/or relapsed cancer.10
factor and tumor necrosis factor-alpha (TNF-α).8 The
suppression of TNF-α in cancer patients may be of CONCLUSION AND
particular palliative benefit since high levels of TNF-α FUTURE DIRECTIONS
have previously been linked to cachexia and tumor- Future preclinical and clinical studies will need to define
related malaise. the best agents for use according to tumor type, the
number of agents to be incorporated, the doses of each
METRONOMIC CHEMOTHERAPY IN agent to be used alone or in combination, and the timing
ADULT CANCERS of drug administration. Generally, this type of therapy is
Till date majority of clinical trials investigating continued till progression of the disease. By combining
metronomic chemotherapy in adults have been done well-known drugs “of the past” with an innovative
in patients with breast carcinoma . Many investigators treatment schedule, these metronomic chemotherapy
have used various metronomic chemotherapy regimen regimen appears to be well tolerated and associated with
for patients with advanced and recurrent ovarian possible cancer stabilization for few months.
carcinoma, advanced multiple myeloma, hormone
resistant prostate cancer, nonhodgkin lymphoma and REFERENCES
others. These regimens showed only modest response 1. Shimizu K, Oku N. Cancer anti-angiogenic therapy. Biol
rate to metronomic chemotherapy and overall clinical Pharm Bull. 2004;27:599-605.
2. Fidler IJ, Ellis LM. Chemotherapeutic drugs: more really is
benefit. There has been no other randomized clinical not better. Nat Med. 2000;6:500-2.
study comparing metronomic chemotherapy with 3. Folkman J. Tumor angiogenesis: therapeutic implications. N
conventional chemotherapy in progressive malignancies Engl J Med. 1971;285:1182-6.
4. Gasparini G. The rationale and future potential of 8. Yoneda T, Alsina MA, Chavez JB, Bonewald L, Nishimura
angiogenesis inhibitors in neoplasia. Drugs. 1999;58:17- R, Mundy GR. Evidence that tumour necrosis factor plays
38. a pathogenetic role in the paraneoplastic syndromes of
5. Kosmaczewska A, Ciszak L, Potoczek S, Frydecka I. The cachexia, hypercalcaemia, and leukocytosis in a human
significance of Treg cells in defective tumor immunity. Arch tumour in nude mice. J Clin Invest. 1991;87(3):977-85.
Immunol Ther Exp. (Warsz). 2008;56:181-91. 9. Patil V, Noronha V, D’cruz AK, Banavali SD, Prabhash K.
6. Browder T, Butterfield CE, Kräling BM, Shi B, Marshall Metronomic chemotherapy in advanced oral cancers. J
B, O’Reilly MS, Folkman J. Antiangiogenic scheduling of Cancer Res Ther. 2012;8(Suppl):S106-10.
chemotherapy improves efficacy against experimental drug 10. Rome A, André N, Scavarda D, Gentet JC, De Paula
resistant cancer. Cancer Res. 2000;60:1878-86. AM, Padovani L, Pasquier E. Metronomic chemo
7. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. therapyinduced bilateral subdural hematoma in a child
Cyclooxygenase regulates angiogenesis induced by colon with meningeal carcinomatosis. Pediatr. Blood Cancer.
cancer cells. Cell. 1998;93:705-16. 2009;53:246-7.
13
SECTION
Rheumatology
Asymptomatic Hyperuricemia: What to Do? Clinical Approach to a Patient with Vasculitis
Arup Kumar Kundu, Shyamashis Das N Subramanian
Polyarteritis Nodosa: An Enigma Osteoporosis Screening, Prevention, and
Ghan Shyam Pangtey, Paramjeet Singh Treatment
Tanu Shweta Pandey
Chikungunya Arthritis
CHAPTER
136
Asymptomatic Hyperuricemia: What to Do?
Arup Kumar Kundu, Shyamashis Das
EPIDEMIOLOGY with deposition of MSU crystals within the joints or other

Hyperuricemia is a common biochemical abnormality, tissues. Uric acid remains in the serum and extracellular
found in up to 20% of adult males and to a lesser extent fluids mostly as urate ion at pH 7.4. When the serum
in females, though gout affects only 2% of western urate concentration exceeds the solubility of urate [a
population in comparison to <0.5% in India. Normal concentration above 6.8 mg/dL (approximately 7 mg/dL)
serum uric acid levels in adult men exceed those in in physiological condition], supersaturation of urate
women of reproductive age due to increased renal urate results in MSU crystal deposition.
clearance in females by the effect of estrogen. Serum In asymptomatic hyperuricemia, serum uric acid level
uric acid level in women gradually starts rising after is higher than that of normal controls but the patients
menopause and becomes close to the value of men of remain totally asymptomatic, i.e, there is no history of
same age group. Women represent only 5–20% of all gouty arthritis, tophus formation, nephrolithiasis or
patients with gout. Initial attacks of gout in men generally uric acid nephropathy. After a variable period of silent
occur between the 4th and 6th decades, whereas women hyperuricemia, appoximately 20% patients may develop
experience the same after menopause. The occurrence clinical features of gout in course of time though majority
of gout increases with increasing age in both men and of patients never become symptomatic.
women.
Hyperuricemia can be classified as symptomatic (i.e. WHY HYPERURICEMIA OCCURS?
gout) and asymptomatic. Treatment of asymptomatic The final product of purine degradation is uric acid,
hyperuricemia (AH) is a disputed topic, which is which needs the help of rate-limiting enzyme xanthine
described in this monograph. oxidase. Humans lack uricase (urate oxidase), and thus
cannot convert urate to soluble and easily excreted
DEFINITIONS allantoin. Therefore, excessive concentration of uric acid
Universally acceptable definition of hyperuricemia in blood can lead to urate crystal deposition resulting in
is not available. Hyperuricemia is defined as serum gout in humans. In health, urate is freely filtered at the
uric acid >6.8 mg/dL (404 µm/L), measured by glomerulus—then, most of filtered urate is reabsorbed
automated enzymatic (uricase) method, while gout is from the proximal tubule; this is followed by secretion in
the inflammatory response to monosodium urate (MSU) the proximal tubules and postsecretory reabsorption in
crystals formed secondary to hyperuricemia, associated the last portion of the proximal tubules.
812 SECTION 13: Rheumatology
TABLE 1: Causes of hyperuricemia formation, chronic and acute urate nephropathy, and
(A) Urate underexcretion (>90%): uric acid nephrolithiasis. It has been demonstrated in
zz Primary hyperuricemia (genetic polymorphism of urate longitudinal studies that there are increased risk of gouty
transporters: SLC2A9, SLC22A12, ABCG2) arthritis and nephrolithiasis with increasing degrees of
zz Secondary hyperuricemia hyperuricemia and hyperuricosuria. Studies showed that
—— Chronic renal failure (clinical gout rare)
the incidence of gout increases with increasing blood
—— Inhibition of urate secretion (ketoacidosis, lactic acidosis)
level and duration of hyperuricemia both; one of such
—— Pre-eclampsia
studies showed the annual incidence of gout was only
—— Drugs (thiazide and loop diuretics, low-dose aspirin,
cyclosporine, ethambutol, pyrazinamide, angiotensin 0.1% in people with serum uric acid levels lower than
converting enzyme inhibitors, non-losartan angiotensin II 7.0 mg/dL, rising to 0.5% in people with uric acid levels
receptor blocker)
from 7.0 to 8.9 mg/dL, and to 4.9% with uric acid levels
—— Lead nephropathy (saturnine gout)
higher than 9.0 mg/dL ; in this study, the sum total
—— Others—hypertension, primary hyperparathyroidism,
ethanol intake incidence of gout was 22% after five years, when the uric
(B) Urate overproduction (approximately, 10%): acid level in serum is ≥ 9 mg/dL. In another study, the
zz Primary hyperuricemia incidence of gout was 12% where patients with serum
—— Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) urate levels between 7 and 7.9 mg/dL were followed
deficiency for 14 years. The initial episode of gout usually occurs
—— Phosphoribosyl-pyrophosphate (PRPP) synthetase after nearly two decades of AH. Studies have shown
overactivity
that increased levels of GM-CSF, IL-8 and TNF-α in AH
—— Glucose-6-phosphatase deficiency with glycogen storage
disease could be a predictor of gouty arthritis. In patients with
zz Secondary hyperuricemia AH, likelihood of progression to gout increases with
—— High nucleotide turnover (severe psoriasis, myeloproliferative increased amounts of alcohol intake, excessive meat/
and lymphoproliferative diseases, hemolytic disorders, seafood ingestion, hypertension, obesity and use of
malignancy, etc.)
certain drugs like thiazide or loop diuretics, etc.
—— Excessive dietary purine or fructose intake
Increased urinary uric acid excretion is associated
—— Ethanol intake
with elevated risk of urate (not calcium oxalate) stone
—— Vigorous exercise
formation. Uric acid stones account for 5 to 10% of all
(C) Combined:
zz Ethanol intake
renal stones. An epidemiologic study showed that the
zz Tissue hypoperfusion annual incidence of nephrolithiasis was 0.3% in patients
with AH and 0.9% in those who are suffering from gout.
Hyperuricemia occurs due to deranged uric acid Acute uric acid nephropathy occurs after a sudden
rise in uric acid production and hyperuricemia,
metabolism, such as, increased production, decreased
commonly seen in tumor lysis syndrome in patients
excretion, or both (Table 1). Prevalence wise, most
with lymphoproliferative or myeloproliferative disorders
patients with gout are underexcreters. Patients with
after initiation of chemotherapy. This reversible and
gout excrete about 40% less uric acid, due to decreased
potentially preventable cause of acute renal failure is
proximal tubular secretion, than healthy individuals for
due to deposition of uric acid in the renal tubules and
any given level of serum uric acid concentration.
collecting ducts resulting in obstruction of urinary
flow. In contrast to tumor lysis or related syndrome,
CLINICAL CONSEQUENCES OF where urate overproduction is the main pathology,
PERSISTENT HYPERURICEMIA hyperuricemia in chronic kidney disease occurs due to
This can be broadly classified as urate crystal deposition impaired capacity of kidney to excrete urate.
disorders and noncr ystal deposition disorders. Non-crystal deposition disorders, e.g. systemic
Deposition of MSU crystals causes gouty arthritis, tophus hypert ension, chronic renal insufficiency, coronary
CHAPTER 136: Asymptomatic Hyperuricemia: What to Do? 813
artery diseases, metabolic syndrome, diabetes mellitus or hyperechoic cloudy areas. Crystal deposition in joints
and insulin resistance have all been associated with has been observed in a considerable number of persons
hyperuricemia. But, it has not been definitely established with traditionally defined AH, especially of long duration.
as a causal factor in any of these disorders. However, further studies are required to say that AH with
MSU crystal deposits predict an earlier onset and/or
EVALUATION OF PATIENTS WITH worsened outcomes of clinical gout.
ASYMPTOMATIC HYPERURICEMIA
Elevated urate levels should be confirmed by repeating Are There Any Beneficial Effects
the test after at least one week interval. In case of of Hyperuricemia?
confirmed AH, it needs to identify the following: It has been observed that antioxidant effects of
Patients at particularly high risk for gouty arthritis, hyperuricemia lessen oxidative damage in DNA .
tophi, or urolithiasis and who warrant urate lowering Neurological disorders like Parkinson’s disease, multiple
therapy (ULT) by allopurinol, febuxostat, probenecid sclerosis, Huntington’s chorea and Alzheimer’s disease
or uricase. may be related to low uric acid level in serum. On the
Hyperuricemia-inducing drugs or toxins that can be other way round, increased serum uric acid is associated
removed or replaced for normalization of serum uric with greater intelligence, achievement-oriented behavior
acid level. and good school performance.
Individuals whose hyperuricemia is a sign of another
underlying disease or toxin exposure. WHEN TO TREAT ASYMPTOMATIC

The initial evaluation should include a thorough HYPERURICEMIA?
history and physical examination. Special attention Regarding this, most of the trials are short-termed and
should be given to comorbid conditions, dietary habits, not randomized though only a few prospective, long-
addiction, medications or environmental exposure. term, randomized trials have been performed in last
Laboratory testing should include a complete blood couple of years. It is still controversial whether AH should
count, renal function test, serum electrolytes, liver be treated or not. In one word, as of now, there is lack of
function tests and urinalysis, over and above meticulous definite evidence to initiate pharmacotherapy in AH.
clinical examination. Estimation of 24-hour urinary uric AH itself is not a disease, rather an epiphenomenon
acid excretion helps to determine whether hyperuricemia than a cause of the diseases described, and therefore
is caused by overproduction or underexcretion. It should treatment is offered in restricted conditions only, such
be considered in patients with kidney stones, family as, patients on chemotherapy or radiotherapy, history
history of gout or kidney stones, or gout at a young of nephrolithiasis/gouty attacks/tophi formation/
age. On a normal diet, urinary uric acid excretion very strong family history of gout, hyperuricemia with
greater than 800 mg/day or 12 mg/kg/day is defined as moderate renal impairment, and patients with very high
hyperuricosuria. Fractional urinary excretion of urate levels of uric acid (i.e. 12 mg/dL in males and 10 mg/dL
(FEur) using a spot urine also gives similar information. in females).
MSU crystal deposition in joints and tendons can be Patients should be advised for lifestyle modifications
detected by ultrasonography and dual-energy computed to lose weight, if obese, and to reduce consumption of
tomography (DECT). Recent studies support a positive alcohol and foods high in purine and fructose; fluid
role for ultrasound in the early diagnosis of gout and in intake should be > 2 L/day to prevent nephrolithiasis. A
monitoring treatment response. Ultrasound may depict patient of AH with hypertension or dyslipidemia should
urate deposition over the superficial layer of hyaline be treatred by losartan and fenofibrate respectively. As
cartilage as an irregular echogenic line producing the body uric acid load mostly comes from endogenous
“double contour sign” (sensitivity 69%, specificity 100%) sources, dietary counseling should be only adjunctive to
medical management, when ULT is indicated. For ULT, similar to keep the serum uric acid level below 6 mg/dL
the clinical consequences from hyperuricemia should (360 micromol/L) to prevent the consequences, if there
be weighed against the potential benefits and risks of is any.
lifelong pharmacotherapy.
There is paucity of evidences regarding the outcomes
BIBLIOGRAPHY
of patients with clinically AH but MSU crystal deposition
1. Das S, Ghosh A, Ghosh P, et al. Sensitivity and specificity of
demonstrated by imaging; therefore, ULT is yet not
ultrasonographic features of gout in intercritical and chronic
recommended in such condition. Similarly, urate-
phase. Int J Rheum Dis. 2017;20(7):887-93.
lowering pharmacotherapy for prophylaxis against
2. Kundu AK. Hyperuricemia revisited. In: Das AK, Ed.
nephrolithiasis is not justified in most individual in AH.
Puducherry: Indian College of Physicians. Postgraduate
Due to lack of definite evidence, ULT is not indicated Medicine. 2009; XXIII:257-63.
if hyperuricemia is associated with different non- 3. Neogi T. Clinical practice. Gout. NEJM. 2011;364:443-52.
crystal deposition disorders like systemic hypertension, 4. Poon SH, Hall HA, Zimmermann B. Approach to the
cardiovascular disease, metabolic syndrome, etc. treatment of hyperuricemia. Medicine and Health, Rhode
As is the case with nontophaceous gout, the aim of Island. 2009;92(11):359-62.
ULT in persons with sustained but AH (if indicated) is 5. Richette P, Bardin T Gout. Lancet. 2010;375:318-28.
CHAPTER
137
Polyarteritis Nodosa: An Enigma
Ghan Shyam Pangtey, Paramjeet Singh
CASE VIGNETTE
A 19-year-old young boy presented with a ten months
history of intermittent fever, colicky abdominal pain.
He also gave history of Raynaud’s phenomenon,
subcutaneous nodules over forehead and recently
diagnosed hypertension. There was no history of
oral ulcers, alopecia, malar rash, skin tightening or
arthritis. Neither there was any history of blood in
stool or urine. On examination, he had multiple small
1 cm2 subcutaneous nodules on his forehead, which
were painless, soft to firm in consistency and with
overlying skin normal. He was febrile to touch; his
pulse rate was 102 beats per minute, blood pressure
150/100 mm Hg in right arm, supine position. Rest of the Fig. 1: Digital subtraction angiography (DSA) of right kidney showing
multiple pseudoaneurysms (arrows)
systemic examination: chest, CVS and CNS was within
normal limits. On laboratory evaluation, he had mild
of medium-sized arteries, the findings were consistent
hypochromic microcytic (HCMC) anemia, neutrophilic
with a diagnosis of classical-PAN. The patient was
leukocytosis and raised erythrocyte sedimentation rate
started on oral prednisolone 1 mg/kg/day, resulting in
(100 mm Hg/1st hr). His renal function was normal but
immediate feeling of well-being and resolution of fever.
liver function and liver function was normal. Blood test
for HBsAg and anti-HCV were negative. Antineutrophil The skin nodules and abdominal pain also resolve in
cytoplasmic autoantibody (ANCA) was also found to few days. His hypertension was persistent for which he
be negative by indirect immunofluorescence method. was prescribed oral enalapril 5 mg once a day. He was
Conventional digital subtraction angiography (DSA) discharged after 10 days of treatment with prednisolone.
revealed multiple micro-aneurysmal dilatation up Considering his young age the decision to start on
to 1 cm involving the parenchymal branches of the cyclophosphamide was withheld and prednisolone was
hepatic artery, splenic artery, renal artery (Fig. 1), and tapered after 6 weeks of treatment. He was prescribed
splanchnic vessels (Fig. 2). Biopsy of the subcutaneous azathioprine as steroid sparing agent and planned to
nodule over forehead revealed necrotizing inflammation continue the same for at least 3 years.
Fig. 2: Angiography of abdominal aorta and its branching showing Fig. 3: Non-healing ulcer over leg in a patient of polyarteritis nodosa
renal micro-aneurysms (white arrows) and splanchnic vessel
aneurysm (white arrow head)
INTRODUCTION arterioles, capillaries or venules; and not associated with

Polyarteritis nodosa (PAN) is a systemic necrotizing anti-neutrophil cytoplasmic autoantibodies (ANCA).”
vascultis of predominantly involving medium-sized This definition excludes ANCA-associated Vasculitis
arteries. It may also involves small arteries but small (AAV), which is distinct category of small vessel vasculitis.
vessels (arterioles, capillaries and venules) are This distinguishes microscopic polyangiitis (MPA), which
characteristically spared. As the name itself suggest it is an AAV from PAN as both these were clubbed together
involves inflammation of arteries of multiple organs in previous classifications. Such discrimination is useful
with or without nodularity (aneurysmal dilatations) in because both PAN and AAV can have pathologically and
the arteries which can be appreciated via angiography, clinically indistinguishable features. However many
histopathological studies or during post-mortem conditions previously labeled as PAN are now designated
examination of tissue. The classification of vasculitis has as MPA which makes classic PAN a very rare disease.
undergone many modifcations since its inception. The The decrease in prevalence of hepatitis B viral (HBV)
first internationally accepted classification was released disease due to global immunization has also contributed
in 1990 by American College of Rheumatology (ACR) and significantly in decresing the incidence of PAN. Classic
is well known as ACR criteria for classifciation of primary PAN is characterized by segmental necrotizing arterial
vasculitis. The ACR criteria of PAN clubbed together both lesions frequently with microaneurysm formation
classic PAN as well as microscopic polyangiitis (MPA) as and resulting in ischemic infarction and hemorrhage.
during that time MPA was not a entity. The classification Microscopic polyangitis (MPA) is responsible for
and nomenclature criteria was updated and revised in glomerulonephritis and lung capillaritis, while PAN is
2012, which is now known as International Chapel Hill characterized by vascular nephropathy and never affects
Consensus Conference (CHCC 2012) criteria for primary lungs.
vasculitis. The classification is based on vessel size, Polyarteritis nodosa have vide spectrum myriad
antineutrophil cytoplasmic antibody (ANCA) as well as presentation in the form of different organs involvement.
histology. They may present as pyrexia of unknown origin (PUO),
The Chapel Hill Consensus Conference (CHCC) acute or chronic kidney injury, hypertension, acute GI
defines PAN as “a necrotizing arteritis of medium or bleed, cerebrovascular accident, polyarthritis, non-
small arteries without glomerulonephritis or vasculitis in healing ulcers (Fig. 3) and muscle infarcts. Considering
CHAPTER 137: Polyarteritis Nodosa: An Enigma 817
its multi-system involvement and vide spectrum of renal biopsy which were done in the past are rarely
manifestation, the diagnosis of PAN is still an enigma to done in present time considering poor yield and other
the internists as well as rheumatologists. easily accesible tissue availabilty. Renal histology in
classic PAN is of ischemia secondary to renal stenosis,
EPIDEMIOLOGY aneurysm leading to parenchymal infarct. Imaging by
The prevalence of PAN can range from 2 to 33 per million MRI or CT scan and electrophysiological study may help
population. The annual incidence in three regions of in localization of tisse for biopsy as sometime PAN may
Europe was estimated to be 4.4 to 9.7 per million by ACR have patchy tissue involvement.
criteria versus 0–0.9 per million by CHCC definition.
The large variation in estimates may be explained by CLINICAL FEATURES
differences in diagnostic criteria but regional variations Clinically, the PAN can have very varied and weird
may also be there. It can develop at all ages including presentations. PAN can affect virtually any organ like
elderly and children but most cases are between 40 and kidneys, skin, joints, muscles, nerves and gastrointestinal
60 years old, with slight male predominance ratio 1.5:1. tract usually in some combination but the lungs are
Most cases of PAN are idiopathic. It can be associated usually spared. The patient may first visit a dermatologist
with chronic hepatitis B infection (HBV) and also with for skin lesions or to a physician with difficult to diagnose
HIV, parvovirus B19 and HCV infection. Hepatitis B PUO, can land up with neurologist with wrist drop,
infection related PAN usually presents as acute disease foot drop or other neurological deficits, can present to
occurring within 6 months of an HBV infection. As per a surgeon with acute abdomen, to a cardiologist with
WHO report, India have moderate-high prevalence of refractory hypertension or CHF, to an ophthalmologist
HCV and HBV infection, yet we do not see proportionate with acute visual loss and to a nephrologist with acute
cases of PAN for reasons unknown. This may be due kidney injury (AKI). At times, the diagnosis may not
to lack of knowledge of PAN among treating clinicians, be made in first visit or first admission even at the
lack of diagnostic facilities, our genetic constitution apex institutes especially when the patient is in early
or lack of systemic recording of cases. Worldwide stage of disease evolution. It can be a nightmare for the
marked reduction in hepatitis B viral infection has been clinicians when the patient present with acute crisis,
associated with a parallel reduction in prevalence of PAN. such as bleeding GIT or major vessel bleed. The clinical
In addition to infectious causes, PAN also has association manifestations tend to be more severe in case of HBV-
with hematological diseases and malignancies like hairy related PAN.
cell leukemia. In most of the patients of PAN some form of
Classic PAN characteristically involves medium-sized constitutional symptoms are always present, in some
muscular arteries with a tendency to involve branch series it has been reported in upto 90% of cases. The
point of arteries and it is a panarteritis, involving all layers symptoms may includes fever, myalgia, arthralgia,
of the vessel wall. It spares large arteries such as aorta fatigue and weight loss. There can be combination
and its major branches, small vessels lacking muscular of constitutional features with ischemic symptoms.
coat, arterioles, capillaries and venules. Segmental Skin manifestations can occur in 25–60% of patients in
involvement of vessel wall followed by healing leads the form of ulcerations, infarctions, livedo reticularis,
to aneurysm formation and endothelial proliferation subcutaneous nodules. The nodules can ulcerate and
leads to stenosis of the artery resulting in ischemia of the patients can present with non-healing ulcers. Arthralgia
involved organ. or arthritis can be there in around 60% of patients.
Primary vasculitis disgnosis is primarily based on Arthritis is usually asymmetrical, non-deforming. In the
histopathology finding. The various tissues used for very early stage of the disease the patients can have non
biopsies for diagnosis of PAN are muscle biopsy, nerve specific arthralgias. Myositis, myalgias and claudications
biopsy and deep skin biopsy. Testicular biopsy and can be present. Peripheral neuropathy have been found
in up to 85% of patients with PAN. The onset is very acute conventional angiography. Although microaneuryms
and its more common in lower limbs than upper limbs are not pathognomonic, they are commonly present in
and more common in HBV-related PAN. Inflammation of > 60% patients of PAN. The most frequently involved
vasa nervosum can cause mononeuritis which clinically vessels are renal and splachnic vessels branches: hepatic
manifests as wrist drop or foot drop. CNS involvement and mesenteric arteries. The typical angiographic
although less common can include headache, seizures, appearance includes the long segments of smooth
cranial nerve dysfunction and stroke. arterial stenosis with alternating areas of normal or
Renal manifestations are characterized by vascular dilated artery, smooth-tapered occlusions without
nephropathy without glomerulonephritis. Renal infarcts significant atherosclerosis. The dilated segments
can cause renal failure. The patients can have hyper including aneurysms strongly suggests PAN.
tension and proteinuria. Hypertension develops in In some cases, tissue diagnosis can be established by
20–50% of cases and is particularly associated with taking biopsy from potential sites such as skin nodule
HBV related PAN. The patients can have acute severe and involved muscles in patients with myalgias with
postprandial abdominal pain due to mesenteric ischemia or without mononeuritis multiplex. Nerve biopsy from
mimicking acute abdomen though tenderness is not there. involved nerve or sural nerve can be performed when
Some patients presents with acute GI bleeding, diarrhea the patient has distal mononeuritis multiplex. Renal
or pancreatitis. GI involvement can occur in around biopsy is not recommended for PAN as it does not cause
70% of cases and is more common with HBV related glomerulonephritis and involves renal arteries only. One
PAN. Coronary arteritis can lead to acute myocardial of the characteristic feature of PAN on histology is the
infarction but is generally silent. Cardiomegaly is seen coexistence of necrotising vasculitis and a healed lesion
in around 20% of patients. Endocarditis is usually not or normal arteries.
observed in patients with PAN. The cardiac MRI has been
found to be useful in evaluation of coronary arteritis an to PROGNOSIS
assess the extent of myocardium involvement. Orchitis is PAN is classically considered to be a monophasic disease
one of the most characteristic feature of classic PAN but that do not tend to recur once remission is achieved
has been reported in only approximately 20% of patients. with disease modifying antirheumatic drugs (DMARDs)
Lungs are surprisingly spared in PAN for reasons but in our experience this does not holds true. We have
unknown. seen cases of PAN in remission presenting with upper
GI bleed, sudden onset visual loss, recurrent seizures
LABORATORY EVALUATION and non healing wounds or ulcers indicating recurrence.
AND IMAGING These patients have poor prognosis and high mortality
As with other systemic inflammatory illnesses, the rates.
markers of inflammation are raised as reflected by French Vasculitis Study Group (FVSG) developed
raised erythrocyte sedimentation rate (ESR) and CRP Five-Factor Score (FFS) for systemic necrotizing vascu
levels, thrombocytosis and hypoalbuminuria. The litis, which is commonly used for evaluation of prognosis
antineutrophil cytoplasmic antibody (ANCA) is ussually at the time of diagnosis. The prognostic Five Factor Score
negative in classic PAN. Rheumatoid factor when (FFS) includes 5 parameters that are predictors of poorer
present is frequently associated with cryogloblinemia. outcome and mortality. These include proteinuria
Compliment levels (C3 and C4) may be reduced in HBV greater than 1 gm/day, creatinine level (>1.58 mg/dL),
related PAN. cardiac involvement, gastrointestinal involvement and
Conventional angiography is the gold standard CNS manifestations. A FFS of greater than 2 is associated
test for detecting microaneurysms. Digital subtraction with greatly increased mortality although with early
angiography (DSA), CT angiography (CTA) and magnetic diagnosis and appropiate DMARDs use especially
resonance imaging (MRA) can be newer alternatives to corticosteroids and cyclophosphamide, the 5 year
CHAPTER 137: Polyarteritis Nodosa: An Enigma 819
mortality has signifcantly decreased in past few decades. evidence of effectiveness has been coroborated from
The patients with FFS score of one or < 1 can be treated primary systemic vascultis treatment in the past due
with systemic steroid without cyclophosphamide. to rarity of PAN as well as previous clssification (ACR)
clubbing together MPA into classical PAN.
MANAGEMENT Patients with severe disease and FFS score of ≥2
Mortality of untreated PAN is very high and previous should be traeted with cyclophosphamide oral or
studies have documented mortality in first year to be intrvenous. In few studies of systemic vascultis, it
as high as up to 73%. The mainstay of treatment of has been found that intravenous cyclophosphaide is
polyarteritis nodosa (PAN) is by immunosuppression equally effective to oral cyclophosphamide and has
similar to other systemic vasculitis except for patients better toxicity profile. There are various protocol for
with active HBV or HCV infection–related PAN in which cyclophosphamide infusion for PAN and other sytemic
case instead of immunosuppression first control of vasculitis. In one of the commonly used regimen (NIH),
active viral disease is priority and in many cases the intravenous cyclophosphamide is given at dose of
manifestations of PAN may also improve with antiviral 15 mg/Kg every month for 4–6 months as Induction
therapy. Recent development of potent HCV and HBV therapy and this is usually followed by azathioprine,
viral therapy has markedly decreased the incidence MMF, methotrexate or rituximab for next 2–3 years as
of this post-viral PAN to less the five percent of overall maintenance therapy. According to European Vascultis
prevalence. Society (EUVAS) protocol cyclophosphamide infusion is
The treatment of HBV-related PAN is different from given 2 weekly for 3 doses, then 3 weekly for 3–4 months
classic PAN without HBV infection as with institution of to a maximum of 6 more doses for a total of 6 months and
immunosuppression there may be remission of active the total duration depends on response.
vasculitis but it may lead to increased viral replication Rituximab an CD-20 inhibitor has been found to be
leading to hepatic decompensation and death. A short equally effective as compared to IV cyclophosphamide
course of 2–3 weeks of aggressive immunosuppression in induction of remission in patients of ANCA associated
with systemic steroid should be followed by series of vascultis (RAVE trial, RITUXVAS trial). Although classic
plasma exchanges and concomitant antiviral therapy. PAN is ANCA-negative vascultis but still it has been
found to be effective in PAN. Multiple reports has been
Non-HBV Related PAN published in various journals. Rituximab is given at a
Once the diagnosis of non-HBV related PAN is confirmed dose of 375 mg/m2 every week for 4 weeks for induction
my clinicoradiologic and histologic evaluation, they therapy and can be followed by 6 monthly infusion for
should be aggressively treated with immunosuppressive maintenance therapy. It is costly drug as compared to
agents. Acute vasculitis with imminent threat to vital cyclophosphamide with advantage of lesser adverse
organ or life, needs emergency treatment with any of effects, especially cytopenia and ovarian failure in
the one or more of the immunomodulating therapy, females.
which can be life saving: Pulse methylprednisolone, Patients with PAN disease FFS score of < 2 can be
plasmapheresis, intravenous immunoglobulin (IVIG), managed with induction of disease with sytemic steroid
surgery/interventional vascular procedure (vascular with or without oral methotrexate or mycophenolate
embolization, etc.) for acute bleed from microaneurysm, mofetil (MMF) and maintence therapy with azathioprine
and/or renal replacement therapy in case of acute or MMF.
kidney injury. The treatement of non-HBV related
classical PAN is with cytotoxic and immunosuppressive HBV-related PAN
drugs (cyclophosphamide, methotrexate, azathioprine, HBV-related PAN is treated differently compared to
mycophenoalate mofetil (MMF), tacrolimus, cyclosporin) the other primary systemic vasculitis. The underlying
and anti-B cell therapy (Rituximab) but most of the pathogenesis of HBV-related PAN is deposition of
immune complexes over medium and small arteries The characteristic histopathology finding is of focal
secondary to ongoing viral replication. The treatment and segmental transmural necrotising inflammation
of HBV related PAN should be initiated with high dose with fibrinoid necrosis in medium-sized vessels.
systemic steroid for 2–3 weeks to stabilize the patient and Diagnosis of PAN requires strong clinical suspicion
reduce end organ damage secondary to active vascultis. and confirmation by tissue histology or radiologic
The patients who are very sick can also be treated with imaging of micro-aneurysm or stenosis of medium
methyl prednisolone pulse (500–1000 mg/day) for 3–5 and small arteries.
days depending on patient condition. Treatment for non-HBV-related PAN is based on
Once patient is stabilized the plasma exchanges immunosuppression with corticosteroids and
(PE) should be started for physically removing immune cyclophosphamide depending upon Five-Factor
complexes from the circulation. The schedule for PE Score (FFS) for systemic necrotizing vasculitis
developed by French Vasculitis Study Group (FVSG)
depends upon local protocol and availability. In usual
Treatment for HBV-related PAN utilizes a short
setting, for initial three weeks 4 sessions of PE should
course of high-dose corticosteroids, followed by
be done per week, this is followed by 3 sessions per
a combination of antiviral therapy and plasma
weeks for next 3 weeks. The inter session periods is
exchange.
subsequently increased. The ideal endpoint of PE is HBV
PAN is considered to be monophasic disease but
PCR negativity or development of HBsAg or antiHBe
it may have chronic as well as relapsing remitting
antibodies. Antiviral drug against HBV should be
course similar to other primary systemic vasculitis.
started concomitant to PE sessions to reduce viral load
and immune complexes, leading to seroconversion.
BIBLIOGRAPHY
Oral lamivudine 100 mg once a day is the preferred 1. Chatur vedi V, Thabah M. Polyar teritis nodosa. In:
anti-HBV antiviral agent and has shown successful Narsimulu G, Ravindran V. Monograph on vasculitis. Indian
seroconversion. This treatment regimen is based on College of Physicians; 2015. pp. 69-75.
expert advice, as due to the rarity of disease there 2. Das CJ, Pangtey GS. Images in clinical medicine. Arterial
microaneurysms in polyarteritis nodosa. N Engl J Med.
is marked paucity of evidence. Patient whose HBV
2006;355(24):2574.
infections fail to seroconvert or PAN relapses should 3. Guillevin L. Polyarteritis nodosa. In: Sharma A (Ed). Textbook
take expert hepatologist advice for alternative antiviral of systemic vasculitis. The Health Sciences Publisher; 2015.
therapy. Interferon-alpha, adefovir dipivoxil, entecavir, pp. 277-88.
telbivudine and tenofovir are the newer HBV antiviral 4. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross
WL et al. 2012 Revised International Chapel Hill Consensus
agents, which can be used in case of relapse or failure.
Conference Nomenclature of Vasculitides. Arthitis Rheum.
2013;65:1-11.
SUMMARY 5. Luqmani R, Ponte C. ANCA-associated vasculitides and
PAN is a rare form of systemic vasculitis that affects polyarteritis nodosa. In: Bijlsma JWJ, Hachulla E. Textbook on
only medium or small size arteries without involving Rheumatic Diseases, 2nd edition. EULAR; 2015. pp. 717-53.
6. Ntatsaki E, Watts R, Scott DGI. Polyarteritis nodosa and
arterioles, capillaries, venules.
cogan syndrome. In: Hochberg MC (Ed). Rheumatology, 6th
The ANCA test is usually negative in PAN but its edition Elsevier mosby; 2015. pp. 1290-99.
negativity is not absolute and mutually exclusive. 7. Pangtey GS, Jain P. Vasculitis-related Interstitial Lung
Hepatitis B virus (HBV)-related PAN has become very Diseases: Clinical Diagnostic and Management Issues.
rare since the introduction of effective immunization In: Bhalla AS, Jana M (Eds). Clinical Radiological Series:
Imaging of Interstitial Lung Diseases. 2017; Jaypee Brothers
program against the virus.
Medical Publishers, Delhi. pp. 121-31.
Angiography typically demonstrates <1 cm2 micro 8. Polyarteritis nodosa – Management – Approach – Best
aneurysms and focal narrowing in medium-sized Practice – English best practice.bmj.com/best-practice/
blood vessels. monograph/351/treatment/step-by-step.html
CHAPTER
138
Chikungunya Arthritis
Mosquito transmitted chikungunya virus (CHIKV) It is characterized by severe joint pain associated
is common in tropical area. Familarization about with inflammation and tissue destruction and release of
chikungunya by public and doctors in India has been inflammatory cytokines such as IL-1b, IL-6, and TNF-α.
quite evident for last 3–4 years due to its assumed Also the IFN produced by infected fibroblast produce
epidemic proportion in several parts of the country.1 high level of prostaglandin, however exact mechanism
The disease gets its name chikungunya which means responsible for chronic or relapsing form of joint disease
‘bent up’—a posture the patient assumes due to severity are yet not fully understood. It is not entirely clear
of pain in disease. It causes an acute febrile illness with whether joint damage is caused by direct viral effect or by
polyarthralgias which are often severe and debilitating. viral activation of the immune system and its associated
After its discovery in 1952 in Tanzania, few sporadic inflammatory reaction.3 It has been suggested that joint
outbreaks were described in Africa and Asia. In 2005, the pain is immune mediated although regular presence of
virus underwent a mutation that enabled transmission autoantibodies has not been shown.4 Ever since the La
through Aedes albopticus, a widely distributed mosquito, Reunion outbreak, the chronic joint disease associated
has lead to numerous CHIKV epidemics reported in with CHIKV have been reported frequently although
Africa, South-east Asia, the Indian Ocean islands, and prior joint abnormalities have not been excluded. Also,
Europe and thus posing a global public health problem. it is likely that the development of joint disease like
CHIKV spreads through resident dendritic cells osteoarthritis and rheumatoid arthritis later on may
(DCs), including Langerhans cells to target organs, not be related to prior CHIKV infection. Ambiguities
such as muscles, liver, kidney, heart, and brain. regarding CHIKV associated joint disease may be due
Nonhematopoietic fibroblast cells have been reported to non-availability of exactly replicating animal models
to be susceptible to in vitro CHIKV replication and to be which could have helped to know the potential reason
the main cell type infected in target tissues (muscle, joint,
and skin) in mice, and as well as in humans (Table 1).2 TABLE 1: Organ tissue and there respective target cells
Fever experienced by all CHIKV patients is associated Organ tissue Target cells
to the synthesis of cytokines such as interleukin (IL- involved
1b, IL-6) and tumor necrosis factor-α (TNF-α), which Lymphoid tissue Stromal cells, macrophage and dendritic cells
are known pyretics. Arthralgia experienced by CHIKV Joint Fibroblasts
patients closely resembles the symptoms induced by Muscle Satellite cells and fibroblasts
other arthritogenic alphaviruses. Liver, brain Endothelial cells and epithelial

for progressive irreversible joint damage that is reported TABLE 2: Articular manifestation of chikungunya virus
after acute CHIKV infection.3, 4 The association of chronic Acute manifestation
joint pain in CHIKV infection is yet not clear. Many of the Polyarthralgia zz Fingers, wrists, knee, ankle, toes are
chronic patients do not respond well to usual analgesics most frequently involved
zz Symmetric pattern is common
suggesting that pain may not only be nociceptive but also
neuropathic. Myalgia Very common
CHIKV commonly manifest acutely with fever Chronic manifestation

and symmetrical joint pain/swelling associated Polyarthralgia/arthritis zz Fingers, wrists, knee, ankle and toes are
most commonly involved
maculopapular rashes and symmetrical joint and zz Occasionally elbows, shoulders, neck
muscle involvement (polyarthralgias or polyarthritis sacroiliitis and hips are affected

and myalgias). 85–100% of people with symptoms have zz Symptoms may be persistent or
distressing joint manifestation.5 remitting –relapsing
After the fever subsides, patient generally develops Myalgia Very common
oligo or polyarthralgia which are symmetrical. No joint Tenosynovitis/ Common

enthesopathies
is spared although most commonly the distal extremties
Bone erosions Rare
like wrist, metacarpal, interphalangeal joint in the
upper limb and ankle, along with metatarsophalangeal
joints in the lower limb. Knee joint is less commonly and/or tenosynovitis. Articular destruction is rare
reported.5 Atypical presentation like-asymmetry, single in chronic form 15% of patients reported Raynaud’s
and involvement of other less affected joints like elbow, phenomena. The presence of fatiguability and prolonged
shoulder and hip as well as axial skeleton (cervical, morning stiffness indicates the inflammatory bases of
lumbosacral and sacroiliac regions) are also reported. joint involvement. Long-lasting relapsing or lingering
Associated tenosynovitis and enthesopathies may result rheumatic musculoskeletal pain (RMSP) is the hallmark
in paresthesias of the overlying skin. In many cases, these of chikungunya virus (CHIKV) rheumatism (CHIK-R).
manifestations of arthralgia will resolve within 1 to 4 Chopra et al reported high levels of CHIKV IgM antibodies
weeks after the initial onset.5 in a cohart of Indian patients with post-CHIKV RA like
Chronic progressive or relapsing joint disease last disease like syndrome.6 Even edema of hands and feet
months to years and is reported in range 1.6 to 89% of the a notable finding, may be inflammatory in nature and
affected patients. There have been few studies from India resulting RS3PE syndrome.6 It is not clear whether this
about the long-term sequlae of the disease. A prospective viral disease presents with rheumatoid arthritis in a
Indian cohart study of 203 CHIKV infected patients, genetically susceptible individual. Combe et al found 21
found that 46% experienced persistent joint pain 10 cases of RA after the episode chikungunya infection.7,8
month after the acute infection.5 The chronic disease The musculoskeleton manifestation;8,9 as summarized
spares no part of musculosketal system as it involves the in Table 2.
joint synovium tendon and bursae. The presentation Risk factors for developing chronic rheumatic
and distribution of joint manifestation of chronic form symptoms after CHIKV infection have not been clearly
is like the acute form. Ankle joint with associated soft established and reports have yielded inconsistent
tissue edema has been found to be most commonly data. Prospective studies have depicted association
reported in the chronic form.6 Disease tends to affect between development of chronic symptoms with female
the joints with preceding trauma or degeneration.7 The gender, older age, comorbid conditions and severity of
common involvement of DIP joint in chronic CHICKV symptoms at onset of infection. Hypertension, diabetes
arthritis may help in differentiating it from RA despite mellitus, osteoarthritis and dyslipidemia have been
symmetrical involvement in the two disease. The joint associated with the development of chronic arthralgia in
involvement in chronic form may be due to synovitis several longitudinal studies. Predictors of nonrecovary
CHAPTER 138: Chikungunya Arthritis 823
include patients age older than 45 years and presence evidence of similar illness in the family, age of onset,
of underlying osteoarthritis. Patients with two or more absence of serological (RA/anti-CCP), radiological
comorbid condition are likely to experience long lasting changes like erosions, (marginal) and histopathological
musculoskeletal symptoms after CHIKV.10 evidence. Additionaly seronegative spondyloarthritis
Inflammatory marker such as ESR and CRP are (psoriatic arthritis and ankylosing spondylitis have been
frequently elevated in patient with musculoskeletal reported after CHIKV infection particularly in those
symptoms in acute stage. During the acute phase who are HLA B27 positive.12 There is paucity of studies
elevated liver enzyme especially transaminitis and regarding the clinical progression of CHIKV infected
muscle enzymes (creatine phosphokinase, lactate patients having already a preexisting autoimmune
dehydrogenase) have been documented in 50% of rheumatological disease.13
p at i e nt s, o f t e n a c c o m p a n i e d w i t h c y t o p e n i a s The Centres for Disease Control and Prevention
(thrombocytopenia/leukopenia).11 Laboratory results recommends supportive treatment that includes rest,
are normal during chronic stage. Radiolgraphic studies adequate hydration with fluids and acetaminophen
are typically normal or show mild swelling consistent and nonsteroidal anti-inflammatory drugs (NSAIDs) for
with joint pain. Ultrasonography may show evidence fever and joint pain. The role of corticosteroids has been
of tenosynovitis/enthesopathy. MRI finding were studied. Simon et al observed dramatic improvement
joint effusion, bony erosion, marrow edema, synovial of acute and chronic rheumatic symptoms in CHIKV
thickening, tendinitis and tenosynovitis.4,5 infected travelers treated with corticosteroids.14 These
So, the diagnosis of CHIKV infection is based data suggest that a low-dose corticosteroid treatment
on clinical features (fever and arthralgia/arthritis), can be beneficial in relieving the acute rheumatic
epidemiologic factors (residence or return from endemic symptoms of CHIKV infection and in improving quality
area with in 15 days of onset of symptoms) and laboratory of life. However, a prolonged course (1–2 months) with
findings (definitive diagnosis of CHIKV infection is slow tapering may be required to prevent rebound
made by) detection of viral RNA in serum by reverse symptoms.15 Indian study has shown that the persistent
transcription polymerase chain reaction (RT-PCR) arthragia in CHIKV patients mimicking rheumatoid
during first 7 days of infection or detection of IgM and/or arthritis in 70.58 %.5 Therefore DMARD can be effective.
IgG antibodies by ELISA after first 5 days of illness. Combination may help in reducing the dosage of the
Parvovirus B19 may also mimick of CHIKV infection individual drugs which may help in better toleration of
as it causes fever with symmetrical polyarthritis in DMARDS.6,16 Combination of DMARDS or corticosteroids
adults though has seasonal pattern or their is history of with hydroxychloroquine has been successful in treating
exposure to an infected individuals. Moreover patients chronic rheumatic manifestations.17 Early results with
with persistent arthralgias, and particularly those with DMARDS like sulfasalazine and methotrexate are
arthritis, should be followed closely and examined emerging.16 Methotrexate and sulfasalazine combination
for other serious causes of chronic arthritis including was found effective for chronic CHIKV arthritis. TNF
rheumatoid arthritis, systemic lupus erythematosus, blockers were successfully in 6 patients with RA
spondyloartritis and vasculitis. Surprising, a few were diagnosed post-CHIKV infection who failed methotrexate
positive for rheumatoid factor or anti-citrullinated therapy.8 It is not clear when it is appropriate to start
protein antibodies. 5 In a Manimunda’s study it was DMARD therapy for CHIKV induced arthritis. However,
confirmed that the levels of RF/anti CCP were not immunosuppressive agents should be reserved for the
elevated in contrast to what is seen in traditional chronic stages of CHIKV infection.
RA.5 In the same study one-third of patients who had The initiative to stimulate protective immunity as
joint pain met ACR criteria to classify them with RA. a strategy for preventing CHIKV infection in humans
Some of differentiating feature between RA and post- began in the early 1970s. A new formulation using virus-
chikungunya chronic arthritis could be nature of onset, like particles has been shown to induce neutralizing
antibodies in macaques but all are in early phases of trial 9. Win MK, Chow A, Dimatatac F, Go CJ, Leo YS. Chikungunya
to be used in humans.18 fever in Singapore: acute clinical and laboratory features,
and factors associated with persistent arthralgia. J Clin
Clearly, a virus capable of infecting an estimated
Virol. 2010;49: 111-4.
7.5 million people over a 5-year period, resulting in 10. Gérardin P, Fianu A, Michault A, et al. Predictors of
chronic arthralgia in ~30% of these individuals, deserves Chikungunya rheumatism: a prognostic survey ancillary to
more attention. Private and public funding organizations the TELECHIK cohort study. Arthritis Res Ther. 2013;15:R9-
have helped to raise awareness for global health issues 12.
11. Borgherini G, Poubeau P, Staikowsky F, et al. Outbreak
such as HIV infection, malaria and tuberculosis, but this
of chikungunya on Réunion Island: early clinical and
unfortunately represents only a proverbial ‘small bite’ out laboratory features in 157 adult patients. Clin Infect Dis.
of a major problem re-emergent viruses such as CHIKV. 2007;44:1401-77.
12. Malvy D, Ezzedine K, Mamani-Matsuda M, et al. Destructive
REFERENCES arthritis in a patient with chikungunya virus infection
1. Staples JE, Breiman RF, Powers AM. Chikungunya fever: an with persistent specific IgM antibodies. BMC Infect Dis.
epidemiological review of a re-emerging infectious disease. 2009;9:200.
13. Vaughan JH. Viruses and autoimmune disease. J Rheumatol
Clin Infect Dis. 2009;49:942-8.
1996;23:1831-3.
2. Sourisseau M, et al. Characterization of re-emerging
14. Simon F, Parola P, Grandadam M, et al. Chikungunya
chikungunya virus. PLoS Pathog. 2007;3:e89.
infection: an emerging rheumatism among travelers
3. Gardner J, Anraku I, Le TT, Larcher T, Major L, Roques P, et
returned from Indian Ocean islands. Report of 47 cases.
al. Schroder WA, Higgs S, Suhrbier A. Chikungunya virus
Medicine (Baltimore). 2007;86:123-37.
arthritis in adult wild-type mice. J Virol. 2010;84:8021-32.
15. Padmakumar B, Jayan JB, Menon RMR, Krishnankutty
4. Chopra A, Anuradha V, Lagoo-Joshi V, Kunjir V, Salvi S,
B, Payippallil R, Nisha RS. Comparative evaluation of
Saluja M. Chikungunya virus aches and pains: an emerging
four therapeutic regimes in chikungunya arthritis: a
challenge. Arthritis Rheum. 2008;58:2921-2. prospective randomized parallel-group study. Indian Journal
5. Manimunda SP, Vijayachari P, Uppoor R. Clinical progression of Rheumatology. 2009;4;94-101.
of chikungunya fever during acute and chronic arthritic 16. Pandya S. Methotrexate and hydroxychloroquine
stages and the changes in joint morphology as revealed by combination therapy in chronic chikungunya arthritis: a 16
imaging. Trans R Soc Trop Med Hyg. 2010;104:392-9. week study. Indian Journal of Rheumatology. 2008;3:93-97.
6. Ganu MA, Ganu AS. Post-chikungunya chronic arthritis-our 17. Chopra A, Saluja M, Venugopalan A. Effectiveness of
experience with DMARDs over two year follow-up. J Assoc chloroquine and inflammatory cytokine response in
Physicians India. 2011;59:83-86. patients with early persistent musculoskeletal pain and
7. Narsimulu G, Parbhu GD. N Post-chikungunya chronic arthritis following chikungunya virus infection. Arthritis
arthritis . J Assoc Physicians India. 2011;59:81. Rheumatol. 2014;66:319-26.
8. Bouquillard E, Combe B. A report of 21 cases of rheumatoid 18. Akahata, W. A virus-like particle vaccine for epidemic
arthritis following Chikungunya fever. A mean follow-up of chikungunya virus protects nonhuman primates against
two years. Ann Rheum Dis. 2009;68:1505-6. infection. Nature Med. 2010;16:334-8.
CHAPTER
139
Clinical Approach to a Patient with Vasculitis
N Subramanian
INTRODUCTION with microscopic polyangitis (60%) are positive for MPO-

The systemic vasculitides are a constellation of conditions ANCA, and few (30%) are positive for PR3-ANCA.
caused by inflammation and necrosis of blood vessels, During the past 12 months, research on giant cell
causing potentially disabling diseases. Cross sectional arteritis (GCA) pathogenesis has mainly focused on the
study across India in 2006 showed that aortoarteritis, role of varicella zoster virus (VZV) as a trigger of vascular
Wegener’s granulomatosis (now called as GPA) and inflammation.
Henoch-Schönlein purpura accounted for 50% of
patients. The differences in incidence between European CLASSIFICATION
and Indian populations are due to environmental and Vasculitides can be generally classified into infection
genetic differences. This update is a summary of basic related vasculitis, caused by direct invasion and
concepts and recent developments in the evaluation and proliferation of bugs in vessel walls with inflammation,
management of vasculitis. and inflammatory vasculitis, which is caused by immune
mediated antibodies and autoimmune activity triggering
PATHOGENESIS cytokine mediated damage (Fig. 1).
The etiopathogenesis is still unknown but involves Recent Chappel Hill classification in 2012 divides the
interplay of environmental and immunogenic factors in vasculitis based on vessel wall size in to small, medium
a genetically predisposed host. The unifying feature of and large vessel vasculitis and also organ specific
systemic vasculitis is the presence of immune-mediated vasculitis.
fibrinoid necrosis of the vessel wall with karyorrhexis and Common clinical types of vasculitis in India include
red blood cell extravasation.
cutaneous vasculitis, Henoch-Schönlein purpura, anti
IgM and C3 deposition are consistent with a mixed-
neutrophil cytoplasmic antibody (ANCA) vasculitis,
essential cryoglobulinemia. IgA deposition is seen in
Takayasu arteritis and drug induced vasculitis (Table 1).
Henoch-Schönlein purpura. The presence of pauci-
immune vasculitis with minimal immunoreactants
CLINICAL FEATURES
on immunofluorescence is consistent with an anti-
neutrophil cytoplasmic auto-antibody (ANCA) associated Constitutional Features
vasculitis. Patients with Wegener’s granulomatosis are Most patients with systemic disease will manifest with
positive for PR3-ANCA (80%), and about 10% are positive fever, rash, fatigue, weight loss, leg edema and painful
for MPO-ANCA. Conversely, the majority of patients joints the common symptoms with vasculitis.
Fig. 1: Classification of vasculitis

Reproduced from Jennette, et al. Arthritis and Rheumatism. 2013;65(1):1-11.
TABLE 1: Frequency distribution of vasculitic disorders in India Nodular lesions may occur in small vessel vasculitis
(N=1064)*
and livedo reticularis in medium vessel vasculitis. Most
Disease No. Percentage
common type of vasculitis of all times although less
Aortoarteritis 215 20.20 reported.
Giant cell arteritis 35 3.36
Polyarteritis nodosa (PAN) 94 8.83
Small vessel ANCA vasculitis: Common features include
Cutaneous PAN 13 1.22
recurrent sinusitis, cough and breathlessness, rash
Wegener’s granulomatosis 147 13.81
and hematuria apart from systemic features and also
myocardial infarction in eosinophilic granulomatosis.
Microscopic polyangiitis 42 3.94
Churg-Strauss syndrome 19 1.78
Medium Vessel Vasculitis
Henoch-Schönlein purpura 232 21.80
Patients may present with abdominal pain, bloody
Small vessel vasculitis 61 5.73
diarrhea, rash and chest pain, testicular pain, myalgia
Behçet’s disease 145 13.62
and weakness, mononeuritis multiplex.
Kawasaki disease 05 0.46
Undiagnosed 50 4.69 Large Vessel Vasculitis
Others** 6 0.56
Patients come to the consultation with headache, visual
*Based on data from Bangalore, Baroda, Chandigarh, Chennai, Delhi,
loss, absent upper limb pulses and syncope. Stroke
Hyderabad, Kolkata, Lucknow and Mumbai.
**Cogan, Bazins, CNS vasculitis and cerebral bleed in a young patient should raise the
Reproduced from VR Joshi, JAPI 2006. concern about vascultis. Takayasu arteritis may manifest
with absent pulse, claudication pain, and sometimes
Cutaneous Vasculitis gangrene. Giant cell arteritis most commonly presents
Palpable purpuric rash 1 to 3 mm size is the most with headache in temporal region, jaw claudication and
common manifestation and may coalesce and ulcerate. headache.
CHAPTER 139: Clinical Approach to a Patient with Vasculitis 827
Drugs that can cause vasculitis are innumerable but A proof of concept study identified a potential new
common ones include NSAIDs, allopurinol, betalactam use of optical coherence tomography (OCT) to image the
antibiotics, diuretics, diltiazem, ACE inhibitors, and temporal artery but warrants further investigation in the
cocaine. field of large vessel vasculitis.
Infections often coexist with vasculitis like hepatitis
B and C, human immunodeficiency virus, infective MANAGEMENT
endocarditis, and tuberculosis are important secondary Various guidelines have been proposed in the
causes of vasculitis. management of vasculitis. As there is variability of clinical
practice here, most patients are managed following
INVESTIGATIONS the extrapolation of western guidelines. Principles
Vasculitis presents several diagnostic challenges. of management include correct diagnosis, induction
Patients could present with spectrum of clinical of remission and maintenance regimen followed by
manifestations from isolated skin vasculitis to management of flares and comorbidities.
multisystem disease.
Drugs used for acute vasculitis: Prednisolone (oral/
Several medical diagnosis could mimic the pre
intravenous), cyclophosphamide in organ threatening
sentation of vasculitis.
disease—(renal, gut and cerebral) and tocilizumab
Vasculitis could occur as a primary disease itself.
(interleukin–6 blockers) in Takayasu vasculitis resistant
There are five important clinical questions to ask
to cyclophosphamide.
when faced with a patient with possible vasculitis
Rituximab has been proven to be effective in ANCA
(Suresh et al. Postgrad Med Journal 2006).
vasculitis both in remission induction and maintenance
1. Is this a condition that could mimic the presentation
regimen. Despite the increasing use of RTX as an
of vasculitis?
induction agent in AAVs, we still have few data on patients
2. Is there a secondary underlying cause?
with severe renal disease.
3. What is the extent of vasculitis?
Plasma exchange should be considered for patients
4. How do I confirm the diagnosis of vasculitis?
with AAV and serum creatinine of > 5.0 mg/dL in the
5. What specific type of vasculitis is this?
setting of new or relapsing disease. PEX can also be used
G eneral evaluation : Neutrophilia, eosinophilia, for the treatment of severe diffuse alveolar hemorrhage.
thrombocytosis, raised ESR and CRP. Cyclophosphamide has been used for many decades
for life threatening systemic vasculitis as rescue therapy
Immunology
ANCA levels–C ANCA (PR3) specific for granulo
for steroid sparing immune modulation. Van Daalen
et al. assessed the malignancy risk in patients with AAVs
matosis with polyangitis (GPA),
P A N C A ( M P O ) s p e c i f i c f o r e o s i n o p h i l i c
treated with RTX compared to the general public and
granulomatosis with polyangitis (EGPA). Clinical
value of serial measurements of ANCA titers during TABLE 2: Disease specific organ based imaging
the follow-up of AAV patients is still debatable. ANA Diseases Commonest vessels Imaging
and RF are mostly negative, but false positive can Takayasu arteritis Carotid and aortic CT angiography
occur. arch (Fig. 2)
Giant cell arteritis Temporal artery MR angiography
Specific Tests (Table 2) ANCA vasculitis Pulmonary and renal CT thorax (Fig. 3)
Tissue biopsy (skin biopsy, nasal mucosal biopsy, biopsy Polyarteritis Celiac vessels CT angio-abdomen
from lung, renal biopsy and sometimes brain biopsy) nodosa
showing necrotic tissue and granulomatous neutrophilic Retinal vasculitis Retinal vessels CT angio-brain and
infiltration. eyes
Fig. 2: CT angiography showing left subclavian stenosis Fig. 3: CT thorax showing nodules and infiltrates due to pulmonary
hemorrhage in a patient with GPA
to CYC-treated patients and it was lower in RTX-treated Infection may be masking the acute presentation as
patients than in those treated with CYC. with any autoimmune diseases.
Tocilizumab has been effective in Takayasu’s ANCA remains an important tool in diagnosing small
arteritis both in severe disease and also in systemic vessel vasculitis.
vasculitis. Mepolizumab, an IL-5 antagonist, has shown Aggressive early induction therapy and sustained
encouraging results in preliminary studies (82–84) and is maintenance of remission is the key.
currently under investigation in patients with relapsing
and refractory EGPA. CONCLUSION
Vasculitis may be an enigma in emergency setting.
Maintenance drugs: Methotrexate, azathioprine and
Systemic vasculitis is a multisystem disease with
mycophenolate have been proven to be effective in
significant mortality and appropriate management with
disease maintenance regimen and they need to be
the help of specialists would improve the outcome in the
monitored regularly.
long-term.
Recent Indian studies report that relapse occurred in
14/54 (26%) patients after a mean duration of 21 months.
Patients with primary systemic vasculitis should continue
BIBLIOGRAPHY
1. Bambery P, Sakhuja V, Bhusnurmath SR, Jindal SK,
maintenance therapy for 24 months after achieving
Deodhar SD, Chugh KS. Wegener’s granulomatosis: clinical
successful disease remission. Patients who remain ANCA experience with eighteen cases. J Assoc Physicians India.
positive should continue immunosuppression for up to 1992;40:597-600.
5 years. 2. Charles P, Neel A, Tieulie N, Hot A, Pugnet G, Decaux O, et
al. Rituximab for induction and maintenance treatment of
PRACTICAL POINTS ANCA-associated vasculitides: a multicentre retrospective
study on 80 patients. Rheumatology (Oxford, England)
Patient who present with unexplained fever, rash, 2014;53:532-9.
tiredness, leg edema and any systemic organ signs like 3. Jennette JC, et al. Revised International Chapel Hill Consensus
breathlessness, hematoproteinuria, epistaxis should Conference Nomenclature of Vasculitides. Arthritis &
raise the suspicion of vasculitis. Drugs and infections are Rheumatism. 2012;65:1-11, doi: 10.1002/37715.
common causes to exclude before concluding as primary 4. Joshi VR, G Mittal. Vasculitis–Indian perspective. J Assoc
Physicians India. 2006;54(Suppl):12-14.
systemic vasculitis.
CHAPTER 139: Clinical Approach to a Patient with Vasculitis 829
5. Mohammad AJ, Hot A, Arndt F, et al. Rituximab for the 7. Suresh E. Diagnostic approach to patients with suspected
treatment of eosinophilic granulomatosis with polyangiitis vasculitis. Postgrad Med J. 2006;82:483-8. doi: 10.1136/
(Churg-Strauss). Ann Rheum Dis. 2016;75:396-401. pgmj.2005.042648.
6. Nagaraj S, Joshi P, Sharma V, et al. Anca-associated 8. Yates M, et al. Ann Rheum Dis. 2016;75:1583-94.
vasculitis: A retrospective study from western India. Annals doi:10.1136/annrheumdis-2016-209133.
of the Rheumatic Diseases. 2013;71:232.
CHAPTER
140
Osteoporosis Screening,
Prevention, and Treatment
Tanu Shweta Pandey
Osteoporosis is a crippling metabolic bone disorder Mortality higher in men because they are less likely to
characterized by compromised bone strength and receive treatment due to under diagnosis.
skeletal fragility predisposing a person to an increased Osteoporosis has two defining characteristics: (a)
risk of pathological fracture due to low bone mass. It is low bone mass with bone loss but normal mineralization
one of the leading causes of morbidity and mortality and (b) microarchitectural disruption which causes
in elderly men and women. A woman’s chances of fewer, thinner bony spicules resulting in structural
suffering from osteoporosis related fracture is greater weakness. This provides less support and leads to
than the risk of cervical, uterine and breast cancer pathological fractures. There are three types of bone cells
combined. The lifetime risk for women is 40% and for that have different functionalities. Osteoblasts cause
men is 13%. Fractures of the hip and vertebrae are the bone formation. Osteoclasts are responsible for bone
resorption. Osteocytes provide structure and support.
most common and associated with increased mortality
The basic mechanism of osteoporosis is that there is
of 20%. A pathological fracture is defined as one that
more bone resorption as compared to bone formation.
occurs with minimal trauma like a fall from less than
Both processes occur in osteoporosis. “High turnover”
the height of the person. These fractures in osteoporosis
osteoporosis has predominantly increased resorption.
are associated with increased morbidity and mortality
“Low turnover” osteoporosis has predominantly
including poor quality of life, chronic pain, disability, loss
decreased formation. Both can occur in the course of the
of independence, and death. disease.
It is a major public health threat for men and women
above 50 years of age. Globally millions of people have OSTEOPENIA
osteoporosis. In the US alone 12 million men and women Osteopenia is a condition that precedes osteoporosis.
were estimated to have osteoporosis in the year 2012. There is low bone density without having bone loss.
Fifty percent of postmenopausal women are anticipated In the US, almost 35 million people have osteopenia.
to have an osteoporosis-related fracture during their There are many secondary causes of osteopenia
lifetime. In the latest statistics, 25% of women and 5% besides osteoporosis, including hyperparathyroidism,
of men above the age of 65 have osteoporosis. In India, prolonged steroid therapy, chemotherapy or radiation,
a conservative estimate is that 46 million women have osteomalacia, malnutritional states, lack of sunlight, and
osteoporosis–about 20% of all women above age 50. multiple myeloma.
CHAPTER 140: Osteoporosis Screening, Prevention, and Treatment 831
Role of Estrogen for measuring bone mass and measures bone mineral
Estrogen inhibits bone resorption and promotes the density in the lumbar spine and hip. It is a reliable,
deposition of bone matrix by causing calcium and safe, cost-effective, widely available, noninvasive way to
phosphate retention. Postmenopausal women have assess the risk of fractures in postmenopausal women.
low estrogen level and increased bone resorption and Measurement of osteoporosis is done using the T-score.
bone loss. Evidence that women above the age of 70 who It is the number of standard deviations of the bone-
continue to produce small amounts of estradiol have mineral-density measurement above or below the
lower risk of fractures than those who do not. young-normal mean bone density as per WHO.
Normal range is more that -1 standard deviation
Vertebral fractures are the most common type of
T-score of -2.5 SD or below is osteoporosis
pathological fractures in osteoporosis. There are three
T-score of -1.0 to -2.5 SD is osteopenia
types-wedge, compression, and biconcave (or codfish
Severe osteoporosis is a T-score of -2.5 Sd or less with
(or fish)) fractures. Dowager’s hump occurs in elderly
women due to progressive kyphosis resulting from a pathological fracture
multiple compression fractures of the vertebrae. Each At the spine, a T-score of -1 represents about 10% bone
compression fracture causes 1 cm loss of height and 4 cm loss

loss of height causes a 15° kyphosis. The Z-score is the number of standard deviations
from the mean for an age- and sex-specific reference
Risk Factors group. Z-score of -2.0 indicates evaluation for secondary
There are several risk factors that predispose to osteoporosis causes of bone loss. It is more informative in younger
including: patients since it allows comparison of BMD among
Female gender similar patients. It has academic value only and is used
Advancing age in research.
Low body weight
Recent weight loss >5% Risk of Fracture

Maternal history of osteoporosis Absolute risk of fracture with T-score of -2.5 or below
Delayed menarche (after 15), early menopause and no other risk factors:
Smoking —— At age 50 is 5%
High alcohol intake > 2 drinks per day (1–2 drinks —— At age 65 is 20%
increases BMD) Relative risk increases by a factor of 1.5 to 3 for each

Drug induced – steroids, anticonvulsants, aromatase decrease of 1.0 in the T-score
inhibitors, heparin
Physical inactivity Quantitative CT Scan
Low calcium intake Analyzes trabecular and cortical bone separately
Vitamin D deficiency Not recommended for screening
However, the biggest risk factor is a history of Application of T-score to predict fracture risk has not
previous fracture after the age of 50 years. It increases been validated
the risk by 8 times. It is the highest in the first couple More costly
of years. Silent vertebral fractures are common, often Exposure to radiation
diagnosed incidentally on chest X-rays. We must screen Mostly useful in research
for osteoporosis in women who have lost 2 cm in height.
Who should be Screened?
Diagnosis The United States Preventive Services Task Force
The standard diagnostic tool is the DEXA scan–dual recommends screening for osteoporosis in women aged
energy X-ray absorptiometry. It is the gold standard 65 years and older and in younger women whose fracture
risk is equal to or greater than that of a 65-year-old white Are there Any Labs Needed?
woman with no additional risk factors. Current evidence Serum calcium, phosphate, and a metabolic panel
is insufficient to assess the balance of benefits and harms TSH
of screening for osteoporosis in men. The National 25-hydroxyvitamin D
Osteoporosis Foundation recommends screening in all Biochemical markers of bone turnover like
men above 70 years of age. procollagen not indicated
Bone biopsy rarely indicated:
How to Calculate Risk —— Unusual skeletal lesions
The 10-year risk for osteoporotic fractures can be —— Renal osteodystrophy
calculated by using the FRAX tool. It is a questionnaire —— Young patients with severe osteoporosis and no
available online that collect data of an individual and obvious secondary cause
calculates their risk. According to FRAX, a 65-year-old
white woman with no other risk factors has a 10-year Treatment of Osteoporosis
fracture risk of 9.3%. The goal of treatment is to reduce mortality and
morbidity from pathological fractures which decreases
Why is Screening Important? cost of medical care. Overall, less than 20% patients with
Scientific evidence shows that the rate of fractures is pathological fractures get treatment for osteoporosis.
high in women >65 with osteoporosis. Clinical trials Treatment is three pronged and includes lifestyle
show decrease in fracture incidence with treatment of modifications, pharmacologic therapy, and treatment
osteoporosis. Screening and treatment cause reduction of pathological fractures. Lifestyle modifications include
in morbidity and mortality as well as cost of healthcare. smoking cessation, regular weight-bearing exercise,
no more than two alcoholic drinks a day, and calcium
(1200–1500 mg daily) and vitamin D (400–800 units
Absolute Indications for Screening
daily) supplementation. Prior to starting pharmacologic
Pathological fracture
treatment serum vitamin D level should be normalized.
Loss of height >2 cm
Pharmacologic treatment includes:
Drugs like long-term steroids–prednisone >5 mg
Antiresorptive therapy: Reduces bone turnover by
daily for >6 months
decreasing bone resorption
Secondary causes: —— Bisphosphonates
—— Hyperparathyroidism
—— Selective estrogen receptor modulators (SERMs)
—— Hyperthyroidism
—— Estrogens
—— Cushing’s syndrome
—— Calcitonin
—— Hypogonadism
Anabolic therapy: Rebuilds skeletal losses by sti
mulating bone formation

Relative Indications for Screening —— New class of agents
Family history of fragility fracture —— Parathyroid hormone only one available
Low body weight —— Strontium Ranelate
Recent weight loss >5% —— Growth hormone and IGF-1
—— Antisclerostin monoclonal antibodies
When should we Repeat DEXA Scan?

Every two years in patients with osteopenia or Bisphosphonates
osteoporosis These drugs are the first line antiresorptive therapy and
Every 3–5 years in patients with normal BMD work by inhibiting osteoclast-mediated bone resorption.
CHAPTER 140: Osteoporosis Screening, Prevention, and Treatment 833
Due to side effects and long-term therapy compliance is and cardiac events and it is to be used if other therapies
suboptimal. Esophagitis is common and it must be taken are contraindicated or not tolerated.
on empty stomach in the morning and stay upright for
30–60 mins. Rarely osteonecrosis of the jaw can occur Calcitonin
and good dental hygiene is important. Daily, weekly, This works by inhibiting osteoclast activity and thus
monthly and yearly regimens are available as below: reducing vertebral fracture incidence. Only used
Alendronate (Fosamax) - 5–20 mg/day or 35–70 mg/ for pain from spine fractures and not used routinely
wk for osteoporosis treatment. Available as nasal or
Risedronate (Actonel) - 5 mg/day or 35 mg/wk subcutaneous 200 IU.
Ibandronate (Boniva) - 150 mg/month
Zoledronate (Zometa) - 5 mg IV yearly Teriparatide

This is an anabolic parathyroid hormone analog that
SERMs increases the number of bone forming cells, given
These are the first or second line of treatment. They have subcutaneously. It is not to be used for more than 2 years
estrogen-like effects on bone but antiestrogen effects on as it increases risk for osteosarcoma and is expensive. It is
breast and uterus and inhibits osteoclast mediated bone indicated when other medications are not tolerated and
resorption. Raloxifene (Evista) 60 mg daily is a popular there is high fracture risk.
medication. It is, however, more effective for reducing
vertebral fractures than nonvertebral fractures. Side
BIBLIOGRAPHY
1. Cheung AM, Papaioannou A, Morin S. Postmenopausal
effects include hot flashes, nausea, leg cramps, DVT, and Osteoporosis. Osteoporosis Canada Scientific Advisory
stroke. Council. N Engl J Med. 2016;374(21):2096. Review.
2. National Osteoporosis Foundation https://www.nof.org/
Estrogen patients/what-is-osteoporosis/
3. Osteoporosis http://www.mayoclinic.org/diseases-
It is neither the first nor second line of treatment. A
conditions/osteoporosis/home/ovc-20207808.
clinical trial showed reduction in hip fractures by 33% 4. Screening for Osteoporosis: U.S. Preventive Services
and vertebral fractures by 24%, by oral or transdermal Task Force Recommendation Statement. Ann Intern Med.
use. There is increased risk of DVT, CVA, breast cancer 2011;154:356-64. 
SECTION
14
Nephrology
Recipient and Donor Selection for Renal Prevention and Management of
Transplantation in India: Current Status Diabetic Kidney Disease
Sanjay Kumar Agarwal Pritam Gupta, Rajesh Aggarwal, Blessy Sehgal
Rituximab: Panacea of Glomerular Diseases Anemia in Chronic Kidney Disease: Management
Dipankar M Bhowmik, N Rajkanna HK Aggarwal, Deepak Jain, Rahul Chauda
ABO-Incompatible Kidney Transplantation
CHAPTER
141
Recipient and Donor Selection for Renal
Transplantation in India: Current Status
Sanjay Kumar Agarwal
INTRODUCTION CONTRAINDICATION OF RENAL

Organ transplantation is most critical advancement TRANSPLANTATION
of medical science in 19th century. Of the all organ
Absolute
transplants, renal transplant (RT) was earliest done
Reversible renal failure
and still the most widely practiced, successful organ
Active ongoing infection
transplant all over world. First RT in India that too
Advanced extrarenal complications
cadaver, was done in KEM Hospital, Mumbai for a patient
—— Advanced malignancy
of renal carcinoma in 1965. RT provides best form of
—— Severe coronary artery disease
renal replacement therapy (RRT) for any patient with end
—— Severe cerebrovascular disease
stage kidney disease (ESKD) provided patient is fit for RT.
It provides following advantages over life-long dialysis.
Relative
Major psychiatric illness
ADVANTAGES OF RENAL TRANSPLANT Advanced ileofemoral disease
OVER MAINTENANCE DIALYSIS Irreparable lower urinary tract.
Better long-term patient survival If there is no contraindication, recipient has to

Better quality of life undergo the set of investigations based on following
Complete rehabilitation broad principles.
Economically cheaper.
There are certain contraindications of RT. With RECIPIENT EVALUATION

learning curve and development of newer expertise, The objectives of pretransplant assessment is to ensure:
many of the absolute contraindication are slowly being RT is technically possible
removed or changed to relative contraindications. Patient survival improves
Currently, following are taken absolute contraindications Patient has no obvious risk for premature death due
of renal transplant. to other medical problems

838 SECTION 14: Nephrology
Pre-existing conditions do not deteriorate following thallium imaging, stress echocardiography or coronary
transplantation angiography according to local practices and protocol.
Minimal surgery related complications. Patient with a abnormal cardiac test should be further
investigated and treated preferably before RT is done.
Age Other issues, which are important from a point of view
At any age transplantation can be done, however co- of cardiovascular risks, are:
Routine examination of the iliac vessels is not
morbidity related to age can be a limiting factor. There
is disparity between the supply of donor organs and necessary. If there is a history of claudication or
need for RT in India. Therefore, patient >65 years are when physical examination reveals signs of arterial
discouraged to get cadaver renal transplant. insufficiency, non-invasive vascular studies can help
to select patients in whom angiography is indicated.
Preferably should have Matching Blood In patients with a history of transient ischemic
Group attacks, carotid Doppler studies should be performed

to screen for the presence of vascular disease.
Till recently, recipient and donor blood group were
taken based on blood transfusion principles; O group
Malignancy
as universal donor and AB as universal recipient.
In prospective recipients with previous malignancy
However, since last decade or so, ABO incompatible
(except nonmelanoma of skin), renal transplantation
renal transplants are regularly being done in India in
should be considered only if there is no evidence of
many centers. Cost of such transplant is much 3–4 times
cancer at least for two years after the disease treatment.
higher than ABO compatible RT.
For some malignancies (malignant melanoma, breast
carcinoma, colorectal carcinoma, and uterine carcinoma)
Should have Acceptable Systems
this waiting time may be more than 5 years. Prior post-
Complete urine examination
transplant lymphoproliferative disease (PTLD) is not a
Detail biochemistry contraindication to retransplantation. No waiting time
Electrocardiogram (EKG) is necessary in incidentally discovered renal carcinoma,
X-ray chest in situ carcinomas, focal neoplasm, low-grade bladder
cancers, and basal-cell skin cancers.
Cardiac Evaluation
Cardiac disease is second most common cause of post- Recurrence of Primary Disease
transplant mortality in India, after infections. Thus, Recurrent disease are responsible for 5–10% of all
patients with increased cardiovascular risk should be allograft loss. Primary FSGS, IgA nephropathy, type-II
assessed in pre-RT period. This is a controversial area mesangio-capillary glomerulonephritis and diabetic
that how much and with what investigation, one should nephropathy are the common causes of recurrence of
assess the recipient. Current accepted view is that patient primary disease. Pretransplantation counseling should
should be subjected to cardiac stress test before RT if he be done in relation to recurrent disease in appropriate
Is >50 years
patients. However, it is in very rare circumstances that
Has diabetes mellitus the RT is contraindicated because of risk of recurrent
Has an abnormal ECG other than LVH disease. Remission of recurrent FSGS can be induced
Has a history of coronary heart disease with plasmapheresis; therefore, it has been proposed to
Patient who is unable to perform conventional start plasmapheresis prior to a planned RT to prevent
stress test should be subjected to dipyridamole- recurrence.
CHAPTER 141: Recipient and Donor Selection for Renal Transplantation in India: Current Status 839
Should have Acceptable Viral Status Recipient is evaluated to assess that recipient should not
All prospective transplant recipients should be tested have pre-existing antibodies which can reject new kidney
pre-existing viral infections including: and for long-term graft outcome, there should be better
CMV
HLA matching between recipient and donor.
HLA matching for A, B and DR antigen
Epstein-Barr virus (EBV)
Panel reactive antibodies (PRA)
HBV
Cross match test with various methods
HCV
—— CDC (complement dependent cytotoxicity)
Varicella Zoster virus (VZV)
—— Flow crossmatch
Human immunodeficiency virus (HIV).
—— Crossmatch based on luminex platform
Immunization should be given to all hepatitis B (if not
already immunized) and VZV antibody negative patients
Should be Economically Viable
before transplantation. Patients otherwise suitable for
renal transplantation with evidence of chronic hepatitis B
for Transplant Expanses
and/or C or HIV infection should be managed according Transplant is a costly treatment and everybody will not be
to their own merit. It is recommended that the potential able to afford it. In addition to initial cost of surgery, there
RT recipient should have molecular tests, fibroscan is life-long cost of maintenance immunosuppression
(MIS) as well as lifelong cost of investigation and follow-
with or without liver biopsy to assess liver damage and
up. Major cost on follow-up is of MIS medication and
consideration of treatment before transplantation.
it varies depending upon the type of MIS used. On an
EBV negative recipients of an EBV positive donor has a
average, long-term cost is Rs. 12000-15000/ per month.
seven-fold increased risk of post-RT lymphoproliferative
disorder (PTLD). Recipient CMV status at transplantation
DONOR EVALUATION
will be useful to guide antiviral prophylactic strategies.
Renal transplant donors are of following broad category:
The advent of highly active antiviral therapy for HIV has
changed the prognosis of HIV, and recent experience
Living Donor
suggests similar graft and patient survival rates between
Living near relatives
HIV-positive and negative renal transplant recipients.
Living other than near relative
Should have Acceptable Lower Urinary
Deceased Donor (Cadaver Donor)
Tract According to Transplant Human Organ Act (THOA),
Ureter of donor kidney is anastomosed with the recipient near relation includes parents, grandparents, children,
bladder. So, recipient lower urinary tract should be grandchildren, sibling and spouse. Any relation other
normal. It is mostly assessed by than these are included as “other than near relative” and
X-ray [kidney, ureter and bladder (KUB)]
they have to go through a process of clearance from the
Ultrasound abdomen
authorization committee, which include government
Micturating cystourethrogram (MCU)
and non-government members.
Any abnormality should be managed before RT on its In this document, I will restrict to primarily living
own merit. donor evaluation. Donor evaluation should be keeping
following principles in mind:
Should be Immunologically Should be an adult with donation being voluntary
Compatible with Donor There should not be a major systemic illness
Recipient get a kidney from other person and being Donor should not have any transmissible infection/
foreign, recipient body try to reject the new kidney. disease

Donor should have two normal and equally assess these infections, following tests are usually done
functioning kidneys in prospective donor:
Donor should have acceptable anatomy of vessels HBsAg
and ureter Anti-HCV antibodies
HIV
Should be an Adult with CMV (IgG and IgM)
Donation Being Voluntary EBV (IgG and IgM)
Donor should be an adult, > 18 years old. There is no These infections if found, need to be treated and
clear cut upper age limit of the donor. It is renal function donor needs to be declared free from infection before he/
of donor rather than chronological age which is more she can donate the organ. In case of CMV positive donor,
important. Donor with age of 70–75 years have also been depending upon recipient status, CMV prophylaxis is
taken who otherwise are normal in term of renal function used.
and other systemic function.
Donation should be voluntary. There should not Donor should have Two Normal and
be any pressure on the donor. Therefore, a psychiatry Equally Functioning Kidneys
evaluation of all potential donor for RT is must. Donor As donor is giving one kidney to recipient, he/she must
must be able to understand the issues and risk involved have two normal and equally functioning kidneys, so
in the process of donation and should be able to make an that one good functioning kidney goes into recipient and
informed decision. equally good functioning kidney is left in donor so as to
keep donor life free from risk in future while donating
There should not be a Major Systemic one kidney. For assessing this, following tests are done:
Illness Routine complete urine examination
Living donor should not have any major systemic illness, Urine protein/creatinine ratio
which can put him at extra-risk of general anesthesia, to 24 hour urine test for protein
which he will be subjected at the time of surgery. Also, KUB X-ray
he should not have any illness which later affect the US abdomen
remaining single kidney to extra-risk for deterioration Glomerular filtration rate and percentage distribution
after donation of one kidney. For evaluation of systemic of GFR in both kidneys.
illness following tests are done: In above investigations, there should not be any
Complete hemogram evidence of kidney disease. In Indian context, a GFR of
Complete biochemistry 70 mL is acceptable for donation of kidney. Of the 70 mL,
Blood sugar, HbA1c, (GTT if required) nearly 50% each should be distributed in both kidneys.
X-ray chest If there is difference in GFR of two kidneys, better is left
EKG (Echocardiography in selected cases) in the donor and marginal kidney is transplanted in the
Gynecologic evaluation in female donor recipient.
Donor should not have any Transmissible Donor should have Acceptable
Infection/Disease Anatomy of Vessels and Ureter
Donor should not have any infection or disease, which Donor renal artery and veins are anastomosed into
can be transmitted through donation of organ. There are recipient’s pelvic vessels and ureter is anastomosed into
some infections, which can be transmitted from donor recipient bladder. For evaluating donor renal vessels
to recipient through the process of organ donation. To and drainage system, currently CT-angiography is being
CHAPTER 141: Recipient and Donor Selection for Renal Transplantation in India: Current Status 841
done in most of the centers. Usually up to 2–3 renal artery BIBLIOGRAPHY

and 2–3 renal veins are acceptable and there should 1. Abramowicz D, Cochat P, Claas FH, et al. European renal
preferably be one ureter. best practice guideline on kidney donor and recipient
evaluation and perioperative care. Nephrol Dial Transplant.
Marginal Donors 2015;30(11):1790-7.
2. http://kdigo.org/wp-content/uploads/2017/02/KDIGO-
There is gross difference between demand and supply 2009-Transplant-Recipient-Guideline-English.pdf
of kidney as an organ. Therefore, some donors with 3. http://kdigo.org/wp-content/uploads/2017/07/2017-
minor abnormalities are also being accepted. There are KDIGO-LD-GL.pdf
called marginal donor. Some of the examples of marginal 4. Ramos EL, Kasiske BL, Alexander SR, et al. The evaluation
donors are: of candidates for renal transplantation. The current practice
Sibling of diabetic recipient
of U.S. transplant centers. Transplantation. 1994;57:490-7.
5. Taliercio JJ, Nurko S, Poggio ED. Living donor kidney
Donor with impaired GTT
t r a n s p l a n t a - t i o n : a n u p d a te o n ev a l u a t i o n a n d
Mild hypertension without target organ involvement
medical implications of donation. Minerva Urol Nefrol.
Single renal stone with normal metabolic work-up 2011;63(1):73-87.
Borderline GFR
Simple cyst
Localized isolated renovascular disease.

CHAPTER
142
Rituximab: Panacea of Glomerular Diseases
Dipankar M Bhowmik, N Rajkanna
INTRODUCTION TABLE 1: Terminologies used for characterization of the diseases

and treatment response
Glomerular diseases may be primary or secondary
Nephrotic range >3.5 gm/1.73 m2/d
to systemic conditions. The syndromic presentations
proteinuria
of glomerular diseases may be nephrotic (NS),
Complete remission (CR) Proteinuria <0.3 g/d, serum albumin
nephritic, nephrotic-nephritic or rapidly progressive (>30 g/L), and stable renal function
glomerulonephritis. If not treated effectively and early, Partial remission (PR) Proteinuria 0.3–3.5 g/d and/or ≥50%
they may progress to chronic glomerulonephritis. Until reduction in protein excretion from
recently, the standard treatment consisted of steroids, baseline, and stable renal function
cyclophosphamide, mycophenolate mofetil (MMF) and Steroid dependent NS Two consecutive relapses while
(SDNS) receiving prednisolone on tapering
calcineurin inhibitors (CNI). The various terminologies (post initial response), or within 15
used for disease characterization and response to days of its discontinuation
treatment are given in Table 1. Steroid resistant NS Lack of remission despite 16 weeks of
In the last few years, rituximab (RTX) has been used (SRNS) therapy with daily prednisolone (1mg/
kg/d)
to treat several of the glomerular diseases. Rituximab
CNI dependent NS Remission of SDNS is achieved during
is a monoclonal antibody of mixed nature (human
treatment with CNIs (tacrolimus or
and murine). It binds specifically to the CD20 receptor cyclosporin)
present on both the mature and pre B cells. However, this CNI resistant NS No response to therapy CNI therapy for
receptor is absent on plasma cells. Binding of RTX to the 3–6 months
receptor leads to depletion of B lymphocytes through
three mechanisms namely antibody-dependent cellular available evidence are from retrospective observational
cytotoxicity, complement-dependent cytotoxicity, and studies, but lately some of the data are from high quality
induction of apoptosis. Rituximab is FDA approved in controlled trials at least in some specific glomerular
nonhodgkins lymphoma, chronic lymphatic leukemia, diseases. Dosing regimens used in clinical studies
vasculitis and rheumatoid arthritis. Now, it has been (weekly 375 mg/m2 for four weeks or fortnightly 1 gm two
proposed as a promising option for glomerular diseases. doses) found no difference in efficacy or adverse effects.
This article gives a brief review on the efficacy and safety It is prudent to dose according to CD-19 levels after the
of rituximab in glomerular diseases. Much of the earlier first dose to cut down exposure and costs.
CHAPTER 142: Rituximab: Panacea of Glomerular Diseases 843
PRIMARY GLOMERULAR DISEASES GLOMERULAR DISEASES THAT

Glomerular Disease that Cause Nephrotic CAUSE NEPHROTIC SYNDROME:
Syndrome: Nonimmune Complex IMMUNE COMPLEX
Minimal Change Disease Membranous Nephropathy
Minimal change disease (MCD) accounts for about a Membranous nephropathy is the principal cause of
quarter of adult patients with nephrotic syndrome. About NS in adults, among whom idiopathic (primary) MN
a third of these patients will become corticosteroid- accounts for 32–80% of diagnoses. Current therapies
dependent, i.e. steroid dependent nephrotic syndrome include inhibitors of the renin-angiotensin system, and
(SDNS) or have a frequently relapsing disease. For combinations of corticosteroids with alkylating agents or
CNI. RCT data indicate that the above-mentioned agents
this subset of patients, current guidelines suggest oral
can induce remission in 59–90% of patients. However,
cyclophosphamide, calcineurin inhibitors (CNIs)
considering the significant toxicity and high rate of
namely cyclosporin or tacrolimus, or mycophenolate
relapse after stopping these medications (around 60% for
mofetil (MMF). However, treatment with these agents is
CNI), there is need for better treatment. Antibodies in the
associated with significant toxicity. Also, there are high
serum to Phospholipase A2 Receptor (PLA2R) are positive
chances of having relapses. Studies have shown that
in about 75% patients with primary MGN. In a systematic
in patients who are steroid/CNI dependent, rituximab
review of data from 21 studies of RTX in MGN, which
reduces the number of relapses. In fact almost three
included 69 patients with idiopathic MGN the complete
fourths of such patients achieve sustained remission;
remission (CR) was 15–20% and the partial remission
only a quarter may need retreatment to maintain
(PR) was 35–40%. Though this is less than conventional
remission. However, rituximab is less effective in patients
therapy in terms of response, about third of patients in
who have steroid resistant nephrotic syndrome (SRNS).
the above-mentioned studies had been nonresponsive
Hence, rituximab may be used in patients with steroid/
to conventional therapies. The proportion of patients
CNI dependency. Better designed studies are needed in
with membranous nephropathy who achieve complete
patients with SRNS due to MCD. and partial remission increases over time, indicating a
delayed response. It has been shown that PLA2R antibody
Focal Segmental Glomerulosclerosis titers postRTX treatment predicts clinical response.
Focal segmental glomerulosclerosis (FSGS) may be Resurgence of titers were associated with relapse.
primary (idiopathic) or secondary. Secondary causes of Data on Rituximab, though of low quality, is homo
FSGS include HIV, reflux nephropathy and various causes genous to establish its role in difficult to treat MGN (i.e.
of nephron depletion. While treatment is directed to the patients who have contraindication/intolerant to steroids,
underlying etiology in secondary FSGS, corticosteroids CNI, cyclophosphamide or those nonresponsive).
are recommended as the first line therapy in nephrotic The other most important utility is the ability to set
patients with primary FSGS. For patients who are steroid the patient free of steroids and CNI with sustained
resistant, the drugs recommended are CNIs, or high dose remission. Therapy with 2–4 doses of rituximab results
dexamethasone and MMF. There are few studies using in CR in 20–33% and PR in 20–60% of patients who have
rituximab in adults with FSGS. Results of these reports failed conventional therapies. Although patients who
were disappointing when compared to membranous have responded to RTX might relapse, retreatment with
glomerulopathy (MGN) or MCD. Well designed studies, rituximab (even a single dose of 375 mg/m2) is effective
which are adequately powered are needed to evaluate in inducing remission again. Future studies are expected
the efficacy of rituximab in steroid dependent patients to clarify the role of rituximab as the primary treatment
with underlying FSGS. modality.
IgA Nephropathy Diseases Associated with Nephritic

Worldwide, IgA nephropathy (IgAN) is the most Syndrome or Rapidly Progressive
common type of glomerulonephritis. It is characterized Glomerulonephritis (RPGN): Pauci Immune
by deposits of under galactosylated IgA 1, with other
Anti-Neutrophil Antibody – Associated
immunoglobulins/complements in the glomerular
Vasculitis
mesangium. IgAN has a varied clinical and histological
presentation. In patients with subnephrotic proteinuria, The natural history of antineutrophil antibody associated
the initial treatment recommended is ACEi or ARBs. vasculitis (AAV) used to be progressive and fulminant
Corticosteroids may be tried in patients who have with an average survival rate of five months. Currently
persistent proteinuria (>1 g/day) and eGFR >50 mL/min. antineutrophil antibody–associated vasculitis (AAV)
However infective side-effects may be a limiting factor. the treatment of AAV is divided into two phases namely
This has been recently substantiated by the results of induction and maintenance. It is logical to try RTX in
two important RCTs (STOP IgAN, TESTING). Addition such autoantibody mediated disease with significant
of cyclophosphamide, MMF and azathioprine is not evidence of ANCA in their pathogenesis.
advocated except in cases of rapidly progressive crescentic
glomerulonephritis. Evidence for recommending RTX in Induction
IgAN is lacking currently. A well conducted open labeled In life/organ threatening illness the standard of care
RCT (32 patients) failed to demonstrate difference in treatment consists of pulse methylprednisolone followed
proteinuria/e-GFR decline between the rituximab and by oral steroids, cyclophosphamide (oral/i.v). Plasma
placebo arm. exchange is performed in patients with Cr > 5.7 mg/dL
and or diffuse alveolar hemorrhage. This has significant
SECONDARY GLOMERULAR DISEASES morbidity and also mortality. RTX has proven to be
noninferior to cyclophosphamide in terms of inducing
Diseases Associated with Nephritic
remission (RAVE trial), and there is preliminary but
Syndrome or Rapidly Progressive very suggestive evidence of superiority in patients with
Glomerulonephritis (RPGN): Immune relapsing or severe disease (RITUXIVAS trial).
Mediated
Lupus Nephritis Maintenance
Data from observational studies and registries have The 2015 EULAR/ERA-EDTA guidelines recommends
shown that 67–77% lupus nephritis (LN) patients with combination of low dose steroids and either azathio
refractory disease respond to RTX after 6–12 months prine, RTX, methotrexate or MMF. There is also
of follow-up. Major disappointment came from results evidence of superiority of RTX compared to AZA to
of the LUNAR trial which evaluated RTX as on add-on maintain remission with significantly less major relapses
treatment to MMF and steroids. Rituximab failed to (MAINRITSAN trial).
prove superiority. However, this trial was criticized for
being underpowered for detection of PR and had a short ADVERSE EFFECTS OF RITUXIMAB
follow-up. Interestingly, long term results (78 weeks) T h e m o s t c o m m o n a d v e r s e e f f e c t s a re a c u t e
of the same trial has shown superiority in RTX group. infusion reactions (10–50%). This can be avoided by
Rituximab may be considered for patients unresponsive premedications and slow infusion (4–6 hours). Patients
to conventional therapy for lupus nephritis (resistant with NS treated with RTX were found to have increased
lupus). risk for pneumocystis jiroveci pneumonia, so prophylaxis
CHAPTER 142: Rituximab: Panacea of Glomerular Diseases 845
with co-trimoxazole is recommended. Data from SLE follow-up. J Am Soc Nephrol. 2016;28. doi: 10.1681/
patients show increased herpes zoster reactivation. ASN.2016040449.
3. Geetha D, Specks U, Stone JH, et al. Rituximab versus
Other rare but notable side effects being progressive
cyclophosphamide for ANCA-associated vasculitis. N Engl J
multifocal leukoencephalopathy and RTX- associated Med. 2010;363:221-32.
lung injury. 4. Hassan RI, Gaffo AL. Rituximab in ANCA-associated
vasculitis. Curr Rheumatol Rep. 2017;19:6.
5. Jayne D, Rasmussen N, Andrassy K, et al. A randomized
CONCLUSION trial of maintenance therapy for vasculitis associated with
Rituximab induces and maintains remission in steroid- antineutrophil cytoplasmic autoantibodies. N Engl J Med.
dependent nephrotic syndrome. This helps in reducing 2003;349:36-44.
the total dosage of steroids and discontinuation 6. Jones RB, Cohen Tervaert JW, Hauser T, et al. Rituximab
of CNIs. However, in steroid-resistant NS patients, versus cyclophosphamide in ANCA-associated renal
vasculitis. N Engl J Med. 2010;363:211-20.
who also fail CNI therapy, response to rituximab is
7. Mallat SG, Itani HS, Abou-Mrad RM, et al. Rituximab use
less promising. Rituximab may be useful in cases of in adult primary glomerulopathy: Therapeutics and Clinical
resistant lupus nephritis. The role of rituximab in AAV Risk Management. 2016;12:1317-27.
(induction, maintenance) has been established. Its role 8. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety
in membrano-proliferative glomerulonephritis and IgAN of rituximab in patients with active proliferative lupus
needs to be clarified in further studies. nephritis: The Lupus Nephritis Assessment with Rituximab
study. Arthritis Rheum 2012;64:1215-26.
9. Segarra Medrano A, Romero Jaller K. The current evidence
BIBLIOGRAPHY supporting rituximab treatment in primary glomerular
1. Cravedi P. Rituximab in Membranous Nephropathy: Not All diseases causing nephrotic syndrome:. Critical review OA
Studies Are Created Equal. nephron Clinical practice 2016; Nephrology. 2013;1(1):1-11.
135:46-50. 10. Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome:
2. Dahan K, Debiec H, Plaisier E, et al. Rituximab for severe Implications for patient management. Nat Rev Nephrol.
membranous nephropathy: A 6-month trial with extended 2013;9:154-69.
CHAPTER
143
ABO-Incompatible Kidney Transplantation
INTRODUCTION antibodies and modified plasmapheresis reporting a

In patients with end stage renal disease (ESRD), kidney survival rate of 67%. Alexandre et al from Belgium in 1987
transplantation (KT) whenever feasible is the treatment published a protocol for desensitization incorporating
of choice for renal replacement therapy. About 7,500 plasmapheresis and splenectomy which could prevent
kidney transplants are performed in India every year. hyperacute rejection.
With a rudimentary deceased donor program in place, The concept of kidney transplantation from blood
majority of transplants performed are living donor group A2 donors into blood group O recipients was first
transplants. Not all family members and friends can introduced by Thielke et al. 12 of 20 kidney transplant
donate a kidney due to advanced age or other medical recipients maintained good allograft function in the
comorbidities. Additionally 30–40% of potential donors long-term in their study. This technique utilizes the fact
are turned down due to ABO-incompatibility. While that A antigen is expressed very weakly on the RBCs
xenotransplantation using kidneys from pigs, artificial of blood group A2 donors. Unfortunately, only a small
wearable kidneys and differentiation of stem cells into number of patients can benefit from this technique as
functioning organs remain in research stages, paired the prevalence of A2 blood group is very low in the Indian
kidney exchange (donor swap), utilization of altruistic population (~5–6%).
donors and ABO-incompatible (ABOi) KT are the The Japanese started performing ABOi living-
alternate options to address the severe organ shortage. related kidney transplants in 1989 and soon became
ABOi-KT is now a well-established procedure to increase the world leaders in terms of numbers. More than 2,000
the donor pool and has graft and patient survival rates ABOi-KTs had been performed in Japan since 1989.
comparable to ABO compatible transplantations. Ten year-follow-up studies report 1, 3, 5 and 10 years
patient survivals of 95%, 92%, 90%, and 85%, respectively,
HISTORICAL PERSPECTIVE whereas 1, 3, 5, and 10 years graft survival has been 89%,
ABO-incompatibility was previously thought to be 85%, 79%, and 61%. These rates are comparable to ABO
an absolute contraindication to successful kidney compatible transplants.
transplantation. Hume et al published in 1955 the Following the successful outcomes of ABOi KTs in
first reports of ABOi kidney transplantation with 8 Japan, improvements in desensitization protocols and
out of 10 grafts developing graft dysfunction within advent of newer medications for immunosuppression,
the first few days after surgery. In 1981, Slapak et ABOi KT started receiving new attention across the world
al. introduced the concept of depletion of anti-A/B including Europe and USA.
CHAPTER 143: ABO-Incompatible Kidney Transplantation 847
ABO ANTIGENS AND BLOOD GROUPS in peritubular capillaries. By end of second post-
The discovery of ABO system for blood grouping is operative week, accommodation is established and
credited to the Austrian scientist Karl Landsteiner. It exposure to anti-A/B antibodies even at higher titres
is based on the expression of genetically determined causes no harm.
A, B and H blood group antigens. These antigens are
expressed on the surface of a variety of different cell TECHNIQUES OF DESENSITIZATION
types like red blood cells, endothelial cells and kidney Reduction of pretransplant anti-A/B antibody titres
parenchymal cells including the endothelial cells, tubuli below a permissive threshold is the major principle
and glomeruli. Blood group AB individuals are universal of desensitization. Titer thresholds at which one
recipients as they express A and B antigens with no can anticipate damage to the allograft from anti-
A/B antibodies are not clearly established. There is
significant anti-A or anti-B antibodies. People with blood
considerable variation in desensitization protocols
group A have anti-B antibodies while people with blood
across different transplant centers. The goal is to remove
group B have anti-a antibodies. O is the universal donor
as much antibodies as possible and bring anti-A/B
as they do not express the A or B antigens. The Rh factor
IgG antibody titers below 1:8, preferably less than 1:4.
status (positive or negative) is generally not taken into
Desensitization protocols are based on a multi-pronged
clinical consideration in KT because of its insignificant
approach targeting different pathways of the immune
expression on renal parenchymal cells.
system.
Antibody removal to reduce anti-A/B antibody
PATHOGENESIS
levels to empirically defined target titers is done
The presence of preformed iso-hemagglutinins
by pretransplantation apheresis, double-filtration
(antibodies with the intrinsic ability to agglutinate
plasmapheresis or membrane filtration. Number
erythrocytes) that react to non-self ABO antigens is
of sessions needed depends on various factors like
the critical immunological barrier to ABOi KT. This
starting titer values, goal titers, dose of plasmapheresis
natural immunity emerges in early infancy (3–6 month
prescribed, patient weight, hematocrit, etc. A caveat of
of age). It increases in strength until the age of 10–12 plasmapheresis is the elimination of essential plasma
years and then persists throughout life. Natural anti-A/B components, such as albumin and coagulation factors,
antibodies consist of IgM, IgG and IgA classes, with a which limits the volumes of plasma that can be processed
predominance of IgG1 and IgG2 subclasses. Anti-A/B and frequently necessitates plasma substitution.
IgG is generally thought to be complement fixing and In countries like USA where FDA (Food and Drug
of primary pathogenic importance. If recipients are Administration) has not approved immunoadsorption
not appropriately desensitized, preformed anti-A/B techniques, plasmapheresis is the only available method
antibodies activate the complement system and cause for antibody depletion.
severe antibody mediated rejection. In the worst cases, Many desensitization protocols in Europe incorporate
hyperacute rejection leading to immediate renal allograft the technique of immunoadsorption (IA). Single use,
loss occurs. low-molecular weight carbohydrate columns with
immobilized blood-group A or B antigens linked to a
ACCOMMODATION sepharose matrix are used. When patient’s plasma is run
One of the key phenomenon playing a critical role in against them, these columns specifically deplete anti-A or
the success of ABOi-KT is accommodation. Controlled anti-B antibodies. IA columns are routinely used in India.
exposure of antigens in the kidney allograft to anti-A/B In certain patients with very high anti-A/B antibody
antibodies in the early post-operative period results in a titers, we use both IA columns and plasmapheresis to
phenotype exhibiting accommodation. The histological achieve goal reduction in anti-A/B antibody levels. Serial
manifestation of this on kidney biopsy is C4d deposition anti-A/B antibody monitoring is performed before and
during desensitization to guide the intensity of recipient might contain substantial levels of anti-A/B blood group
preconditioning. antibodies which can have a potentially deleterious
Intravenous immunoglobulins (IVIgs) can also be effect. Hence, PRBC transfusions need to be of the
used to modulate the recipient’s immune system and recipient blood type and fresh frozen plasma of AB or
prevent anti-A/B antibody rebound in the early post- donor blood group.
operative period. IVIg may also help to decrease the rates Higher rates of infectious complications like
of infections by substituting immunoglobulins removed pneumonia, wound infection, urinary tract infection and
during plasmapheresis. pyelonephritis have been reported in various studies.
Depletion of B lymphocytes was previously achieved Cytomegalovirus (CMV), herpes simplex and BK viremia
by splenectomy. Considering the risks associated infections are also slightly more common. This can be
with a major surgical procedure and increased rates attributed to the more intensive immunosuppression
of infectious complications, splenectomy gradually used in ABOi-KT. Although speculated to be higher,
gave way to the use of anti-CD20 antibody Rituximab. actual rates of malignancies reported are comparable to
It is administered 2–4 weeks in advance of transplant ABO compatible transplants.
surgery. The dose of Rituximab used was higher in
the past, ranging from 500 mg to 1 gm. Lower doses of CONCLUSION
200 mg are increasingly being studied and are found Owing to the development of effective strategies for
to have non-inferior outcomes. We utilize a single low recipient desensitization, ABOi transplantation has
dose of 200 mg or 100 mg of Rituximab at our transplant become a routinely accepted treatment option with
center (administered 2 weeks preoperatively) and have favorable outcomes. By this approach, about 30% of
observed similar graft outcomes with lesser infections living donors who were rejected in the past due to ABO
complications. incompatibility can now donate their kidneys thereby
Interaction of anti-A/B antibodies with the allograft significantly expanding the living donor pool. Allograft
endothelium results in activation of the complement survival and patient survival rates are comparable to
cascade. Patients are started on a CNI (calceneurin ABO compatible transplantations.
inhibitor like tacrolimus or cyclosporine) and an anti-
metabolite (more commonly mycophenolate than BIBLIOGRAPHY
azathioprine) 7–14 days in advance of the procedure to 1. Christian Morath, Martin Zeier, Bernd Döhler, Gerhard Opelz,
Caner Süsal. ABO-incompatible Kidney Transplantation; Front.
minimize this. Immunol. 8:234
Induction immunosuppressive therapy comprises 2. Gabriel M. Danovitch. Handbook of Kidney Transplantation; 6th
of high dose intravenous corticosteroids and a T-cell edition; Wolters Kluwers; 2017.
depleting agent like anti-thymocyte globulin (ATG) or 3. Georg A. Böhmig, Andreas M. Farkas, Farsad Eskandary,
Thomas Wekerle. Strategies to overcome the ABO barrier in
rarely alemtuzumab. IL-2 receptor blocker antibody
kidney transplantation, Nature Reviews Nephrology. 2015;11:
Basiliximab (Simulect) may also be used. 732-47.
4. Gerold Thölking, Raphael Koch, Hermann Pavenstädt,
COMPLICATIONS Katharina Schuette-Nuetgen, Veit Busch, Heiner Wolters, et al.
Antigen-specific versus non-antigen-specific immunoadsorption
There is increased risk of bleeding complications,
in ABO-incompatible renal transplantation; PLoS ONE 10(6):
particularly in patients who underwent splenectomy e0131465. doi:10.1371/journal.pone.0131465.
in the past. Removal of coagulation factors during 5. Juhan Lee, Jae Geun Lee, Sinyoung Kim, Seung Hwan Song,
plasmapheresis or membrane filtration is a major Beom Seok Kim, Hyun Ok Kim, et al. The effect of rituximab
contributing factor in the current era. An important dose on infectious complications in ABO-incompatible kidney
transplantation; Nephrol Dial Transplant. 2016;31:1013-21.
consideration for the perioperative blood product
6. Milljae Shin, Sung-Joo Kim. ABO Incompatible Kidney
transfusions is that various blood products, such as Transplantation—Current Status and Uncertainties. Journal of
plasma preparations or platelet and RBC concentrates Transplantation; Volume. 2011; Article ID 970421.
CHAPTER
144
Prevention and Management of
Diabetic Kidney Disease
Pritam Gupta, Rajesh Aggarwal, Blessy Sehgal
Diabetes mellitus (DM) is an increasing global public 25 years versus the historical prevalence of 40%. In
health problem. It is the leading cause of CKD and ESRD Asia, higher mortality from DM is more prominent in
in the world accounting for more than 40% ESRD patients. patients age 50–60 years which translates to a reduction
According to the International Diabetes Federation, the in life expectancy of more than a decade. About 50%
number of people with Diabetes worldwide is projected of the ESRD patients have DM. Among this group of
to increase from 382 million in 2013 to 592 million by ESRD with DM, only 60% have diabetic nephropathy
2035, i.e. 10% of whole world population. The rise of DM i.e. normal sized kidneys, proteinuria >1 g with or
and metabolic syndrome is very dramatic in India and without retinopathy, 13% have ischemic nephropathy
because of this India has the dubious distinction of being (i.e. smaller kidney size and modest or no proteinuria).
labeled as “Diabetes capital of the world”. Apart from overt 27% have primary renal disease, i.e. IgA nephropathy,
DM in Indian elderly a phenomenon seen worldwide, membranous, FSGS, analgesic nephropathy, chronic
the concern in India is increasing overt DM, prediabetes interstitial nephritis, SLE, Multiple myeloma, etc.
and obesity in the young. Indian because of genetics
and lifestyle are not only more prone to develop DM but SPECTRUM OF RENAL INVOLVEMENT
also diabetic nephropathy (DN) which progresses faster. IN DIABETES MELLITUS (TYPE 2)
Indian diabetics have higher waist circumference despite Only 60% of Diabetic Kidney Disease (DKD) due to
lower BMI have pronounced insulin resistance, lower
Type 2 DM have retinopathy where as 95% patients of
adiponectin and higher inflammatory markers which
DKD due to Type I DM have retinopathy
leads to more DM and DN. Crux of the problem is lifestyle
causing visceral obesity which in turn causes increased
Only 30–40% of type I and type 2 diabetic develop
insulin resistance and metabolic syndrome. 30–40% of nephropathy.
DM develop diabetic nephropathy (DN). It is 40% more
in Asian Diabetics as compared to Caucasians. Since RISK FACTORS FOR THE DEVELOPMENT
the increased longevity of diabetic patients worldwide OF DIABETIC NEPHROPATHY
due to decreased cardiovascular mortality nowadays
Albuminuria/Proteinuria
prevalence of DN is increasing and more diabetics are
developing ESRD. In western world, prevalence of ESRD
(Microalbuminuria and Macroalbuminuria)
due to DM has stabilized because of good glycemic Proteinuria is a powerful predictor of CVS events, of
control (HbA 1C<7%), blood pressure, weight control, progressive loss of GFR and all cause mortality (20–
lifestyle changes. Studies suggest in Type I DM, good 200 times) as compared to DM without proteinuria
glycemic control of 7%, only 9% will develop ESRD after (Tables 1 to 3).
TABLE 1: Predictors Earlier we use to label (30–300 mg)/day as microalbu-

zz Albuminuric DKD (increased albumin excretion rate with or minuria but now ADA has changed this to persistent
without decreased glomerular filtration) albuminuria (30–300 mg)/day.
zz Normoalbuminuric DKD (normal urinary albumin excretion rate Microalbuminuria reflects functional and potentially
with decreased glomerular filtration rate)
reversible abnormality.
zz Nondiabetic kidney disease
It can occur in hypertension/obesity/CHF/UTI/
zz Diabetic cystopathy (autonomic bladder dysfunction)
uncon-trolled DM, it can be a component of metabolic
zz Disease with increased incidence/severity in DM (but not
exclusive to DM) syndrome.
—— Ischemic renal disease It is not detected by dipstick test, but by ELISA,
—— Urinary tract infections
nephrometry and radioimmunoassay.
—— Emphysematous pyelonephritis
—— Renal papillary necrosis

ADA now recommends persistent proteinuria >300
—— Renal stone disease mg/day which we use to label as macroalbuminuria
or overt nephropathy. Macroalbuminuria may not be
TABLE 2: Risk factors reversible.
zz Familial factors: —— For diagnosing microalbuminuria:
—— Type I DM – In type I DM if first degree relative has nephropathy,

2 of 3 samples in 6 months should be positive.
there are 85% chances of diabetic nephropathy as compared
Preferably second urine sample to be taken
to 17% without family history.
—— Type 2 DM – Familial clustering is seen when there is no UTI, physical exercise, blood
zz Genetic factors: Asians, Africans, Americans, Pima Indians are sugar and blood pressure reasonably well
more prone to get diabetic nephropathy controlled, no fever, hematuria, CHF and
zz Poor glycemic control particularly in first 10 years of onset of exclude nondiabetic kidney disease.
diabetes mellitus type I or type 2
In Type I DM start measuring after 5 years of
zz Systolic blood pressure (type I and type 2)
onset of diabetes.
zz No nocturnal dip – it might be a predictor of microalbuminuria
In Type 2 DM start measuring microalbu
later on
zz Obesity minuria at the time of diagnosis of Type 2 DM.
Yearly thereafter to see if there is any pro
zz Smoking
zz Increased waist to hip ratio gression of disease.
In Type 2 DM microalbuminuria could
zz IUGR, small birth weight and short stature
zz Older age onset of type I and younger age onset of type 2 there be because of HT, obesity, CHF, UTI or
zz Male sex part of metabolic syndrome. Prevalence of
zz Hyperuricemia microalbuminuria is 26.9% in urban citizens
zz High level of LDL and trigylcerides with diabetes in “Chennai urban rural
epidemiology” study and overt nephropathy
TABLE 3: Mortality rate is 2.2%.
Death Annual rate of Best data of natural history of T DM are
2
rate progression provided by UKPDS.
zz Normoalbuminuria <30 mg/24 hrs 0.7% 2% Prevalence of microalbuminuria is 26.9%
zz Microalbuminuria 30–299 mg/24 hrs 2% 2.8% in urban citizens with diabetes in “Chennai
zz Macroalbuminuria >300 mg/24 hrs 3.5% 2.3% urban rural epidemiology” study and overt
zz Raised creatinine 19.2% nephropathy is 2.2%.
CHAPTER 144: Prevention and Management of Diabetic Kidney Disease 851
MANAGEMENT OF MICROALBUMINURIA NATURAL HISTORY OF TYPE I

IN DIABETES DIABETIC NEPHROPATHY
Control blood sugar, HbA1C should be less than or Pre (0–5 years):
—— Increase GFR (25–50%)
equal to 7% and more than 6.5%, no hypoglycemia
—— Renal hypertrophy
and weight gain.
Control blood pressure < (140/90) mm Hg as Incipient (5–15 years):
—— Microalbuminuria 30–299 mg/day
recommen-ded by JNC VIII and DOQI Guidelines.
—— Hypertension
Start ARB/ACE inhibitors.
—— Mesangial expansion
Control weight, regular physical exercise.
—— GBM thickening
Stop smoking and other lifestyle changes. —— Arteriolar hyalinosis
Decrease salt intake and saturated fat intake. Overt (15–25 years):
Dyslipidemia treatment. —— Albuminuria more than 300 mg/day
Avoid NSAIDs , ayurvedic drugs. —— Hypertension
With proper management of miroalbuminuria, —— Decrease GFR
patient can either revert back to normoalbuminuria —— Mesangial expansion and nodules
or lesser number of patients will go towards —— Tubulointerstitial fibrosis.
macroalbuminuria and decreased CVS events and

mortality. TREATMENT TARGET
So microalbuminuria is a valid treatment target. HbA1C
—— Persitently higher HBA
1C that is more than 7%
SCREENING FOR DIABETIC KIDNEY have shown to be a powerful predictor of diabetic

DISEASE nephropathy.
—— It is specifically glycemia in first 10 years of
For following diabetic patients for development of
onset of diabetes that determines long term
diabetic nephropathy, we should keep watch on
cardiovascular and renal outcome.
albuminuria and eGFR. There are many patients of DM
—— If blood sugar is not controlled in first 10 years
who develop decrease in eGFR without developing
of onset of DM and thereafter even if HbA1C is
albuminuria due to ischemic nephropathy, chronic
very well controlled, these patients are more
interstitial nephritis.
likely to develop diabetic nephropathy and
cardiovascular disease. This is called legacy
OTHER BIOCHEMICAL MARKERS effect.
Three new biochemical markers have been identified Before development of albuminuria, good glycemic
that may also predict future development of control is the single most important measure that can
microalbuminuria or decrease in eGFR later on. prevent or delay the onset of renal involvement and
Higher urinary liver type fatty acid binding protein it decreases progression from microalbuminuria to
and type IV collagen may predict decline in renal macroalbuminuria.
function and CVS disease later on even when In overt nephropathy, glycemic control may not delay
microalbuminuria is not there. progression of renal disease however euglycemia
Higher serum level of tumor necrosis factor receptor following pancreas transplant in T1DM was associated
1 and 2 in DM might predict early decline in eGFR in with regression of diabetic glomerulosclerosis after
patients who are not having microalbuminuria. 10 years.
In accord, advance studies, intensive glycemic decreasing progression of renal failure and it is not
control in T2 DM did not decrease CVS events but it just control of blood pressure.
increased risk of hypoglycemia. No role in primary prevention, i.e. in normotensive
Evidence of benefit from HbA 1C is better for normoalbuminuric.
microvascular end point than macrovascular end ACE/ARB inhibitors are first line antihypertensive
point. agents for control of proteinuric diabetic patients
with or without hypertension.
WHAT IS OPTIMAL TARGET HBA1C? For antiproteinuric effect of ACE/ARB inhibitors we
It should be individualized.
can give higher dose of ACE/ARB inhibitors even if
Recently diagnosed diabetic with no complication
BP is controlled.
strict glycemic control HbA1C <7%, no weight gain and
Unfortunately, monotherapy is usually insufficient to
avoid hypoglycemia.
achieve target blood pressure.
Patients with long standing diabetes and known
CVS/CKD stage IV–V > 7%–< 8%.
Escape or nonresponsive to conventional doses of
RAS blocked.
BLOOD PRESSURE CONTROL Add hydrochlorothalidone
In type I DM, microalbuminuria precedes hyper Decrease salt intake to 4–5 gms/day to get ARB/ACE
tension. inhibitor effect. Check 24 hours urinary sodium to
In type 2 DM, hypertension precedes onset of DM confirm salt intake.
in at least 40% type 2 DM. Hypertensive are 25 times Dose escalation of ACE/ARB
more prone to get DM. Aldosterone escape phenomenon after 6–9 months
Control of blood pressure is single most important of ARB/ACE inhibitors therapy. Aldosterone more
factor to decrease the progression of overt diabetic than before starting ARB. So add spirinolactone. Keep
nephropathy and to decrease cardiovascular watch on potassium.
morbidity and mortality. If still BP is not controlled add nondihydropyridine
Higher BP is associated with increasing albuminuria
calcium channel blocker, i.e. diltiazem.
with more rapid progression and cardiovascular
events and retinopathy.
Other Drugs
JNC VIII and DOQI has recommended a target of
BP of 140/90 mm Hg for all diabetic patients with Aliskiren (Antirenin drug): It decreases proteinuria
nephropathy. BP less than this is associated with but with ARB/ACE inhibitors, it increases nonfatal
more CVS problems. strokes, hypotension, hyperkalemia and renal
24 hrs BP measurement is more useful as high complications so trial was stopped prematurely.
night time BP in type I DM preceded the onset of ARB + ACE inhibitors: This combination is not been
microalbuminuria. used any more as it causes more hyperkalemia
doubling AKI events.
BLOCKADE OF RENIN More renal function decline in some patients and
ANGIOTENSIN SYSTEM possible increase in mortality.
In diabetes, RAS is activated. Several other agents like allopurinol, pentoxyphylline,
Blockade RAS with ACE or ARB reduces proteinuria, doxycycline, paricalcital has been investigated for
progression of renal failure and controls blood delaying progress in DN and have not been found to be
pressure. ARB and ACE inhibitors have class effect in very useful.
CHAPTER 144: Prevention and Management of Diabetic Kidney Disease 853
TREATMENT OF DYSLIPIDEMIA IN 3 trial is on to explore the effects of pyridorin on the

DIABETIC NEPHROPATHY progression of diabetic nephropathy.
Cardiovascular risk reduction should be done
Credence trial: It will examine the effect of Canaglifozin
by treating Dyslipidemia according to ‘Kidney (a SGLT2 inhibitor) on slowing progression of diabetic
disease improving global outcome clinical practice kidney disease (stage 2 or 3) having albuminuria >300
guidelines 2003’ mg/day. Results are expected in 2019.
Ecosporin to be used according to ADA guidelines.
So in the years to come, we might have other options
to decrease progression to diabetic nephropathy and
EMERGING AND FUTURE THERAPIES lesser number of patients develop diabetic kidney
There are some major outgoing clinical trials focused on disease.
halting the progression of diabetic kidney disease.
SONAR: Endothelin A receptor antagonists phase 2
BIBLIOGRAPHY
1. Ahmad Abou-Sahek, Steplenc Bais, David JA Gold Smith.
radar trial have successfully tested the hypothesis
Management of Diabetic patient with CKD In: Richard
that low dose atrasentan (75 mg/day) a selective Johnson, Jolin feehally, Jurgen Floege (eds), Comprehensive
EARA reduces albuminuria and slows nephropathy Clinical Nephrology, Fifth edition, Saunders. 2015. pp. 381-8.
pregression in patients who were treated with 2. Collen Majewski, George L Bakris. Managing Diabetic
maximal tolerated dose of ACE inhibitors/ARB. Nphropathies in Clinical Practice: Emerging and future
Higher dose atrasentan 1.25 mg/day decreases Therapies, In: Bakris, et al. Managing Diabetic Nephropathies
in Clinical practice, First Edition, Springer. 2017. pp. 117-26.
albuminuria but caused more edema and weight
3. Daisuke Koya. Patient Assessment and Diagnosis In: Bakris,
gain. et al (ed); Managing Diabetic Nephropathies in Clinical
Phase 3 sonar trial is underway to see for hard end practice, First Edition, Springer. 2017. pp. 47-54.
points, i.e. death, dialysis, doubling of creatinine, 4. Gunter Walf, Kumar Sharma. Pathogenesis, clinical
onset of ESRD in patients of diabetic nephropathy manifestation and Natural History of Diabetic Nephropathy.
with eGFR 25–75 mL/day and urine albumin/ Richard Johnson, Jolin feehally, Jurgen Floege. Compre
hensive clinical Nephrology, Fifth edition, Elsevir Saunders.
creatinine > 300 mg/g of creatinine who are on ACE
2015. pp. 354-78.
inhibitors and ARBS and now atrasentan is added
5. Iyad Mansour, Bijin Thajudeen. Overview of Diabetic
results are expected in 2019. Nephropathy In: Bakris et al (ed) Managing Diabetic
FINERENONE : a steroidal antimineralocorticoid Nephropathies in Clinical practice, First Edition, Springer.
Two separates phase 3 trial 2017. pp. 1-15.
6. Lili Tong, Sharon Alder. Prevention and Treatment of
Fidelio–DKD, Figario DKD Diabetic Nephropathy In: Richard Johnson, Jolin Feehally,
To see effect of finerenone in the progression of DN. Jurgen Floege (eds), Comprehensive Clinical Nephrology,
Fifth edition, Saunders. 2015. pp. 372-9.
Results are expected in 2019.
7. Vivek Kumar, Vinay Sakluja. Current Progress in Diabetic
Inflammatory response inhibitor: Pyridorin decreases Nephropathy. C. Ponticelli, R Kasi Visweswaran. Current
oxidative stress and reduces AGE formation which Progress in Nephropathy, First edition, Tree life media.
causes structural damage to kidney. Pioneer phase 2016. pp. 137-58.
CHAPTER
145
Anemia in Chronic
Kidney Disease: Management
HK Aggarwal, Deepak Jain, Rahul Chauda
ANEMIA IN CHRONIC Isolated normocytic normochromic anemia is typical

KIDNEY DISEASE: MANAGEMENT picture of anemia in CKD but other factors can lead
Anemia is universal complication of chronic kidney to change in these parameters as deficiency of iron or
disease (CKD) and contributes considerably to morbidity, inherited hemoglobinopathies may lead to microcytosis
mortality and poor quality of life in these patients. As whereas folate or vitamin B 12 deficiency may lead to
the renal function declines, the severity and incidence macrocytosis. Anemia of CKD is usually not associated
of anemia progressively increases. The primary cause with white blood cells or platelet dysfunction. In addition
for anemia in CKD is insufficient erythropoietin (EPO) to Hb measurement renal anemia evaluation should
production with several other factors contributing to it. include complete hemogram, absolute reticulocyte
Anemia results in various symptoms including lack of count, serum ferritin level, serum transferrin saturation
energy, breathlessness, dizziness, angina, poor appetite, (TSAT), serum vitamin B12 and folate levels. Due to relative
impaired cognition and mental acuity, decreased rather than absolute deficiency of EPO, measurement of
exercise tolerance and impaired host defence against its concentration is not helpful.
infection resulting in increased morbidity. Thus, there
is a strong rationale for managing anaemia in CKD
TREATMENT
patients and yet the optimal treatment strategies are still Iron Therapy
incompletely defined. For effective heme synthesis, adequate amount of iron
is essential (Table 1). Poor appetite and dietary intake,
DIAGNOSIS AND EVALUATION blood losses from GIT and hemodialysis are important
Anemia is best diagnosed by measuring Hb concentration causes for iron deficiency in CKD patients. Iron loss
rather than haematocrit because of stability and direct
measurement of Hb in standardized process. Anemia TABLE 1: Elemental iron in different iron preparations
is defined as Hb concentration of less than 13.0 g/dL in Iron salt Dose Elemental iron
men and less than 12.0 g/dL in women, according to the
Ferrous gluconate 300 mg 35 mg
most recent definition in the “Kidney Disease: Improving
Ferrous fumarate 200 mg 65 mg
Global Outcomes (KDIGO) guidelines.” These thresholds
Ferrous sulphate 300 mg 60 mg
meant for diagnosis of anaemia and evaluation for the
Ferrous sulphate, dried 200 mg 65 mg
causes should not be interpreted as being thresholds for
treatment of anemia. Sodium feredetate 190 mg 27.5 mg
CHAPTER 145: Anemia in Chronic Kidney Disease: Management 855
may be up to 5–6 mg/day in hemodialysis patients. In formulations are equally effective and have similar side
patients with renal anemia, iron absorption capacity is effect profile.
lower particularly due to systemic inflammation and up IV iron preparations include iron dextran, iron
regulated hepcidin which decrease iron absorption from sucrose, iron gluconate and newer preparations like ferric
the gut and enhance iron sequestration in macrophage. carboxymaltose, ferumoxytol, and iron isomaltoside
Because of these factors, oral iron is less effective as 1000. Stability of preparation decides the maximum dose
compared to parenteral iron. However, because of low which can be administered in single dose as 1000 mg
cost and patient convenience a trial of oral iron therapy of iron sucrose may be given in single dose compared
is justified in CKD non dialysis patients for 1–3 months. to iron gluconate which can be given maximum upto
Intravenous (IV) iron should be started if response to oral 125 mg in single dose. Ferric carboxymaltose and iron
therapy is insufficient. IV route of iron administration is isomaltoside may be given up to 1000 mg in single
preferred in CKD 5D and this is supported by evidence administration whereas usual dose of ferumoxytol is
from various RCTs. Intravenous iron administration has 510 mg. There is risk of hypersensitivity reactions with all
shown a greater improvement in Hb level, a lower ESA the IV preparations.
dose or both.
Untreated or inadequately treated iron deficiency ERYTHROPOIESIS STIMULATING
is one of the important causes of hyporesponsiveness AGENTS (ESAs)
to Erythropoiesis Stimulating Agents (ESAs). Iron ESA therapy is an option if there is suboptimal response
status tests should be performed to assess the level of to iron or serum ferritin is ≥100 µg/mL in the absence
iron in tissue stores or the adequacy of iron supply for of inflammation. The KDIGO guidelines recommend
erythropoiesis. Iron status assessment is most commonly use of ESAs in CKD 5D patients when the hemoglobin
done by serum ferritin which indicates storage iron status is between 9.0–10.0 g/dL to prevent the Hb level falling
and by transferrin saturation (TSAT) which measures the below 9 g/dL with the general consideration that ESAs
availability of iron to support erythropoiesis. Percentage are not to be used at Hb level more than 11.5 g/dL. ESA
of hypochromic red cell (PHRC), soluble transferrin therapy should be deferred in CKD patients with Hb
receptors, zinc protoporphyrin and reticulocyte Hb >10 g/dL, however in patients with Hb ≤10 g/dL, therapy
content (CHr) are the other important tests for assessing must be individualized based on fall of Hb, symptoms
iron status. Serum ferritin level <30 ng/mL indicates attributable to anemia, prior response to iron therapy, the
severe iron deficiency. risk associated with blood transfusion and ESA therapy.
The recent KDIGO guidelines suggest a trial of iron Recombinant human erythropoietin (rHuEPO) has
when transferrin saturation (TSAT) is ≤30% and ferritin been a major advancement in treatment of anemia
level is ≤ 500 ng/mL in CKD patients with anaemia who in CKD patients. Before initiation of ESA therapy
are not taking iron supplement and ESA therapy. It is also all correctable causes (including iron deficiency
recommended in patients on ESA therapy in whom an and inflammatory states) should be treated. First
increase in Hb concentration or a decrease in ESA dose generation ESAs include epoetin-alfa and epoetin beta,
is required. Routine use of iron is not advised in patients which have short half-life (6–8 hours after intravenous
with ferritin level >500 ng/mL and TSAT >30% because of administration) and need to administer two to three
risk of iron toxicity. times per week. Darbepoetin alfa is a second generation,
200 mg elemental iron must be provided by oral long acting ESA and it is a supersialylated analogue
iron preparation for effective erythropoiesis. Among all of EPO. Darbepoetin has approximately three times
available oral preparations, commonly used preparation longer half-life than epoetin alfa after intravenous
is ferrous sulphate because of its easy availability and administration. Pegylated derivative of epoetin beta
cheaper cost. Various studies have shown that all iron known as continuous erythropoietin receptor activator
(CERA) is a third generation ESA. It has half-life of around BLOOD TRANSFUSION

130 hours and can be administered either intravenously In CKD, no consensus is available about when transfusion
or subcutaneously. is indicated. Acute clinical settings that may require red cell
The usual starting dose of epoetin-alpha and beta transfusion include acute hemorrhage or unstable CAD
is 25–50 IU/kg body weight 2–3 times weekly by either or where preoperative correction of anemia is required.
intravenously or subcutaneously. Darbepoetin-alfa Transfusion is also indicated in symptomatic severely
dosing usually initiated at 0.45 mg/kg body weight once anemic patients, patients with ineffective response to ESA
weekly by SC or IV administration or 0.75 mg/kg body therapy (e.g. bone marrow failure, hemoglobinopathies,
weight once every 2 weeks by SC administration. CERA ESA resistance) or in patients where the risks of ESAs
dosing starts at 0.6 mg/kg body weight once every 2 therapy may outweigh the benefits.
weeks by SC or IV administration for CKD ND and CKD To minimize the risk of allosensitization blood
5D patients or 1.2 mg/kg body weight once every 4 weeks transfusion should be avoided in CKD patients,
by SC administration for CKD ND patients. Response to especially eligible for renal transplant. However, the
ESAs starts as early as within 3–4 days with increase in potential benefits of avoiding or minimizing blood
reticulocyte count and within 1–2 weeks Hb starts rising transfusions should be balanced against the risks of
by 0.25–0.50 g/dL/wk. However, care must be taken to harm in individual patient when prescribing ESA and
avoid a rise in Hb of more than 2.0 g/dL over 4 weeks. iron therapy. Volume overload, hyperkalemia, citrate
Dose adjustment should be made slowly and preferably toxicity, metabolic alkalosis, hypothermia, hypocalcemia
only after 4 weeks of first dose. Dose reduction by 25% is are frequently encountered complications associated
needed if Hb rises to 11.5 g/dL and even after this if Hb with blood transfusion. Transmission of infections is also
continues to increase, ESA therapy should be stopped a major concern. Immunologically mediated transfusion
and reinitiated with 25% lesser than previous dose, once reactions including transfusion related acute lung injury
Hb begins to decrease. Minimum two weeks interval (TRALI) and iron overload though uncommon can have
should be present between ESAs dose adjustment. Hb fatal outcome.
measurement should be done at least monthly in CKD
5D and atleast 3 monthly in CKD ND patients on ESA OTHER THERAPIES
therapy. Androgens have been used as treatment of anemia
Major side effects of ESA therapy include increased in CKD patients since long before advent of rHuEPO.
risk of thromboembolic events and increase in blood
pressure. ESA therapy should be used cautiously in TABLE 2: Factors causing ESAs hyporesponsiveness
patients with history of venous thromboembolic events, Fully treatable Partially treatable Uncorrectable
history of stroke and patients with active cancer.
Absolute iron Inflammatory Hemoglobinopathies
deficiency conditions
ESAs Hyporesponsiveness Vitamin B12 deficiency Infections Bone marrow
Absolute definition to ESAs hyporesponsiveness is disorders
Folic acid deficiency Hemolysis
lacking but it is defined if patients have no increase in Hb
Nonadherence to drug Malnutrition
concentration from baseline after the first month of ESA
therapy
on appropriate weight-based dosing or if after treatment Hypothyroidism Bleeding
with stable doses of ESA, patient requires increase in Under dialysis
doses up to 50% beyond the dose at which they had been Hemolysis
stable previously. Intensive search should be done to Hyperparathy-
identify any potentially correctable factors responsible roidism
for hyporesponsiveness (Table 2). Malignancy
CHAPTER 145: Anemia in Chronic Kidney Disease: Management 857
Previous studies have suggested a positive effect of multimodality approach is required including treatment
androgen on renal anemia. The mechanism of action of multiple factors to achieve target Hb. Recognition of
of androgens on erythropoiesis is still not completely various causes by detailed history, clinical examination
understood and proposed mechanisms of action of and investigations contributes to more logical treatment
these drugs include increased erythropoietin production and better survival and quality of life in these patients.
from renal or nonrenal sites, increased sensitivity of
erythroid progenitors to the effects of erythropoietin and BIBLIOGRAPHY
increased red blood cell survival. However, because of 1. Agarwal R. Iron deficiency anemia in chronic kidney disease:
various side effects like acne, virilization, priapism, risk Uncertainties and cautions. Hemodialysis Int. 2017;21:78-
82.
for peliosis hepatis, liver dysfunction and hepatocellular
2. Appel GB, Radhakrishnan J, Agati VD. Secondary glomerular
carcinoma regular use of androgens have lost favor.
disease. In: Skorecki K, Chertow GM, Mardsen PA, Yu ASL,
Although deficiencies of vitamin B 12 and folate are Taal MW, eds. Brenner and Rector′s The Kidney, 10th edn.
important causes of anemia but rarely associated with Elsevier Health-US; 2015.pp.1091-160.
ESAs hyporesponsiveness. There is no concrete evidence 3. BonominiM, Vecchio LD, Sirolli V, Locatelli F. New treatment
to suggest that in the absence of documented deficiency approaches for the anaemia of CKD. Am J Kidney Dis.
2016;67(1):133-42.
of these vitamins they are useful adjuvants in patients on
4. Elliott J, Mishler D, Agarwal R. Hyporesponsiveness to
ESAs therapy. The KDIGO guidelines do not recommend
erythropoietin: Causes and management. Adv Chronic
use of androgen, folic acid, vitamin C, vitamin D, vitamin Kidney Dis. 2009;16:94-100.
E, pentoxifylline and L-carnitine as an adjuvant to ESAs 5. Hsu CY, McCulloch CE, Curhan GC. Epidemiology of
in treatment of anemia of CKD. anaemia associated with chronic renal insufficiency among
adults in the United States: Results from the Third National
OPTION IN FUTURE Health and Nutrition Examination Survey. J Am Soc Nephrol.
2002;13: 504-10.
Continuous research in field of CKD with anemia is
6. Hung SC, Tarng DC. ESA and iron therapy in chronic kidney
going on to develop new molecules with improved disease: a balance between patient safety and haemoglobin
characteristics and/or easier manufacturing processes target. Kidney Int. 2014;86(4):676-8.
than those currently available. All these are currently 7. Jodie L, Babitt, Lin HY. Mechanisms of anaemia in CKD. J
being tested in Phase I to III clinical trials. The Hypoxia Am Soc Nephrol. 2012;23(10):1631-4.
Inducible Factor (HIF) stabilizers (Roxadustat, 8. Kidney Disease: Improving Global Outcomes (KDIGO)
anaemia work group. KDIGO clinical practice guideline
Molidustat) inhibit degradation of HIFα and cause an
for anaemia in chronic kidney disease. Kidney Int.
increase in endogenous EPO production. Activin traps 2012;2(Suppl):279-335.
(Sotatercept, Luspatercept) act by trapping circulating 9. Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio
activin and other members of the TGFβ superfamily L, Goldsmith D, et al. Kidney disease: Improving global
which are involved in regulation of erythropoiesis either outcomes guidelines on anaemia management in chronic
by directly affecting erythroid progenitor or precursor kidney disease: a European renal best practice position
statement. Nephrol Dial Transplant. 2013;28(6):1346-59.
cells or by altering the behavior of bone marrow accessory
10. Macdougall IC, Eckardt KU. Anaemia in chronic kidney
cells. EPO mimetic peptides are synthetic cyclic peptides disease. In: Feehally J, Floege J, Johnson RJ, eds.
capable of stimulating the EPO receptor. Others include Comprehensive clinical nephrology. 5th edn. Philadelphia:
EPO fusion protiens, antibody agonist to EPO receptor, Mosby Elsevier 2015.pp.967-74.
EPO gene therapy. 11. Parfrey PS. Critical appraisal of randomized controlled trials
of anemia correction in patients with renal failure. Curr Opin
Nephrol Hypertens. 2011;20:177-81
CONCLUSION
12. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovic L, Shpilberg O,
Correction of anemia leads to significant improvement Gafter U. Intravenous versus oral iron supplementation for
in physical and mental wellbeing and better quality the treatment of anaemia in CKD: Systematic review and
of life in CKD patients. In majority of CKD patient’s meta-analysis. Am J Kidney Dis. 2008;52:897-906.
SECTION
15
Geriatrics and Genetic
Geriatric Teaching Indian Relevance Management of Gender Dysphoric Persons, Sex
OP Sharma Change Surgeries and Our (Indian) Experience
Therapeutic Uses of Human Endothelial
Progenitor Cells Anemia in Elderly: Experience at a Large
Ananda Bagchi, Aradhya Sekhar Bagchi Tertiary Center
CHAPTER
146
Geriatric Teaching Indian Relevance
OP Sharma
AGEING
Ageing is progressive, generalized impairment of
function resulting in loss of adaptive response to stress
and in increasing risk of age related diseases. This is a
physiological phenomenon. The WHO report on ageing,
which predicted that by the year 2000, 61% of elderly
population will be in developing countries (Figs 1 and
2). Further the declaration in the UN Assembly on 01st
October 1998 by Secretary General Dr. Koffi Annan that
1999 will be International Year of Older Persons.
The world over the governments started focusing on
the welfare of older persons and no wonder health was
among one of the measures to be taken. Fig. 1: WHO report on ageing
The branch of medical science which deals with

elderly is called Geriatrics, a term coined by Dr. Ignatz
Leo Nascher, an Austrian Physician working in US in the
year 1930. In UK the same was popularized by a crusader
of Geriatrics, Dr. Marjory Warren in the year 1939. This
branch of medicine attaches to itself heterogenicity and
immunosenescence which are responsible for increased
infections and degenerative disorders. In India the
moment started in the year 1982 by a group of doctors
and picked up momentum by the Government of India
in the year 1999 after UN declaration.
The rise in number of elderly has been phenomenon
Fig. 2: Elderly population
in last three decades, projecting the number to be around
10.70 percent of total population by the year 2021.
862 SECTION 15: Geriatrics and Genetic
In an article in Oxford textbook of Geriatrics, Dr. O. P. Needs of Elderly

Sharma under “Health Infrastructure for Elderly in India” The elderly are a hetrogenes grow grossly divided in
quoted the pattern of diseases in Rural and Urban elderly, three segments i.e. young elderly, middle elderly and
which was the same. The diseases were Hypertension, old elderly, in the age groups 60–70, 70–80 and above 80
Cataract, Osteoarthritis, Chronic obstructive airway respectively.
disease, Ischemic heart disease, Diabetes, Benign Their requirements also vary as per their physical
prostate Hypertrophy, Dyspepsia, Constipation and health and financial standards. The young being gainfully
Depression. employed are still independent and need medical
standards at par with adult population. The middle
MEDICAL INFRASTRUCTURE elderly requires more of nursing assistance then medical
Currently, we have more than 25 thousand PHCs, 900 expertize while the old elderly is mostly dependent or
District Hospitals, Govt. Tertiary Care Hospitals, 460 disabled in require institutional cares equal medical and
Medical Colleges Hospitals, PSU Hospitals, Military nursing support.
Hospitals, 1.3 Lakhs Private Practitioners besides
other systems of medical treatment like Ayurveda, Geriatric Teaching
Unani, Homeopathy, Naturopathy, etc. for our entire Post Graduate Courses in Geriatric Medicine have been
population of 1.33 Billion. Our Medical and Paramedical started in many institutions. They include Government
infrastructure grossly falls short for delivering adequate Medical College Chennai, All India Institute of Medical
medical services for our population. When comes to Sciences, Delhi, Christian Medical College, Vellore,
elderly whose number is 11.7 million, we have almost no Mahatma Gandhi Missions Medical College, Mumbai
trained Geriatricians and beds for elderly in hospitals. and Amrita Institute of Medical Sciences, Cochin, Kerala.
Indira Gandhi Open University has a distance
GERIATRICS SERVICES education post graduate certificate course in Geriatrics.
Geriatric Clinics have been started in Kasturba Medical IMA AKN Sinha Institute has a postal course in Geriatrics.
College Mangalore, M S Ramaiah Medical College
Bengaluru, Rajiv Gandhi Chest Foundation Bengaluru, Geriatric Medicine—How Different?
BMC Bengaluru, BLDEU Shri B M Patil Medical College Elderly apart from all the diseases which adults suffer,
Hospital and Research Centre Vijayapura, AIIMS additionally have the load of degenerative disorders.
Bhubaneshwar, JSS Medical College Mysuru, Deccan This is the reason the word double burden is used in
Medical College Hyderabad, KLEU Prabhakar Kore Geriatrics – infection and degeneration. The organ and
Hospital Belagavi, Bharati Vidyapeeth Medical College organ systems continue to have the physiological process
Pune, Osmania Medical College Hyderabad, SVS of ageing which jeopardizes their functions affecting the
Medical College Mahabubnagar, Telangana, St John’s clinical presentations and course of disease process.
Health Sciences Bengaluru, Yenapoyya Medical College With age everything comes down i.e. Vision,
Mangalore and S N Medical College Bagalkot, Karnataka. Movement, Motility, Secretions, Immunity, Cognitive
In addition to above clinics, in last two decades and Hearing, etc. while because of atherosclerosis the
Geriatric wards have been commissioned in Government incidence of vascular problems like Stroke, IHD and
Medical College Chennai, AIIMS Delhi, AIIMS Cochin, Hypertension increase.
CMC Vellore, St John’s Health Sciences Bengaluru, KMC The clinical presentation depends on both factors
Mangalore, MGM Mumbai and Five Government District i.e. organs systems already affected by ageing as well as
Hospitals in Karnataka. affected by disease.
CHAPTER 146: Geriatric Teaching Indian Relevance 863
In elderly whatever may happen, the clinical Hypotension, Diabetic Neuropathy, and Hypoglycemia
presentation is in the form of Acute Confusion, and Poor Vision.
Depression, Incontinence, Heart Failure, Fall and
Fainting. NEED V/S AVAILABILITY
There are certain organs which are commonly Currently, the estimated number of senior citizens
affected and they are called weak links. These includes is 112 Million and we have only handful of trained
Brain, Lower Urinary Tract, CVS and Musculoskeletal Geriatricians in the country. As such whatever the
System. number of Geriatricians, they are all located in metros,
In elderly one organ is affected but the other organ hence the elderly in rural and semiurban are totally
may show symptoms. For example, an elderly suffering deprived of trained medical as well as paramedical
from Pneumonia, like adults may not have Fever, Cough, personal. As the number of elderly grows every year, the
Septicemia but on the contrary, may present with existing gap will continue to widen.
confusion, fall and incontinence. Similarly, an elderly
suffering from hyperthyroidism may not show tremors, NEED BASED SOLUTIONS
weight loss, increased appetite but may present with
With five teaching medical institutions producing eight
heart failure.
Geriatricians every year, we will never be able to meet
An elderly sometimes with mild changes; the
the demand of Geriatricians in the country. It is therefore
symptoms may be disproportionately more i.e. mild
good to take a practical approach and divide our
increase in serum calcium due to hyperparathyroidism
requirements as immediate need and future planning.
may present with cognitive impairment. An elderly
with slight enlargement of prostate may present with
Immediate Need
retention of urine. An elderly with slight ischemia with
As on now we have 112 million senior citizens, whom we
preexisting diastolic relaxation abnormality may present
can divide in two categories. First category are those with
with cardiac failure.
minor problems and usually in the age group of 60–75
In elderly certain things may not be significant i.e.
years. They mostly consult family physicians. Second
few ventricular premature contractions, bacteriuria,
category are the people with complicated medical
impaired GTT (Specially if fasting normal PP high), while
problems or above the age of 75 years. They approach
for many things one has to be more vigilant like anemia,
incontinence and confusion. physicians or respective specialists. The second category
It is usual in adults to explain the symptoms with a has to mostly visit institutions and occupy majority of
single disease while in elderly every sign/symptom may beds in hospitals. For the first category the updating to
have different explanation i.e. in a young patient having family physicians will greatly help them serving elderly
Fever, Anemia, Retinal Embolism and a Heart Murmur (Fig. 3). This updating may be done in routine ways as
– one thinks of Infective Endocarditis on the contrary in well as need based in cases of emergency.
elderly the fever may be Viral in origin, Anemia may be The updating of family physicians may be done by
due to Aspirin Induced Blood Loss, Retinal Embolism establishing four centers in the four corners of country
may be due to Cholesterol Embolus and Heart Murmur and starting telemedicine which provide help and also by
may be due to a Calcified Valve. printing small booklets, doing CME’s and an electronic
In elderly one symptom like confusion may occur due newsletter.
to Mild Dementia, Deafness, Poor Vision, and Electrolyte For emergency situations like poisoning, adverse
Imbalance and Heart Failure. Similarly, one symptom drug reactions, sudden outbreak of diseases, etc., the
like falls may occur because of many reasons like same telemedicine centers may provide help or SMS in
Transient Ischemic Attacks, Drugs induced Orthostatic regional languages may be sent to practitioners.
(Frailty, etc.), Gerio Pharmacy and Drug Interaction,

Preventive Aspects, Physiotherapy and Diet, etc.
The distance education courses as of IGNOU may
be encouraged. In M.D. Medicine curriculum the
exposure to geriatrics may be increased. However, M.D.
in geriatrics may be started in selected centers.
A practical approach like the one mentioned above
will take care of immediate medical and health needs
of current segment of elderly and the future preparation
may be done with the cooperation of Medical Council of
India by suitable changes in the curriculum.
Fig. 3: For updating family physicians BIBLIOGRAPHY

1. Government of India, Ministry of Health & Family Welfare,
For complicated medical problems and people above Director General of Health Services. National Program for
75 years there are 460 medical colleges hospitals and health care of the elderly. Operational Guidelines 1-53,
2011.
other tertiary care institutions.
2. http://www.geriatricindia.com/ last accessed on
03/09/2015
For Future 3. http://www.helpageindia.org/ last accessed on
46000 medical graduates (100 M.B.B.S. doctors per 03/09/2015
medical college) are being produced every year. Geriatrics 4. Schedule to the Indian Medical Council Act 1956. New
may be added in their four and a half year curriculum in Delhi, Medical Council of India. 1995.
5. Sharma OP, Introduction: Principles & Practice of Geriatric
every subject. This way the M.B.B.S. doctors produced
Medicine, Viva Books, New Delhi, 2015. pp. 1-6.
will have a formal education of geriatrics in preclinical, 6. World Health Organization. Targets for health for all 2000
paraclinical and clinical subjects. 1985: WHO, Copenhagen.
Stress may be laid on the process of Ageing, Drugs
Metabolism, Clinical Differences, Geriatric Syndromes
CHAPTER
147
Therapeutic Uses of Human Endothelial
Progenitor Cells
Ananda Bagchi, Aradhya Sekhar Bagchi
INTRODUCTION Genesis of Endothelial Progenitor

The significance of systemic vasculature in moderating Cells and Endothelial Cell Markers
optimal delivery, exchange and expulsion of gases, Hemangioblast differentiation advances to Hemopoietic
nutrients and regulatory cells and molecules to the Stem Cells (HSC) and Endothelial Progenitor Cells
tissues and organs of a mature subject has long been (EPC). Successively, these cells contribute to all the cells
appreciated. More recently,1 the task of the vasculature of blood and endothelia respectively. The fact that HSCs
in promoting stem cell homeostasis, organogenesis and EPCs differentiate from a common precursor cell4
during development, preserving of injured tissues has led to the specificity that these cell types express
following an ischemic or hypoxic challenge, and the a number of surface markers including CD31, CD34,
growth and spread of cancer cells within the body has FLK-1, FLT-1, Tie2 and VE-cadherin (Table 1). They
widened exponentially as investigators have probed also emerge concurrently during development from
newer perspectives for cellular therapies in all areas the mesodermal precursors,5 originally thought to be
of health and disease. Collaterally with these interests present during embryonic development, endothelial
in translational research, investigators have become progenitor cells are currently known to exist in adult
fascinated with the uncovering of novel adult stem/ bone marrow. EPCs differentiate into endothelial cells
progenitor cell populations are involved in the evolution, that formulate the vasculature. Thus the function of EPCs
repair or regeneration of systemic vasculature. in angiogenesis is targeted towards cancer therapies
Although the likelihood of the existence of adult in order to prevent metastasis.6 Research into the role
endothelial precursors, was proposed four decades ago, of endothelial progenitor cell may disclose methods
Ashara et al in 1997, first reported,2 the segregation of encouraging recovery following injury to the endothelial
putative adult endothelial precursors, which is currently
recognized as Endothelial Progenitor Cells (EPC).3 They TABLE 1: The complete list EPC markers
are a heterogenors society of cells in different phases of
zz VE Cadheirin zz CXCR4
maturation which evolve from bone marrow, able to be
zz CD31/PECAM -1 zz ETV2/ER71
differentiated into mature endothelial cells and assist
zz CD34 zz MCAM/CD146
repair of damaged endothelium. Steadily increasing
zz CD45/CD45.1 zz Tie-2
studies have committed to these enigmatic cells in the
zz CD 45.2 zz VEGFR2/KDR/FLK-1
latest years and also their close relationship with several
zz CD 117/C-Kit zz VEGF R3/Flt-4
markers of cardiovascular system is now well recognized.
tissue and stimulating neovascularization7 of ischemic or Colony-forming–unit-endothelial cell (CFU-EC)

vandalized tissues. colony assay.8
The fundamental properties of EPC are: However, there is no evidence to the existence of
A circulating cell giving rise to progeny exhibiting culture derived cells in vivo, and also, the relevance of
clonal proliferative potential and differentiation these cells has not been functionally expressed in clinical
restricting to the endothelial lineage. context.
Ability to form lumenized capillary–like tubes in vitro
(cells to display cytoplasmic vacuolation capacity). THERAPEUTIC USES OF EPC

Ability to form firm human blood vessels (cells to Apart from the diagnostic and prognostic point of view,
secrete a basement membrane) when implanted EPCs can be an agreeable target for the treatment and
into tissues (with or without a scaffold) to become an also, be used in an attempt to stimulate vasculogenesis,
integral part of host circulatory system. angiogenesis, and cardiac performance.
Vasculogenesis is the process by which blood vessels Over the past 15 years several studies have focussed
are born de novo from endothelial progenitor cells. These on the function of EPCs in different human clinical
cells participate in the pathologic angiogenesis found in conditions like:
retinopathy and tumor growth. Cardiovascular diseases (CAD, AMI, HF)
Various growth factors, cytokines and hormones Cerebrovascular diseases (Stroke)
cause hematopoietic cells, and associate endothelial Diabetes mellitus
progenitor cells to be mobilized into the peripheral Tumor growth
circulation leading to the formation of blood vessel. Endometriosis
Endothelial progenitor cells can be marked by Wound healing
using the inhibitor of DNA binding I (ID-I). This allows Peripheral arterial obstructive disease.
tracking of EPCs from bone marrow to blood, then into

tumor stroma and eventually incorporating the tumor EPCs AND CARDIOVASCULAR
vasculature. RISK FACTORS
EPC attributes are linked with presence of diverse CV risk
ISOLATION OF EPC factors. EPC function or levels or both can be affected.
Isolation of EPC and characterization are still debated; Present day studies have established an association
in literature two approaches are used to evaluate EPCs: between circulating EPCs levels and cumulative CV risk
1. Identification of subpopulations on the basis of profile;9 e.g. Hill et al, hypothesized that EPCs extracted
surface markers from fresh blood and colony or from bone marrow play a role in progressing endothelial
culture assays. Methods for the isolation of circulating repair and consumption of these cells contributes in the
cells include the adherence culture of overall progression of cardiovascular disease.10 Thus, the EPC
mononuclear cells obtained from the fresh blood by counts can be used as a biological marker for vascular
using density gradient centrifugation method. functionality and also related to cumulative CV risk.
2. Positive preselection of mononuclear cells by the Smoking causes depletion in EPC counts but
antibodies against the surface marker, and finally nicotine may have a beneficial and positive result on
analysis by flowcytometry method. Distinct culture EPC numbers 11 and functional activity at reduced
methods were mode by divergent working groups, concentrations; application of nicotine patches to an
which vary between them for time of growth, for extent enhances the magnitude of the hike in EPC level12
media used and also for the cell phenotypes. The after smoking has been terminated.
standard methods used are – a) EPC culture assay; Increased physical activity boosts EPC health with
b) Endothelial colony forming cells (ECFC) and c) regards to quantity functional capacity and also by
CHAPTER 147: Therapeutic Uses of Human Endothelial Progenitor Cells 867
preventing apoptosis. 13 Physical activity positively EPCs to common CV disorders like CAD, AMI and heart
influences both peripheral and bone-marrow EPC failure (HF).
counts. Low concentrations of circulating EPCs have shown
Hypercholesterolemia negatively influences both EPC to be the independent predictors of atherosclerotic
count and its function, indeed EPC levels have an inverse CV disease progression. Endothelial integrity has an
relationship with TC and LDL-C levels. 14 Increased excellent balance between endothelial damage and
oxidative stress linked with dyslipidemia may partly be repair. Atherosclerotic risk factors are linked with
involved in the impaired regulation of EPC maturation, reduced counts and activity of circulating EPCs, it is
mobilization and survival; of note, circulating EPCs are possible that advancement of atherosclerosis is driven by
too sensitive to oxidized LDL, thus causing premature an impairment of EPC repairing capacity. Additionally,
apoptosis. Also LDL-C levels have an inverse relation disease process that hamper the endothelium per se
with EPC migratory capacity. Elevated LDL-C and also lead to endothelial tissue detachment, causing elevated
oxidized LDL concentrations impair EPC migration, via concentrations of circulating endothelial cells (CEC)
VEGF mediated pathway, and blocks VEFG-included in the blood. An inverse association has been found
EPC migration by inhibiting NO production.15 between EPCs and CECs 19 as high number of CEC
Systolic blood pressure has a negative association on have been seen in patients with CAD whereas decline
the concentration of circulating EPCs, but the clonogenic in the count of circulating EPCs has been linked with
potential is retained by the arterial hypertension. CAD20 especially multivessel CAD. In contrast, Guven
et al demonstrated that the count of EPCs was elevated
Angiotensin II speeds up the onset of EPC senescence,
in patients with significant CAD especially in those
resulting in impaired proliferation of EPCs; that may
who require coronary intervention, and EPC counts
be inhibited by angiotensin II type 1 receptor blocker
corresponded to the maximum severity of angiographic
like valsartan. Ramipril also revamps proliferation and
stenosis. Quantification of EPCs is of predictive value for
migration of EPCs, and also, in vitro, vasculogenesis in
CV consequences in patients with stable CAD. There is a
CAD patients. These observations were finalized in the
link between baseline values of EPCs and crucial adverse
Endothelial Progenitor Cells in Coronary Artery Disease
cardiac events. This relationship was independent of
(EPCAD) Study,16 demonstrating that ACEI treatment
CAD severity, CV risk factors and pharmacological
was linked with enhanced counts and also improved
therapies known to impact CV results. Also, EPC count
clonogenic potential of circulating EPCs, as compared
and activity is closely linked with coronary endothelial
to patients who were not consuming angiotension-
function. Multivariate analysis exhibited that the count
converting enzyme inhibitor drugs.17
of EPCs forecasted severe endothelial impairment
Although techniques linking CV risk factors and independently of classical CV risk factors.
impaired EPC mobilization and function are not well Acute coronary syndrome (ACS) is linked with
understood, the studies strongly indicate that oxidative elevated levels of inflammatory and hematopoitic
stress and chronic inflammation may play a censorious cytokines, which mobilizes EPCs from the bone-marrow
role, in spite of substantial resistance of endothelial and this mobilization is not affected by the type of
progenitors to the oxidative burden.18 revascularization whether primary angioplasty or
thrombolytic therapy.21 However, ischemia may be a
EPC AND ATHEROSCLEROTIC primary factor for EPC mobilization, given a significant
CARDIOVASCULAR DISEASE increase in the EPC counts in patients with unstable
Physiological and conventional risk factors for angina, an inflammatory state shown by increased CRP
atherosclerosis are related to the variations in the counts levels, is also involved in modulating adhesive properties
and function of EPCs and may be the bridge, associating of EPCs in ACS.
EPCs are notably upregulated in heart failure effect on the echocardiographic parameters of diastolic
(NYHA Class I-II) but their mobilization is depressed function in patients after AMI.26
in patients with advanced heart failure (NYHA class III- It is crucial to note that, in all these trials the
IV) irrespective of origin of the disease.22 Reduction in reproducibility of the reinfusion therapy and the safety
EPCs has been associated with elevated levels of TNF-α have been under lined.
indicating endothelial precursors as victims of excessive
inflammation seen in heart failure. EFFECT OF CARDIAC DRUGS ON EPCs
Restenosis after coronary artery stenting remains a
Statins
notable problem in the clinical practice of interventional
The consequence of statins on EPCs are too complex. It
cardiology. Here EPCs are singly responsible for stent
is related to an increase in the count of circulating EPCs
restenosis, because of a strong correlation between
in CAD patients. While short term treatment with statins
circulating CD34+ cells and late luminal loss after
have shown to increase both EPC count and activity,
coronary angiography. 23 The activity of EPCs in
long term treatment with statins may have effects to be
postarterial injury recovery/impairment is complex.
contradictory. Indeed, statins have a biphasic effect on
Inoue et al, have confirmed an elavation in EPC counts
EPC numbers. Statins aid to mobilize early EPCs which
following bare metal stent implantation in CAD patients
is very crucial in acute ischemic conditions such as AMI,
and the extent of EPC elevation in counts correlated with
but long term positive effects of statins is partly explained
risk of stent restenosis. In contrast, DESs (e.g. sirolimus
by expansion of ECFC which is believed to be the true
drug eluting stents) are able to prevent procedure related
EPC responsible for the vasculogenesis.
EPC mobilization.
EPCs AND CARDIOVASCULAR TRIALS ACE INHIBITORS AND ANGIOTENSIN II

TOPCARE–AMI Study: In 2001, the transplantation of
RECEPTOR BLOCKERS
progenitor cells and the regeneration enhancement ACEI and AT II receptor blockade elevates the EPC
in acute myocardial infarction was started. In this numbers, an effect which appears to be common to
study, the intracoronary infusion of EPCs was linked ARBs. VEGF seems to be involved in ARB mediated
with a significant elevation in LVEF, a gain in wall EPC stimulation. Both these groups of drugs increases
motion abnormalities in infarct area and a significant the activity of EPCs as seen by their process of
decrease in end-systolic LV volume 4 months after the proliferation, migration, adhesion and finally by the in
AMI suggesting a beneficial effect on post infarction vitro vasculogenesis. It has been revealed that ramipril 5
remodelling processes.24 mg daily for 4 weeks in CAD patients was linked with an
approximately 1.5 fold elevation in the circulating EPCs
REPAIR-AMI Trial: In this study, it has been observed count within 7 days of initiating treatment.
that intracoronary transfer of autologous BM cells does Another drug, Enalapril also triggered a 6 fold
not enhance recovery of overall LV function after AMI but elevation in contributing bone marrow derived EPCs to
favorably could affect infarct remodelling. In addition, the ischemia induced neovascularization.
encouraging results derived from this reinfusion of
enriched progenitor cells and infarct remodelling in AMI CD34 ANTIBODY COATED STENTS
trial, in which LV angiography was utilised to assess LVEF
Recently, revascularization of coronary arteries have
before and after 4 months of BM cells delivery; patients
been tried with another type of stent (apart from BMS
with severely reduced systolic function at baseline
and DES), based on EPC capture technology (ECS) - the
achieve the greatest benefit from BM cells therapy.25
CD34 antibody coated stents which showed decreased
BOOST Trial: In the boost trial, intracoronary autologous restenosis and also decrease in the stent thrombosis
BM cells transfer results in a sustained global treatment rate. The effectiveness of CD34 coated stents 27 has
been examined in several studies done under the on EPCs demonstrating that the inhibitory effects of
HEALING (Healthy Endothelial Accelerated Lining hyperglycemia on EPC can be reversed by the NO
Inhibits Neointimal Growth) programme, the results are donors, but not by other antioxidants.
encouraging. First in man and HEALING II study have So, the conclusion is adverse metabolic stress factors
shown efficacy and safety of ECS (EPC Coated Stent) in diabetes are linked with decreased EPC counts and
and a favorable clinical result after 1 year. In addition, angiogenicity and this dysfunction of EPC contributes to
untimely stoppage of dual antiplatelet therapy may be the pathogenesis of vascular complications of diabetes.
possible in reducing their inherent risk. Administration of PPAR-gamma agonists has been
linked with elevated EPC counts and improvement of
Uses of EPCs in Cerebrovascular Disease their activity. Han et al, showed PPAR–gamma agonists
The number of EPCs was significantly lower in patients regulate CFU-EC, thus promoting vasculogenesis, 32
with cerebrovascular disease (Acute or Chronic). In there are also provasculogenic effects of PPAR-gamma
patients with history of cerebral ischemic episodes,28 agonists on ECFCs. The hormone estrogen augments
Taguchi et al, found no relation between the degree of the creation and survival of EPCs, thereby elevating
cerebrovascular atherosclerosis and EPCs conversely, the circulating levels of EPCs. 33 Moreover, estrogens
after an acute cerebral infarction, the EPCs were not only enhance EPC count, but also are capable of
increasing moderately, coming back to baseline levels effectively reaching to sites of vascular lesions. Estradiol
after nearly a month. 29 Impaired EPC levels during may enhance EPC mobilization through NO-mediated
acute phase were linked with absence of crucial adverse pathways.
clinical results. It has been demonstrated that patients
with reduced EPC number have a decreased capacity ROLE OF EPCs IN TUMOR GROWTH
for angiogenesis, repair of the endothelial damage and EPCs are important in growth of tumor and are critical
development of the collateral vessels. Similarly, other for angiogenesis and metastasis. Ablation of EPCs in
studies have reported a better prognosis linked to the the bone marrow lead to a significant decline in tumor
elevated EPC number during an ischemic event. growth so EPCs has become a novel therapeutic target.
Lately, it has been found that miRNAs modulate
USES OF EPCs IN DIABETES MELLITUS EPC biology and tumor angiogenesis.34 This research
Type 1 diabetes mellitus is associated with reduced by Plummer et al, found that, in particular targeting of
vascular repair, as indicated by impaired wound healing the miRNAs, miR-10b and miR-196b led to significant
and reduced collateral formation in ischemia. Recently deficiency in angiogenesis mediated tumor growth by
EPCs have been identified as important regulators of reducing the mobilization of EPCs to the tumor. These
these processes because EPCs are dysfunctional in finding indicate that directly targeting these miRNAs
diabetics and their numbers in type I DM patients are in EPC may bring about a novel strategy for inhibiting
44% lower as compared to age and sex matched control tumor angiogenesis.
subjects, this reduction was inversely related to levels of
HbA1C.30 ROLE EPCs IN ENDOMETRIOSIS
Hyperglycemia significantly decreases the production In endometriosis, about 37% of microvascular
of eNOS by EPCs with a corresponding reduction in endothelium of ectopic endometrial tissue emerges from
NO bioavailability. The effects of hyperglycemia could the endothelial progenitor cells.35
be made unsatisfactory by the coincubation of EPCs
with the NO donor like sodium nitroprusside or P38 USES OF EPCs IN WOUND HEALING
mitogen-activated protein kinase inhibitor, and declined The responsibility of EPCs in wound healing remains
by eNOs inhibitor.31 In contrast, other antioxidants like uncertain. Blood vessels have been shown infiltrating
Vit C, N-acetylaysteine, etc. have no significant effect ischemic tissue by mechanically forced entrance of
existing capillaries into the avascular compartment, to identify CV disease and to forecast better/worse CV
and mainly instead of through sprouting angiogenesis.36 sequelae, thus proposing their evolution as a rational
These observations refute sprouting angiogenesis marker in various defined clinical scenarios. There are
driven by the EPCs. By and large with the incapacity many promising clinical studies to suggest EPCs as a
to find bone-marrow derived endothelium in the new novel therapy for CV disease. A broad consensus seems
vasculature, there is now small material support for to be needed for defining EPC, as well as the other cell
postnatal vasculogenesis. Instead, angiogenesis is types co-operating in vivo with EPCs and operating
possibly driven by the process of physical force. as the support cells. Recent clinical studies should be
The practicality of EPC implantation has been shown referred to the definition of standardized methods for
by genetic retardation of glycogen synthase kinase - 3β the identification and application of EPCs as diagnostic,
signalling in human EPCs that was linked with significant prognostic and therapeutic indices in clinical practice.
improvement of their angiogenic possessions in an
animal model of ischemia. In addition, the angiogenic ABBREVIATIONS
prospective of EPCs can be revamped by nongenetic ex AMI: Acute myocardial Infarction
vivo stimulus (e.g. by exposure to hypoxia). However, BM: Bone marrow
clinical application of these approaches needs further EPC: Endothelial progenitor cell
exploration. ECFC: Endothelial colony forming cell
CFU–EC: Colony forming unit – endothelial cell
USES OF EPCs IN PERIPHERAL CV: Cardiovascular
ARTERIAL OBSTRUCTIVE DISEASE ECS: EPC capture stent
The gold standard treatment of peripheral arterial NO: Nitric oxide
obstructive disease is surgical or endovascular revascu VEGF: Vascular endothelial growth factor
larization. However, one third of these patients are not
suitable for invasive interventions. Recent studies have REFERENCES
confirmed the favorable role of EPC therapy in declining 1. Stump MM, De Bakey ME et al. Endothelium grown from
major amputations, improving distal perfusion, partial circulating blood on isolated intravascular Dacron hub. Am J
pressure of oxygen and ankle brachial index, increasing Pathol. 1963;43:61-7.
2. Ashara T, Murohara T, Sulivan A, et al. Isolation of putative
the walking distance and reducing agony.37
progenitor endothelial cells for angiogenesis; Science.
1997;275:964-7.
CONCLUSION 3. Dong C, Goldschmidt–Clemont P. Endothelial progenitor
In current years, EPCs have performed a major role in cells: a promising therapeutic alternative for cardiovascular
scientific research for the diagnosis and prognosis of disease. J Intervent Card. 2007;20:93-9.
CV disease, although the identification, function and 4. Gehling UM, Ergun S, Wagener C. In vitro differentiation
of endothelial cells from AC 133-positive progenitor cells.
characterization in vascular biology of the circulating
Blood. 2000;95:3106-12.
progenitor cell subset are still being argued. Due to their 5. Ashara T, et al. Bone marrow origin of endothelial
capability to originate, proliferate and circulate functional progenitor cells responsible for postnatal vasculogenesis
progeny, interest has been aimed also to therapeutic in physiological and pathological neovascularization. Circu
application of progenitor cells in atherosclerotic disease. lation Research. 1999;85(6):221-8.
It is logical that EPCs are involved in vascular 6. Lyden D, Hattori K, Dias S, et al. Impaired recruitment
rearrangement during endothelial damage or insult. of bone marrow derived endothelial and haemotopoietic
precursor cells blocks tumor angiogenesis and growth.
After endothelial damage, a mechanism of repair
Nature medicine. 2001;7(11):1194-201.
begins, and the circulating progenitors contribute to 7. Bhattacharya V, Bruno B, Nash R, et al. Enhanced endo
this process. EPCs exhibited and shared their ability thelialisation and microvessel for-mation in polyester grafts
seeded with CD34+ bone marrow cells. Blood. 2000;95: approaches to attenuate restenosis after percutaneous
581-5. coronary interventions. J Am Coll Cardiol. 2004;44:733-9.
8. Yoder MC, Mead LE, et al. Redifining endothelial progenitor 24. Assmus B, Tenpe C, et al. Transplantation of progenitor
cells via clonal analysis and haematopoietic stem/ cells and regeneration enhancement in acute myocardial
progenitor cell principals. Blood. 2007;109(5):1801-9. infarction (TOPCARE-AMI). Circulation. 2002;106(24):3009-
9. Fadini GP, Agostini C, Sar tore S, et al. Endothelial 17.
progenitor cells in the natural history of atherosclerosis. 25. Assmus B, Erbs S, et al. Intracoronary infusion of bone
Atherosclerosis. 2007;194(1):46-54. marrow derived mononuclear cells abrogates adverse left
10. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial ventricular remodelling post AMI-insights form the reinfusion
progenitor cells, vascular function and cardiovascular risk. of enriched progenitor cells and infarct remodelling in AMI
N Engl J Med. 2003;348:593-600. (REPAIR-AMI) trial. European Journal of Heart Failure. 2009;
11. Kondo J, Hayashi M, Jakeshita K, et al. Smoking cessation 11(10):973-9.
rapidly increases circulating progenitor cells in peripheral 26. Meyer GP, Wollert KC, et al. Intracoronary bone marrow cell
blood in chronic smokers. Arterioscler Thromb Vasc Biol. transfer after AMI-5 year follow up from the randomized
2004;24:1442-7. – controlled BOOST TRIAL. European Heart Journal.
12. Wang XX, Zhu JN, Chen JZ. Effects of nicotine on the number 2009;(24):2978-84.
and activity of circulating endothelial progenitor cells. J Clin 27. Inoue T, Masataka S, Fakuda D, et al. Mobilization of CD34+
Pharmacol. 2004;44:881-9. bone marrow derived cells after coronary stent implantation:
13. Rehman J, Karlsson G, Panchal VR, et al. Exeercise acutely impact on restenosis. Circulation. 2007;115:553-61.
increases circulating endothelial progenitor cells and 28. V Ghani, Asalam, et al. Endothelial progenitor cells during
monocyte/macrophage derived angiogenic cells. J Am Coll cerebrovascular disease. Stroke. 2005;36(1):151-3.
Cardiol. 2004;43:2314-8. 29. Yip HK, Chang LT, et al. Level and value of circulating
14. Vasa M, Adler K, Aicher A, et al. Increase in circulatory endothelial progenitor cells in patients after acute ischemic
endothelial progenitor cells by statin therapy in patients stroke. Stroke. 2008;39(1):69-74.
with stable coronary artery disease. Circulation. 2001;103: 30. Specific role of impaired glucose metabolism and diabetes
2885-90. mellitus in endothelial progenitor cell characteristics and
15. Chavakis E, Dernbach E, Mondorf UF, et al. Oxidized LDL function. Arteriosclerosis, thrombosis and vascular biology.
inhibits VEGF-induced endothelial cell migration by an 2014;34:1136-43.
inhibitory effect on the AKT/eNOs pathway. Circulation. 31. Chen YH, Lin SJ, Wu TC, et al. High glucose impairs early and
2001;103:2102-7. late endothelial progenitor cells by modifying nitric-oxide
16. Werner N, Kosiol S, Ahlers P, et al. Circulating endothelial related but non-oxidative stress mediated mechanisms.
progenitor cells and cardiovascular outcomes. N Engl J Med. Diabetes. 2007;56:1159-68.
2005;353:999-1007. 32. Werner C, Kamani CH, Laufs U, et al. The perioxisome
17. Min TQ, Xiang WX, Hui JZ, et al. Improvement in endothelial proliferator activated receptor gamma agonist pioglitazone
progenitor cells from peripheral blood by ramipril therapy increases number and function of endothelial progenitor
in patients with stable coronary artery disease. Cardiovasc cells in patients with CAD and normal glucose tolerance.
Drug Ther. 2004;18:203-9. Diabetes. 2007;56:2609-15.
18. Shantsila E, Watson T, Lip GY. Antioxidant protection: yet 33. Strehlow K, Werner N, Nickenig G, et al. Estrogen increases
another function of endothelial progenitor cells? J Hum bone marrow derived endothelial progenitor cell production
Hypertens. 2007;21:343-6. and diminishes neointima formation. Circulation.
19. Vasa M, Aicher A, Adler K, et al. Number and migratory 2003;107:3059-65.
capacity of circulating endothelial progenitor cells inversely 34. Mellick AS, Plummer PN, et al. Using the transcription
correlate with risk factors for coronary artery disease. Circ factor inhibitor of DNA binding I to selectively target
Res. 2001;89:1-7. endothelial progenitor cells offers novel strategies to inhibit
20. Kunz GA, Liang G, Gregg D, et al. Circulating endothelial tumor angiogenesis and growth. Cancer Research. 2010;
progenitor cells predict coronary artery disease severity. Am 70(18):7273-82.
Heart J. 2006;152:190-5. 35. Laschke MW, Giebels C, et al. Vasculogenesis: A new piece
21. Shintani S, Murohara T, Honma T, et al. Mobilization of the endometriosis puzzle. Human Reproduction Update.
of endothelial progenitor cells in patients with acute 2011;17(5):628-36.
myocardial infarction. Circulation. 2001;103:2776-9. 36. Kilarski WW, et al. Biomechanical regulation of blood vessel
22. Rigolin GM, Porta MD, Bugli AM, et al. CD34 + and growth during tissue vascularization. Nature Medicine.
endothelial progenitor cells in patients with various degrees 2009;15(6):657-64.
of congestive heart failure. Circulation. 2004;110:1209-12. 37. Schaffer RG, Greene S, Arshi A, et al. Effect of acute
23. Kipshidze N, Dangas G, Leon MB, et al. Role of endothelium exercise on endothelial progenitor cells in patients with
in modulating neointimal formation: vasculoprotective peripheral arterial disease. Vasc Med. 2006;11:219-26.
CHAPTER
148
Management of Gender Dysphoric
Persons, Sex Change Surgeries and
Our (Indian) Experience
Unlike the earlier rigid views in respect to sex and gender, ie presence of genital organs, while conversely, gender
the modern society and medicine recognizes that there reflects the role, that this person’s brain wishes to play
are many shades of gray to a person’s sexuality. The in society, i.e. masculine or feminine. Generally, the
phenomenon is well known to Indian mythology in ‘sex’ of a person is in alignment with ‘gender’.1 However,
the form of Ardhanarishwara, considered the supreme in certain individuals, this is not so. As a result, these
form of God, King Ila during Ramayana period and, individuals are at conflict with society and their own
Shikhandinini during the Mahabharata period. Arjuna, bodies, and experience a discomfort, known as ‘Gender
one of the greatest warriors of his time, spent a year in Dysphoria’. Some Gender Dysphoric (GD) persons
trans-sexed condition.1 The phenomenon is visible to experience a severe form of discomfort, leading to
most of us, as we travel and come across transgenders depression, attempts to suicide and an existential
in the streets and during course of our work. It also crisis. They feel trapped in their physical body, and
gets highlighted by media, when celebrities like Bruce need to change it, to bring it into alignment with their
Jenner transitions to Caitlyn Jenner. What caused an gender identity. This subset of individuals is known
Olympic Gold Medal winning decathlete, an event which as trans-sexuals.1 This group of individuals, otherwise
determines the champion of champions amongst men, genotypically and phenotypically normal men and
and the father of famous Kadarshian/Jenner sisters, to women are the candidates for surgical and hormonal
opt, to become a woman? change of ‘sex’.
Recent data suggests that nearly 0.6% of US The trans-sexuals, who transition form man to
population (1.4 million people) may be transgenders.2,3 woman are known as transwomen (MTF) and, the
‘Transgenders’ is a diverse and broad group of individuals, reverse as transmen (FTM). The incidence varies from
who transcend the norms for gender role, as defined 1:19000 to 1:45000 for transwomen, and 1:30400 to
culturally, by a society. This umbrella term includes 1:200000 for transmen, as per the meta-analysis by De
genderqueer individuals such as pangender, bigender, Cuypere (2007).5 The MTF incidence is thus 3–5 times
agender and gender fluid individuals. It also includes that of FTM. This may also be since boys behaving like
the individuals, who identify with a third gender, as well girls may be more noticeable and less acceptable in
as the ‘trans-sexuals’.4 To understand the trans-sexual society, and hence report to the medical profession
phenomenon, we need to understand the difference earlier and more often. In authors gender identity
between sex and gender. An individual’s sexual identity clinic (GIC) however, the number of FTMs are 5 times
is the one, that is assigned at birth based on phenotype those of MTFs. This may be a case of selection bias,
CHAPTER 148: Management of Gender Dysphoric Persons, Sex Change Surgeries and Our (Indian) Experience 873
since the authors center is well known worldwide, for psychiatric disorders, which can sometimes mimic the
performance of phalloplasties, an FTM operation, which condition, and treats the underlying conditions such as
is performed in very few centers, compared to MTF depression. The criteria for diagnosis of trans-sexualism
procedures. The trans-sexual etiology is multifactorial. are:1
Sexually dimorphic hypothalamic nuclei, such as BSTc, A sense of discomfort and inappropriateness about
with a sex reversed volume and number of neurons in one’s sex.

transsexuals, may play a role.6-10 Other important causes A wish to be rid of one’s genitalia and live in the
could be, sexually dimorphic genes, critical period in opposite sex.

gestation, heritable component, and androgenization The disturbance has been continuous for two years
of brain, during the first period of testosterone surge at and not limited to period of stress.
12 weeks gestation.11,12 An abs ence of physical inters ex or g enetic
As per World Professional Association for Transgender abnormality.

Health (WPATH), expression of gender characteristics, Absence of a mental disorder such as schizophrenia.
which are at variance from one’s assigned sex at birth, The psychiatrist assesses the impact on patient,
is a common and culturally diverse phenomenon of any stigmas attached to the condition and, the
and should not be viewed with skepticism.5 Yet, these available surrounding support structure. In addition,
individuals, continue to face ridicule and sarcasm, not the psychiatrist helps the patient through his transition
only from public, but from medical profession as well. by encouraging role playing, and involving people at
It is not as if, a man decides to become a woman, or vice patient’s workplace/ educational environment. The
versa, on the spur of a moment. As the field of psychiatry psychiatrist also counsels the patient regarding means
advanced rapidly, from the last years of 19th century, so of gender expression and treatment options in the
did the understanding of transgenders and transsexuals. form of hormone therapy and surgery. A vital part of
Works of Sigmund Freud, Magnus Hirschfeld, Arthur the long-term diagnostic therapy is the so called real-
Koestler, Harry Benjamin, Stoller and Norman Frisk life experience, in which the patient lives as a member
led to an organized and structured diagnosis and of the desired sexual role continually and in all social
treatment of trans-sexuals. In 1979, Harry Benjamin spheres to accumulate the necessary experience. At the
International Gender Dysphoria Association (HBIGDA), end of assessment and psychotherapy, the psychiatrist
was founded and published the first version of Standards issues a certificate incorporating the patient’s diagnosis,
of Care (SOCs). HBIGDA is now known as WPATH, resolution of all psychiatric issues to his satisfaction and
and has published the seventh SOCs for treatment of patient’s mental fitness for consenting and undergoing
transsexuals, transgenders and gender nonspecified further treatment in the form of hormone therapy
individuals in 2011. The management of trans-sexuals is and surgery. In general, opinion of one psychiatrist is
largely based on the 7th SOCs, as published by WPATH, required for instituting hormone therapy, or performing
but as specified by WPATH itself, the treatment needs to breast surgery. Two different psychiatry opinions
be modified by local sociocultural situations, in view of are required before performing any genital surgery.5
regional variations and diversities. Authors prefer to take both psychiatry opinions prior to
The trans-sexuals are best treated at Gender Identity initiating hormonal and surgical treatment. Of these, one
Clinics (GICs), where the various specialists required to psychiatrist belongs to the author’s GIC and the other,
treat them are available and can provide a comprehensive preferably from a different institution.
and seamless management. The specialties of Hormone therapy is the second pillar, on which
psychiatry, plastic surgery and endocrinology provide treatment of trans-sexuals is based. Initially there was
the three pillars, on which, the treatment is largely based. some ambiguity regarding the age at which hormone
Psychiatrist diagnoses the condition, rules out severe therapy should be started in these individuals. For a
few years, in countries such as Netherlands, hormone the breast dimensions achieved on hormone therapy.
therapy was started before the onset of puberty. This Similarly, many MTF transsexuals opt for facial and
approach had clear advantages in view of the fact, that the body hair removal measures such as lasers, especially if
puberty was totally suppressed, and the phenotype of GD hormone therapy has been delayed.
individual (in terms of body dimensions) developed in The cross-sex hormone therapy is now without risks.
the direction of his/her perceived gender. However, later Feminizing hormone therapy may result in increased
it was found that in 80–95% of children, the GD abated risk of venous thromboembolic disease, hypertension,
spontaneously, leading to a considerable incidence of Type 2 diabetes and hypertriglyceridemia. Masculinizing
regret.5,13 The works of Dr Cohen-Kettenis have shed hormone therapy may result in increased risk of
considerable insight into the timing of hormone therapy cardiovascular diseases, hypertension, Type 2 diabetes,
for GD individuals (transsexuals). hyperlipidemia, acne, polycythemia, androgenetic
In cases of clear cut GD, GnRH may be started in the alopecia, etc.5 Hence, the cross-sex hormone therapy
age range of 12–16 years, with parental consent. This has is started only after proper patient evaluation, consent,
the effect of delaying/freezing the puberty, and gives the understanding implications of long term therapy and
individual, the necessary time to explore with the mental ongoing and periodic examination and lab investigations,
health professional, his/her wish for sexual reassignment, under the guidance of an endocrinologist.
as well as to spend this period productively, in the Sex reassignment surgery (SRS) is the third and final
company of peers, without the obvious disadvantages of pillar of treatment of GD individuals. This surgery is also
GD and associated depression and social phobias. The called Gender Affirmation Surgery (GAS), as, ‘Gender’
effects of GnRH analogues are reversible and stopping being hardwired into brain, cannot be changed, and can
these will allow puberty to progress. Cross-sex hormones only be affirmed by bringing the patient’s phenotype,
are not indicated at this stage. The cross-sex hormone into alignment.
treatment is started after Tanner stages 2–3 of puberty, at SRS for MTF transsexuals include vaginoplasty, penec
age 16–18 years or later, with parental consent.14,15 tomy, orchidectomy, clitoroplasty, labiaplasty, breast
Hormone therapy, though not necessary for life, augmentation, facial feminizing surgery, feminizing
helps in transitioning of the individual in his/her new laryngoplasty (voice change and laryngeal shaving), and
sexual role and alleviates GD. Masculinizing hormones ancillary procedures such as rhinoplasty, abdominoplasty,
given to FTM trans-sexual will result in facial and hair transplants to correct hairline and androgenetic
increased body hair growth, redistribution of body alopecia, laser removal of facial and body hair, etc. For
fat to masculine, cessation of menses and clitoral FTM transsexuals, surgical procedures may include
enlargement in 3–6 months. It will also cause scalp hair phalloplasty (penile reconstruction), urethroplasty,
loss with more masculine hairline, increased muscle scrotoplasty, testicular and penile implants, hysterectomy,
mass and strength and deepened voice in 6–12 months. bilateral salpingo-oophorectomy, vaginectomy, bilateral
Feminizing hormones given to MTF trans-sexuals breast reduction and ancillary procedures such as
will cause softening of skin, redistribution of body fat lipoplasty, abdominoplasty, chest wall contouring,
to feminine, breast growth, decreased muscle mass, rhinoplasty, masculinizing laryngoplasty, etc.
stopping of progression of male pattern baldness and Not all the procedures that are listed above are
decreased testicular volume in 3–6 months. There is also necessary. Psychiatric, endocrine and plastic surgical
thinning and slowed growth of facial and body hair in interventions (the three pillars, or triad) are carried
6–12 months.5 Breast growth may continue usually up out on an, as needed basis, only to alleviate the gender
to 18 months, and does not increase in size after that. dysphoria suffered by the patient, unless legally
Around 25–50% of MTF trans-sexuals opt for breast necessary in that country, for change of sex in patient’s
augmentation and the remaining are satisfied with legal and official documents. Some sporting events
CHAPTER 148: Management of Gender Dysphoric Persons, Sex Change Surgeries and Our (Indian) Experience 875
TABLE 1: Surgeries performed by author’s Gender Identity Clinic

in 2016
Type of surgery Numbers
FTM breast reduction 41
Phalloplasty, scrotoplasty, urethroplasty 37
Hysterectomy, salpingo-oophorectomy and 33
vaginectomy
Vaginoplasty, penectomy, orchidectomy, 21
clitoroplasty, labiaplasty
MTF breast augmentation 09
Others – Facial feminizing, voice change surgery, 35
testicular and penile implants, etc.
Total 176
transgender, and gender-nonconforming people, 7th

version, 2012 published by World Professional Association
for Transgender Health, downloaded from www.wpath.org.
Fig. 1: Percentage of different SRS procedures carried out in 6. Kruijver FP, Zhou JN, Pool CW, Hofman MA, Gooren LJ,
author’s GIC in the year 2016 Swaab DF. Male-to-Female Transsexuals Have Female
Neuron Numbers in a Limbic Nucleus. J Clin Endocrinol
such as Olympics, and contact sports such as boxing, Metab. 2000;85:2034-41.
allow athletes to participate only if they have completed 7. Swaab DF, Chung WC, Kruijver FP, Hofman MA, Ishunina
the triad of therapy, as well as a minimum of 2 years of TA. Structural and functional differences in the human
hormone therapy. hypothalamus. Horm Behav. 2001;40:93-8.
8. Grossmann R, Jurkevich A, Kohler A. Sex dimorphism in
The author’s Gender Identity Clinic in New Delhi
the avian arginine vasotocin system with special emphasis
provides comprehensive, multispecialty and seamless to the bed nucleus of the stria terminalis. Comp Biochem
management to around 150 new transsexuals every year Physiol A Mol Integr Physiol. 2002;131:833-7.
and performs a wide variety of surgeries. The percentage 9. Chung WC, De Vries GJ, Swaab DF. Sex differentiation of the
of different SRS procedures carried out in 2016, in bed nucleus of the stria terminalis in Humans may ext. end
author’s GIC is given in Figure 1. Table 1 depicts the into adulthood. J Neurosci. 2002;22:1027-33.
10. Zhou JN, Hofman MA, Gooren LJ, Swaab DF. A sex difference
absolute number of procedures carried out in the same
in the human brain and its relation to transsexuality. Nature.
period (1st January to 31st December 2016). 1995;378:68-70.
11. Hines M. Parental endocrine influences on sexual orientation
REFERENCES and on sexually differentiated childhood behavior. Front
1. Gupta R, Murarka A. Treating transsexuals in India: History, Neuroendocrinol. 2011;32(2):170-82.
prerequisites for surgery and legal issues. Ind J Plast Surg. 12. Hines M, Constantinescu M, Spencer D. Early androgen
2009;42(2):233-40. exposure and human gender development. Biology of sex
2. Flores AR, Herman JL, Gates GJ, Brown TNT. How many defferences. 2015;6(3):1-10.
adults identify as transgender in the United States? Los 13. Cohen-Kettenis PT. Gender Identity Disorder in DSM? J Am
Angeles, CA; 2016: The Williams Institute. Acad Child Adolesc Psychiatry. 2001;40(4):391.
3. Meerwijk EL, Sevelius JM. Transgender population size in 14. Cohen-Kettenis PT, Delemarre-van de Waal HA, Gooren
the United States: a meta-regression of population-based LJ. The treatment of adolescent transsexuals: changing
probability samples. Am J Pub Health. 2017;107(2):e1-e8. insights. J Sex Med. 2008;5(8):1892-7.
4. Transgender. Downloaded from Wikipedia in Sep 2017. 15. Hembree WC, Cohen-Kettenis PT, Delemarre-van de Waal
https://en.wikipedia.org/wiki/Transgender. HA, Gooren LJ, et al. Endocrine treatment of Transsexual
5. Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, persons: An Endocrine Society Clinical Practice Guideline. J
et al. Standards of care for the health of transsexual, Clin Endocrinol Metab. 2009;94:3132-54.
CHAPTER
149
Anemia in Elderly: Experience
at a Large Tertiary Center
INTRODUCTION
Anemia in elderly is not due to old age but due to
some disease which need to be investigated. The
common cause of anemia in elderly are chronic kidney
disease (CKD), anemia due to iron efficiency (IDA),
anemia of chronic disease (ACD) or anemia of chronic
inflammation, and malignancies rather than IDA which
is commonly seen in 30% of population in the world
(WHO).1 Etiological spectrum of anemia in elderly at
PGIMS Rohtak, Haryana 2015–16 is shown in Figure 1.
In a n o t h e r stu dy , t h e e t i o l o g i ca l sp e c t r u m Fig. 1: Etiological spectrum of anemia at
PGIMS Rohtak, Haryana, India
of Pancytopenia at PGIMS Rohtak, Haryana shows
Megaloblastic anemia is most commonly seen (39%)
followed by aplastic anemia (29%) and aleukemic TABLE 1: Etiological spectrum of pancytopenia at PGIMS Rohtak,
leukemia (15%) (Table 1). Haryana, India
S. no. Diagnosis Female Male Total
CLASSIFICATION OF ANEMIA N (%) N (%) (%)
Anemia can be classified on the basis of: 1 Megaloblastic anemia 21 (53.8) 18 (46.2) 39
Etiology of anemia
2 Aplastic anemia 11 (37.9) 18 (62.1) 29
Red cell morphology (Table 2) 3 Aleukemic leukemia 5 (33.3) 10 (66.7) 15
4 Lymphoma 0 (0.0) 4 (100) 4
Based on Etiology 5 Multiple myeloma 2 (50.0) 2 (50.0) 4
6 MDS 1 (50.0) 1 (50.0) 2
Anemia Due to Blood Loss
7 Myelofibrosis 2 (100) 0 (0.0) 2
It may be due to acute blood loss or chronic blood
8 Infection 0 (0.0) 2 (100) 2
loss. Acute loss may be external (e.g. as after trauma or
9 Hyperplenism 0 (0.0) 2 (100) 2
obstetric hemorrhage) and or internal (e.g. as bleeding
10 SLE 1 (100) 0 (0.0) 1
from GI tract, rupture of spleen, ruptured ectopic
Total 43 57 100
pregnancy, subarachnoid hemorrhage). Chronic blood
CHAPTER 149: Anemia in Elderly: Experience at a Large Tertiary Center 877
TABLE 2: Based on morphology anemia can be normocytic, TABLE: 3 Etiology of iron deficiency anemia
microcytic and macrocytic
Increased demand Increased iron loss Decreased iron intake
Type MCV and MCHC Conditions for iron or absorption
Normocytic (MCV-76-96fl, Acute blood loss, liver zz Rapid growth zz Chronic blood zz Inadequate diet
Normochromic MCHC-30-35g/dL) disease, endocrinopathy, in infancy or loss, menses
anemia of infections, etc. adolescence
Macrocytic (MCV->96, MCHC- Vitamin B12 and folic acid zz Pregnancy zz Acute blood loss, zz Malabsorption from
30-35g/dL) deficiency, etc.
blood donation disease (sprue,
Microcytic (MCV-<76fl, MCHC- Iron deficiency anemia, crohn’s disease,
30g/dL) thalassemia, sideroblastic, postgastrectomy)
pyridoxine deficiency, etc.
zz Erythropoietin zz Phlebotomy as zz Acute or chronic
therapy treatment for inflammation
loss could be due to worm infestation, menses, repeated polycythemia
blood donation, repeated phlebotomy as treatment of
polycythemia vera, etc.
TABLE 4: Etiology of vitamin B12 deficiency anemia
Hemolytic Anemia Due to Destruction of RBCs Nutritional Malabsorbtion Gastric causes Intestinal
Hemolytic anemia may be due to the destruction Pure Pernicious Congenital Intestinal
o f R e d Bl o o d C e l l s d u e t o h e re d i t a r y d e f e c t s vegetarian anemia intrinsic factor stagnant loop
deficiency, syndrome: jejunal
(hemoglobinopathies, enzymopathies, membrane- partial or total diverticulosis,
c ytoskeletal defects, familial hemolytic uremic gastrectomy ileocolic fistula.
syndrome) or acquired defects (Paroxysmal nocturnal Tropical sprue,
transcobalamin
hemoglobinuria, toxic agents, drugs, infections or
II deficiency, ileal
autoimmune diseases, etc.) resection and
crohn’s disease,
Impaired RBC Production fish tapeworm
Defective proliferation and differentiation of stem cells: It
may be seen in aplastic anemia, chronic renal failure,
TABLE 5: Etiology of causes of folic acid deficiency anemia
endocrinopathy (defective production of hormones
of pituitary, thyroid, suprarenal glands and testis). Dietary Malabsorbtion Drugs
Defective proliferation and maturation of differentia- Infancy, poverty, Tropical sprue, Anticonvulsants,
tion of the blasts : It may be due to defective DNA decreased gluten induced antitubercular
synthesis (Vit B12, folic acid deficiency), defective intake, chronic enteropathy, diabetic drugs tetracycline,
alcoholism enteropathy nitrofurantoin
hemoglobin synthesis (Haem–iron deficiency and,
pyridoxine deficiency and Globin-thalessemia
and hemoglobinopathies), sideroblastic anemia,
TABLE 6: Causes of aplastic/hypoplastic anemia
anemia of chronic disease (infections, inflammation,
Acquired causes Inherited causes
neoplasms) and myelophthisis anemia due to
Radiation Fanconi anemia, dyskeratosis
infiltration of bone marrow.2
zz
zz Viruses congenita, etc.

Nutritional anemia: It is of three types. (1) Iron zz Immune diseases
deficiency anemia, (2) Vit B12 deficiency, (3) Folic acid zz Pregnancy
zz Paroxysmal nocturnal
deficiency (Tables 3 to 5)
Hemoglobinuria
Aplastic/hypoplastic anemia zz Drugs
It is of two types i.e. due to acquired causes or inherited zz Idiopathic
causes (Table 6).3

Anemia of Chronic Diseases/Inflammation General Physical Examination

This includes anemia as a result of inflammation, Look for pallor, icterus, lymphadenopathy, tachycardia,
infection, tissue injury and various cancers. This is cardiac murmur, hepatomegaly, splenomegaly, edema
due to increase in inflammatory cytokines – IL-1, IL-6, feet, petechial spots, etc. Signs of iron deficiency include
TNF-α, and γ-interferon. It is reflected by decrease in pallor of palpebral conjunctiva, koilonychia, leukonychia,
serum iron; normal to increase ferritin, increase red fissured tongue and angular chelosis.
cell protoporphyrin, hypoproliferative marrow, and
transferrin saturation is low-15–30%. Hepcidin level are Special Features of B12 and Folic Acid Deficiency
high-normal (n-5–350 ng/mL). Patients experiences gastrointestinal (GI) symptoms,
such as anorexia, nausea, vomiting, abdominal pain, and
DIAGNOSIS OF A CASE WITH diarrhea, especially after meals. Reproductive symptoms
ANEMIA IN ELDERLY include infertility, fetal loss.3
History Taking in Anemic Patient
Special Features of Hemolysis
History taking is very important for making a diagnosis
In acute hemolysis there is fever, headache, body pains
in elderly cases. Onset of anemia – whether, recent or
of varying degrees and circulatory collapse. Jaundice
long standing. Previous history of blood transfusion,
is invariably present. Very severe cases may develop
Recent hospitalization, recent surgery, previous disease
hemoglobinuria and acute renal failure.
such as chronic renal failure (CRF), rheumatoid arthritis,
malignancy or intake of anticancer drugs. History of
Special Features of Aplastic Anemia
drug intake like antimalarial, sulphonamides, analgesics
Clinical manifestations are proportional to the peripheral
and others should be eliminated as and these can cause
blood cytopenias and may include dyspnea on exertion,
hemolysis in G-6-PD patients. Alcohol abuse can cause
fatigue, easy bruising, petechia, epistaxis, gingival
B12 and folic acid deficiency as well as gastrointestinal
bleeding, heavy menses, headache, and fever. Signs
bleeding. Parasitic infestation may cause both B12 and
are—severe pallor, there is no hepatosplenomegaly,
iron deficient. Racial background and family history
there is no lymphadenopathy.
is important to find out thalassemia trait and other
hemoglobinopathies.
INVESTIGATIONS IN
Symptoms in Anemic Patient ANEMIA IN ELDERLY
The clinical presentation of anemia include weakness, Important Investigations
fatigue, difficulty in breathing on exertion, tinnitus, Complete blood count (with WBC differential, platelet
palpitation, headache, poor concentration, syncope, and count, and RBC parameters [MCV/MCH/MCHC]).
pale skin, blood loss.4 Examination of peripheral blood smear (form and shape
of red cells, platelets defects and any abnormal cells,
Signs of Nutritional Anemia reticulocyte count) (Table 7).7,8
The clinical presentation include atrophic glossitis,
magenta tongue, conjunctiva and facial pallor, angular Bone Marrow Examination
stomatitis, dysphagia, osteomyelitis and paraesthesia/ May reveal:
anesthesia of the mental nerve, orofacial petechiae, A primary marrow disease (e.g. MDS, aplastic anemia)
conjunctival hemorrhage, nasal-bleeding, spontaneous Marrow involvement of nonmarrow diseases (e.g.
bleeding from gingiva and prolonged postextraction infection, lymphoma)

bleeding (Figs 2A to D).5 Nonmalignant marrow processes
A B
C D
Figs 2A to D: Koilonychia (spoon shaped nails), fissured tongue, angular stomatitis and frequent ulcerations
TABLE 7: Various cells with different etiology Evaluation of Iron Deficiency Anemia
Type of cells Possible diagnosis Typical findings include MCV <76 fl, MCHC <30 gm/
Sickled cells Sickle cell anemia dL, MCH <25 pg. Serum ferritin is low with a level of
Spherocytes Hereditary spherocytosis <12 ng/mL. Serum iron is decreased. Total iron-binding
Elliptocytes Hereditary elliptocytosis capacity is increased. Transferrin saturation is at low
Schistocytes Microangiopathic hemolytic anemia level of <15%. Hepcidin level are low. Fecal occult blood
Heinz bodies G6PD deficiency
test, urine analysis for blood/hemosiderin, colonoscopy,
upper GI endoscopy, small bowel endoscopy, antitissue
Target cells Liver diseases and HbSc diseases
transglutaminase antibodies are reliable investigations.4-6
Parasites Malaria
Evaluation of Macrocytic Anemia

Bone Marrow Biopsy The findings include MCV >96fl, MCHC=30–35 gm/
A bone marrow examination is indicated in all patients dL, MCH = 30 pg. Vitamin B–12–a level of <200 pg/mL
who required RBC transfusion.9,10 ( n-200-900 pg/mL). Folate-<2 ng/mL (n-5-20 ng/mL).
Reticulocyte count is increased. Serum haptoglobin level adequate, up to 300 mg elemental iron/day can be
is reduced. Serum homocystiene level increased (n-5- given depending on patients requirement. Oral iron
15). Serum MMA level is increased to 1–20 (n-<0.04). supplements are available as: Iron sulphate 325 mg (65
mg of elemental iron), Iron gluconate 324 mg (30 mg
Evaluation in Hemolytic Anemia
of elemental iron), Iron fumarate 324 mg (106 mg of
Typical finding shows that indirect bilirubin is increased.
elemental iron). The total amount of iron needed can
PBF may show abnormalities in shape of red blood
be calculated by using formula: body wt. (kgs) × 2.3 ×
cells. Absolute reticulocyte count is increased. Serum
(15- patients Hb) + 500 or 1000 for reduced iron stores.
haptoglobin is decreased. Direct and indirect Coombs
Roughly elemental iron total dose in mg is 1500 mg if Hb
tests may be positive urine hemosiderin, LDH is markedly
is less than 9 gm%.5
raised. Osmotic fragility, bleeding and coagulation
profile may show abnormaility.7-10
Parental Iron Preparations
Investigations in Anemia of These are Iron dextran, Ferumoxytol (Feraheme) which
Chronic Disease/Inflammation deliver 510 mg of iron per injection, Sodium ferric
Investigations included are ESR, Mauntox test, Chest gluconate (Ferrlecit) which delivers 125 mg of iron per
X-ray, CRP, RA factor. AntiCCP, ANA, antihistone, injection, Iron sucrose (venofer) delivering 200 mg of
DS-DNA, Hepcidine, serum EPO level, TSH, serum iron and Ferric carboxymaltose (Injectafer) delivering
creatinine and estimated glomerular filtration rate. 750 mg of iron per injection.6
Some other important investigations required are serum
protein electrophoresis, especially if total globulins are Treatment of Megaloblastic Anemia
elevated, blood culture, Widal, Mantoux test and Hepatic Megabloblastic anemia is managed using oral and iv B12
transaminases. and folic acid therapy to correct deficit and replace body
stores. The two preparation of B12 available are hydroxy
Evaluation of Hematological Malignancy
and cyanocobalamin. Cyanocobalamin 100–1000
Investigations included are peripheral blood film, CD
µg must be given daily for 2 weeks then weekly until
panel, bone marrow aspiration, lymph node biopsy and
hematocrit values are normal then monthly for life. Folic
serum electrophoresis.
acid 3–5 mg should be given orally.
Unexplained Anemia
It’s a serious disorder (5–15%), mostly normocytic. This Treatment of Hemolytic Anemia
anemia is generally mild Hb (9–12 g/dL), normocytic, Incriminating drug/toxin should be eliminated. Treatment
include corticosteroids (IHA), splenectomy (hereditary
and hypoproliferative [low reticulocyte count]. To be
spherocytosis), immunoglobulins, transfusion therapy,
differentiated from ACD by CRP and IL-6 levels. It may
plasmapheresis in TTP, eculizumab (anti CD 5 in PNH, regular
mimic occult MDS, when MCV >100, TLC <3000/cumm,
folic acid supplementation (1 mg/dL) in those patients.
Plt <1.5 lakh. Investigations such as serum ferritin,
methylmalonic acid, soluble transferrin receptor are Treatment of Anemia of Chronic
normal.
Kidney Disease
This includes erythropoietin stimulating agents Epoietin –
MANAGEMENT OF ANEMIA IN ELDERLY
alpha (eposis) and Darbopoietin–alpha (Arnasp,
A Management of Iron Deficiency Anemia Cresp). The adverse effect of these can be hypertension,
Oral Therapy Treatment of Iron Deficiency thrombosis and potential of increase in malignancy.
Iron deficiency is managed using oral and IV iron Erythropoietin is indicated when hemoglobin is < 10 g/dL.
preparations. In asymptomatic patients oral iron is Iron to be given according to serum ferritin level.
Treatment of Anemia of Chronic Disease and other indices. In the management of anemia in
Treatment of anemia due to hematopoietic malignancy elderly it is important to manage the cause along with the
will require treatment of the primary disease. In ACI/ replacement of deficiency of iron or vitamins.
ACD, Erythropoietin can be given at the dose of is 50–150
U/kg three times a week S/C. REFERENCES
1. Jatav RK. Prevalence of anemia in adult patients: a hospital
based study in South India. Int J Adv Med. 2014;1:9-12.
Treatment of Unexplained Anemia 2. Verma P, Singh S. Prevalence of anemia in adults: A hospital
In anemia of unknown cause symptomatic treatment based study of North India. Int J Biol Med Res. 2012;3:2422-8.
including blood transfusion will be required till the cause 3. Chib R. Statistics on prevalence of anemia in adults: A
community based study in Jammu City. Indian J App Res.
of anemia will be found.
2014;4:2249-555.
4. Kim ki Soon, et al. The prevalence of anemia and iron depletion
INDICATIONS OF BLOOD TRANSFUSION in the population aged 10 years and older. Korean J Hematocol.
Blood transfusion is required if Hb is less than 7 g/ 2011;46:196-9.
5. Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia
dL in asymptomatic patients. If hemoglobin is less on mortality, cognition, and function in community-dwelling
than 10 g/dL transfusion is needed in patients for elderly. Am J Med. 2006;119:327.
a predetermined therapeutic programme such as 6. Normal erythropoiesis. In: Hematology in Clinical Practice,
Hillman RS, Ault KA (Eds), McGraw-Hill, New York 2001. p. 3.
bone marrow suppression i.e. PNH, aplastic anemia.
7. Hillman RS, Ault KA, eds. Clinical approach to anemia. In:
Symptomatic anemia resulting in–Tachycardia, mental Hematology in clinical Practice. McGraw-Hill, New York.
states changes, and angina/ECG changes of ischemia, 2011. pp. 29-42.
SOB, light headedness and dizziness on mild exertion are 8. Prakash KG, Devendrappa, Madhukumar KR, Priyashri MH,
Avinash BH. Clinical profile of anemia in elderly: A cross
other indications for blood transfusion.
sectional from a tertiary care center. Sch J App Med Sci.
2015;3(3C):1266-70.
SUMMARY 9. Chavhan B Nilesh, Natu A Sanjay. A study of clinical profile and
Anemia is the most common (30%) clinical condition etiology of severe anemia in children aged 6 months to 5 years.
Global J Research Anal. 2016;5(6):2277-8160.
seen in general medical practice. While investigating
10. SR Pasricha, J Black, S Muthayya, et al. Determinanats of
one should try to interpret simple investigations like anemia among young children in rural India. Pediatrics.
complete blood count with peripheral blood picture 2010;126(1):140-9.
SECTION
16
Social Issues
Medical Ethics Cooking Oils: Which to Use?
Hem Shanker Sharma Sonia Arora, Vitull K Gupta, Meghna Gupta
Soul and Spiritual Health IT Solution in Regulation of Medical Education and
SP Yoganna Medical Practice
Ajay Kumar
CHAPTER
150
Medical Ethics
Hem Shanker Sharma
INTRODUCTION It is governed by the principle, “the greatest benefit to

Medical profession is as old as human civilization. There greatest number.”
is just one aspect that has been the heart and soul of the
profession and that is the moral values attached it. The Right-based Theory and Duty-based
Vedas proclaim Ahimsa as Paramdharma that is the Theory
complete absence of ill-will to all human beings. ‘Charak Both of these are based on interest of individual rather
Samhita’ prescribes an elaborate code of conduct. It than collection of people. Unlike utilitarianism the
says, that “He who practices not for caprice or for money interest of people cannot be summed up or aggregated,
but out of compassion for living beings is the best of all for instance the combined moral obligations of removal
physicians.” No one is bestowed with blessings as much of warts cannot eclipse the need of someone dying with
as a doctor is when he steals life out of the jaws of death. some serious heart disease. All right and duty based
Medical ethics is a field which separates legal obligations theories come across conflicts between rights and duties.
from moral obligations and the relationship anticipates a
bond of confidence for doctors duty towards his patients. Virtue Ethics
It rejects all actions based on moralities including
THEORIES OF MEDICAL ETHICS utilitarian right and duty based in favor of character-
Moral Relativism, Moral Objectivism based values. It rejects the idea that of judgment of duty
and Moral Pluralism and obligations to perform the right actions are the most
Moral objectivists believe that moral beliefs are capable basic moral concept.
of being objectively valid in the sense of being true or
false. On the other hand moral relativists hold that moral Compromise Position
believe are incapable of being objectively valid. Moral It is a collection of moral principle drawing atoms from
beliefs do in facts differ from person to person and other four. It is essentially a miscellaneous category
culture to culture. capturing almost innumerable moral positions not all of
which are coherent, for example, suppose a patient wants
Utilitarianism to sell his organs for money, than principle of autonomy
It is a collection of theories that morally requires to seek tells us to let him do so because it his autonomous
the best possible balance between utility and disutility. decision to sell his organ, on the other hand, the principle
886 SECTION 16: Social Issues
of nonmalificence tells the doctors not to inflict harm to Controversy arises when one seeks second opinion.
his patient when he knows that there is no indication to Is it breach of confidentiality when one share every
do so. details of the patient to some other doctor who is not
There are some important ethical points which are the part of the team? This is said that even though
of utmost importance and needs to be applied in day-to- one seeks second advise, care should be taken before
day practice: disclosing all the information to the colleagues.
Ethics around informed consent: This is false but Confidentiality: Doctor has no legal obligations to
common belief in India that doctors need not take inform the police except some limited statutory
consent from its patients for everything because of the exceptions. This, however, is ethical to give
diffusely scattered illiteracy and notion that patient information about patients, concealing of which
would not be able to understand the sophistications might cause injury to others. It all comes down to a
and intricacies associated with the medical diagnosis balancing act between nature of confidential matter
and treatment on account of being illiterate. and importance of public interest.
In contrast, every human has equal right to know Family: Female seeking contraception without the
what is being done to his or her own body. prior consent from his partner, the doctor is bound
In Indian context, the doctors are given paternal by his duty of confidentiality to her for concealing the
importance in such a way that “whatever the doctor
information. In fact, the partner or husband has no
does is best for the patient” but now more and
right about the child in the uterus.
more GOOGLE educated patients are seeking
The primary aim of doctor should be to convince
logical reasoning behind each and every medical
the patient that this should be a joint decision.
intervention given to the them.
Public interest: Medical records can be disclosed in
Disclosure: In US and Canada, the courts have obliged
courts if it is necessary. The confidentiality is always
the doctors to disclose all the relevant information
in conflict with public interest. If the beam slings
regarding the procedure and let the patients choose
towards the importance of disclosure, then it must be
his or her own fate. In clinical scenario, this is at
undertaken in place of confidentiality.
times not possible to shower upon the patient all the
Patients autonomy: Right to autonomy is sometimes
minute details of all the tricks and traps applied by the
overridden by interest of masses. The respect of
doctors to catch and kill the disease, hence a pathway
in between is to be chosen in away that patient are autonomy is, however, the cornerstone of doctor-
told whatever they are interested in knowing. patient relationship. Even touching the patient
Disclosing the ultimate grief: Both Charaka and
without consent is an assault even, if this was in
Susrata believed that patient should be carefully told greatest good for patient.
Dignity: The human rights are based on human of
about the incurable disease, in any case, it should
never be told bluntly. human rights takes this very well in account. This
There are arguments for and against the same. It is encircles the controversial matter of Euthanasia
quite logical that a person if told about their untreatable failing which may prevent patient dignity this
diagnosis it would cause severe depression and stress. foundation was laid after the World War II, the
This is against ethical conscience. The argument in preamble and universal declaration from Dying with
support of the disclosure is that patient has the right Dignity.
to think and decide about his own life and choose his Although none of the ancient literature support
own path to life and exercise his autonomy. euthanasia but there are supporters of the fact that
Sharing information with healthcare team: Medical treatment should be abandoned in terminally ill.
profession is not a game of one man army it is But before that treatment should be given to
rather a team play which involves doctors, nurses. decrease the sufferings when recovery is not possible.
CHAPTER 150: Medical Ethics 887
Fertility and abortion artificial insemination: The CONCLUSION

MTP allows termination of pregnancy in greater In recent time, commercialization has engulfed the soul
good of the patient but here again there is conflict in of profession which used to be, service of mankind.
between the interest off growing fetus and the mother The balance between service and business is seeing
in whose womb baby is flourishing. an increased inclination towards business. In Indian
Artificial insemination is against the medical ethics scenario where the doctors are still seen as Gods on
despite of the fact it is being increasingly used this
earth there is still some hope left because the human is
again is debatable.
still alive in hearts of most of the Doctors and this lamp
should enlighten the lives of people. In light of recent
GOVERNING BODIES AND RULES
attack on the doctor community, it must be emphasized
The Medical Council of India and State Medical Council
that patients and their attendants are not always at fault
have the power to take disciplinary action against
and we need to introspect that why the Godly figures on
misconduct.
Earth are being treated like demons.
It is unethical for the doctors to follow “no money
no care rule.” Although the doctor has the right to
BIBLIOGRAPHY
choose whom to treat, but this is almost necessary to
1. Berger D. Corruption ruins the doctor-patient relationship in
give primary care to the one who need it in emergent India. BMJ. 2014;348:g316.
conditions. At the same time, a doctor must fearlessly 2. Code of Medical Ethics Regulation, 2002 (Amended upto
disclose the unethical and unprofessional deeds of 8th Oct 2016) published in part III, sec 4 of the Gazzette of
corrupt persons of the same profession. India, dated 6th April, 2002; MCI Notification.
There are several rules of conduct published by MCI 3. Kanchan T. The Medical Termination of Pregnancy
which must be followed by a general practitioner, inability (Amendment) Bill, 2014—Progressive Or regressive? Indian
J Med Ethics. 2015;12(4):255.
of which shall constitute professional misconduct
4. Kulkarni R, et al. Accreditation of Ethics Committees:
and liable to punished including erasure of the name Experience of an Ethics Committee. Indian J Med Ethics.
from Indian Medical Registrar. The important offences 2015;12(4):241-5.
are: adultery, advertising, abortion, association with 5. Sarkar S, et al. Dealing with requests for faith healing
unqualified persons, addiction and alcohol. treatment. Indian J Med Ethics. 2015;12(4):235-7.
CHAPTER
151
Soul and Spiritual Health
SP Yoganna
The word ‘spiritual’ is formed by combination of two energy got imprignated into the exploded particles of
words, ‘spirit’ which means ‘soul’ and the word ‘ritual’ the primary matter. Each such particle later evolved in
meaning religious practices, ultimately meaning, the it’s own gynecological pathway till today and resulted in
religious practices that keeps the soul healthy. The soul the creation of different components of present universe.
means energy. Spirituality includes science about energy Life came into existence at one point of time of evolution
and philosophy about spiritual lifestyle, thus spiritual process, after the formation of all the necessary required
health is a combination of science and philosophy. infrastructure for the survival of living beings. Human
Spiritual health is concerned with the health of soul being made appearance at one point of time in the
which is an atom of transcendental energy present in the evolution process of life. It is not known as to whether
human being, which has connection with the universe. male and female appeared separately since the beginning
There are many misnomers about spirituality. It is or later get differentiated from bisexual human.
misunderstood by many people as superstitious beliefs, Since all the components of the universe including
which is not true. On other hand, it is superconscious the man have come from the same primary source of
facts of universal truths. To understand spiritual health primary matter and energy, each component of the
the knowledge about origin and evolution of universe, universe is connected with each other including the man.
human development and his connection with the This integration may be visible or invisible, perceivable
universe is essential. or imperceivable by normal senses. Spirituality involves
the knowledge of knowing the process of origin of
ORIGIN AND EVOLUTION OF universe and all connections of man with the universe.
UNIVERSE—MATTER AND ENERGY The available scientific evidences establishes that the
THEORY (BIG BANG THEORY) creation evolution and happenings in the universe and
The exact time and mode of origin of the universe is man are preprogrammed.
not know till today. It is said that about 14 billion years
ago universe came into existence. Matter and energy NATURAL PRINCIPLES OF UNIVERSE
collusion hit theory is accepted to be the mode of origin The universe has evolved it’s own natural principles
of universe, as on today. The primary matter hit the to maintain it’s preprogrammed processes, so that
primary energy resulting in explosion of the primary “universally integrated natural chains are regulated and
matter into various pieces, during the process primary maintained constantly. If they are distributed, it results in
CHAPTER 151: Soul and Spiritual Health 889
imbalances of nature and human functions. The nature the source of energy and matter of the body is ultimately
finds its own methods to reset even the disturbed chain from the universe, which have come from sun and
so as to continue its preprogrammed evolution. These food, etc., human being is a form or manifestation of
natural principles of universe are called ‘universal truths’ universal energy. Like this every component of universe
of the nature, which are not completely understood is a manifestation of supreme universal energy and
even by modern science. Birth, growth, development, hence are connected with each other.
changes, transformation (death) and rebirth are the
ultimate universal truths of creation. Nothing can HUMAN BEING IS THE MINIATURE
either be created or destroyed but something can be OF THE UNIVERSE
transformed from one form to other. Each component When human being appeared in the universe during
of the universe continuously undergoes recycling in its evolution is still not known. However, it is estimated
the universe by a process of transformation. So also by podology and fossils survey that about 20 crores
human being. The future evolution of the universe is not years ago the human race might have appeared and
known to the modern science. But the available spiritual has evolved to the present status of modern man. The
knowledge reveals that human being is the ultimate age of the present modern man is estimated to be about
most evolved component of the universe and there is no 10 to 15 thousand years. The human being is the most
further evolution in man with reference to the physical evolved component in the universe and hence has all the
body. It is said that there is further evolution to individual foot prints and mirror images of all the components of
mind, where in it can acquire supernatural power which the universe from which he has evolved and vice-versa.
is capable of understanding the preprogrammed natural For example, the replica of technologies of IT and BT
principles of the universe. Some of the natural principles may be noticed in the functions of nervous system and
of nature and human being are perceivable even to immune system. For discovery of them the functions of
normal senses. Whereas others are perceivable only to the human body itself were the source of inspiration. The
superconscious mind, which is not present in ordinary events that are noticed in the universe can be noticed in
human beings. the human body either directly or indirectly through an
analogous event. Hence, human being is the miniature
HUMAN IS A MANIFESTATION of the universe. Hence, the entire universe could be
OF UNIVERSAL ENERGY understood by understanding human and vice-versa.
The matter and energy present in human being is the
contribution of the universe. The bioelectrical energy HUMAN BEING IS HOLISTIC
(action potential) which is the prime energy source in the Mind is the most evolved component in the human
human body is converted into different types energy, in being and also in the universe. It has influence on each
different parts of the body so as to carry out the work and cell of the human body and the universe. Since man has
functions of the concerned system. In cardiovascular, evolved from the universe, he has symbiotic biological
respiratory and musculoskeletal system bioelectrical relationship with each component of the universe, which
energy is converted into kinetic energy to move the heart, may be visible or invisible, perceivable or imperceivable
blood, air and joints respectively. In reproductive system, by normal senses. Man is connected through waves
it is converted into reproductive energy to reproduce. with the universe. Hence, universe influences the health
The capacity to do a work undertaken is energy. The status of the human and vice-versa. The slogan of the
capacity of an individual to do the work depends upon WHO that “Think Globally, Act Locally” is based on this
the capacity of the individual mind and hence there scientific fact. Since man is connected with the universe
shall be mental energy with reference to mind. Since and he has to be viewed holistically.
What is Human Being? observations even with reference to evolution of man will
Human being is defined as a spiritual being composed of establish this fact. The structural components of modern
soul (energy), body and mind having constant regulation man especially the mind, the brain and others organs of
by the universe. The human life starts with combination the body have also evolved systematically to the present
of soul, body and mind and exists till they are intact. state of progression from primitive state only, without
Life ends when disintegration of these components any retrospective regression.
occurs. Hence, ‘Human life may be defined as a constant The matter and energy of the human is cycled
integrated state of body, mind, soul and universe’. The continuously between birth, life span, death and
life exists for a fixed duration, i.e. life span, which is also rebirth in the universe. In the same way, all other
predetermined. The life style followed during the life components of the universe also undergo continuous
transformations. The minute zygote is transformed into
influences the life span. The human life exists in human
preprogrammed mega fetus through preprogrammed
life cycle which is composed of Birth–life – Life span,
stages of development by the nutrients supplied to it
Death and Rebirth.
from the universe in the womb. Soon after birth, the
child again passes through the preprogrammed stages
What is Birth?
of infancy, childhood, adolescence, adulthood, old age
The sperm and ovum which are also produced by the
and death. The specific physical, mental and emotional
products of universe gives raise to zygote which develops
changes that appears during each of these stages are also
into fetus by the food supplied by the universe. Hence,
predetermined.
birth is a transformation of universal products of sperm,
The physical growth of different organs of the body
ovum, food into a form of fetus.
also occurs over a definite specified period. For example,
though the sexual organs are present since birth in the
What is Death?
body, they mature and start functioning only at puberty.
Death results due to loss of integration between body,
Even during puberty though millions of ovum are present
soul, mind and universe. After death, these separated
in the ovaries, only one ovum matures and get ovulates
components joins the universe and forms the raw
during one menstrual cycle from each ovary alternatively.
materials for the rebirth of something else. This is the In the digestive system, as soon as the food enters one
concept behind rebirth. Hence, there is no destruction part of the intestine, the next distal part gets ready to
or loss of anything in death. It is only transformation receive the food, by automatically relaxing and proximal
from one form to other. Hence, death is defined as a state part contracts pushing the contents forward producing
of separation of soul, body and mind from the human peristalsis. Even the secretion of digestive juices and the
being. It is a type of transformation in the universe. Birth, activation of the proenzymes also occur systematically
life, death and rebirth are the different forms or state of and automatically in a sequential manner. As soon as
matter and energy. glucose enters the Cryb’s cycle the further activation
of inactive enzymes is automatic till the final product
PREPROGRAMMED EVOLUTION citric acid is formed. Like this preprogrammed biological
AND HUMAN BODY FUNCTIONS reactions can be observed in several physiological
Though, both progressive and destructive events have reactions of the body. All these facts establishes that
constantly occurred in the process of evolution of the even the physiological functions of the human body
universe, it is worth observing that the progressive is predetermined. The circadian biorhythms, diurnal
events have always superseded the destructive events. and geographical variations of body functions, further
Otherwise, the universe would not have progressed to establishes that body physiology is preprogrammed. Like
the present state of progression, since its origin. The this plenty of examples can be adduced to establish that
body functions and all the happenings in the universe are Internal and External Happiness
preprogrammed. Happiness is a state of ease felt by the mind. Source
Each cell is programmed for its duration of survival of happiness may be internal or external. Internal
which is called “apoptosis”. When the modern medical happiness comes from within and is genetic. It is not
knowledge has accepted the concept of apoptosis, the influenced by external environmental factors. The mind
concept of predetermined birth and death advocated is in a constant state of happiness in the womb and also
by spiritual knowledge has to be believed, as the soon after birth. The child becomes discomfortable and
body is made of millions of cells, whose life span is
unhappy only when it’s natural instincts like hunger,
preprogammed.
defaecation and micturation etc. are not satisfied and
expresses the discomfort by way of crying, otherwise the
Purpose of Human Life is to be Happy child will be always in a state of happiness expressing
The purpose of universal creation and the human
lough. This state of mind is called “innocent mind” as it
life is mysterious and both have not been completely
has no external influence.
understood by modern science till today. It is a well-
established natural principle that nothing happens in
Conditioning of Mind
the universe without a reason and purpose. Each human
As the child grows the external environmental factors
soul while it is in the body shall be happy and when it is
influences the mind and precondition the mind on
not in the body i.e., when it is in the universe, it shall be a
various issues. Depending upon the environmental
part of universal energy, is the universal truth.
influence the child starts developing it’s own sense
The purpose of human life can be understood
of discrimination, priorities, likes and dislikes and
by observing the effects of physiological acts of the
accordingly the innocent mind gets attached to external
body itself. All the physiological acts of body gives
sources of happiness and gets preconditioned to them.
sense of happiness (ease). The physiological acts like
eating, defaecation, micturation, sexual activities, and The inborn internal happiness thus gets surrounded by
sleep etc., produce sense of comfort and happiness external happiness and becomes pushed into the deeper
and any disturbances in them results in discomfort layer of mind over a period of time. The happiness
and unhappiness. Man does all the activities in life induced by external factors is external happiness.
to get happiness. The state of happiness produces The external happiness inducing factors are multiple,
positive biological effects on the body functions and variable and not constant.
causes physiological balance between sympathetic and Thought generation in the mind is the route
parasympathetic nervous system, resulting in positive cause of all actions which ultimately determines the
state of health. On the other hand, state of unhappiness happiness and unhappiness. Fulfillment of desires
and discomfort produces negative effects on the health by produce happiness, whereas unfulfilled desires produce
increasing the sympathetic nervous activity. Happy state unhappiness. Thought generation is under the influence
of mind influences psycho-neuro-endocrino-cellular of environment. Desires cannot be constant. After the
axis positively so as to regulate the normal physiological fulfillment of one desire the mind aspires for another
functions positively. Endorphins are released during desire, like this the mind gets entangled in a visceous
happiness which helps to maintain normal homeostasis. cycle of happiness and unhappiness. The preconditioned
Whereas Adranaline, Noradranaline and Cortisol adult mind for external happiness starts hunting for
increase during unhappiness disturbing the homeostasis. happiness one after the other and hence constant
All these establishes that the purpose of human life is to happiness becomes impossible. The mind which gets
be happy. attached to external happiness is called ‘ignorant mind’.
The ignorant mind is unhappy most of the time and is the well coordinated so as to achieve the state of normal
route cause of genesis of ill health. homeostasis. The mind influences each cell of the body
The mind can be spiritually trained in such way that through “psycho-neuro-endocrino-cellular axis” and
it will not get influenced by external source of happiness maintains normal homeostasis. Mind is influenced by
thereby allowing the inborn internal happiness to external environmental factors through hypothalamus.
blossom, so that mind always generates such thoughts Mind receives kinesthetic, other subconscious and
which results in constant happiness. An adult mind conscious sensations through afferent nervous system
which has been preconditioned for external happiness and send efferents to regulate the body functions.
can be spiritually trained to decondition it from the Mind is very much vibrant and it always swings
influence of external happiness. When it happens between calmness and tremulousness (unease). The
automatically internal happiness blossoms gradually to mind is genetically predetermined to develop both
the superficial plane, which is a constant happiness. This positive and negative emotions like love, courage,
state of mind is called “enlightened mind”. Enlightened patience, happiness, lough, desires, sense of universality,
mind also acquire superconscious power. etc. (positive emotions) and hatredness, fear, anger,
unhappiness, weep, etc., (negative emotions). Though
Unscientific Mind in a Scientific Body both positive and negative emotions are acquired
The structure and functions of the body are universally genetically, positive feelings dominates over negative
same in all the individuals. Scientific facts are universally feelings genetically, since birth. But the external
true. Hence body is scientific. Whereas same thing is environment plays an important role in further culturing
not true with the mind. The character and behavior of these emotions in a child after birth. Thus mind may be
the mind varies from individual to individual and in preconditioned more for either the positive or negative
the same individual from time to time. The influence of emotions by the environment. Positive emotions give
environment on mind is more sensitive than the body. raise to happiness, whereas negative emotions give raise
Mind is always engaged in one thought or the other to unhappiness. Depending upon emotions, thoughts
and is always vibrant. For the same stimulus, the mind are generated in the mind. State of positive emotions give
reacts differently in different individuals and in the same raise to genesis of universal thoughts, whereas negative
individual differently under different circumstances. emotions result otherwise. Thoughts also influences
Nothing can be universally generalized with reference to emotions. Hence, emotions and thoughts generation are
mind unlike that of body. Hence, there is an unscientific interrelated.
mind in a scientific body. This paradoxical combination Mind always exists in thoughts, even in sleep as
is the route cause of many problems of the human being. dreams. Thoughts result in actions (Karma) which inturn
Spiritual religious practices converts the unscientific mind influence the happiness and unhappiness. Emotions,
to a scientific mind and brings coordination between thoughts, actions, unhappiness and happiness areinter-
the body, mind and soul and helps the mind to acquire related.
superconscious power, by which it can understand the Thoughtless and positive thought mind is peaceful
ultimate universal truths which are not perceived by the and happy. It is impossible for a common man’s mind
ordinary senses of the mind. to be thoughtless. The mind has to trained in such a way
that either it is thoughtless or generates only positive
Spiritual Culturing of Mind thoughts, the execution of which keeps it happy without
Human mind is the most evolved component in producing unhappiness. Positive thoughts intiate the
the human being and in the universe. Mind is an human to take up only such actions which strengthen
instrument through which the milieu interior and the universal truths. The process of training the mind
exterior are regulated and body, soul and universe are to develop positive thoughts and ultimately making
the mind thoughtless and peaceful is called “spiritual connection of man with the universe. It explains both the
culturing of the mind”. vertical and horizontal aspects of universe. The modern
science explains in depth about a particular component
Spiritual Knowledge of the universe (vertical) not giving much importance
Truths about the creation and happenings in the to its other horizontal connections, whereas spiritual
universes is knowledge. False things cannot be knowledge. knowledge is both horizontal and vertical. Hence,
The spiritual knowledge comprises perceivable and spiritual knowledge is holistic.
imperceivable universal truths by normal senses about
the creation and the man. It specifically contains truths Philosophy of Spirituality
about birth, life and death and truths which are beyond Man being the most evolved component of universe,
birth, death and life which are not perceivable by he is entrusted with the responsibility of protecting
ordinary mind. Some of them are appreciable even by and promoting the natural principles of universe by
a common man and some are appreciable only by the the creator. Hence, his thoughts and actions are to
superconscious mind. be generated accordingly. Actions which are against
Spiritual knowledge can be broadly classified as the natural principles of nature not only disturbs the
worldly and transcendental spiritual knowledge. Worldly preprogrammed process of the nature but also disturb
spiritual knowledge contains the truths of life and the human homeostasis, making his life miserable.
universe which can be appreciated by normal special Philosophical aspects of spirituality involves culturing
senses, following of which will keep the man happy in the mind spiritually, so as to make it to generate, positive
the wordly business. Transcendental spiritual knowledge thoughts and acquired superconscious power.
contain the ultimate truths of the creation which can Spiritual knowledge also deals with the purpose
only be appreciated by super conscious mind, not by of life, priorities, desires, likes, dislikes and lifestyle
ordinary special senses. It contain the knowledge about measures which assists the universal principles of
transcendental power and the union of the soul with that nature. The lifestyle measures which protects and
super power to attain eternal happiness. Individuals who promote the natural principles of creation are religious
acquire spiritual energy will be able to appreciate the practices or (Dharma). Since each component of the
transcendental energy. universe has come from the same source of primary
There are two schools of thoughts regarding the origin matter and energy and all are interconnected, any
of spiritual knowledge. One school of thought is said that measure undertaken by the human should not destroy
Rishis, the ancient spiritual scientists by their constant the predetermined natural bondage that exists between
spiritual effort were able to acquire superconscious each component of the universe. On the other hand, it
power to their mind which was able to know the entire shall further protentiate such bondages. The religious
science of creation and the same was propogated by practices preaching love, equality, nonviolence, peace,
them to others by oral tradition. Later Vyasa Maharishi etc., that are practiced by human beings since his
the ancient spiritual scientist reduced this knowledge to appearances in the universe came to be practiced on
writing in the form of Vedas. Vedas are the first ancient this principle. That is how the ‘Dharma’ (Religion) came
literature known to man in the World. The other school into existence. Valmiki wrote “Ramayana” epic and
of thought is that, the creator who created the universe Vyasa wrote “Mahabharatha” incorporating all aspects
himself explained about all the aspects of creation at of Vedas and preaching spirituality through practical
the first instance itself when the creation was done. The lifestyle stories. These two epics and Bhagavath Githa are
spiritual knowledge explains, the processes of creation the treasuries of spiritual knowledge, preaching natural
and the interlinks between the different components of principles of creation to the mankind through practical
the creation. It explains the universal truths regarding stories and examples. Later many saints, preachers,
writers, poets, like Buddha, Patanjali, Christ, Mohammad Effects of Spiritual Energy
Paigambar, Einstein, Worldsworth, Shakespear, etc., The effects of spiritual energy are variable depending
around the world preached the spiritual knowledge in upon the quantity of energy acquired. The effects
their own ways in different languages and forms. are only perceivable cannot be demonstrated in the
The knowledge regarding, the source of energy laboratory. Can happiness, unhappiness, hunger, etc.,
in the human being, its evolution, functions and its be demonstrated by any evidence in the laboratory ?. No,
connections with the universe constitute the science of they have to be experienced like this effects of spirituality
spiritual health. Whereas the lifestyle practices which has to be felt by the body and mind. The effects can be
strengthens the bondage of this energy with the different summarized as below.
components of universe constitute the philosophical It calms down the mind and cultures the mind
aspects of spiritual health. spiritually and mind acquires different planes of

positive feelings depending upon the quantum of
LIFE ENERGIES energy.
Super consciousness: Normally only 25% of, the brain
In the body, the bioelectricity produced inside the cell
is the primary energy source. This primary electrical cells Alveoli, Nephrons, Coronary capillaries are
energy is converted into various other types of energies active and rest of them are inactive. The spiritual
i.e., kinetic, mental, biochemical (ATP, etc.) reproductive energy makes the inactive brain cells to become
and spiritual energies. Not much is understood about active, thus brain acquires newer dimensions
these life energies by modern medical science. But the and functions which are not present in normal
individuals. The spiritual energy opens the dormant
spiritual literature contains informations about these
body functions so that body acquires newer positive
energies.
transcedental dimensions.
C o n s c i o u s n e s s , s u b c o n s c i o u s n e s s a n d
Spiritual Energy
unconsciousness are the three normal planes of mind
Spiritual energy is generally present in the body in
in a common man, subconscious mind is the place of
primitive level. As age advances it will gradually
synthesis of thoughts based on the inputs it gets from
increases to evolve to superficial plane. Spiritual
different parts of the milieu interior and exterior. The
practices accelerates the spiritual energy in the body.
conscious mind is the business mind and screens the
The spiritual energy through its effect on the mind inturn
thoughts generated in the subconscious mind and
regulates body functions positively. It also gives the mind executes them as per the need. The conscious mind
extraordinary superconscious power to understand acts as per the selected thought depending upon the
the happenings both inside and outside the body. The circumstance and unselected thoughts are buried
effects of the spiritual energy is directly proportional in the subconscious mind. The role of unconscious
to the quantum of spiritual energy acquired. The mind is not known. It may contain the past history of
reproductive energy is converted into spiritual energy Atma if it opens one may be able to appreciate them.
inside the body. During the process of acquiring spiritual Superconsciousness is the supreme dimension
energy, individual becomes hypersexual. This stage of of mind, which can only be acquired by constant
hypersexuality is to be managed carefully so as to convert spiritual practice. Superconscious mind will be able
it into spiritual energy by specific spiritual practices, to appreciate the Atma, history of Atma and it will also
otherwise the energy will be wasted in excessive sexual be able to understand everything about the universe.
activity and ultimate spiritual achievement may not be It cannot only able to regulate its own body but also
reached. of others and the universe. Superconscious mind will
appreciate the super natural power and its influence energy by constant mild to moderate spiritual practice
in the body. There are many such people (Yogis) who is quiet sufficient to regulate psycho-neuro-endocrino-
have acquired this power. cellular axis, so as to maintain normal homeostasis.
Alternative pathways: There are alternative metabolic The ancient spiritual literature has described spiritual
and other physiological pathways in the human body energy centers located in the midline of the body
which are in primitive state since birth, but they do probably in the spinal cord. The lowest center called
not work normally. Example – Anaerobic pathways ‘Muladara’ situated in the perineum (coccygeal segment)
of respiration, alternative speech ways (lip reading), and highest center ‘Sahasarara’ situated in the vertex
alternative energy pathway like utilization of solar (Brain), the other 5 centers are situated in between them,
energy, for body energy, appreciation of waves in the in the pubis, umbalicus, epigastrium, root of the neck
environment, etc. The spiritual energy makes these and globella respectively from below upwards. Body
alternative pathways to evolve, so that they come acquires different types of feelings and activities when
to the superficial plane and works. There are many the energy flows up from the bottom center muladara
living examples even to day wherein Rishis in the to the top center sahasrara through other centers.
Himalayas live without food and water for many years Ascend of spiritual energy depends upon the quantity of
by using the solar energy. spiritual energy acquired. There are channels in the body
(Kundalis) through which this energy flows energizing
Spiritual Energy Centers the body.
Spiritual energy centers have been identified by ancient
spiritual scientists (Table 1). These centers have been SOUL (ATMA)
named to explain different types of feelings, produced Soul means energy. Atma is a Sanskrit word which also
due to different planes of spiritual energy acquired. At means energy. Human soul has different dimensions,
the height of acquisition of spiritual energy, the mind both scientific and philosophical. Soul being a
acquires superconscious power. Everyone may not attain component of universal energy has universality and
such high degree of spiritual energy in the process. It universal connections and appreciation of it will produce
needs constant and vigorous spiritual practice to acquire universal feelings, which constitute philosophical
such supreme state, which may take one’s entire life dimension. Hence, Soul can be defined as.
span. But acquisition of even little to moderate spiritual Part of universal energy in the human being
and
TABLE 1: Site and effects of spiritual energy centers Sense of universal awareness and oneness
Name of spiritual Location Effects

energy center Part of Universal Energy
Muladara Perineum Sexual activities All the components of the universe being composed of
Swadisthana Pubis Contentment, feeling of matter and energy, the total sum of all the energies in
selfishness
different components (matter) of the universe constitute
Mannipur Umbilicus Questioning the purpose
life, spiritual feelings
“Universal energy” (cosmic). The energy will be drawn
Anahutha Epigastrium Love, kindness,
from this universal energy pool for the genesis of new
cooperation feelings, etc. matter and new forms of energy in the universe. Human
Vistiddi Lower part of neck Creativity, poetness being a product of universe has a part of universal energy
Agna (3rd Eye) Globella Self realization, creativity, in him, which has connection with the universal energy
music interest pool. The body being a matter is also a contribution
Sahasrara Vertex Enlightenment, from the universe. Energy is not visible and its effect can
superconscious power only be noticed. It is this energy which is responsible
for vitality and life. The soul that comes out of the body an inborn component of universal awareness in him/her
during death is again used for birth of other components which has to be allowed to blossom in life. Hence each
of the universe which is called “rebirth”. Hence the individual feels that he/she belongs to universe and all
concept that soul has no death and has rebirth is are one. This feeling constitute the philosophical aspect
scientific in this way. of Atma. Once the feeling of universality appears, the
mind acquires all positive feeling like love, happiness,
What is Soul? coordination and concern to universe, etc., which are
Soul has scientific and philosophical components. Soul philosophical aspects of spirituality. Once the positive
means energy. Energy is defined as the capacity to do emotions appears negative emotions automatically
work. The energy that does the work in the human body disappears producing the state of ease.
is bioelectricity produced inside the cell by electrolytes,
sodium and potassium. It is the bioelectrical energy Personal Identity
in the cells which is ultimately responsible for all the Though all the human beings are the products of
activities of the cell and ultimately the human body. Loss the same universe, each individual differs in his or
of the electrical activity of the cell is the most important her identity. Even the twins differs. The Iris, thumb
abnormality noticed in individual cell death and in the and palmar impressions and palmar arch of each
death of the human being. Cardiac arrest will stop the individual are different and are taken for identification
circulation and will halt the supply of oxygen and other of individuals. This fact throw a strong evidence that
nutrients necessary to synthesize the bioelectricity in each individual has his or her own identity by his own
the entire body cells, resulting in abrupt cessation of Atma component, which has its own identity and historic
production of bioelectricity resulting in the death of evolution pathway.
the physical body. This energy is synthesized from the
components of the universe and hence the energy in the Religions (Dharma)
human body is a component of universal energy. Hence, Religions are the human life style practices evolved by
soul is defined as a component of universal energy in the human beings based on basic spiritual knowledge so
human body. The resting action potential that is present as to protect and promote the universal truths of the
inside the cells of the body, at the time of death comes Universe. Religious practices affects life styles and mental
out of cell and merges in the universe, as energy cannot health thereby influencing health. During the vedic
be destroyed. It is this energy which may be defined as period, there was only vedic religion. But later as many
soul. Like this, every component of universe has its own people understood the vedic knowledge they started
soul. interpreting it in their own ways which gave birth to
The bio energy present in the body comes out and many religious preachers and thus many religions came
joins the universal energy and the body matter also joins to be practiced.
the universe in different forms soon after death. These, “Hinduism” is the oldest religion known to man. Later
forms the raw materials for the birth of another life or “Christianity” established by Christ and Islam established
matter in the universe, which is defined as rebirth. These by Mohammad Paigambar are popular religions in
changes goes on continuously in the universe in a cyclical the world today. The religious preachers made further
manner from one form to other in all the components of branches in these basic three religions giving birth to
the universe, both in living or nonliving things. much more sub-religions. In the process, some of the
preachers misunderstood and misinterpreted the real
Universal Awareness and Oneness spirit of vedic spiritual knowledge and introduced their
Since human being is a product of universe and he/she own views and polluted the basic vedic religion and
is connected with each components universe, there is introduced the life style practices which are against the
natural principles of universe. These practices even first instance which is called “Self Union” and later it
contain the practices, which destroys the basic natural brings the union of onself with the universe which is
principles of nature thus giving birth to Adharma. called “Universal Union”. These unions already exists as
Adharma preaches things which are against the natural man is connected with the universe. But yoga brings the
principles of creations. There is no universality in awareness of these unions and further strengthens them.
Adharma, whereas there is universality in Dharma.
Dharmic life styles brings coordination between body, Components of Yoga
mind, soul and universe and brings happiness whereas The great ancient spiritual scientist Patanjali about five
Adharmic life styles disturbs the coordination of the thousand years ago described and documented the Yogic
body, mind, soul and universe resulting in spiritual ill practices. There are four major components in yogic
health and unhappiness. practice. Though each one of them will produce desired
effects, all of them if followed in combination constantly,
WAYS OF ACQUIRING will produce optimum effects. The components are
SPIRITUAL ENERGY Jnana Yoga
Karma Yoga
The different ways of acquiring spiritual energy are:
Genetic Bhakti Yoga
Age Raja Yoga (Asthanga Yoga). There are eight
Spiritual practice - Yoga components in this

Other religious practices —— External Yoga
God and Godman These are called External Yoga as they involve
external components
Genetic and Age Niyama – (Do’s)
The spiritual energy comes from genes itself but it will Yama – (Do not Do’s)
be at lower plane. The spiritual life style practices further Asanas – (Postures)
enhances this energy. As the age advances the energy —— Internal Yoga
gradually increases naturally. This can be appreciated by These are called Internal Yoga as they involve
the observations of appearance of spiritual feelings in old inversion of mind into the body and soul.
age naturally in all individuals even without any routine Pranayama (Breathing exercises)
spiritual practices. Yogic and other religious life practices Pratyahara (Deconcentration of mind)
further enhances this energy. Meditation (Concentration of mind)
Samadhi (Superconscious state)
Spiritual Practice—Yoga Jnana Yoga deals with spiritual knowledge. Mear

On the background of spiritual knowledge, to protect understanding about the spiritual knowledge itself
and promote the principles of nature, the spiritual life will induce spiritual energy. Karma Yoga preaches the
practices have been evolved, since the inception of karmas i.e. the works one has to do in day to day life,
human race. The most ancient, undisputed and accepted which will give the human, happiness and also the works
spiritual practice that is documented is ‘Yoga’. Later, on which shall not be done as they cause unhappiness.
the principles of Yoga many spiritual practices have come The works (actions) which strengthens the natural
into existence over period of time. Yoga contains life style principles of nature will give happiness, on the other
practices which helps in acquiring spiritual energy which hand the works which are against the principles of
in turn helps the mind to acquire superconscious power. nature and weakens or destroys the natural bondage
Yoga is a Sanskrit word which meaning “Union”. Yoga between different components of the universe, including
brings union of mind, body and soul, in the body in the the man will give unhappiness, as they disturb the
natural predetermined chains of connections with the Meditation practices train the mind to be less vibrant,
human beings. Karma yoga also precondition the mind nonvibrant, peaceful and culture the mind spiritually. It
for generation of spiritual thoughts which intiates the initiates generation of spiritual thoughts in the mind and
mind to do such Karmas which strengthens the natural keeps the mind stress free. It makes the mind to acquire
bondages in the universe. ‘Bhakti Yoga’ contains the such power to deal stressful situations without much or
materials, the practice of which not only will calm down no damage to the body. It also helps the mind to acquire
the mind but also remove arrogancy and anger thereby supernatural power of understanding the imperceivable
helps to imbibe the qualities of superego, i.e. feelings of universal truths which are beyond birth, death and life.
reasoning, sacrifice and cooperation etc. It helps to acquire a personality of enjoying each present
‘Raja Yoga’ deals with the practices which train movement of life without the influence of past and future.
the mind to coordinate the body, mind, soul and ‘Samadhi’ is a state of self and universal union, i.e.
transcendental energy and makes the mind to acquire merging of the human being with that of the universe and
supernatural power. It contains eight components, hence transcedental energy. The mind becomes completely
it is also called ‘Asthanga (eight) Yoga’. Niyama deals with thoughtless in this state. It is the ultimate state attained
the simple principles of life that are to be followed in by all the spiritual practices. When this happens one
routine day to day life. Most of them are also advocated feels that he is a part of the universe and is inseparable
by modern Medical Science. It contains mostly food and from the universe. In this state, the mind acquires the
personal habits. ‘Yama’ deals with the practices that are capacity of understanding all the happenings of the
not to be practiced in life as they injure health and brings universe, past, present and future. There are plenty of
unhappiness. Most of them are also with reference to examples in the history, who have achieved the state of
actions, food and habits. Samadhi. Christ, Mohammad Paigambar, Ramakrishna
‘Pratyahara’ deals with practices of deconcentration Paramahansa are few among them.
of mind. It trains the mind to deconcentrate it from The basic principles of all the religions i.e., Hinduism,
sources of external happiness and makes it to concentrate Christianity and Islam, etc. can be traced to different
on inner happiness. ‘Asanas’ are particular postures in components of yoga which is the most ancient spiritual
which one can be very much comfortable for long time so practice in the world. The spiritual practices makes the
as to do meditation. It contains different types of ‘Asanas’ positive feelings to supercede the negative feelings, so
in which the particular part of the body or organ can that there is always genesis of constant state of happiness.
be stimulated to be healthy. There are about more than
8,000 described Asanas. GOD AND GOD MEN
‘Pranayama’ is a process of controlling the mind and What is God?, Who is God?, Where is he?, whether
enhancing the spiritual energy through breath. There God is there or not, whether he is a creation of man or
is inverse physiological relationship between mind creator of the universe, is God only a belief or is he really
and respiration. Whenever there is increased mental or there, whether he has form or forms or formless, is it the
physical stress the rate of respiration increases and depth supreme transcedental energy, can it be seen or felt are
of respiration decreases. Whereas whenever the body certain questions surrounding the God.
and mind are peaceful, the rate of respiration decrease Belief in God is the prime requisite of spirituality.
and depth becomes shallow, thus ventilating the lungs “God can be traced to transcedental energy which is
better. Pranayama contains practices which harmonizes the creator and regulator of the universe”. Marching of
the mind, soul and body through respiration. Respiratory evolution of the universe including the man since its
movements are supposed to be the reflection of kinetic origin only towards progression till today establishes
energy of the body. Pranayama regulates the body energy the fact that origin of universe and its evolution is
through the respiratory kinetic energy and vice-versa. preprogrammed with a creator and regulator. The
whole universe is made up of matter and energy. The It regulates the body, mind, soul and universe so that
components of the universe are different manifestations all of them are well coordinated and constant state of
of prime matter and energy, which gave birth to ease is maintained.
the present universe. The prime energy from which It regulates psycho-neuro-endocrino-cellular axis
different components of the universe have evolved is so that natural biorhythms are maintained so as to
regulating them, towards preprogrammed evolution. maintain constant homeostasis.
This transcedental, regulating energy, has been named It triggers the anabolic metabolism and regulates the
as ‘God’ in spirituality. Since each component of the catabolism so that the body is energized.
universe, is a manifestation of God, i.e. the transcedental Mental health is regulated so that mind becomes
energy of God can be felt in each component of the less vibrant and peaceful. Mind acquires a
universe. Hence, each component of the universe is also supernatural power of understanding the invisible
viewed as God. This gave way for worshipping rivers, and imperceivable universal truths which are not
animals, earth, sun, eclipses as God. This give birth to perceivable by ordinary mind. Mind gets cultured
different names and forms of Gods. Since God is in the spiritually and it acquires quality of nonattachment
form of energy it has to be felt by experience and by its to external happiness, so that internal happiness
effects. blossoms, which comes to the surface so that constant
The preachers of spirituality who either acquired ease is attained.
spiritual energy and/or felt the God later became Psycho-neuro-endo-immuno-cellular axis is
God men. People started understanding spirituality strengthened so that the body develops natural
and experience of God through these God men. Thus immunity to combact the diseases by natural
different God men came into existence. To draw the immunological process at the preliminary stages of
visual attention of the common man for the purpose the disease itself.
concentration and preaching the spirituality idols of God Maintains harmoneous balance between sympathetic
men were made. This has given birth to idol worships, and parasympathetic nervous system so that the
which is also a type of meditation and form of Bhakti adverse effects of catecholamines are prevented.
Yoga. The life stories of these God men, who practiced The body acquires the strength to deal both physical
spirituality came to be written and thus sacred religious and mental stressful situations without injury or
books, like, Mahabharata, Bible, Kuran, etc., came into much injuries to the body.
existence. It regulates the predetermined physiological
functions, so that they are not altred to lead on to
WHAT IS SPIRITUAL HEALTH? pathophysiological state.
“The spiritual health can be defined as the ultimate state It creates universal feeling and belongingness of one.
of constant ease (happiness) that is produced due to the
integrated effect of physical, mental and social health DIAGNOSTIC APPROACH
ultimately leading on to union with the transcedental The diagnosis of spiritual health is both subjective and
energy. The spiritual life style practices bring such objective and is very complex unlike physical, social and
integration between different aspects of health”. The mental health. However, the following informations will
spiritual life style involves both philosophical and help broadly to assess the status of spiritual health of an
scientific aspects. individual.
Effect of Spiritual Health Subjective

The effects of spiritual health can be summarized as below. The beliefs of the individual about god, religion,
It increases spiritual energy levels in the body. feeling of universality and knowledge on happenings
in the nature, belief about god and spirituality Objective

indicates positive spiritual health. There is no specific objective method to evaluate
Assessment of life style measures, whether they the spiritual energy and spiritual health. However,
belong to spiritual life style or not. Practice of spiritual the following objective evidences will give a broad
life style indicates positive spiritual health. assessment about spiritual health.
His opinion regarding the purpose of life. Spiritual Vital signs: BP, pulse and respiratory rate, temperature
man thinks that the purpose of life is to be constantly and other biorhythms normal vital signs, happy
happy. charmful face, normal biorhythms, good physical
The reaction to stressful situations whether the and social health indicates normal spiritual health.
individual reacts aggressively or peacefully to stressful Alteration indicates ill health. Bradycardia, slow and
situations, etc. Spiritually healthy individuals reacts shallow respiration are features of good spiritual
calmly and peacefully to stressful situations. health.
The attitudes of the individual to other human beings Assessment of mental health: Good mental health is
and the universe, as to whether he has sense of love, an evidence of good spiritual health.
cooperation and sense of oneness and universality, Endocrinal assessment: Normal endocrinal functions
etc. Spiritual individual will have positive outlook to are evidence of good spiritual health.
these feelings. Biochemical parameters: Normal blood biochemical
Whether the spiritual practices are practised since parameters are evidences of good spiritual health.
childhood or later. Individuals practicing spirituality
since childhood will have better spiritual health.
CHAPTER
152
Cooking Oils: Which to Use?
Sonia Arora, Vitull K Gupta, Meghna Gupta
During the past decades, the world, particularly the supplies more than double the calories as compared to
developing countries like India have witnessed rapid carbohydrate or protein making it an important dietary
changes in diets and lifestyles. General improvement component with concentrated source of energy. Fat
in the standard of living has been accompanied by intake gives taste to diet, is metabolically important
unhealthy dietary patterns and insufficient physical constituent of the body, helps absorption of fat soluble
activity resulting in increased prevalence of lifestyle and vitamins A, D, E, and subcutaneous fat helps insulates
diet-related chronic diseases worldwide. World Health the body.
Organization states that by 2020 the place of largest
causes of death and disability will be occupied by CVDs COMPOSITION OF FATS
and prevalence of obesity, T2DM and hypertension Fats or lipids consist of fatty acids which are of two types:
which are considered to be chronic diseases related to 1. Saturated fatty acids (SFAs): SFAs are saturated with
the diet and lifestyle is also increasing. hydrogen atoms as carbon atoms have no double
bonds in the fatty acid chain comprising of lauric
INTRODUCTION acid, palmitic acid and stearic acid which provide
Diet includes foods and nutrients which provide energy stability to saturated fats and are usually solid at
and are essential for normal metabolism, physiologic room temperature because single bonds between
and biochemical processes, growth and physical well- the carbon atoms are more stable than double
being. Diet essentially comprises of macronutrients bonds. Fat intake increase total cholesterol (TC) and
like proteins, carbohydrates, fats and micronutrients LDL cholesterol which is an important risk factor
like vitamins and minerals which are required in for CVDs, certain cancer and also impairs insulin
small quantities. Triglycerides are components of sensitivity. SFAs is present in milk products (cream,
fat comprising of esters of alcohol glycerol and fatty ghee, butter, khoya, paneer), animal tallow, palm oil,
acid chains. Generally, the words “lipids”, “oils” and coconut oil, etc.
“fats” are used interchangeably. Fats that are liquid at 2. Unsaturated fatty acids (USFAs): USFAs comprises
room temperature are called “oils” and generally have of monounsaturated fatty acids (MUFA) and
unsaturated or short fatty acid chains. Word “fats” polyunsaturated fatty acids (PUFA). MUFA contain
broadly means solid fats at room temperature and one double bonds and PUFA contain more than one
word “lipids” include all oils and fats in general. Fat double bonds within the fatty acid chain.
MUFAs: Lipid peroxidation occurs to a lesser degree and N-3 are converted into biological active components
in MUFA as compared to PUFA as MUFA contain one by competing for the common enzymes so when one
double bond only, e.g. oleic acid, erucic acid. Studies component is consumed more than the other, it leads to
have shown decrease in total mortality and CHD imbalance in the metabolism of N-6 and N-3 gradually
deaths with increased intake of MUFA. It is suggested affecting several metabolic processes. Recommendations
that MUFAs are useful because it helps decrease free suggest that adequate intake of N-6 and N-3 depends on
cholesterol by promoting cholesterol esterification in several factors like age, gender and life style, etc. and
liver, promote receptor mediated LDL uptake, lower LDL several organizations have recommended different ratios
and increase HDL. Recent evidence stress on exploring like N-6:N-3 of 4:1 (Institute of Medicine), 5:4 (World
the role of ratio of SFA, PUFA and MUFA in diet and Health Organization) and several suggest that ratio near
intake of individual fat components as they influence 1:1 may be considered as optimal ratio. Several foods
LDL/HDL ratio and lipoprotein metabolism. Dietary are good sources of both N-6 and N-3 and ratio may be
sources of MUFA include almonds, peanuts, fruits like different like N-6: N-3 ratio is 4:1 in walnuts, 1689:1 in
olives and avocados, olive oil, rice bran oil, groundnut almonds. In green-leafy vegetables, the ratio is less than
oil, canola oil and mustard oil. 1. So to improve the ratio several food combinations are
PUFAs: Contain two or more double bond, e.g. linoleic suggested to get the ration of at least 10 to 1.
acid, linolenic acid, arachidonic acid, eicosapentaenoic
acid (EPA), docosahexaenoic acid (DHA). PUFA intake TRANS FATTY ACIDS (TFAs) OR
decreases LDL and increases insulin sensitivity. Dietary PARTIALLY HYDROGENATED
sources include invisible fats present in pulses and FATTY ACIDS
cereals, sunflower oil, corn oil, safflower oil. Incomplete hydrogenation of vegetable oils results in
formation of Trans fats (TFs) and complete hydrogenation
Omega-3 and omega-6 fatty acids: Omega-3 (alpha-
linolenic acid) and omega-6 (linoleic acid) fatty acids results in formation of SFs. TFs may confer texture to food
are unsaturated “essential fatty acids” (EFAs) because and structural stability. Lamb and beef contain small
human metabolism cannot create them. quantity of natural trans fatty acids (TFAs). A review
suggested that even low consumption of 1–3% of total
Omega-6 fatty acids (linoleic acid N-6): At N-6 position, calorie intake of TF leads to increased risk of CAD and TFs
there is double bond between carbon-carbon atoms and are more dangerous to cardiovascular health than any
more number of double bonds make omega-6 fatty acids other macronutrient even on a per-calorie basis because
more prone to lipid per oxidation. Studies have shown it can lead to increase in LDL, triglycerides, lipoprotein
beneficial effects with lower incidence of T2DM and (a) and decrease in HDL adversely affecting metabolism
substantial reduction in risk of CHD. But, the beneficial of EFA and prostaglandins promoting thrombogenesis
effect of omega-3 is reduced by intake of more quantity of and insulin resistance. Sources of TFs include Dalda and
omega-6. Dietary sources include invisible fat in cereals Vanaspati ghee, margarines, baked foods, readymade
and pulses, margarine, safflower oil, corn oil, sunflower mithais and processed foods and ready to eat snacks.
oil, kardi oil, etc.
Cholesterol: Cholesterol, an essential component of
Omega-3 fatty acids (alpha-linolenic acid N-3): Omega-3 animal life is found in animal fats including dairy
consists of double bond at N-3 carbon atom and is
products and non-vegetarian foods. Chemically
precursors to anti-inflammatory products in the body.
cholesterol is a waxy sterol of fat. Very small amount of
Dietary sources include legumes, green-leafy vegetables,
cholesterol is present in plants so generally plant oils
citrus fruits and nuts and fish especially fatty fish.
are devoid of cholesterol. It is thought that absorption of
Omega 6 (N-6) to omega 3 (N-3) ratio: Balanced ratio of cholesterol from intestine is decreased by phytosterols, a
N-6 and N-3 is important for efficient body functions. N-6 plant product because both phytosterols and cholesterol
CHAPTER 152: Cooking Oils: Which to Use? 903
compete with each other for absorption in intestine. It is high smoke point are useful, fat composition of various
recommended to restrict the cholesterol consumption to oils, ratio between SFA, MUFA and PUFA or the shelf life
less than 200 mg by decreasing animal fat consumption. of oil or other specific qualities or flavor determine the
Adverse effects of increased consumption of cholesterol preference for use of that oil.
are because it increases total cholesterol and LDL but
Mustard oil: Mustard oil is economical, vegetarian oil
the adverse effects are relatively less as compared to
with characteristic pungent aroma and hot nutty taste,
increased consumption of SFAs and TFAs. Cholesterol
popularly used in East and North India containing 70%
broadly is of two types, low density lipoprotein (LDL)
MUFA (42% erucic and 12% oleic acid), 22% PUFA (10%
and high density lipoprotein (HDL). LDL is considered
N-3 and 12% N-6) and SFA is 8%. Evidence suggest that
as “bad cholesterol” responsible for atherosclerosis and
mustard oil which was previously thought to be harmful
CAD where as HDL is “good cholesterol” help prevent
because of high erucic acid content, is now considered
and retard progression of atherosclerosis.
as one of the best as it has near ideal N-6:N-3 ratio of 6:5
Cold pressed oils: Cold pressed oils are called when and contain low SFAs and high MUFAs and PUFAs along
ancient methods of hydraulic press is used to produce with high amount of antioxidants. Cold pressing adds to
oils and oils such produced are in natural state retaining the nutritional value of this oil. Studies indicate a dose
natural odor, taste, color, flavor and nutrition. dependent benefit of intake of vegetables/use of mustard
Refined oils: Refined oil are produced using mechanical oil on IHD risk.
and chemical extraction methods from seeds and Rapeseed oil (canola oil): It is produced from plant
vegetable products and these methods affect taste, belonging to Brassica family which is related to mustard
destroy antioxidants, generate free radicals and are more plant. It has high MUFA and low SFA contents with
susceptible to turn rancid but refined oils are relatively favorable omega-3 levels and is also known as “Canola
pure. oil” after the term ‘Canadian oil’.
Unrefined oils: Oils which are extracted from seeds or Olive oil: As the name indicates olive oil is extracted from
other vegetable material by exerting continuous pressure
olives and considered to be the best oil as it has 75%
at high temperature of 200–250°C are called unrefined
MUFA and numerous useful antioxidants (hydroxytyrol).
oils and these are different from ‘cold pressed’ oils called
High levels of MUFA and antioxidants (oleuropein or
‘expeller pressed’ oils. Unrefined oils retain antioxidants,
tyrosol) are present in extra-virgin or virgin olive oil which
other nutrients, flavor so these oils are considered better
is produced by minimum processing and intake of MUFA
and recommended for use.
is known to decrease LDL and increase HDL which exerts
antiinflammatory, antithrombotic, antihypertensive and
WHAT ARE COOKING OILS?
vasodilatory effect. Evidence suggests that antioxidants
Fatty acids triesters with glycerol which are in liquid
(oleuropein or tyrosol) have beneficial effect against
form at room temperature are the class of lipids known
some cancers, increases arterial elasticity, decreases risk
as oils and are generally found in both plants and
of stroke and IHD. Big disadvantage is its unfavorable
animals. Triglycerides that are solid or semisolid at
N-6:N-3 ratio.
room temperature are classified as fats and occur
predominantly in animals. Any material which has an Soya bean oil: Soya bean oil is one of the most commonly
oily or greasy feel and cannot be mixed with water is used cooking oils which is rich in PUFA and contains 51%
called “oil”. linoleic acid, 23% oleic acid and 7–10% alphalinolenic
acid (unsaturated fatty acids) and 10% palmitic acid and
Which Oils to Use? 4% stearic acid (SFAs). Soya bean oil should be used fresh
Out of numerous available oils, which oil to use depends because it tends to turn rancid earlier. It is suggested that
on the purpose of their use like for deep frying, oils with to achieve the combination of high PUFA and MUFA
contents by combining the oils rich in MUFA or PUFA because its consumption may decrease total cholesterol,
like olive oil, mustard oil or groundnut oil to achieve LDL as well as HDL cholesterol. Other disadvantage is
optimum health benefits. that PUFA may turn rancid or toxic on exposure to high
temperatures.
Rice bran oil (RBO): RBO is produced from rice husk
and germ and contain 47% MUFA, 33% PUFA and 20% Palm oil: Fruits of palm are used to extract palm oil
SFA making it oil with most favorable constituents rich which is economical and has high smoke point making
in phytosterols, gamma-oryzanol and vitamin E. Its mild it favorable for frying. Cardiac benefits of palm oil are
flavor and high smoke point (254°C) makes it useful for controversial as it may contain 48% SFAs and unfavorable
deep frying. Only disadvantage is unfavorable N-6/N-3 N-6:N-3 ratio of 20:1. Red palm variety of palm oil is rich
ratio of 23:1. in carotenes like coenzyme Q10, glycolipids tocotrienols,
Sunflower oil: Sunflower oil is a good cooking medium tocopherols and phytosterols.
with clean taste and has high PUFA, low SAFs and low Coconut oil: Coconut oil is a plant fat extracted for
TFs with high contents of waxes, carotenoids, lecithin coconut fruit and contains high levels of SFAs (90%) very
and tocopherols. Sunflower oil has high levels of N-6 and little PUFA, MUFA, no cholesterol, vitamin E, vitamin
unfavorable N-6/N-3 ratio of 120:1. Moreover evidence of K and minerals such as iron. Coconut oil is primary oil
health benefits of high N-6 intake is limited. used by tropical people and its SFAs consist of lauric
Cotton seed oil: Cotton seed oil is economical, stable acid which differs from SFAs of animal origin. Lauric
for frying, has long shelf life because of natural rancid acid is responsible for increasing HDL levels and thereby
free property and contain 18% MUFA, 52% PUFA with increases total cholesterol.
naturally occurring SFAs (myristic, palmitic, stearic Butter: Butter is from animal source with high contents
acids) thereby called as “naturally hydrogenated” oil. of cholesterol and SFAs. Butter can increase total, LDL
It’s very high SFA and very low MUFA contents make and HDL cholesterol and its low smoke point makes is
its health benefits controversial. Moreover because of unfavorable for deep frying.
excessive use of agrichemicals, cotton seeds and so
cotton seed oil tends to contain high levels of pesticides, Ghee: Ghee is made by clarifying butter which has high
which may cause adverse health effects. It is commonly smoke point making it favorable for frying.
used in various types of processed and snack foods. Vanaspati ghee: Vanaspati ghee is made by hydrogenation
Corn oil: Germ of corn is used to extract corn oil (maize of refined vegetable oil. Hydrogenation increases TFAs,
oil) which contains 55% PUFA, 30% MUFA and 15% SFA. makes it less likely to turn rancid, more stable, increases
It is cheap and because of high smoke point useful for shelf life, but it does not contain bioactive compounds,
frying purposes. Its increased level of N-6 as compared natural vitamins or antioxidants and because of low
to N-3 may cause or predispose to some disease and smoke point it is not favored for deep frying. It is
depression. considered to be responsible for development of IHD
because of its adverse lipid profile.
Ground nut oil: Ground nut oil has a pleasant taste, high
smoke point and contains 56% MUFA (oleic acid), 26% CHOOSING THE RIGHT OIL
PUFA (linoleic acid) and 8% SFA (palmitic acid) which
Properties of cooking oil like fatty, acid contents,
makes it cardiac friendly oils because it rich in MUFA and
micronutrients, shelf life, smoke point, etc. are helpful
a balanced oil.
in selection of right cooking oil. Among the available
Safflower oil: Safflower oil has high smoke point favorable cooking oils, none of it fulfills the recommended profile
for frying and contains low SFAs (6%), low MUFA (13%) because if oil has high MUFA which is desirable, it may
and high PUFA (76%). It is not considered healthy oil not have desired N-6:N-3 ratio or appropriate ratio of
CHAPTER 152: Cooking Oils: Which to Use? 905
MUFA, PUFA or SFAs. So, it is recommended to rotate the various lipid contents, it is desirable to blend or rotate
oils like mustard oil, groundnut oil, canola oil, rice bran different cooking oils with favorable lipid contents and
oil, etc. to achieve the desired lipid contents. limit the use of visible fat content for achieving desired
favorable cardiovascular and overall health benefits.
WHY BLENDS ARE NEEDED?
Evidence suggest that cardiovascular health is greatly BIBLIOGRAPHY
influenced by dietary fat profile and type of fat affects the 1. Bester D, Esterhuyse, Truster EJ, van Rooyen J.
lipid profile of the individual increasing or decreasing Cardiovascular effects of edible oils: a comparison between
the CVD risk. Total cholesterol and LDL cholesterol are four popular edible oils. Nutr Res Rev. 2010;23:334-48.
2. Bockisch M. Fats and Oils Handbook. Champaign, IL: AOCS
increased with increased intake of SFs. Intake of TFAs
Press; 1998. pp. 95-6.
increase LDL cholesterol and decrease HDL cholesterol. 3. Cicero AF, Gaddi A. Rice bran oil and gamma-oryzanol in the
Intake of PUFA greatly reduces the CVD risk as compared treatment of hyperlipoproteinemias and other conditions.
to MUFA. CVD protection is imparted by both N-6 and N-3 Physiother Res. 2001;15:277-86.
by various mechanisms like vasodilation, antiarrhythmic 4. Connor WE. Alpha-linolenic acid in health and disease. Am J
effect, anti-inflammatory effects, improves endothelial Clin Nutr. 1999;69(5):827-8.
function, decreased platelet aggregation and reduces 5. Harris WS. Fish oils and plasma lipid and lipoprotein
metabolism in humans: a critical review. J Lipid Res.
collagen deposition. Evidence suggests that different lipid
1989;30(6):785-807.
components have different favorable and adverse health 6. Hill EG, Johnson SB, Lawson LD, et al. Perturbation of the
effects. No cooking oil can fulfill the recommended ratio metabolism of essential fatty acids by dietary partially
of different lipid components for favorable health and hydrogenated vegetable oil. Proc Natl Acad Sci USA.
CVD effects, necessitating the need to blend cooking oils 1982;79(4): 953-7.
to achieve desired lipid contents for health benefits. 7. Howell WH, McNamara DJ, Tosca MA, et al. Plasma lipid and
lipoprotein responses to dietary fat and cholesterol: a meta-
analysis. Am J Clin Nutr. 1997;65(6):1747-64.
CONCLUSION
8. Joshi S, Joshi SR. Medicine Update 2013: Chapter 140.
In this present era of consumerism, people are exposed www.apiindia.org/medicine_update_2013/chap140.pdf.
to different type of cooking oils glorified with tall 9. Kris-Etherton P, Daniels SR, Eckel RH, et al. Summary
health claims and benefits, advertizing various cooking of the scientific conference on dietary fatty acids and
oils with attractive slogans, highlighting presence or cardiovascular health: conference summary from the
absence of different lipid contents to influence people’s nutrition committee of the American Heart Association.
choice of cooking oils. This chapter discusses various Circulation. 2001;103(7):1034-9.
10. Marina AM, Che Man YB, Amin I. Virgin coconut oil: emerging
lipid contents, their harms and health benefits, desired
functional food oil. Trends in Food Science & Technology.
composition of different lipid contents and composition 2009;20(10):481-7.
of different cooking oils in an attempt to demystifying the 11. Martin G, et al. Health effects of oxidized heated oils.
fancy statements for all the people. Out of the discussed Foodservice Research International. 2001;13:41-55.
edible oils, none of the oils fulfill the recommended 12. Mishra S, Manchanda SC. Cooking oils for heart health. J.
criteria of lipid contents but two oils rapeseed and Preventive Cardiology. 2012;1(3):122-31.
mustard oil which have high PUFA and MUFA, low SFA 13. Rastogi T, et al. Diet and risk of ischemic heart disease in
India. Am J Clin Nutr. 2004;79(4):582-92.
content and highest N-3/N-6 ratio seems to be imparting
14. Tarrago-Trani MT, et al. New and existing oils and fats used
most health and CVD benefits. Evidence suggests use of
in products with reduced trans-fatty acid content. J Am Diet
ghee and butter as a cooking oil should be limited and Assoc. 2006;106(6):867-80.
use of reheated fats and oils should be avoided. Since 15. Turner R, et al. Antioxidant and anti-atherogenic activities of
none of the available cooking oils fulfill the criteria of olive oil phenolics. Int J Vitam Nutr Res. 2005;75(1):61-70.
CHAPTER
153
IT Solution in Regulation of Medical
Education and Medical Practice
Ajay Kumar
IT has percolated into the human life globally through of Clinical Establishments, approval system for medical
different modalities. It has a major role to play in modern colleges. The admission to medical and dental colleges
day activities. To think life without IT solutions is like of the country has been made online. Other activities
boat without a rudder. Like rudder of the boat, IT helps like National Organ and Tissue Transplant Organization
to navigate life in an intended direction. Delivery of (NOTTO), Central Drug Standard Control Organisation
healthcare to the people of today cannot be imagined (CDSCO) have their separate web portals.
without the help of IT solutions. E-governance provides The healthcare providers in public and private
the ground for IT driven healthcare. India stands at sector and also the health insurance companies are
54th position in e-governance. With the vision and transforming the activities through IT solutions for better
mission of our beloved Prime Minister Shri Narendra patient care. There is also fast growing sector of tele-
Modi e-governance is growing leaps and bounds in our health, mobile health and wireless health to benefit the
country. rural masses which constitutes 75% of the population
E-health has been launched by Govt of India which of the country. Smart hospital are the future of the
has got multiple components. Ministry of Health and country which is about transforming health towards
Family Welfare has taken initiative to streamline the decentralized and connected care.
medical education. It has amended the MCI regulation With a wide geographical economical, social and
early this year to make it compulsory for all medical cultural diversity and excessive population burden where
colleges of the country to monitor the faculty attendance few island of prosperity is draining the resources of vast
and live streaming of teaching activities. MCI, through sea of poverty, it is mammoth task to provide healthcare
its Digital Mission Mode Project (DMMP) has been to the last door step of the country.
actively pursuing the IT based activities including With a positive mindset of the government and
OFAMOS (Online faculty attendance monitoring system) enlightened minds supported by electronic solutions
for medical colleges and generation of UPRN for every we are inching forward to improve the healthcare in our
practioners of the country registered with Medical country across the board. I conclude with a famous poem
Council of India. Live streaming of the teaching activities of Robert Frost.
in medical colleges is underway which will be monitored “The woods are lovely, dark and deep,
by MCI. But I have promises to keep,
Through e-governance portal the Ministry of Health And miles to go before I sleep,
and Family Welfare has started many activities. Registry And miles to go before I sleep.”
SECTION
17
Miscellaneous
Changing Trends in Medicine: Past, Present and An Approach to Recurrent Falls in the Elderly
Future S Ramnathan Iyer, Revati R Iyer
Ultrasonography in Critically Ill Patients
Isoniazid Preventive Therapy: Operational Sameer Gulati, Bhupendra Gupta
Guidelines
Imaging Parameters in Pulmonary
Thromboembolism
Hypnotherapy in Medical Disorders Priya Jagia, Niraj Nirmal Pandey
CHAPTER
154
Changing Trends in Medicine:
Past, Present and Future
INTRODUCTION in the medical trends. In ancient times of Egyptian,

The enormous scientific and technological advancement Greek and Indian civilization, disease was considered
in past few decades has completely changed the way either due to curse of god or secondary to derangement
medicine was taught and practiced. As we move into of humor or disequilibrium. In modern medicine, it is
the future it is becoming increasingly clear that the possible to pinpoint the exact cause of disease in most
biomedical sciences are entering the most exciting of the diseases, in some ailments we can find the exact
phase of their development. This exponential growth in protein or gene defect and treat accordingly. This chapter
the scientific technology has given new hope for cure reviews the various changes and trends in development
for more and more diseases and possibility of human of medicine from ancient time to present and future. It
winning over ageing and may be death. Paradoxically, will also briefly describe the various important historical
on the other hand the modern medicine and healthcare inventions and ideas, followed by what are the trend
is also passing through a phase of increasing uncertainty setting important discoveries in and around 20th century
due to advanced science and technology leading to and lastly what is in store in near future of medicine.
excessive industrialization, urbanization and rural to
urban migration. The developed countries are also
MEDICINE BEFORE THE 20TH CENTURY
observing rapid growth of geriatric population due From the earliest documentary evidence surviving from
to extension of life expectancy secondary to better the ancient civilizations of Egypt, Babylonia, China and
healthcare. The spiraling cost of health care system is India. It is clear that longevity, disease and death are
another major problem faced by the developing as well among humanity’s oldest preoccupations.
as developed world. The people of many developing Ancient Egyptian Civilization: developed a fruitful
countries are still living in dire poverty with dysfunctional medical tradition, which dates back to 3000 BC.
health care systems and extremely limited access to basic Renowned Greek historian Herodotus described the
medical care and it will take few extra years before they Egyptians as one of the healthiest of all men and
can also enjoy the fruit of modern medical technological according to him the practice of medicine was so
advances which at present is available in very few specialized among Egyptians during ancient times that
developed nations only. each physician was a considered healer of one disease
Against this complex background, the present state only. Edwin Smith Papyrus details the cures, ailments
of medicine and healthcare has seen constant changes and anatomical observations, it is regarded as a copy
910 SECTION 17: Miscellaneous
of several earlier works and was written c. 1600 BC. various ailments later formed large part of Ayurveda.
It is an ancient textbook on surgery from Egypt and It means “complete knowledge for long life” is another
describes detailed examination, diagnosis, treatment medical system of India. Charaka and Sushruta are the
and prognosis of various diseases known during that two famous divisions of Ayurveda and its date backs
time. to around 600 BC. According to the compendium
of Charaka, the Charakasamhitā, which dealt with
Ancient Greek Civilization: is known for having good
medical-nonsurgical part of Ayurveda, according to it
medical knowledge and therefore also considered
the health and disease are not predetermined and life
to be the stepping-stone for modern medicine. The
may be prolonged by human effort. The compendium of
most famous Greek physician Hippocrates is well
Suśruta, the Suśrutasamhitā, which dealt with surgical
known to everyone. The Hippocratic oath was first
part of medicine, described detailed surgical procedure
written in 5 th Century BC in Greece and even today
of various forms of surgery, which included rhinoplasty,
every physicians swear upon it on entry into medical
ear lobes repair, perineal lithotomy, cataract surgery, and
profession. Hippocrates stressed that doctors should
several other excisions, and other surgical procedures.
carefully observe the patients symptoms and take note
Both these ancient Indian compendia include details of
of them. Although, on one hand most Greeks believed
the examination, diagnosis, treatment, and prognosis of
in their god of healing called Asclepius. The sacrifices
numerous ailments.
or offerings were gifted to the god by the diseased and
In western world from ancient times up to Renaissance
people even used to sleep overnight in the temple with
period of 14 th century the knowledge of living world
the belief that, god would visit them overnight in their
changed very little and any distinction between animate
sleep (i.e. dreams) and this will heal them. At the same
and inanimate objects was blurred and speculations
time, few Greek doctors developed a rational theory
about living being were based of old prevailing ideas of
of disease and sought their cures. However, one did
the society.
not replace the other. The cult of Asclepius and Greek
Advances in science and philosophy throughout
medicine existed side by side.
the 16 th and 17 th centuries in Europe led to equally
Medical schools were formed in Greece and in
momentous changes in medical sciences. Belgian
Greek colonies around the Mediterranean. A number of
anatomist Andreas Vesalius also known as founder
Greeks speculated that the human body was made up
of modern anatomy, swept away the centuries of
of elements; if they were properly balanced the person
misconceptions about the human body structure
will be healthy. However, if they became unbalanced
and function. He published the first illustrated book
the person will fall ill. Similarly, Aristotle (384–322 BC)
of human anatomy “de humani corporis fabrica” in
brought the idea that the human body was made up of
16th century. The work of Isaac Newton, and Robert
four humors. They were phlegm, blood, yellow bile and
Boyle disposed of the basic Aristotelian elements of
black bile. If a person had too much of one humor they
earth, air, fire, and water; Robert Hooke invented the
fell ill. For instance, if a person had a fever he must have
first medical microscope, which showed the world
too much blood. The treatment was to cut the patient
microscopic organisms, which were invisible till then.
and let him bleed. The ancient Greek people also knew
In 1628, William Harvey described the circulation of the
that diet, exercise and cleanliness are important part of
blood, a discovery that, because it was based on careful
health.
experiments and measurement, signaled the beginnings
Ancient India: The Atharvaveda, a sacred text of Hinduism of modern scientific medicine.
is one of the first Indian textbooks dealing with medicine. After steady progress during the 18th century, the
The Atharvaveda contained herbal prescription for biological and medical sciences began to advance at
various ailments. The use of herbal medicines to treat a remarkable rate during the 19th century, which saw
CHAPTER 154: Changing Trends in Medicine: Past, Present and Future 911
the genuine beginnings of modern scientific medicine. Clinical Epidemiology and Public Health
Charles Darwin’s “theory of evolution” changed the Modern epidemiology came into existence during the
whole course of biological thinking, and this was followed later part of 20th century, when increasingly sophisticated
by Gregor Mendel’s ground breaking fundamental laws of statistical methods were first applied to the study of
inheritance, which are the root to modern genetics. Louis noninfectious disease to analyze the patterns and
Pasteur and Robert Koch founded modern microbiology. associations of diseases in large populations. The
Koch’s postulated the causal relationship between emergence of clinical epidemiology marked one of the
microbes and disease production thus giving rise to most important successes of the medical sciences in the
modern microbiology. These advances in the biological 20th century.
sciences were accompanied by practical developments The epidemiologic information about the frequency
at the bedside, including the invention of the stethoscope and distribution of noncommunicable disease (NCD)
by Lennec and sphygmomanometer by SS Karl Ritter von cancer, diabetes, stroke heart attack, etc. and in particular,
Basch in 1881. The first use of X-rays, the development the speed with which their frequency increased in
of anesthesia, the early development of the use of association with environmental change, provided
statistics for analyzing data obtained in medical practice excellent evidence that many of them have a major
occurred in the 19th century. All these were the major environmental component. The first major success of
advancement in medicine, which played pivotal role in clinical epidemiology was the demonstration of the
shaping modern medicine. relationship between cigarette smoking and lung cancer
Significant advances in public health occurred on by Austin Bradford Hill and Richard Doll in the United
both sides of the Atlantic. After the cholera epidemics Kingdom. This work was later replicated in many studies.
World Health Organization estimation suggest that
of the mid 19th century led to significant advancement
upto 8.8% of deaths (4.9 million) and 4.1% of disability-
in public health on both sides of Atlantic, public
adjusted life years (59.1 million) are secondary to
health boards were established in many European and
tobacco use.
American cities. The Public Health Act, passed in the
The other major development that arose from
United Kingdom in 1848, provided for the improvement
the application of statistics to medical research was
of streets, construction of drains and sewers, collection
the development of the randomized controlled trial.
of refuse, and procurement of clean domestic water
Ronald Fisher first set out the principles of numerically
supplies. Equally important, the first attempts were made
based experimental design in the year 1920s. Evidence
to record basic health statistics.
based medicine (EBM) is another valuable addition
in the way medical professional think on the basis of
MEDICINE IN THE 20TH CENTURY judicious, conscientious use of best available evidence
There was rapid gain in life expectancy during 20 th before making decisions about the care of individual
century largely due improvement in public health patients. The EBM comes from previous experience,
and lesser due to progress in medicine. The slow trials and research and this has lead to development of
development in medical sciences was most likely due good clinical practice in medical profession. It integrates
to burden of two world wars. The position changed clinical experience and patient values with best available
dramatically after World War II, a time that many still research information, particularly implementation, or to
believe was the period of major achievement in the say getting research into practice.
biomedical sciences for improving the health of society.
Some major developments and the effect they have had Control of Infectious Diseases
on medical practice in both developed and developing The control of communicable infections has been
countries will be highlighted in this section. another major achievement in the medical science
of 20th centur y. The contribution of improved and more vengeance. The ‘Edinburgh method’ of
environmental conditions and betterment of public combined anti tubercular therapy was first developed
health had significant role in controlling these infection. by Sir John Crofton and his team in the 1950s. This has
The development of successful immunization against been recognized as the single-most important treatment
childhood infections, discovery and treatment of newer of tuberculosis (TB) and was adopted worldwide. This
pathogens with antibiotic chemotherapy were vital in significantly reduced death rates from TB and is one of
achieving the reduction in mortality and morbidity due the major finding of the century.
to communicable diseases. Currently, 29 vaccine (live In summary, although the 20 th century witnessed
or killed) against common communicable diseases remarkable advances in the management of
has been licensed for use worldwide; these are based communicable disease by developing newer antibiotics,
on bacterial polysaccharides, bacterial toxoids or viral the current position is uncertain due to development
particle based. The best example of the vaccination of resistance. The emergence of new infectious agents,
success is the eradication of smallpox from the world as evidenced by the severe acute respiratory syndrome
since year 1977. (SARS) epidemic and recent Ebola virus infection in
The World Health Organization’s (WHO) launched Africa is a reminder of the constant danger posed by
Expanded Program on Immunization (EPI) in year the appearance of novel organisms. More than 30 new
1974, which was introduced in India after four years in infective agents have been identified worldwide since
1978. In 1985, the EPI program was renamed by Indian 1970.
Government as Universal Immunization program (UIP)
and under the program vaccination of pregnant woman Management of Noncommunicable
with tetanus toxoid vaccine was also added, while Diseases
typhoid vaccination was removed. The various vaccines The second half of the 20 th century has resulted in
given under UPI schedules are Bacillus Calmete-Guerin significant improvement in knowing the pathophysiology
(BCG), oral Polio vaccine, DPT vaccine and measles. and management of NCD especially cardiac disease,
Recently Haemophilus Influenzae type b, Hepatitis B cancer and gastroenterology. This phase of medical
vaccine, and rotavirus vaccine has also been added to sciences also evidenced significant advancement
the UPI vaccination program, which is better known as secondary to developments in the pharmaceutical
“Mission Indradhanush”. industry, and had led to a situation in which few
The discovery of penicillin and sulphonamide noncommunicable disease (NCD) exist for which there
antibiotic around World War II remarkably changed is no treatment.
the scenario of infectious disease. The effectiveness of Cardiovascular advances: Cardiovascular system (CVS)
these antibiotics is still considered one of the greatest received major technological advances in 20th century,
achievements for the medical science. This was followed which has led to better appreciation of cardiac physiology
by further progress and discovery of other antimicrobial and pathology of CVS. Electrocardiography, left and right
agents, which were found to be effective against bacteria, heart catheterization, development of echocardiography
fungi, viruses, protozoa, and helminths. In spite of and recent development of radiologic and nuclear
more than half century of successful use of antibiotics imaging (Cardiac CT, Cardiac MRI and radioisotope
we are now on the verge of losing these potent tools to scanning of heart). Development and effectiveness
fight microbes due to irrational antibiotics use as well of various CVS drugs (beta blockers, ACE inhibitors,
as development of smart pathogens that can escape diuretics and anticoagulants, etc.) has also played
these drugs by developing antibiotics resistance. These major role in reducing cardiac mortality and improving
antibiotics resistant microbes can become multi drug patient’s quality of life in 20th century. Cardiothoracic
resistance (MDR) pathogen leading to higher virulence surgery (on and off pump), coronary bypass surgery,
balloon angioplasty are the additional achievements MEDICAL SCIENCE AND TECHNOLOGY
of cardiology. Development of implantable cardiac IN 21ST CENTURY
defibrillator and pacemaker has also saved many Newer technological advances in medical field have
cardiac patients from end stage heart failure and markedly improved the diagnosis and management of
sudden arrhythmias. Recent successful Heart and Lung many diseases. Considering rapid growth in technology
transplantation has given more hope to these heart in last two decades, the expectation is very high that
failure patients. many more disease and condition can be cured or
Cancer: Oncology is another medical branch after controlled. The sections that follow briefly outline some
cardiology, which has seen significant improvement in examples of the new technologies that should help
achieve these aims.
patient’s diagnosis, with development of sophisticated
diagnostic technology. Management has also with
Genomics, Proteomics, and Cell Biology
improved secondary to better advanced localized
In the last couple of decades, there have been some major
radiotherapy machines and the use of powerful
development in the field of molecular and cell biology.
anticancer drugs. This approach has led to remarkable
The human genome project was partially completed
improvements in the outlook for particular cancers,
in 2001 but till date not much have been achieved with
including childhood leukemia, some forms of lymphoma,
it. As we know that the majority of common diseases
testicular tumors, and tumors of the breast.
clearly do not result from the dysfunction of a single
Gastroenterology: Development of flexible endoscopy gene, most diseases can ultimately be defined at the
and proton pump inhibitor therapy markedly improved biochemical level. The human genome project also
the natural history and management of acid peptic encompasses many infectious agents, animals that
disease. Further improvement in endoscopic techniques are valuable laboratory models of human diseases,
leading to further diagnostic and therapeutic utility disease vector and wide variety of plants. The study of
revolutionized gastrointestinal field and improved human genome will require identification and analysis
patient’s experience and safety as well as physicians of function of up to 25000 gene (proteonomics) and the
satisfaction. mechanisms whereby genes are maintained in active
or inactive states during development (methylomics). It
High Technology Cost and Its Economic will also involve the exploration of the roles of the family
of regulatory ribonucleic acid (RNA) molecules. All this
Consequences
information will have to be integrated by developments
The health care expenditure has increased exponentially
in information technology and systems biology. These
with development of sophisticated modern medical
tasks are time consuming and may take many decades to
practices. The problem has become so severe that it’s fully elucidate human genome.
becoming difficult for even industrialized countries to The first application of DNA technology in clinical
bear the cost of it, while for developing countries like practice is being done by using candidate gene approach
India; it is becoming impossible to control. The cost or using DNA markers of monogenic diseases. This
escalation of medical healthcare may be due to higher information is being used in clinical practice for carrier
cost of newer technology as well as other reasons such as detection, for prenatal diagnosis, and for defining
overpopulation, greater public awareness and consumer of the mechanisms of phenotypic variability. It has
demand for medical care, and greater ability to control been particularly successful in the case of the most
most chronic illnesses. This will need further research common monogenic diseases, the inherited disorders
and improvisation in health care delivery system to make of hemoglobin synthesis, which affect hundreds of
it cost effective so that it can reach poorest of poor. thousands of children in developing countries.
In developing countries, rapid diagnostic kit are person’s genetic profile for metabolism of common
being made using DNA technology. These methods use drugs can be worked out. This will lead to individualized
PCR technique to identify pathogenic organism antigen drug treatment and care; this may be become part of
or DNA in blood or tissue. These approaches are being physicians toolkit in coming years.
further refined for identifying organisms that exhibit
drug resistance and also for subtyping many classes Stem Cell and Organ Therapy
of bacteria and viruses. The Cartridge Based Nucleic Organ transplant surgeries have its limitations in organ
Acid Amplification Test (CB NAAT)/ Gene expert test availability, expensive surgeries and follow up costs;
for diagnosis of rifampicin resistance in Mycobacterium the successful stem cell therapy can overcome these
tuberculosis (MTB) is classic example of this techniques limitations by readily supplying the cells to replace the
use in clinical practice, which has drastically improved tissues. The pluripotent stem cells can be obtained
diagnosis of MDR/rifampicin resistance in MTB. from various tissues; early embryos, placenta, bone
Although much remains to be learned about the cost- marrow, etc. Therapeutic cloning is an area of research
effectiveness of these approaches compared with more in cellular biology that is raising great expectations and
conventional diagnostic procedures. Another example of bitter controversies too. Bone marrow transplantation
this type of technology being used is in identification of has been successfully done in wide range of blood
new organisms like coronavirus, which was responsible
diseases. The technique of somatic cell nuclear transfer
for SARS outbreak in 2002. The remarkable speed with
involves adult cell nuclei transfer into egg without
which a new corona virus and its different subtypes were
nucleus leading to development of embryo, which can
identified was amazing and helped a lot in managing and
be used for regenerative therapy for particular donor
tracking the SARS infection.
cells. This, follows similar lines to those that would be
Genomics is likely to play an increasingly important
required for human reproductive cloning, therefore
role in the control and management of cancer. It is now
raising number of controversies. If society is able to
well established that malignant transformation of cell
overcome the various terms of ethical issues, this field
populations usually results from acquired mutations
holds considerable promise for correction of a number of
in two main classes of genes oncogenes or tumor
different intractable human diseases.
suppresser gene. Chronic myeloid leukemia (CML) due to
Philadelphia chromosome resulting from translocation
between chromosomes 9 and 22: t(9:22)(q34:q11) is
Immunotherapy for Cancer
classical example of genetics being successfully used CAR T cells immunotherapy for leukemia: Chemeric
in cancer diagnosis and management. The disease antigen receptor T cell therapy has been the most
can be treated with Tyrosine kinase inhibitor, whose recently approved treatment of refractory and relapsed
transcription results from this translocation. acute lymphoblastic leukemia (ALL). It’s a form of
Array technology, which examines the pattern of emerging immunotherapy approach also known as
expression of many different genes at the same time, is adoptive cell transfer. In this technique, the patients
already providing valuable prognostic data for cancers of own immune cells (T cells in this case) are collected
the breast, blood, and lymphatic system. This technology and modified in vitro so that they recognize the cancer
will become an integral part of diagnostic pathology cells receptors and kill the cancer cells once they are
in the future, and genomic approaches to the early reintroduced back into the body. Many more CAR T
diagnosis of cancer. based drugs are in pipeline for various indications from
Pharmacogenomics is another potential develop leukemia, lymphoma to solid tumor as well. The only
ment from the genomics revolution. Each individual has major problem at present with the drug is exorbitant
considerable variability in the metabolism of drugs. In pricing. The FDA approved Novartis drug Kymriah with
future, clinical medicine can reach a stage where every price of $475,000 for relapsed ALL.
Information Technology 2.5 billion people and projected food requirement will be
The explosion in information technology has important more then double. Considering there is regular decline
implications for all forms of biomedical research, clinical in annual rate of cereal production in world and 20–40%
practice, and teaching. Genomic public database of potential production is lost to pathogens in developed
biomedical research has been kept securely in triplicate and developing countries, respectively. Considering the
in the following places in three different continents upcoming shortage of food in future the GM plants have
(Europe-European Bioinformatics Institute, United considerable potential for improving food shortage in
the world. The main aim of GM crop is to enhance the
States-GenBank and Japan-DNA Data Bank of Japan).
nutritional value of crops and make them resistance to
Twenty first century also brought the emergence
pathogens so that crop loss is minimal. Concerns are
of Electronic publishing of high-quality journals and
also expressed about the safety of GM crops, and a great
related projects and international biomedical website,
deal more research is required in this field. The results
which helped in linking scientists in industrial countries
of biosafety trials in Europe raise some issues about the
with developing countries. The increasing availability of
effects of GM on biodiversity.
telemedicine education packages will help disseminate
Researchers are also trying to produce GM plants,
good practices in resource limited setting (rural and
which can be used for controlling disease. The GM plants
developing countries).
can be modified to produce molecules that are toxic to
disease carrying vectors or they may also be modified
Minimally Invasive Surgery to make edible vaccine. These edible vaccines will be
Minimally invasive surgery (MIS) has been a game cheaper then conventional vaccines and will also have
changer in medical-surgical field in 21st century. It has the advantage of easy transportation, as they can be
changed the hospital admission and discharge practice freeze dried and shipped anywhere in the world. Edible
of inpatient care by reducing the number of days of Hepatitis B vaccine is being made in transgenic plant for
stay of post surgical patients leading to significant cost oral immunization.
reductions and reduced morbidity. The advances in
endoscopic imaging and instruments have also made Newer Technologies and Developing
many open procedures as day care procedures, which Countries
can be done endoscopically. The following procedures: The scientific technology has given the hope of
the gall bladder surgery, treatment of adhesions, removal improvement in medical healthcare by leaps and bounds
of fibroids, nephrectomy, and many minor pediatric but there is also major apprehension about it, especially
urological procedures are being done routinely as MIS. considering the poor economic, social and health care
infrastructure state in developing countries. According to
Robot in Medicine WHO, it may be too early to consider that the full benefits
Robot’s use in surgeries like Heart, Cancer, Prostate, of genomics and related technology will be available
Kidney and Brain is very common which minimizes the to developing countries of Asia and Africa, instead the
complications, blood loss and helps in early mobility. industrialized-developed countries will only exploit the
Intravascular injections of chemotherapy for targeting most pressing and potentially exciting developments
inoperable cancers are also being done by robots. from the new scientific technologies.
Nutrition and Genetically Modified Crops FUTURE MEDICAL INVENTIONS

Genetically modified (GM) crops are available for past few These inventions, tests and ideas are in early phase of
years, these GM crops have high yield and are resistant development. Once they are fully developed and become
pathogens and chemicals. It is estimated that by year mainstream, these technologies can solve may problem
2030 the world population is going to be approximately in quick time.
Liquid biopsies for circulating tumor DNA: the NCD taking over communicable diseases. The future
technological advancement in genetics can detect appears bright with significant contribution coming
early cancers by analyzing blood samples for cell free from developments in science and technology. The
circulating tumor DNA (ctDNA). This test is called liquid average life expectancy has increased in most countries.
biopsies and studies to formalize this test by detecting But with these developments, some different form of
ctDNA are in early phase of clinical trials. Experts believe problems has arisen: urbanization, increasing geriatric
it’s only a matter of time before diagnosing and treating populations and spiraling healthcare cost. Another
cancer become a routine like a annual medical checkup. major issue is regarding disparity in distribution and
availability of medical technology research. There is
Genome editing or CRISPR-Cas9: Clustered Regularly
very wide gap in world research funding with majority
Interspaced Short Palindromic Repeats and CRISPR-
of disability and premature mortality occurring in poor
associated protein 9 is adapted from naturally occurring
developing country while the research area and topics
genome editing bacteria. These gene-editing technologies
are severely tilted towards industrialized countries of
allow genetic material to be added, removed, or altered
Western countries. This bias needs against developing
at particular locations in the genome. The CRISPR-Cas9
countries needs to be corrected before we work towards
system has generated a lot of excitement in the scientific
universal healthcare coverage for all.
community because it is faster, cheaper, more accurate
Although with advancement of technology, medical
and efficient than other methods.
fraternity has got extra edge in overall patient care,
CRISPR-Cas9 was adapted from a naturally occurring
making appropriate diagnosis and treatment; but this
genome editing system inside bacteria. The Cas-9,
technological dependence has also led to deterioration
endonuclease of bacteria breaks DNA of invading viruses
of practice of clinical medicine. We have lost the art of
and uses them to create CRISPR arrays. The CRISPR
proper history taking, doing relevant examination and
arrays allow the bacteria to “remember” the viruses
the art healing touch as we are more and more relying
(or closely related ones). If the viruses attack again, the
on laboratory and radiologic test reports. We have
bacteria produces RNA segment from the CRISPR arrays
developed some so advanced technological centers
to target the viruses’ DNA and disables the virus.
where there is no patient-physician interaction, instead
only machine-patient interaction, with these centers we
SUMMARY
also lost the opportunity to show empathy with patient
The exponential development in the medical science
and their care givers.
and technology has markedly improved medical
We have to take middle path where we should
healthcare and reduced the suffering of human mankind.
keep the art of clinical medicine, healing touch and
Disease treatment, methods, dental procedures and
soothing empathetic words intact and combine it with
scriptures have been found since ancient civilizations
newer technological advances, and then only we can
of Egypt, Babylon, China and India; but the foundation
progress as a true healer. We will have to make our
of modern medicine was laid down after renaissance
medical practice more patient oriented and empower
period in Europe (14th Century) with development of
our patients in decision-making. This middle path will
important scientific theories and scientific methods.
also keep check on spiraling cost of medical care that is
The medical healthcare showed rapid growth and
going out of reach of general population and bring more
developed into modern medicine in 19 th–20th century
patient’s satisfaction.
with maximum pace of growth seen after World War
II. Significant advances were reported in specialty
BIBLIOGRAPHY
of cardiology, oncology, gastroenterology and renal 1. Alber ti G. Noncommunicable diseases: Tomorrow’s
medicine. India as well as many developing countries Pandemics. Bulletin of the World Health Organization.
is in epidemiologic transition phase with burden of 2001;79(10):907.
2. Bumol TF, Watanabe AM. Genetic information, genomic 5. Weatherall D, Greenwood B, Chee HL. Science and Technology
technologies, and the future of drug discovery. Journal of for Disease Control: Past, Present, and Future. In: Jamison
the American Medical Association. 2001;285(5):551-5. DT, Breman JG, Measham AR, et al., editors. Disease Control
3. Cooter R, Pickstone J. Medicine in the Twentieth Century. Priorities in Developing Countries. 2nd edn. Washington (DC):
Amsterdam: Harwood acdemics. 2000. The International Bank for Reconstruction and Development/
4. https://ghr.nlm.nih.gov/primer/genomicresearch/genome The World Bank; 2006. Chapter 5. Available from: https://
editing. www.ncbi.nlm.nih.gov/books/NBK11740/Co-published by
Oxford University Press, New York.
CHAPTER
155
Isoniazid Preventive Therapy:
Operational Guidelines
INTRODUCTION TABLE 1: TB burden as per data collected in India in 2015
Tuberculosis is a highly infectious disease with TB burden Number (lakhs) Rate per 100,000
significant mortality. It is estimated that every year about India Global India Global
2 million people develop TB in India. WHO had declared Incidence 28.4 104 217 142
tuberculosis as a Global Emergency in 1993. Table 1 and Mortality 4.8 14 32 19
2 shows epidemiology of TB in India and its comparison
globally.
TABLE 2: MDR-TB burden
TB AND HIV MDR-TB burden India Global
The estimated annual incidence of HIV–TB co-infected % of new cases with MDR/RR 2.5 3.9
patient in India is 1,10,000. As per notification under % of previously Rx cases with 16 21
RNTCP, it has been found that due to HIV and TB MDR/RR
coinfection, the death rate is as high as 15% in India. Incidence of MDR/RR 1.3 lac (79000 5.8 lacs
among notified)
HIV-TB COLLABORATIVE ACTIVITIES 9.9/lac 7.9/lac
The National AIDS Control Programme (NACP) and Notified in RNTCP 28876 1.32 lacs
RNTCP have undertaken joint collaborative efforts in Put on Rx 26966 1.25 lacs
this direction. A National framework was developed Abbreviations: MDR, Multidrug Resistance; RR, Rifampicin resistance
in 2008 and 2009 which was later updated in 2013. It
incorporated the National AIDS control organization
All HIV patients should be screened with 4-symptoms
(NACO) and central TB division (CTD) to initiate an (4s) algorithm for TB (Figs 2 and 3).
integrated TB and HIV services. The emphasis is laid on Availability of car tr idge based nucleic acid
preventive measures to ensure a reduction in incidence amplification Test (CBNAAT) for all PLHIV to detect
as well as mortality (Fig. 1). TB at the earliest stage. This detects rifampicin
resistance as well.
SINGLE WINDOW SERVICES Dispensing of daily ATT.
In order to deliver seamless services for early diagnosis, Dispensing of INH for prophylaxis in PLHIV.
treatment and prevention of tuberculosis; single window Dispensing co-trimoxazole (CTM).
approach has been adopted by the government of India. Educational activities regarding AIC.
CHAPTER 155: Isoniazid Preventive Therapy: Operational Guidelines 919
Fig. 2: TB screening in PLHIV patients
Fig. 1: Preventive strategy for HIV-TB co-infection.

IPT in children
IPT in PLHIV
IPT in pregnant woman.
IPT and MDR-TB
IPT in noncompliant cases.
IPT in Children
As per standard 16 of TB care in India following groups of
children require IPT:
Any child below 6 years of age who is in close contact
with an index case should be evaluated for active TB.

After excluding active TB, should receive INH for 6
months.
Any child on immunosuppressive treatment because
of any other disease such as nephrotic syndrome

or leukemia; with positive montoux test; should be
treated with INH
If a mother is diagnosed to have TB during pregnancy,
the newborn child should be given INH for 6 months

after excluding congenital TB along with BCG
Fig. 3: Algorithm for ICF and IPT at ART centre vaccination.
ISONIAZID PREVENTIVE THERAPY IPT in HIV

The Joint United Nations Programme on HIV/AIDS All HIV patients should be asked for cough, fever,
(UNAIDS) and National Framework for HIV/TB weight loss or night sweats (4s complex). Any patient
Collaborative activities in India have adopted IPT as with positive symptom should be further evaluated
major intervention for prevention of TB in PLHIV. for active TB. Asymptomative patient should be
We will discuss role of IPT in following groups of receive IPT for six months. INH is recommended,
patients. even if the patients are on ART.
If a patient while on IPT develops active TB, he should EVALUATION OF THE PATIENTS
get drug sensitivity test followed by appropriate (BEFORE STARTING IPT)
treatment. Following things should be ruled out:
If a person develops TB after completing IPT, he Active and chronic hepatitis
should be treated as a new case. History of heavy alcohol intake.

An HIV patient (adult or child), who has been treated Peripheral neuropathy should be ruled out by asking
for TB in the past, should receive INH for 6 months symptoms of numbness and burning sensation.
(secondary prophylaxis). It should be given in PLHIV
irrespective of their degree of immune status. REGIMEN PLAN FOR IPT
In an HIV patient who has just completed ATT; INH The regimen plan and dosing charts are given below
should be given for another 6 months. (Tables 3 and 4)
IPT in Pregnant Woman CONCOMITANT USE OF IPT WITH ART

Like in other patients a pregnant women with HIV It is strongly recommended by WHO that IPT should be
should be screened for active TB and started on IPT given along with ART irrespective of immune status of
irrespective of gestational period. the patient. Similarly, ART should be started while the
INH should be continued in breast feeding. patient is on INH.
If on IPT, a woman becomes pregnant, she should
complete the 6 months course of INH. CAN CO-TRIMOXAZOLE BE DISPENSED
WITH IPT?
IPT and MDR TB Cotrimoxazole and IPT can be safely co-administered.
IPT is not to be given to the contacts of MDR TB patients. Infact it is strongly recommended to dispense at the
Also PLHIV patients who have been treated for MDR-TB same centre as a part of single window policy.
in the past should not receive INH for prophylaxis.
TABLE 3: Dosing chart for IPT
IPT in Noncomplaint Cases Weight range Dose in mg Number of Number of
If a patient has taken INH for less than a month, (kg) 100 mg INH 300 mg (Adult)
restart IPT for a total of six months. tablets tablet (for 6
months)
If he has discontinued for more than a month, he
<5 50 ½ tablet -
should under go ICF screening, and if found to be
5.1–9.9 100 1 tablet -
asymptomatic should be given IPT for a total of six
10–13.9 150 1½ tablet or ½ tablet
months. 14–19.9 200 2 tablets -
IPT should not be given to a patient who has 20–24.9 250 2 ½ tablets -
discontinued for 3 months or if he has discontinued >25 300 3tablets or 1 tablet
for more than once. Adults 300 3tablets or 1 tablet
(Dose of INH in pediatric group is 10 mg/kg/day)
WHY INH FOR IPT?
TABLE 4: Dosing chart for pyridoxine
Being the most potent bactericidal drug, INH prevents
both endogenous reactivation, i.e development of Weight (kg) Number of tablets of pyridoxine (50 mg)
(for 6 months)
latent TB infection to active disease and exogenous
1–13.9 kg Quarter tablet daily
reactivation, i.e. TB infection after exposure to an open
14–25 kg Half a tablet daily
case. In previous studies it has been found that INH is as
>25 kg One tablet daily
effective as rifampicin, PZA or rifapentine in preventing
active TB. Adults One tablet daily
CHAPTER 155: Isoniazid Preventive Therapy: Operational Guidelines 921
DRUG RESISTANCE WITH IPT BIBLIOGRAPHY

The fear of development of INH resistance should not be 1. Central TB Division, National AIDS Control Organisation;
Ministry of Health and Family Welfare, Government of India.
a concern for initiation of IPT as it is found that there is Operational Manual For Isoniazid Preventive Therapy. 2016
no risk of developing INH resistance TB in such cases. 2. Central TB Division. RNTCP Technical and Operational
Guideline 2016. CTD Ministry of Health and Family Welfare,
Government of India, New Delhi, 2016.
SUMMARY/CONCLUSION 3. Delphine Sculier, Haileyesus Getahun. Scaling up TB
1. IPT is an important key intervention of Single window screening and Isoniazid preventive therapy among children
policy which protects latent TB developing into active and adults living with HIV: new WHO guidelines. Africa
Health; 2011; pp. 18-23.
TB (Endogenous reactivation).
4. Integrated training module for TB HIV collaborative activities
2. It also prevents postexposure TB (Exogenous 2015; National AIDS Control Organisation; Ministry of
reactivation). Health and Family Welfare, Government of India, New Delhi,
3. The algorithm for 4s symptom complex should be 2015.
5. National AIDS Control Organisation Ministry of Health
adopted before initiating IPT. & Family Welfare Government of India. Guidelines on
4. Among PLHIV montoux test is not a pre-requisite for Prevention and Management of TB in PLHIV at ART Centres.
initiating IPT. 2016
6. National Framework for Joint HIV/TB Collaborative Activities:
5. IPT regimen of 6–12 months shows similar efficacy.
November 2013 National AIDS Control Organisation;
6. All Children with HIV should receive IPT after Ministry of Health and Family Welfare, Government of India,
excluding active TB. 2013.
7. All PLHIV after exclusion of active TB have to be given 7. National Guidelines on diagnosis and treatment of Pediatric
Tuberculosis. 2012.
IPT. 8. National Strategic Plan (2012-17) for Tuberculosis.
8. Those completed TB treatment should receive Directorate of Health Services, Central TB Division, Ministry
additional 6 months of INH of Health and Family Welfare (MoHFW), Government of
India, New Delhi. www.tbc.nic.in
9. IPT is safe in pregnancy and breast feeding. 9. Padmapriyadarsini C, Bhavani PK, Sekar L, et al.
10. IPT should not be given to contacts of MDR-TB and Effectiveness of Isoniazid Preventive Therapy in Reducing
PLHIV who have received MDR-TB treatment in the Incidence of Tuberculosis among PLHIV in Programme
Settings in India; IPT Study Phase II (under publication)
past.
National Institute for Research in Tuberculosis; Ministry of
Health and Family Welfare, Government of India, 2016.
10. World Health Organization. Standards for TB Care in
India. 2014.
CHAPTER
156
Hypnotherapy in Medical Disorders
INTRODUCTION hypnosis in various areas of application in medicine.

Hypnosis is an altered state of consciousness in which During a hypnotic trance, the conscious mind is put to
there is an increased suggestibility which can enable sleep and the hypnotherapist is able to gain a rapport
one to unfold one’s potentialities through suggestions with the subconscious mind of the hypnotized person.
and function at the best level. It could also enable one The suggestion reprograms the subconscious mind
to gain access to an inner power for influencing not only which ultimately gives one the desired effect. The
the body but also the mind, even transcending them at suggestion may require reinforcement if a prolonged
times. Though this science was known in ancient times, effect is desired.
its knowledge was gradually lost with the passage of time.
In modern times, Franz Anton Mesmer (1734-1815), a AREAS OF THE BRAIN AFFECTED
Viennese physician was the first to initiate studies in this BY HYPNOSIS
methodology and called it animal magnetism. After him, Research using positron emission tomography (PET)
this science was called Mesmerism. The father of modern has demonstrated that hypnosis involves the anterior
hypnotism was James Braid (1795-1860), an Edinburgh cingulate cortex and that actual changes occur in
surgeon who called it ‘Hypnotism’ from the Greek word the brain’s perception that do not occur when a
‘Hypnos’ which means sleep. Thereafter, hypnosis was suggestible person simply follows instructions. Hypnosis
studied by many scientifically-trained people. The actively reduces a person’s subjective and objective
two world wars resulted in the rise of hypnosis and its perception of and emotional response to pain through
re-educative possibilities were recognized. In 1953, the midcingulate cortex modulating a large cortical
the British Medical association officially approved its network. Scans show that pain is not perceived during
medical use, followed by its approval by the American hypnotic trance. PET shows that the right anterior
Medical Association in 1958. cingulate cortex is activated both when individuals hear
Hypnosis is akin to ‘yoganidra’ or yogic sleep, widely sounds and when hearing sounds is suggested under
promoted by various yoga teachers. The basic difference hypnotic trance but not when they simply imagine
between the two states is that a hypnotic trance is hearing sounds. Functional magnetic resonance imaging
induced through suggestions, while for entering into studies have shown significant activity and connectivity
a state of ‘yoganidra’, no suggestion is given. There is involving the brain’s default mode network (DMN) and
substantial empirical evidence for the effectiveness of other areas in hypnotized subjects. The DMN, which
CHAPTER 156: Hypnotherapy in Medical Disorders 923
includes the medial temporal lobe, part of the medial The worst hypnotic subjects usually have very short
prefrontal cortex, the posterior cingulate cortex, the attention spans, tend to focus on past and future rather
adjacent ventral precuneus and inferior parietal cortex, than present, are overly critical, use logic instead of
is considered to generate spontaneous thoughts and to emotions, have lower IQ’s and have great difficulty in
be essential for creativity. letting themselves go. Senility, brain damage, mental
retardation, inability to understand the language of the
PHYSIOLOGICAL EFFECTS OF HYPNOSIS hypnotherapist and overall cynical attitudes also inhibit
Hypnosis is a natural body-and-mind phenomenon. the induction of hypnotic trance.
A constellation of physiological changes is produced
during hypnosis, in addition to shifts in perception. Levels of Hypnosis
Generally, there is an increase in the production of alpha For simplicity, it is possible to divide hypnotic
rhythms. This EEG pattern is similar to that of relaxation. susceptibility into five stages. Stages three, four and five
In addition, there occurs an increase in basal skin are clinically relevant.
resistance, decrease in respiration, basal metabolism, 1. Insusceptible
cardiac output and an increase in body temperature. So it 2. Hypnoidal-precursor to hypnotic state, no symptoms
resembles relaxation physiologically while cognitively, it 3. Light stage
looks more like dreaming. Neurophysiologic studies have 4. Medium stage
shown that despite similarities, hypnosis is more than 5. Deep stage
and different from simple imagination, relaxation, sleep It is important to keep in mind that hypnosis is like
and the placebo response. any other therapeutic modality: it is of major benefit to
some patients with some problems, and it is helpful with
FACTORS AFFECTING many other patients, but it can fail, just like any other
THERAPEUTIC RESPONSE clinical method.
Subject Suggestibility and Induction of Hypnotic Trance

Hypnotizability Factors Inducing a hypnotic trance is the only difficult and
Hypnosis is essentially a ‘consent’ state. Hypnosis will be important thing in the process of hypnosis. Induction
optimally effective when the patient is highly motivated to of a hypnotic trance can be done through various
overcome a problem and when the hypnotherapist is well techniques, like eye-fixation techniques with or without
trained in both hypnosis and in general considerations sleep suggestions, hand-clasp technique, progressive
relating to the treatment of the particular problem. Some relaxation, arm-levitation technique, child induction
individuals seem to have higher native hypnotic talent techniques, mechanical techniques and Erickson’s
and capacity that may allow them to benefit more readily confusional techniques, etc. Different approaches in
from hypnosis. 95% of the subjects can be placed in at using hypnotherapy are indicated depending on the
least a light hypnotic trance. The best hypnotic subjects hypnotizability of the patient and the nature of the
are intelligent people who have an excellent memory ailment. After achieving the goal, the therapist simply
and good concentration, can visualize scenes vividly, are commands the patient to return to the normal state.
not overly critical, can express emotions easily and who Group hypnosis also, can have strong positive effects on
can become deeply involved in the plot while reading many types of disorders.
or while seeing a movie. Women are more susceptible
for hypnosis than men. Children are excellent subjects TYPES OF HYPNOSIS
because of their imagination, lack of resistance and Heterohypnosis is the trance state induced in one person
skepticism and respect for authority. by another person, the hypnotherapist. If a hypnotic
trance is achieved by a subject without another person’s TABLE 1: Common examples of medical disorders or conditions
help, this is called self-hypnosis. There is no difference where hypnotherapy is useful
between the hypnotic states of heterohypnosis and self- zz Cardiovascular disorders
—— Hypertension
hypnosis, and their effect is the same. —— Coronary artery disease
Having experienced the hypnotic trance once, patient —— Cardiac arrhythmias
—— Raynaud’s disease
may be able to self-induce a hypnotic trance without
zz Neurological disorders
needing someone else to do it. Therefore, good subjects —— Cerebrovascular disease
should always be taught self-hypnosis and to give —— Migraine
—— Tension headache
themselves helpful suggestions.
—— Parkinsonism
—— Tremors
APPLICATIONS OF HYPNOTHERAPY —— Tics
IN MEDICAL DISORDERS —— Torticollis
—— Writer’s cramps
As a Modifier of Reaction to Stress —— Speech disorders: Stammering, Stuttering
—— Blepharospasm
Stress is a vital factor in many diseases and hypnosis —— Tinnitus
is a valuable method of counteracting it (Table 1). —— Dyslexia
zz Gastrointestinal disorders
Hypnotherapy can be expected to help in two ways: as
—— Peptic ulcer
a prophylactic agent and in the cushioning of shock. —— Irritable bowel syndrome
Hypnotherapy can relax an individual and thus raise —— Ulcerative colitis
—— Crohn’s disease
the threshold for fear, shock and stress. It can produce
—— Hyperemesis gravidarum
a rapid insight for the patient. Moreover, by its power —— Chemotherapy-induced nausea and vomiting
of relaxation and tension removal, it helps both psyche zz Respiratory disorders
—— Bronchial asthma
and soma and might increase an individual’s capacity
—— Hay fever
to withstand any further emotional difficulty. It can —— Vasomotor rhinitis
facilitate physiological/biochemical healing processes zz Endocrine and metabolic disorders
and apparently, influence, or even arrest, the progression —— Diabetes mellitus
—— Obesity
of actual organic disease.
zz Musculoskeletal disorders
The best technique to use in many of the cases is —— Rheumatoid arthritis
a state of complete tranquillity. Verbalization or any —— Osteoarthritis
—— Fibromyalgia
method of recall is allowed but often a state of peace
zz Genitourinary disorders
and relaxation followed by a few minutes suggestion —— Renal failure
at the end of session may be found the most beneficial —— Psychogenic retention of urine
—— Incontinence
technique of all.
—— Eneuresis
—— Impotence
Direct Symptom Removal —— Frigidity
zz Bleeding disorders
Hypnotherapy can be used for direct symptom removal.
—— Hemophilia
It can be used to alleviate acute or chronic pain in
zz Dermatologic disorders
conditions like cancer, tension headache, migraine, —— Eczema
rheumatoid arthritis, osteoarthritis and backache. —— Herpes
—— Neurodermatitis
A mechanism for analgesic hypnosis has been
—— Psoriasis
demonstrated in a PET study revealing significant —— Pruritus
changes in pain-evoked activity within the anterior —— Warts
—— Psychogenic purpura
cingulate cortex consistent with the encoding of perceived
CHAPTER 156: Hypnotherapy in Medical Disorders 925
unpleasantness, whereas the primary somatosensory which assesses not only the somatic part of an illness,
cortex activation was unaltered. A National Institute but also the underlying psychological factors adversely
of Health panel found strong evidence for the use of affecting the individual. Hypnotherapy in combination
hypnosis in alleviating pain associated with cancer. with medicine may be effective in this connection.
Hypnosis is useful for sleep management in patients with
disturbed sleep particularly those with cancer. BIBLIOGRAPHY
1. Ezra Y, Gotkine M, Goldman S, Adahan HM, Ben-Hur
As a Modifier of Allergic Response T. Hypnotic relaxation vs amitriptyline for tension-type
headache: let the patient choose. Headache. 2012;52:785-
The hypnotic state is capable of a bridging function 91.
in the supposed dualism between mind and body. 2. Faymonville ME, Boly M, Laureys S. Functional neuroanatomy
Many studies have shown a link between the use of of the hypnotic state. J Physiol Paris. 2006;99:463-9.
hypnosis and a changed response to an allergic stimulus 3. Gay MC. Effectiveness of hypnosis in reducing mild
or to a lessened bronchial hyper-reactivity. There is essential hypertension: a one-year follow-up. Int J Clin Exp
Hypn. 2007;55:67-83.
some evidence for an influence on the neurovascular
4. Häuser W, Hagl M, Schmierer A, Hansen E. The efficacy,
component of the allergic response. safety and applications of medical hypnosis. Dtsch Arztebl
Int. 2016;113:289-96.
HYPNOANALYSIS 5. Iserson KV. An hypnotic suggestion: review of hypnosis for
clinical emergency care. J Emerg Med. 2014;46:588-96.
In many cases, hypnoanalysis can detect the actual cause
6. Peters SL, Muir JG, Gibson PR. Review article: gut-directed
of the disease lying at the subconscious level and can be
hypnotherapy in the management of irritable bowel
used as psychocathartic i.e. abreaction instrument. The syndrome and inflammatory bowel disease. Aliment
process of hypnosis allows a repressed incident to come Pharmacol Ther. 2015;4:1104-15.
to consciousness and to be abreacted with subsequent 7. Samim A, Nugent L, Mehta PK, Shufelt C, Bairey Merz
relief of the symptom. CN. Treatment of angina and microvascular coronary
dysfunction. Curr Treat Options Cardiovasc Med.
Contraindications to hypnosis are psychosis,
2010;12:355-64.
constitutional predisposition to severe psychoneurotic 8. Wortzel J, Spiegel D. Hypnosis in cancer care. Am J Clin
reactions or antisocial behavior. Hypn. 2017;60:4-17.
9. Xu Y, Cardeña E. Hypnosis as an adjunct therapy in the
PROSPECTS management of diabetes. Int J Clin Exp Hypn. 2008;56:
63-72.
In all branches of medicine today, one can witness a
10. Zech N, Hansen E, Bernardy K, Häuser W. Efficacy,
revival of interest in psychogenic elements as causative acceptability and safety of guided imagery/hypnosis in
or aggravating factors of a disease. Much can be fibromyalgia - A systematic review and meta-analysis of
accomplished for a patient by an all-embracing approach randomized controlled trials. Eur J Pain. 2017;21:217-27.
CHAPTER
157
An Approach to Recurrent Falls in the Elderly
S Ramnathan Iyer, Revati R Iyer
INTRODUCTION Most falls result from a complex interplay of predisposing

Falls are considered as one of the “geriatric giants”. A fall and precipitating factors in the subject’s environment.
is defined as, a person coming to rest on the ground or
another lower level; sometimes a body part strikes against Causes of Falls
an object that breaks the fall. It must be appreciated that Intrinsic Factors
events caused by acute disorders (e.g. stroke, seizures) Old age especially after 75 years
or overwhelming environmental hazards (e.g. struck by Home bound
a moving object) are not considered as falls. The cause Living alone
of falls in elderly is often multifactorial demanding a Use of walker
multidisciplinary approach. Recurrent falls (RF) are History of previous falls
a marker of poor physical and cognitive status. RF is Obesity
defined as 2 or more falls within 6 months. Majority of the Acute illness like acute myocardial infarction, pneu
elderly subjects fall at home (70%) and about 20% require monia, hypoglycemia, hyponatremia, gastrointestinal
hospitalization. According to Ministry of Stastitics and bleed.
programming the size of the elderly population over the Chronic diseases like chronic obstructive pulmonary
age 60 years is fast growing and constitutes about 8% of disease, sleep apnea, chronic sleep deprivation,
the total population (2011 Census). accidental falls from bed while sleeping due to
restless sleep, osteoporosis, parkinsonism.
Age Related Changes and Falls Gait disturbances, posterior column dysfunction-
There are several changes in body systems with aging. positive Romberg’s sign
In focus would be (i) Decrease in muscle mass resulting Orthostatic hypotension
in decreased strength. (ii) Decreased visual acuity and Balancing disorders like vertigo
hearing coupled with decreased proprioception. (iii) Visual disorders like cataract, glaucoma, macular
Central obesity. (iv) Upper airway narrowing. High degeneration
prevalence of obstructive sleep apnea (OSA) is observed Decline in night vision and peripheral vision
in elderly and postmenopausal women. These contribute Confusion (geriatric giant) and cognitive impairment
to reduced balance and altered gait predisposing the Syncopal attacks particularly in patients with venous
subject to falls even while performing routine activities. pooling (varicose veins)
CHAPTER 157: An Approach to Recurrent Falls in the Elderly 927
Cardiac arrythmias Clinical Examination

Painful arthritis It must include Romberg’s sign, examination of joints
Medications like sedatives, hypnotics taken for and mobility. Obesity is an important factor related
insomnia (Insomnia can coexist with sleep apnea. to falls in elderly as it negatively impacts balance and
Hypnotics aggravate pharyngeal collapse). Tricyclic postural sway thereby increasing the risk of functional
antidepressants, antihypertensives (caution-postural limitation that lead to falling. Timed up and Go test is a
hypotension), phenytoin useful clinical tool. This test uses the time that a person
Alcohol and substance abuse. takes to rise from chair, walk 3 meters, turn around, walk
back to chair and sit down. The subject should walk with
Extrinsic Factors usual footwear and also use his walking aid. Results are
Poor Illumination read as follows: 10 secs or less normal mobility. 11–20
Very bright illumination secs are normal for frail and disabled patients. More than
Unfamiliar surroundings 20 secs means the person needs assistance outside and
Irregular floor surfaces indicates further examination and intervention. A score
Slippery floors of 30 or more suggests that the person may be prone
Household furniture too low or too high to falls. Timed and Go test may have limited ability to
Faulty footwear predict falls in community dwelling elderly and should
Obstacles on floor like rugs, mats, etc not be used to identify individuals at high risk of falls in
Broken footpaths, potholes the elderly.
Performing unwanted activities in bathroom like Detailed clinical examination of all systems
killing insects, etc. including cardiovascular, neurological, respiratory,
ophthalmological are important.
Clinical Aspects
History Prevention of Falls
A detailed history from the patient and also from Education and counseling of elderly subjects and
caregiver/attendant is of utmost importance. History their caregivers.
of previous fall-its likely cause and consequence must Use of walking aids and hip protectors.
be enquired. Whether the cause has been treated? Weight loss measures must be seriously considered.
The previous physician/family physician may provide Mobile phone and landline phones should be easily
important clues. The role of attendant/caregiver is of accessible.
utmost importance. Drug history in detail including Vitamin D supplementation in doses of 800 iu/day or
consumption of ayurvedic drugs must be recorded. more have shown to decrease the incidence of falls in
Elderly tend to hoard drugs. Also they share medications long term care.
with their friends especially during morning meetings. Exercises: Various exercise programmes have been
Their sleep times and sleep disturbances such as snoring, studied to reduce falls. The American Geriatric
nocturia need special mention. Nocturia is a prominent Society and British Geriatric Society include
symptom of obstructive sleep apnea in elderly. Sleep exercise programmes like Tai Chi or physiotherapy
times can be delayed because the loved ones may sleep is recommended. Tai Chi helps in gait and balance.
late and rebound sleep deprivation may result. Nocturnal Practising yoga is also beneficial.
awakenings need special attention. Hypnotics are often Sleep disturbances: Sleep complaints like insomnia,
consumed by elderly. They significantly impair body disturbed sleep, nocturia, snoring should receive
balance. attention. Daytime tiredness and sleepiness may
precipitate a fall. Management of sleep disorders CONCLUSION

is highly rewarding. Oxidative stress of sleep apnea Recurrent falls in the elderly requires meticulous
can aggravate aging. Sleep and aging are closely examination and investigation. Multidisciplinary
associated. approach must be implemented. Members of family
Medications: The presence of several disorders in and caregiver sometimes provide important clues.
elderly demand many drugs (polypharmacy). Drug Polypharmacy must be dissected from every angle viz
interactions and adverse effects need to be carefully adverse effects, drug-drug interactions. Counseling and
scrutinized. Particular mention is for orthostatic complete elderly care go a long way to prevent falls.
hypotension. Nocturia can be bothersome. The
cause must be detected and treated. Obstructive
sleep apnea often presents with cognitive decline BIBLIOGRAPHY
and nocturia in elderly. Frequent visits to washroom 1. Emma B, Galvin R, Koegh C, Hargan F, Fahey T. Is the
can be prevented by urine pot kept near the bed. It timed up and go test a useful predictor of risk of falls in the
is advisable to carry walking aid while visiting toilet. community dwelling older adults-a systematic review and
metanalysis. Biomed Central Geriatrics. 2014;14:14.
Also attempts to lock the toilet from inside should be
2. Fjeldstaad C, Fjeldstaad AS, Acree LS, Nickel KJ, Gardner
strongly discouraged. Oil application over body in
AW. The influence of obesity on falls and quality of life. Dyn
bathroom must be discouraged. At night, adequate Med. 2008;7:4
illumination must be made available in bathroom/ 3. http://wihealthyagingorg/_data/files/../WIHA_Yoga_falls_
toilet. A torch embedded on the handle of the walking presentation_V2_1pdf. Yoga and fall prevention –Wisconsin
aid may be helpful. An alarm bell near the bed is Institute of Healthy Aging
welcome. 4. http:/www.censusindia.gov.in/vital_statistics/srs_
Visual disturbances: Optimal illumination helps report/9chap%202%20- %/202011.pdf.
5. Iyer SR, Iyer RR, Sonavdekar RB. Schamberg’s disease in
in having better vision. All correctable ophthalmic
a case of severe obstructive sleep apnea-a case report.
disorders must be attended on an urgent basis. New
Indian J Sleep Med. 2014;9(4):183-5.
pair of glasses may be uncomfortable and may need 6. Iyer SR. Sleep-is it the hidden agenda in the aging
acclimatization. Bifocal lenses can carry a higher risk programme? Dr.G.S.Sainani oration delivered at Ahmedabad
of falls. Progressive lenses may be more useful. APICON 2011 Indian J Sleep Med. 2014;9(3):96-101.
Environment: Flooring at home needs to be taken 7. Iyer SR, Iyer RR. The Healing Heptagon. Ist edn. Shree
care of. It should not be slippery. Adequate support in Ambika Publications. Dombivli, 2009.
toilet (railings) is of great help. Subjects must not do 8. Luk JK, Chan TY, Chan DK. Falls prevention in the elderly:
any adventurous things in toilet/bathroom e.g. killing translating evidence into practice. Hong Kong Med J.
2015;21:165-71.
insects, lizards, etc. There should be no obstacles in
9. Mets MA, Volkerts ER, Olivier B, Verster JC. Effect of hypnotic
the walking path.
drugs in body balance and standing steadiness. Sleep Med
Feet and legs: A careful examination of feet and Rev. 2010;14(4):259-67.
legs is important. One must look for deformities, 10. Podsialdlo D, Richardson S. The timed up and Go: A test for
callosities, fungal infections. Presence of varicose veins, basic functional mobility for frail elderly persons. Journal of
Schamberg’s disease should raise the suspicion of OSA. the American Geriatric Society. 1991;39(2):142-8.
CHAPTER
158
Ultrasonography in Critically Ill Patients
Sameer Gulati, Bhupendra Gupta
INTRODUCTION waterproof keyboard. A machine with a 3–5 MHz convex

Ultrasonography (USG) is being increasingly used for probe with a small footprint is favored, as it is easily
assessment and monitoring of patients who are critically positioned on intercostal spaces. A high frequency
ill and are admitted in intensive care units (ICU). linear transducer (5–10 MHz) is required for doing
Ultrasonography based algorithms have been devised the compression USG to locate lower extremity deep
to facilitate simple, swift and efficient management vein thrombosis. Whereas, the optic nerve is typically
of respiratory and circulatory failure. USG facilitated evaluated utilizing a linear probe (7–15 MHz ) with a
cardiopulmonary resuscitation is being increasingly smaller footprint probe matching the eye socket size.
promoted because of its ability to save precious lives.
Besides, more and more intensivists are getting trained PROCEDURE: LUNG
to do interventions with aid of USG so as to minimize ULTRASONOGRAPHY
the associated complications. The pleura, heart, veins Any acute disease of the lung may reduce aeration
and abdomen can be assessed and monitored to resolve pattern or may disturb the pleura, which in turn will
respiratory and circulatory failure. The objective of the generate diagnostic patterns on USG (Table 1). The lung
present review is to sensitize the reader to the application US may be done over the entire chest by applying the
of USG as a diagnostic modality in critically ill patients. probe longitudinally over the intercostal spaces and by
moving it transversely in defined standardized areas.
EQUIPMENT The chest is divided into three parts (anterior, lateral and
The ultrasound (US) machines in the ICU should be posterior) and each part is further divided into two zones.
compact and light enough to facilitate multiple transports The dorsal segments of upper lobes cannot be scanned
for bedside evaluations. A simple low cost grayscale by ultrasound as they are hidden behind the scapula.
machine, without doppler facilities, and with immediate The complete assessment of these six zones may take 15
start up time is adequate to meet the requirements of minutes. Since, intensivists need to conduct a focussed
critical care imaging. It is important that the selected examination in a much shorter period, Lichtenstein
machine can undergo multiple decontamination proposed a BLUE protocol utilizing only three points
procedures so as to stop transmission of nosocomial (upper BLUE, lower BLUE and the PLAPS points) on
infections. This may be facilitated by an accompanying each chest. The lung is located by placing two hands
TABLE 1: Important signs (all signs arising from pleural line) in lung ultrasonography
1 Pleural line Horizontal hyperechoic line sliding half a centimeter under the ribs.
2 Bat sign Acoustic shadows of two ribs and the sliding pleural line in between resemble a flying bat.
3 Merlin space An area in between the acoustic shadows of two adjacent ribs.
4 A line Horizontal repetition artefacts of the pleural line.
5 Lung sliding To and fro movement at the pleural line.
6 Lung pulse Heart beats are identified at the pleural line because of a non inflating lung. This discriminates
pneumonia and atelectasis.
7 B line An artifact, due to coexistence of elements with a major acoustic impedance gradient such as fluid and
air, with 7 features - hydroaeric comet tail artifact, emerging from the pleural line, hyperechoic, well
defined, spreading up indefinitely, erasing A lines and moves together with lung sliding.
8 Seashore sign (M mode) A stratified pattern above and a sandy pattern under the pleural line.
9 Stratosphere sign (M mode) A stratified pattern under and over the pleural line indicating pneumothorax.
10 Lung point At a precise location, in patients with A’ profile, lung signs such as transient B lines and lung sliding
suddenly appear with respiration. This location is called as lung point, which is pathognomonic of
pneumothorax.
11 Dynamic air bronchogram Inspiratory centrifugal movement of hyperechoic air in branching echogenic structures of the
consolidated lung, which is seen in alveolar consolidation.
TABLE 2: Different profiles in lung ultrasonography and their diagnostic significance

1 A profile Anterior lung sliding with A lines Normal lungs. If associated with evidence of LEDVT,
then A profile may be seen in pulmonary embolism
2 A’ profile ‘A profile’ with absent lung sliding Pneumothorax (+ lung point), cardiopulmonary
arrest, one lung intubation, esophageal intubation,
chronic adherences/fibrosis
3 B profile Anterior lung sliding with lung rockets (B lines) Interstitial syndrome - hemodynamic pulmonary
edema
4 B’ profile B profile with abolished lung sliding Interstitial syndrome - pneumonia, ARDS
5 C profile Indicates anterior lung consolidation. Shred or Non translobar alveolar consolidation
fractal sign: shredded or fractal margin separating *In contrast, translobar consolidations identified with
consolidation from the underlying aerated lung help of tissue like sign (looks like liver)
6 A/B profile Observation of A profile in one lung and B profile Unilateral diffuse or focal interstitial syndrome
in another
7 PLAPS profile This is looked for after observation of an A profile Pleural effusion - the lung line and pleural line comes
(PosteroLateral alveolar and a normal venous scan in a dyspneic patient. closer as the patient inspires. This is observed as the
and/or Pleural syndrome) The profile incorporating A profile, free veins, and “sinusoid sign” in M Mode. The pleural and the lung
PLAPS is termed A-V-PLAPS profile line are bounded by the shadows of the ribs forming a
kind of a quad, thus generating the “quad sign”
8 Nude profile A profile with no DVT and no PLAPS Asthma or COPD
over the anterior chest, upper hand touching the clavicle. posterior axillary line corresponds to the PLAPS point.
The upper and lower BLUE points will correspond Such a three point assessment may cut down the
to a place which lies at the center of the upper and duration of examination to three minutes. The distinct
lower hand respectively. A position at the junction of a sonographic lung patterns have been enumerated in
horizontal line through the lower BLUE point and the Table 2.
CHAPTER 158: Ultrasonography in Critically Ill Patients 931
PROCEDURE: COMPRESSION downwards into the Hunter’s canal/Adductor canal

ULTRASONOGRAPHY FOR DEEP VEIN where it becomes the popliteal vein. The compression
may be difficult as the SFV nears the adductor canal. The
THROMBOSIS
popliteal vein is examined at the popliteal fossa where it
A two point compression ultrasonography (common
is easily compressed. Here, the vein usually lies anterior
femoral region and the popliteal fossa) has been
to the artery. The compression maneuver is continued
found to be equivalent to the whole leg color doppler
until the trifurcation into the calf veins caudally. The
ultrasonography in diagnosis of proximal lower extremity
same procedure may be repeated for the second leg.
deep vein thrombosis (LEDVT). Although very few
additional LEDVT may be picked up by scanning the
PROCEDURE: BEDSIDE
remaining venous system, few intensivists carry out
OCULAR ULTRASOUND
compression ultrasonography (CUS) of the complete
Bedside eye ultrasound evaluation is done with the
venous system extending from the common femoral
patient supine (head of bed at 0 degree) and the eyelid
vein right up to the branching of the popliteal vein with 2
closed without any clenching. The eye may be covered
cm increments. The procedure is done by using B mode
with a tegaderm and a good amount of gel is applied over
with a high frequency (5–10 MHz) linear transducer. The
it to function as an acoustic stand off. A high frequency
operator should have a working knowledge of the lower
linear probe is ideal for an ophthalmic evaluation.
extremity venous anatomy.
The depth and the gain should be appropriately set to
The patient should be in supine position with thigh
visualize all the structures of the globe with the posterior
externally rotated and knee flexed at 45 degree angle.
chamber visualized as a hypoechoic structure. Eye is
To begin with, the common femoral artery is located
evaluated both in transverse and longitudinal planes.
running laterally to the common femoral vein (CFV). The hemispherical lens is seen as the most anterior
A compression maneuver is done at this point, in the structure of the eye. The hemispherical anterior
transverse plane, with the probe held perpendicularly and chamber is separated from the posterior chamber by the
with marker to the patient’s right. Complete compression hyperechoic ciliary body and iris. The posterior chamber
of the vein with minimal deformation of the adjacent is anechoic in younger subjects with vitreous opacities
artery is indicative of absence of thrombosis. On the appearing in older patients. The normal retina is not
other hand, noncompressibility with pressure enough distinguishable from other choroidal layers. The optic
to deform the adjacent artery and/or the presence of nerve is visualized centrally just posterior to the eye as a
echogenic substance in the lumen of the venous vessels hypoechoic linear structure extending posteriorly. The
are diagnostic of venous thrombosis. Most of the acute nerve and its sheath appear hypoechoic and hyperechoic
thrombi are hypoechoic, which makes their visualization respectively.
difficult. However, if a thrombus is visualized then a The intensivists are particularly interested to measure
compression maneuver should not be done as it may optic nerve sheath diameter (ONSD), as a surrogate for
dislodge the thrombus. Longitudinal scanning may help intracranial pressure (ICP), in patients with suspected
in confirming the intraluminal echogenic thrombus. The intracranial process in a critical care unit. The ONSD
great saphenous vein (GSV) joins the CFV in vicinity expands due to the transmission of the increased ICP
of the inguinal ligament. Compression maneuver is to the subarachnoid space enclosing the optic nerve.
done again at the junction of GSV and the CFV. The The measurement of ONSD is done along an axis
CFV split into profunda femoris vein and the superficial perpendicular to the optic nerve and sheath at a point
femoral vein (SFV) approximately 2 cm proximal from which is 3 mm behind the posterior globe. The normal
the inguinal ligament. The superficial femoral artery ONSD is <5 mm. If it is measured to be > than 6 mm then
usually lies anterior to the SFV and the profunda femoris it signifies an increased ICP. Measurements between 5
moves deep between the muscles. The SFV is followed and 6 mm require clinical correlation.
PROCEDURE: FOCUSSED if RV:LV is 0.6-1.0 and critical if this ratio is more than 1.
ECHOCARDIOGRAPHY The interventricular septum is shifted towards the left in
The purpose of goal directed echocardiography is presence of RV overload (e.g. acute pulmonary embolism,
to immediately identify life threatening causes of acute respiratory distress syndrome, or ventilation with
hemodynamic failure, to categorize shock in order to high pressures). Due to the right ventricular overload, the
plan initial management strategy and to identify any left ventricle changes it’s normal circular shape to a “D”
other coexisting diagnosis. shape on left parasternal short axis view.
The focussed echocardiography may be utilized by
the intensivist for the following purposes (Table 3): Diagnosis of Pulmonary Embolism
Right ventricular dilatation and dysfunction in presence
Assessment of Right and of a positive CUS for LEDVT is highly suggestive of
Left Ventricular Function pulmonary embolism. The pattern of RV dysfunction
“Eyeball” estimates of the LV function, as assessed by involving mid septum with apical sparing is quite distinct
skilled examiner, is similar to calculated ejection fraction. for acute pulmonary embolism.
Frequent echocardiographic evaluations may be done to
monitor the efficacy of therapeutic interventions. The Diagnosis of Pericardial Effusion
right ventricular (RV) function may also be assessed Pericardial effusion is revealed as an echo free space
visually. The RV dilatation is assessed by calculating around the heart. The collapse of the right atrium (RA)
RV:LV ratio. The ratio is considered normal when it along with RV in the diastole suggests the occurrence
is <0.6 (moderate dilatation = ratio 0.6-1.0; critical of cardiac tamponade. A hemodynamically significant
dilatation = ratio >1). Dilatation is considered moderate pericardial effusion is identified if RA collapse
TABLE 3: Important views of echocardiography

View Probe placement Structures seen
Apical At apex beat; marker facing the left axilla Four chamber view comprising of atria, ventricles, interventricular
and interatrial septa
Apical 5 chamber Acquire the apical four chamber view Proximal segment of ascending thoracic aorta, the aortic valve and
followed by tilting the probe upwards left ventricular outflow tract
PLAX*# Second or third intercostal spaces close to Right ventricle, left ventricle, mitral valve, left atrium, descending
the left sternal border; marker faces the right aorta, aortic valve, aortic root, pericardium, right ventricular inflow
shoulder and outflow tracts
Parasternal short axis# Acquire the PLAX view, thereafter rotate The short axis view between the apex and the base of the heart is
probe 90° clockwise to face towards the head made at three levels:
Mitral valve: Fish mouth view of mitral valve, left ventricular walls
and right ventricle
Mid papillary: Papillary muscles, left ventricular wall and right
ventricular wall
Aortic level: Aortic valve, pulmonic valve, tricuspid valve and right
atrium
Subcostal Right of the xiphoid notch; facing the left hip Four cardiac chambers, right ventricular outflow tract, aorta and
vena cava
Inferior vena cava Begin in the subcostal 4 chamber view and The IVC will be seen in the long axis. The measurements may be
then rotate the transducer counterclockwise made by utilizing M mode
90° angling towards the liver
*PLAX=Parasternal long axis view
#Parasternal views: The inspiratory pressures and positive end expiratory pressure levels may be reduced for some time to improve recognition
of the lung in a patient on mechanical ventilator.
CHAPTER 158: Ultrasonography in Critically Ill Patients 933
persists beyond one third of the RR interval. The real may help in determining the appropriateness of a fluid
time echocardiography may also help in draining a challenge.
hemodynamically significant pericardial effusion.
PROCEDURE: SCREENING
Assessment of Hypovolemia ABDOMINAL ULTRASONOGRAPHY
Assessment of hypovolemia and volume responsiveness A screening abdominal USG may be done by the
is achieved by determining the size of inferior vena intensivists to identify intra abdominal fluid and
cava (IVC) and it’s respiratory variedness. An increased examination of the aorta in a hypotensive patient.
IVC diameter (≥2 cm), in a patient with spontaneous Examination of aorta in its complete path, with special
respiration, is suggestive of raised pressures of the attention to aorta below renal arteries, is crucial to
right heart. Variability of IVC diameter (≥12%) with eliminate possibility of an aneurysm. It is scanned right
respiration is a predictor of improvement in cardiac through the epigastrium to the division of the iliac
output after volume expansion. Besides, hypovolemia arteries. The transducer is oriented transversely, directing
is also recognized by identification of “kissing sign” on towards the posteriorly placed aorta. Abdominal aorta is
the PLAX view (systolic effacement of the LV cavity at the placed left to the inferior vena cava just anterior to the
level of papillary muscle). vertebral body. Evaluation should be done in short axis
plane in order to determine the maximum diameter
Echocardiographic Assessment During of aorta (distance between outer wall to outer wall).
Cardiopulmonary Resuscitation An abdominal aortic aneurysm (AAA) is diagnosed if
Focussed echocardiography may help to determine vessel diameter exceeds 3 cm. Presence of echogenic
the reversible causes of arrest and to observe activity thrombus or an intimal flap with differential doppler flow
of the heart during cardiopulmonary resuscitation in suggestive of aortic dissection should also be ruled out.
presence of absent pulse. This modality can pick up A longitudinal assessment of the aorta will complete the
causes such as pneumothorax, hypovolemia, aortic examination.
dissection, cardiac tamponade, PE and coronary artery US evaluation is not a good modality to rule out
disease. Identification of the correct cause may help in aortic dissection. Still it has been utilized to diagnose
determining the best intervention to save a patient. The aortic dissection in certain settings. Screening for
USG evaluation is carried out through the subcostal aortic dissection should include transthoracic
window during brief periods of pulse checks during the echocardiography to look for signs of dilatation of aortic
cardiopulmonary resuscitation. root, aortic regurgitation, pericardial effusion and/or
aortic intimal flap.
Assessment of a Hypotensive Patient
A systematic USG approach can help the intensivist ULTRASONOGRAPHY IN TRAUMA
in determining the cause of hemodynamic instability. The focussed assessment with sonography in trauma
Echocardiographic assessment can help in ruling out (FAST) examination has substituted peritoneal lavage in
systolic dysfunction of LV, massive PE, hypovolemia recognition of the origin of intra abdominal hemorrhage.
and cardiac tamponade. An enlarged RA and RV may be An initial negative FAST may be repeated in appropriate
indicative of acute PE. As discussed previously, “kissing clinical settings. A positive examination in presence
sign” on PLAX view may be observed in hypovolemia. of hemorrhagic shock may call for urgent operative
The IVC diameter and its variation with respiration management. The extended FAST (eFAST) evaluation,
must be determined to assess volume status. Finally, in the setting of thoracic trauma, is done to incorporate
the presence or absence of B profile on lung ultrasound ultrasonographic examination of anterior chest, lateral
chest and the heart through the subcostal view. Such BIBLIOGRAPHY
an examination may pick up pericardial tamponade, 1. Bouhemad B, Zhang M, Lu Q, et al. Clinical review: Bedside
pneumothorax and/or hemothorax. Hence, the “point of lung ultrasound in critical care practice. Crit Care. 2007;
11(1):205.
care” US is considered to be a best imaging method for 2. Chacko J, Brar G. Bedside ultrasonography: Applications in
emergent assessment of thoracic and abdominal trauma. critical care: Part I. Indian journal of critical care medicine:
peer-reviewed, official publication of Indian Society of
ADVANTAGES AND LIMITATIONS Critical Care Medicine. 2014;18(5):301.
3. Di Bello C, Koenig S. Diagnosis of deep venous thrombosis by
Critical care sonography has found widespread critical care physicians using compression ultrasonography.
acceptance because of certain advantages. It is a bedside Open Crit Care Med J. 2010;3:43-7.
modality which may be done rapidly to help in making 4. Ha YR, Toh HC. Clinically integrated multiorgan point of care
ultrasound for undifferentiated respiratory difficulty, chest
a diagnosis or to follow up patients after therapeutic pain, or shock: a critical analytic review. J intensive Care.
interventions. The patients do not need to be transferred 2016;4:54.
out of the ICU for the procedure and there is no exposure 5. Karim A, Arora VK. Applications of ultrasonography in
respiratory intensive care. Indian J Chest Dis Allied Sci.
to ionizing radiation. Significantly, the inter and intra
2014;56(1):27-31.
observer variability is small (<5%). 6. Kilker BA, Holst JM, Hoffmann B. Bedside ocular ultrasound
The goal directed USG also has its limitations. It is in the emergency department. European Journal of
limited in scope and requires formal training to acquire Emergency Medicine. 2014;21(4):246-53.
7. Lichtenstein DA, Meziere GA. Relevance of lung ultrasound
necessary knowledge and skills in image acquisition in the diagnosis of acute respiratory failure: the BLUE
and image interpretation. Fortunately, the time required protocol. Chest. 2008;134(1):117-25.
to achieve these skills is short except those needed to 8. Lichtenstein DA, Mezière GA. The BLUE-points: three
standardized points used in the BLUE-protocol for ultrasound
identify pneumothorax. It may be difficult to conduct an
assessment of the lung in acute respiratory failure. Crit
USG evaluation in obese patients and in patients with Ultrasound J. 2011;3:109-10.
large thoracic dressings and subcutaneous emphysema. 9. Lichtenstein DA. BLUE-protocol and FALLS-protocol: two
To conclude, point of care US should complement applications of lung ultrasound in the critically ill. Chest.
2015;147(6):1659-70.
clinical examination of the critically ill patients. It may 10. Lichtenstein DA. Lung ultrasound in the critically ill. Ann
be utilized to make swift diagnosis of life threatening Intensive Care. 2014;4(1):1.
emergencies so that appropriate interventions may be 11. Seif D, Perera P, Mailhot T, et al. Bedside ultrasound in
resuscitation and the rapid ultrasound in shock protocol.
carried out immediately to save lives. More and more
Crit Care Res Pract. 2012;2012:503254.
intensivists should undergo training to utilize US to its 12. Whitson MR, Mayo PH. Ultrasonography in the emergency
maximum potential. department. Critical Care. 2016;20(1):227.
CHAPTER
159
Imaging Parameters in Pulmonary
Thromboembolism
Priya Jagia, Niraj Nirmal Pandey
INTRODUCTION TABLE 1: Different radiologic tests available for patients with

suspected PE ± DVT
Pulmonary embolism (PE) is a condition difficult to
Ventilation-perfusion (V/Q) scintigraphy
diagnose due to its nonspecific clinical presentation.
However, early diagnosis of this condition is essential Single-photon emission computed tomography (SPECT)
as immediate institution of treatment gives the best Compression ultrasonography

results. Most cases of PE are consequent to deep venous Pulmonary CT angiography and indirect CT venography
thrombosis (DVT), while about 70% of patients with PE Pulmonary MR angiography and MR venography
have associated lower limb DVT. Catheter pulmonary angiography
DIAGNOSIS OF PULMONARY
EMBOLISM AND DEEP VENOUS varies with different pretest clinical probabilities of PE,
the patient’s clinical condition, availability and cost of
THROMBOSIS
the particular modality, inherent risks accompanying
A diagnosis of PE cannot be reliably excluded nor
exposure to iodinated contrast medium and ionizing
confirmed solely on the basis of clinical examination,
radiation.
symptomatology and use of routine laboratory tests.
However, combining these variables can be used
IMAGING MODALITIES
to determine the clinical probability of PE. Recent
guidelines advocate the clinical probability assessment Chest Radiograph
of PE before deciding upon the diagnostic modality to be Chest radiograph depicts abnormalities in most cases
used. of pulmonary embolism but the findings are most
Estimation of plasma d-dimer levels has been shown often non-specific. The classic radiographic findings
to have a high negative predictive value (NPV) and a low of pulmonary infarction include a Hampton’s hump
positive predictive value (PPV) for the diagnosis of PE. (a wedge-shaped, pleural-based triangular opacity) or
Hence, it is the diagnostic test of choice in patients with a the Westermark sign (focal oligemia). Although these
low to moderate pretest probability of PE. findings are highly suggestive of pulmonary embolism,
Various radiologic tests are utilized in the diagnostic they are not frequently observed. Other findings include
algorithm of PE and DVT and they are listed in Table 1. a prominent central pulmonary artery, presence of right
The diagnostic modality adopted in a particular scenario sided chamber enlargement and pulmonary edema.
A normal chest radiograph in a patient presenting TABLE 2: Diagnostic criterion employed in CT angiography for the
with severe dyspnea and hypoxemia, in the absence of any diagnosis of acute and chronic PE
evidence of bronchospasm or a cardiac shunt, strongly Acute PE
suggests the presence of pulmonary embolism. Occluded artery due to a large filling defect with the diameter of
the involved artery seen to be larger than the adjacent uninvolved
vessel
Ventilation-Perfusion Scintigraphy
Partial intraluminal filling defect outlined by contrast (Figs 1 and 2)
or SPECT
Peripheral filling defect within the lumen forming an acute angle
Before the advent of CT pulmonary angiography, with the vessel wall (Figs 1A and 2)
V/Q scan or SPECT showing ventilation/perfusion Other nonspecific findings which may be observed include:
mismatch were the main diagnostic modalities used. zz Peripheral wedge shaped infarcts in the lungs
zz Linear band like opacities

However, these frequently have intermediate probability
(nondiagnostic) scans which necessitate supplementary Chronic PE
diagnostic testing. Occluded artery due to a filling defect with the diameter of the
involved artery seen to be smaller than the adjacent uninvolved
vessel
Compression Ultrasonography and CT Peripheral filling defect within the lumen forming an obtuse angle
Venography for DVT with the vessel wall (Figs 3A and B)
Compression ultrasonography (CUS) of the lower limb Contrast opacified vessels showing smaller lumen and thicker walls
venous system is the modality of choice for diagnosing – representing recanalized vessels
DVT, owing to its high sensitivity (>90%) and specificity Contrast opacified vessels showing webs or membranes within
(Fig. 3D)
(about 95%) for proximal DVT.
Eccentric vessel wall thickening with calcification
CT venography may be done along with pulmonary CT
Abnormal vessel tapering and “cutoffs” (Fig. 3C)
angiography using a single intravenous contrast injection
In chronic thromboembolic pulmonary hypertension (CTEPH):
but it only marginally enhances the DVT detection rate zz Dilated central pulmonary arteries, often larger in diameter than
while significant increasing the amount of ionizing the aorta, with or without calcified walls
zz RV hypertrophy along with right atrial enlargement
radiation and hence is not routinely recommended.
zz Presence of bronchial or systemic collaterals
zz Mosaic perfusion in the lungs (Fig. 4B)
CT Pulmonary Angiography
With the advent of multidetector computed tomography
ECG gated CT angiography: Obtaining retrospective
(MDCT) scanners, CT angiography has become the
ECG gated scans produces less motion artefacts and also
modality of choice for imaging the pulmonary vessels
enables functional assessment of right ventricle (RV).
for suspected embolism owing to its high spatial and
The latter helps to prognosticate patients as presence of
temporal resolution. It has been accepted as the standard
RV dysfunction is associated with worse prognosis.
diagnostic test in patients with a high pretest probability
of PE, and also in patients having low to moderate pretest Triple rule out CT: It is a tailored ECG-gated examination
probability but with concurrent positive d-dimer test. planned to enable simultaneous assessment of the
The findings seen on CT angiography for the diagnosis coronaries and the aorta along with the pulmonary
of acute as well as chronic PE are listed in Table 2. vasculature and adjacent intrathoracic structures, in
MDCT angiography has a high sensitivity (83%), a patient presenting with atypical acute chest pain.
specificity (96%), PPV (86%) and NPV (95%) for diagnosis Although it is an attractive option for evaluation and
of PE. The positive predictive value however varies triaging of patients with chest pain in the emergency
according to the location of the embolus with values of department, its use is associated with increased radiation
97%, 68% and 25% when PE is in main or lobar artery, exposure and hence is recommended in selected cases
segmental and sub-segmental arteries respectively. only.
CHAPTER 159: Imaging Parameters in Pulmonary Thromboembolism 937
A B
Figs 1A and B: Acute pulmonary embolism. CT Pulmonary angiogram (A) axial and (B) coronal images demonstrates a partial filling defect
(*) within the left descending pulmonary artery surrounded by contrast material suggestive of an acute thrombus. Axial images (A) also show
presence of thrombus (*) within the right descending pulmonary artery (RDPA) forming acute angles with the vessel wall
However, MR angiography here has many disadvan

tages with a high proportion of technically inadequate
studies, longer examination times, limited availability,
and various contraindications to MRI that might be
present in patients e.g. implanted pacemakers.
Recent studies advocate use of pulmonary MR
angiography only in patients having contraindications to
standard diagnostic tests.
Catheter Pulmonary Angiography

In the current era, it has no role for the purpose of
diagnosis only. Poor visualization of small thrombi
and subsegmental arteries has limited the use
Fig. 2: Acute central pulmonary embolism. Oblique coronal CT of catheterization to only when catheter directed
pulmonary angiogram images demonstrates acute thrombus (*) thrombolysis is being done simultaneously.
within the right pulmonary artery (RPA) extending into the right
descending pulmonary artery (RDPA)
ASSESSMENT OF PULMONARY
Dual energy CT: Dual-energy pulmonary CT angiography EMBOLISM SEVERITY AND
can provide high-quality morphologic analysis and PROGNOSTICATION
functional information on the pulmonary circulation Stratification of the risk is imperative as the subsequent
from the same dataset, along with generation of workup, monitoring, and treatment of PE varies vastly
pulmonary perfusion maps. with the overall prognosis. The cause of death in patients
with fatal PE is typically rapid onset RV failure with
Pulmonary MR Angiography circulatory collapse. Hence, RV dysfunction should
With MR pulmonary angiography, besides detection be identified promptly to recognize patients in whom
of the embolus, functional assessment of the RV is also thrombolytic therapy would be of benefit. Pulmonary
possible which helps in prognostication. CT angiography can also assess the RV function. The
A B
C D
Figs 3A to D: Chronic pulmonary embolism. Oblique coronal CT pulmonary angiogram image (A) shows presence of peripheral filling defect
(indicated by arrows) in the left pulmonary artery (LPA) forming obtuse angle with the vessel wall, suggestive of chronic thrombus. Coronal
image (B) shows extension of the chronic thrombus (*) into the left descending pulmonary artery (LDPA). Maximum intensity projection images
(C) show presence of abnormal tapering of the upper lobe branches. Coronal CT pulmonary angiogram images (D) of another patient shows
presence of web (indicated by thick arrow) within the left descending pulmonary artery (LDPA)
ancillary findings used to diagnose RV dysfunction are TABLE 3: Various measurements made on pulmonary CT
enumerated in Table 3. Volumetric assessment of the RV angiography and ancillary findings used to diagnose RV
dysfunction
along with calculation of LV and RV ejection fractions is
possible on ECG-gated CT angiography. RV size to left ventricle (LV) size ratio in short axis view more than 1
(Fig. 4A)
Thrombus burden scores can be used to assess
the severity of PE. These include angiographic scores Ratio of diameters of the main pulmonary artery diameter to that
of aorta greater than 1
adapted for CT such as Miller and Walsh scores along
Presence of a dilated IVC with or without reflux of contrast into the
with dedicated CT scores such as the Qanadli and
IVC
Mastora scores. However, it has been shown that central
Leftward bowing or S-shaped configuration of the interventricular
location of the embolus is more important in predicting
septum (Fig. 4B)
short term mortality in patients with PE rather than the
total percentage of pulmonary obstruction.
CHAPTER 159: Imaging Parameters in Pulmonary Thromboembolism 939
A B
Figs 4A and B: (A) CT scan reveals that the right ventricle (RV) (short axis diameter) is wider than that of the left ventricle (LV) with mild leftward
bowing of the interventricular septum (*), indicating presence of right ventricular strain. (B) Axial CT images (lung window) shows mosaic
attenuation in both lungs in the presence of chronic thrombus in both right and left interlobar arteries
Flow chart 1: Proposed diagnostic algorithm in a patient with suspected pulmonary embolism
DIAGNOSTIC ALGORITHM IN A PATIENT investigation of choice for suspected PE. Pulmonary

OF SUSPECTED PE MR angiography is recommended in cases where a CT
angiography is contraindicated. Presence of central
In patients of suspected PE with low or moderate pretest
location of thrombus and RV dysfunction are two most
probability, and a negative d-dimer test, no further
important factors affecting the prognosis in these
testing is warranted. However, patients with low or
patients.
moderate pretest probability and a positive d-dimer
test, should undergo further evaluation with preferably a BIBLIOGRAPHY
pulmonary CT angiography. Patients with a high pretest 1. Hutchinson BD, Navin P, Marom EM, Truong MT, Bruzzi JF.
probability should directly undergo imaging evaluation Overdiagnosis of pulmonary embolism by pulmonary CT
with a CT angiography (Flow chart 1). angiography. Am J Roentgenol. 2015;205(2):271-7.
2. Kohli A, Rajput D, Gomes M, Desai S. Imaging of pulmonary
CONCLUSION thrombo-embolism. Ind J Radiol Img. 2002;12:207-12.
3. Ohno Y, Yoshikawa T, Kishida Y, Seki S, Karabulut N.
With the development of higher generations of
Unenhanced and contrast-enhanced MR angiography
multidetector computed tomography (MDCT), CT and per fusion imaging for suspected pulmonar y
pulmonary angiography is now considered as the thromboembolism. Am J Roentgenol. 2017;208(3):517-30.
4. Qanadli SD, El Hajjam M, Vieillard-Baron A, Joseph T, 7. Stein PD, Fowler SE, Goodman LR, Gottschalk A, Hales CA,
Mesurolle B, Oliva VL, et al. New CT index to quantify Hull RD, et al. Multidetector computed tomography for acute
arterial obstruction in pulmonary embolism: comparison pulmonary embolism. N Engl J Med. 2006;354(22):2317-27.
with angiographic index and echocardiography. Am J 8. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè
Roentgenol. 2001;176(6):1415-20. N, Pruszczyk P, et al. Guidelines on the diagnosis and
management of acute pulmonary embolism: the Task Force
5. Sadigh G, Kelly AM, Cronin P. Challenges, controversies,
for the Diagnosis and Management of Acute Pulmonary
and hot topics in pulmonary embolism imaging. Am J
Embolism of the European Society of Cardiology (ESC). Eur
Roentgenol. 2011;196(3):497-515. Heart J. 2008;29:2276-315.
6. Sostman HD, Stein PD, Gottschalk A, Matta F, Hull R, 9. Wittram C, Maher MM, Yoo AJ, Kalra MK, Shepard JA, McLoud
Goodman L. Acute pulmonary embolism: sensitivity and TC. CT angiography of pulmonary embolism: diagnostic
specificity of ventilation-perfusion scintigraphy in PIOPED II criteria and causes of misdiagnosis. Radiographics. 2004;
study. Radiology. 2008;246(3):941-6. 24(5):1219-38.
INDEX
Note: Page numbers followed by f or t represent figures or tables respectively.
A Acute coronary syndrome (ACS), 867 thrombolysis and endovascular

in dual antiplatelet therapy (DAPT), therapy, 388
AAA. See Abdominal aortic aneurysm
91 Acute kidney injury (AKI), 457
(AAA)
duration of dual antiplatelet therapy Acute necrotic collection (ANC), 428,
Abatacept, 292–293
in patients presenting with, 430
Abdominal aortic aneurysm (AAA), 933 92–93 management of, 431–432
Abdominal ultrasonography, 933 treated with CABG, 93 Acuteonchronic liver failure (ACLF),
ABG analysis. See Arterial blood gas treated with fibrinolysis, 92 461
(ABG) analysis treated with medical therapy alone, Acute pancreatic fluid collections
ABO-incompatible (ABOi) KT, 846–848 92 (PFC), 428
accommodation, 847 treated with PCI, 92–93 management, 431–432
and blood groups, 847 Acute disseminated encephalomyelitis Acute pancreatitis, 243, 421–432
complications, 848 (ADEM), 395–396, 396f, 397t, classification, 422t, 424–426,
desensitization and, 847–848 398, 398t, 399f 425t–426t
historical perspective, 846 Acute encephalitis syndrome (AES), clinical features, 423
pathogenesis, 847 556–561
diagnosis, 423
Absence seizures, 378 case definition, 556
differential diagnosis, 423
Acarbose, 449 cerebrospinal fluid study, 559
endoscopic retrograde cholangio
ACE inhibitors (ACEI), 69, 868 clinical features, 558
pancreaticography (ERCP),
and ARB, 77 diagnosis, 558–559 428, 428f
Acetaminophen, 823 electroencephalography, 559 enzymes, 423
Acetic acid, 437 epidemiology, 557–561 etiopathogenesis, 421, 422t, 424f
ACLF. See Acuteonchronic liver failure etiology, 556, 557t imaging, 423, 424f
(ACLF) imaging, 558–559, 559f incidence, 421
ACOS. See Asthma chronic obstructive and JE, differentiation of, 558 indications, 432
plumonary disease (COPD) prevention and control, 560
management (acute phase), 427f
overlap syndrome (ACOS) recent trends, in India, 561
antibiotics as prophylaxis and
Acquired immune deficiency syndrome serology, 559 treatment, 427
(AIDS). See HIV/AIDS transmission, 557 fluid resuscitation, 426–427
ACS. See Acute coronary syndrome treatment of, 559–560, 560t nutrition, 427
(ACS) Acute inflammatory demyelinating pain alleviation, 426
Actinobacteria, 436 polyradiculoneuropathy
management (early phase), 428–432
Acute cardiorenal syndrome, 138, 141 (AIDP), 398–400, 399f, 400t
acute necrotic collection (ANC),
Acute chest syndrome. See also Sickle Acute ischemic stroke, thrombolysis
428, 430, 431–432
cell disease (SCD) for, 386
acute pancreatic fluid
aplastic crisis, 612 complications, 387–388
collections (PFC), 428,
hydroxyurea, role of, 612–613 dosage, 387
431–432
hyperhemolytic crisis, 612 intraarterial tPA, 388
indications, 432
initial management, 611–612 outcomes, 386–387
pancreatic ductal disruption
priapism, 612 rates of, 386 (PDD), 430–432, 431f
sequestration crisis, 612 sonothrombolysis, 387 percutaneous/Endoscopic/
stroke, 612 telestroke, 387 Surgical procedures,
transfusions, role of, 613 tenecteplase, 387 432
942 Medicine Update 2018
walled-off necrosis (WON), 428, etiology, 415, 415t newer vaccines, 627
430, 431–432 incidence rates, 415 dengue, 627
mortality against, 422t management, 416, 419f hepatitis E, 627
overview, 421 medical therapy, 417 HIV/AIDS, 627
prevention, 432 prevention of re-bleed, 419, 419f malaria, 627
scoring systems, 424–426, 425t–426t risk factors, 415–416 pneumococcal vaccine, 625
severity assessment, 424–426, stigmata of recent hemorrhage typhoid vaccine, 626–627
425t–426t (SRH), 417 varicella and zoster (shingles)
Acute peripheral vestibulopathy, 404 surgical treatment, 418 vaccines, 624–625
Acute pulmonary embolism (PE), Adaptive immune system, HBV yellow fever vaccine, 626
153–155, 153t infection and, 466–467 Adult-onset GHD (AOGHD), 313.
Acute renal failure, infective ADEM. See Acute disseminated See also Growth Hormone
endocarditis, 131 encephalomyelitis (ADEM) Deficiency (GHD)
Acute renocardiac syndrome, 138–139, Adenosine triphosphate citrate lyase AECC. See American-European
141 inhibitor, 215 consensus criteria (AECC)
Acute respiratory distress syndrome Adhesive capsulitis of the shoulder AED. See Antiepileptic drug (AED)
(ARDS), 508–512 (ACS), 204 Aedes albopticus, 586, 821
Berlin definition vs. AECC Adipocytokine signaling pathways,
definition, 508, 509t Aerobic exercise, 303
NAFLD-related HCC risk and,
defined, 508, 509t AES. See Acute encephalitis syndrome
444
(AES)
diagnosis, 508, 509t Adipose tissue (AT)
Affective psychosis, seizure, 378
fever with, 564 composition, 192
Age/ageing, 861–862, 861f. See also
management, 508, 510t, 511–512, macrophage infiltration in white,
Geriatrics
511t 192–193
ACOS incidence and, 501
extracorporeal membrane Adjunctive therapies, in CAP, 531
oxygenation (ECMO), blood pressure changes with, 41–42
Adolescents
512 high altitude and, 41
ambulatory blood pressure
higher PEEP, 512, 512t monitoring in, 13 ‘newer oral anticoagulants’
low tidal volume ventilation, (NOACs), 88
growth phase, 334
508, 511 status epilepticus (SE), 381
Adoptive cell therapy (ACT), 802
prone positioning, 511 Age-related demographics, 28
A-DROP, 528
recruitment maneuvers, 512 AIDP. See Acute inflammatory
Adult immunization, 622–627. See also
mimics, 509t demyelinating
Vaccines/vaccination
recognition, 508, 509t polyradiculoneuropathy
cholera vaccine, 626
risk factors, 509t Air pollutants, sources, 200–201
diphtheria, pertussis and tetanus
vs. CPE, 509t Air pollution, 533–535
vaccines, 624
Acute rheumatic fever diabetes and, 200–201, 200f
Hemophilus influenzae vaccine,
medical treatment, 124 626 effects on different organs
mitral valvuloplasty, 124, 124f hepatitis A vaccine, 624 cardiovascular system, 534
surgical treatment, 124 hepatitis B vaccine, 622–624 gastrointestinal system, 535
Acute symptomatic seizure, 372 HPV vaccine, 626 nervous system, 535
Acute tubular necrosis (ATN), 453 indications and dose schedule, 622, pregnancy and, 535
Acute upper gastrointestinal (UGI) 623t psychiatry, 535
bleeding, 415–419 influenza vaccine, 626 respiratory system, 534
angiographic therapy, 418–419 Japanese encephalitis vaccine, 626 urinary system, 535
clinical presentation, 416 measles, mumps and rubella global effects, 533
endoscopic therapy, 417–418, 417t, vaccine, 624 health effects, mechanisms, 533
418t meningococcal vaccine, 625 pollutants types, 534
Index 943
Airways prediction of CV events, 8–9 due to blood loss, 876–877

diseases related to, dyspnea and, suspected white-coat HTN, 7–8 etiological spectrum of, 876, 876f
485 elderly patients, 13–15 etiology of, 876–878, 877t
protection, UGI bleed and, 416 fundamentals of, 7 hemolytic, evaluation of, 880
Albiglutideis, 241 guiding management of HTN, 9–10 investigations in, 878–880, 879t
Albumin, with vasoconstrictors, for patients with atrial fibrillation, 13 iron deficiency, evaluation of, 879
HRS treatment, 454 position in hypertension guidelines, macrocytic, evaluation of, 879–880
midodrine with octreotide, 454 13 management of, 880–881
noradrenaline, 454 pregnant women, 13–15 Anesthetics, super-refractory status
terlipressin, 454 AME. See Autoimmune mediated epilepticus, 382
Albuminuria, 140 encephalopathy (AME) Angina, 83–84
Albunimuria/proteinuria, 849–850, American Academy of Neurology Angiogenesis–chemotherapy model,
850t (AAN), 374 806
Alendronate, 833 American Diabetes Association (ADA), Angiography
173–180 for polyarteritis nodosa, 818
Alirocumab, 77
American-European consensus criteria for UGI bleeding, 418–419
Alkalinization, of urine, 682–683
(AECC), 508 Angioplasty, renovascular hypertension
Allogeneic HSCT, 760, 764–766
definition of ARDS, 508, 509t (RVHT), 31
Alogliptin, 187, 188t, 189t
American Society of Hypertension/ Angiopoietin like 3 (ANGPLT-3), 216
Alpha-1 adrenergic blockers, 70 Angiotensin-converting enzyme (ACE)
International Society of
Alpha-blocker agents, nocturia, 365 inhibitors, 198
Hypertension (ASH/ISH), 21
Aluminium phosphide poisoning Angiotensin converting enzyme
American Thoracic Society (ATS), 500,
(celphos poisoning), 737 inhibitors, isolated systolic
525
AMBITION trial, 127 hypertension (ISH), 47
Amylase, 423
Ambulatory, automatism, 377 Angiotensin II receptor blockers (ARB),
Anabolic failure, 80
Ambulatory blood pressure monitoring 198, 868
Anabolic therapy, 832
(ABPM), 10–11, 11f American Society of Hypertension/
Anaerobic exercise, 303 International Society of
additional information derived
from, 10, 10t Anagliptin, 188t, 189t Hypertension (ASH/ISH),
Anakinra, 295 21
assessment of treatment, 11–13, 12f
Analgesia, SCD and, 611 beyond blood pressure lowering
blood pressure variability, 6–7, 6f
ANC. See Acute necrotic collection effects, 18
challenges in using in special Eighth Joint National Committee
population, 13 (ANC)
ANCA-associated vasculitis (AAV), 816 JNC VIII, 21
obese patients, 13 European Society of Cardiology
children and adolescents, 13 Anemia, dyspnea due to, 485
(ESC) Hypertension
in diabetes patients, 10 Anemia, in CKD, 854–857 Management Guidelines
as diagnostic tool, 7–10 diagnosis of, 854 2016, 21
ABPM guiding management of evaluation of, 854 evolution of, 17–18, 18t
HTN, 9–10 future options, 857 Indian Guidelines of Hypertension,
ABPM in diabetes patients, 10 iron therapy for, 854–855, 854t 21
additional information derived management of, 854 isolated systolic hypertension (ISH),
from ABPM, 10, 10t therapies for, 856–857 47–48
ambulatory BP measurements treatment of, 880 recommendations from the
vs. home Kidney Disease Outcomes
Anemia, in elderly, 876–881
measurements, 9 Quality Initiative (KDOQI)
of chronic diseases/inflammation, Guidelines for Treatment
dippers vs. nondippers, 8, 8t 878 of Hypertension Associated
masked hypertension, 8 classification of, 876–878, 877t with Chronic Kidney
night-time blood pressure, 8, 8t diagnosis of, 878 Disease, 21–22
Antibiotic resistance medications, 59–61 Anxiety, postmenopausal

alternates use and, 718 Anti-inflammatory drugs, 77, 195 hypertension, 25
defined, 716 Antimicrobial therapy Aortic dissection, 135–136
genetic transmission of bacterial in CAP APACHE, 424
resistance, 717 in inpatients, ICU, 530, 530t Apnea hypopnea index (AHI), 497
judicial use of antibiotics and, 718 in inpatients, nonICU, 530 Apnea-waking cycles, 495
mechanisms, 716–717 international guidelines, 530, Apolipoprotein A1 (Apo A1) mimetics,
microbiology laboratory, 718 531t 215
newer interventions, 718 in outpatient setting, 529, 529t Apolipoprotein B (Apo B)
threat in India, 718 treatment protocol for, 530–531 antisense oligonucleotide against,
214
Antibiotics infective endocarditis, 129–132, 130t
Arbovirus(es)/arboviral infections, 545,
early and empiric, in sepsis, 700– Antineutrophil cytoplasmic antibody
547–552
703 (ANCA), 816
chikungunya, 551
de-escalation, 701 Antiplatelet therapy, in OSA, 498
classification, 547, 547t
duration of therapy and dosing, Antiresorptive therapy, 832
701–702 clinical findings, 548
Antiretroviral drug toxicity, 657, 658t
first dose administration time, Crimean-Congo hemorrhagic fever
Antiretroviral therapy (ART)
700–701 virus (CCHFV), 552
for HIV infections, 652–658
monotherapy vs combination dengue, 550–551
antiretroviral drug toxicity, 657, epidemiology, 548
therapy, 701 658t
regimen selection, 702–703, Japanese encephalitis (JE), 549–550
considerations before initiation
702t–703t Kyasanur forest disease, 551–552
of, 654–656, 655f
judicial use of, 718 overview, 547
first line regimen selection, 656,
as prophylaxis, in acute pancreatitis, 656t transmission, 547–548, 548f
427 goals, 652, 652t vaccination, 548–549
UGI bleed and, 417 integrase inhibitors, 653, 654t yellow fever vaccine, 549
Antibodies, multiple cranial nerve neurological manifestations, 666 ARDS. See Acute respiratory distress
palsy, 361 syndrome (ARDS)
non-nucleoside reverse
Anti-CD20, 292 transcriptase inhibitors, Arginine vasopressin (AVP), urinary
Anti-CD3 antibodies, 292 653 volume, 363
Anticoagulants poisoning, 740 nucleoside/nucleotide reverse Array technology, 914
Anticoagulations, PE and, 154 transcriptase inhibitors, Arrhythmias, 117, 149
Antidiabetic medicines, 183–184 653 ART. See Antiretroviral therapy (ART)
Antidiuretic hormone (ADH), patient monitoring, 656–657, Artemisinin based combination
nonosmotic release of, 452 657t therapy (ACT), 574, 574t
Antidiuretic therapies-Desmopressin, principles, 653, 653t Arterial blood gas (ABG) analysis,
nocturia, 365 protease inhibitors, 653 705–714
Antiepileptic drugs, super-refractory regimens, 656 accuracy of, 705–706
status epilepticus, 382 treatment failure, 658 acid base analysis, 709–710, 710t
Antiepileptic drug (AED) therapy, 371, Antisense approach against in ARDS, 508
372, 374 lipoprotein, 215 blood samples collection and
Antihyperglycemic agents, 187, 265 Antisense molecules, HBV infection transportation, 705
Antihyperglycemic therapy, 284 and, 466 case history/provisional diagnosis,
Antihypertensives Antisense oligonucleotide against 710–714
high altitude systemic apolipoprotein B (Apo B), 214 in dyspnea, 491
hypertension, 42–43 Anti-TB drugs, 553 eectrolyte analysis, 707–709, 708f
isolated systolic hypertension (ISH), Antithyroid drug (ATD), thyroid gas analysis, 706–707, 707f
47–48 nodule, 338 methods, 705–710
Index 945
Arterial stiffness, postmenopausal cholesterol absorption inhibitor, 77 Autoimmune mediated

hypertension, 26 ACE inhibitors and ARB, 77 encephalopathy (AME), 395–
Arthralgia, chikungunya virus and, 821 alirocumab, 77 396, 396f, 398, 398t, 399f
Arthritis, 817 anti-inflammatory agents, 77 Autologous HSCT, 760, 763–764
Arthropod vectors, 505–506 evolocumab, 77 Automatism, seizure, 377–378
AS1842856 (forkhead transcription fibrates, 77 Autonomic dysfunction, urinary
factor), 295 volume, 364
hypertriglyceridemia, 77
Ascites Azathioprine, 828
PCSK-9 inhibitors, 77
large volume, 457 NMO, 369
common risk factors for, 75t
low volume, 457 Azilsartan
CT coronary angiography, 76
moderate volume, 457 cardio-renal protection, 20–22
drug therapy, 76–77
treatment of, 456–457 direct AT1R effects of, 19
intravascular ultrasound (IVUS), 76
Aseptic meningitis, 600 guidelines recommendations
management of, 76 on management of
Aspirin, 415, 419
optical coherence tomography hypertension secondary to
allergy, 95, 95t (OCT), 76 renal impairment, 21–22
PE and, 154 overview, 73 pleiotropic effects beyond BP
resistance, 94–95, 95t prevention and risk factors, 75t, 76 lowering, 19–20
Asthma chronic obstructive plumonary statins, 76–77, 76t potent AT1 receptor binding, 19
disease (COPD) overlap tolerability, 18–19
Atherosclerotic cardiovascular disease
syndrome (ACOS), 500–502
(ASCVD), 212–213 unique features of, 22
age and, 501
Atma. See Soul
clinical features, 501
Atrial fibrillation (AF)
contributing factors, 501 B
cather ablation of, 163
defined, 500 BACTEC MGIT 960 system, 577f
echocardiographic navigation in
diagnosis, 501–502 management of, 158–166 Bacteria/bacterial infections, 545. See
higher frequency of, 501
left atrial appendage structure also specific names
incidence, 500–501 and function, 163–166, HIV/AIDS and, 669–670
overview, 500 164f, 165f nonspecific, at different sites, 593
pathogenesis, 501 left atrial function assessment, TTIs of, 543
pre-existing respiratory illness and, 161–162, 161f Bacteroides, 437
501 left atrial/left atrial appendage Bacteroidetes, 436, 475
prognosis, 502 clot, 158–159, 158f–159f Balloon atrial septostomy, 128
sex and, 501 left atrial size, 159–160, 160f Basal-bolus insulin treatment, 271f
smoking status and, 501 role of LA function assessment Basal insulin, 221–222
treatment, 502 in clinical decision
barriers to, in type 2 diabetes
Asymptomatic hyperuricemia, 811 making, 162–163
mellitus, 222–223
evaluation of patients with, 813 incidence of, 157
concept and evolution of, 221–222
treatment of, 813–814 outcomes after cardioversion, 162
Baseline dyspnea index (BDI), 489
Atherosclerosis overview, 157–158
Bedaquiline, for M/XDR-TB, 554
assessment of, 75 prediction of, 162 Bedside eye ultrasound evaluation, 931
assessment of plaque morphology, prevalence of, 157 Bedside Index of Severity in Acute
76 Atrial septostomy, 128 Pancreatitis (BISAP) score,
cardiac CT and calcium scoring, 75 Atypical mycobacterial IRIS, 674 424, 425t
cardiac MRI (CMRI), 76 Autism, 472 Behavioral methods, OSA and, 498
carotid intima-media thickness Auto Fuel Policy (2002), 535 β-endorphin, 685
(CIMT), 75–77 Auto Fuel Vision Committee, 535 Bendroflurazide, 34
Benign paroxysmal positional vertigo Bisphosphonates, for osteoporosis, Body weight, metformin and, 263–264
(BPPV), 406–407 832–833 Bone age, 335
Benign prostatic hyperplasia (BPH), Bladder relaxant therapies, nocturia, Bone marrow
nocturia, 366 365 biopsy, 879
Benzodiazepines poisoning, 740–741 Bleeding examination, 878
Berlin definition, of ARDS, 508, 509t re-bleeding, 417, 419 BOOST Trial, 868
vs. AECC definition, 508, 509t UGI (See Acute upper Brain, DM and, 187
Bernard score, 424 gastrointestinal (UGI)
Brain natriuretic peptide (BNP), 491
Beta adrenergic blocking agents, 70 bleeding)
Brainstem lesions
alpha-1 adrenergic blockers, 70 Blood, multiple cranial nerve palsy, 361
multiple cranial nerve palsy
centrally acting alpha-2 agonists, 70 Blood cultures, CAP investigations and,
526 causes of, 359–360
side effects, 70 diagnosis, 361
Blood pressure (BP)
Beta blockers, high altitude systemic intermediate syndrome, 361
hypertension, 42 ageing and, 41
investigations in, 361
Bethesda System of reporting thyroid ambulatory measurements vs.
home measurements, 9 sites of lesion, 360–361, 360t
cytology (TBSRTC), 338
azilsartan and, 19–20 British Thoracic Society (BTS), 525
Bhakti Yoga, 898
behaving with aging in people guidelines, 530, 531t
Bifidobacterium, 437, 440
chronically exposed to high Bronchoscopy, 597
Biofilms, production of, 717
altitude, 42 of SPN, 520–521
Biomarkers
changing with aging, 41–42 Bronchus sign, SPN, 517
ACOS assessment and, 501
control of, 852 Bruising, lipohypertrophy (LH), 348,
of AKI, 141 350
conclusion and perspectives, 54
in CAP, 528 Butter, 904
improving the impact of
in cardiorenal syndrome (CRS), guidelines, 53–54, 53t Butyric acid, 437
140–141, 140t
JNC 1974 to 2003 (1 to 7), 51–54, By-products, 199
in heart failure, 97–99 51t–53t
cardiac troponin, 98 management of hypertension,
diagnosis, 97–98 50–51 C
HFpEF, 98–99 hypertension in diabetes, 56–57 CABG. See Coronary artery bypass
overview, 97 night-time, 8, 8t grafting (CABG)
prognostic value of NP, 98 in OSA, 498 CAD. See Coronary artery disease
in HRS, 453 variability, 6–7, 6f (CAD)
in sepsis, 695–698 Blood pressure instruments, 70–71 Calcineurin inhibitors (CNIs), 843
applications, 695, 695t benefits of automated, 71 Calcitonin, and osteoporosis, 833
combinations, 698 blood pressure monitoring, 71 Calcium channel blockers, 69
C-reactive protein (CRP), features, 71 ACE inhibitors, 69
697–698 pressure and target organ damage, action, 69
diagnostic criteria, 695–696, 696t 71 isolated systolic hypertension (ISH),
examples, 697t time of measurement, 71 47
ROC curves, 696, 696f Blood tests side effects, 69
Biopsy of donor for FMT, 474 Calcium scoring, 75
liquid, 916 in dyspnea, 491 Calcium-sensing receptor (CSR), 341
for polyarteritis nodosa, 818 Blood transfusion, 881 Canaglifozin, 853
Birth, 890 B-lymphocytes, 292 Cancer biology, 264
BISAP score. See Bedside Index of BODE index (Body mass index, airflow Cancer(s), 913
Severity in Acute Pancreatitis obstruction, dyspnea, immunotherapy for, 914
(BISAP) score exercise capacity), 502 infection associated, 539–542
Index 947
agents, 540, 541t Cardiac troponin, 98, 140 Carpal tunnel syndrome (CTS), 204–
chlonorchis, 540 Cardiogenic pulmonary edema (CPE), 205
detection and proving 508 Cartridge Based Nucleic Acid
association of agents, vs. ARDS, 509t Amplification Test (CB NAAT),
540, 541t–542t, 542 Cardiology, mega trials in, 115–120 914
Epstein Barr virus, 540 Cardiopulmonary manifestations, of Carvedilol, 456
HBV, 540 HIV/AIDS, 667–670 Catabolic activation, 80
HCV, 540 bacterial infections, 669–670 Cathelicidins, 472
Helicobacter pylori, 540 cardiotoxic drugs, 668 Catheter based reperfusion, 155
human papilloma virus, 540 coronary artery disease, 668–669 Catheter related blood stream infection
human T-lymphotropic virus fungal infections, 670 (CRBSI)-, 728
type 1, 540 malignant neoplasms, 670 Cavernous sinus syndrome, 360
IARC classification, 539–540, pericardial disease, 667–668 Cavernous sinus thrombosis, 360
540t pulmonary manifestations, 669 Cavitation, SPN, 518
incidence, 539 Cardio-renal protection, 20–22 CCHFV. See Crimean-Congo
Kaposi Sarcoma-Associated Cardiorenal syndrome (CRS) hemorrhagic fever virus
Herpes Virus, 540 biomarkers in, 140–141, 140t (CCHFV)
opisthorchis, 540 defined, 138 CD34 antibody coated stents, 868–869
pathogenesis, 539 management, 141–142 Cell biology, 913–914
Schistosoma Hematobium, 540 neurohormonal activation, 139 Centilator associated pneumonia
metronomic chemotherapy other factors, 140 (VAP), 726, 726t
(See Metronomic oxidative stress, 139–140 Centrally acting alpha-2 agonists, 70
chemotherapy) pathophysiology, 139–140, 140f Central obesity, 497
Cancer viruses, 539. See also specific renal biomarkers, 140–141, 140t Cerebrospinal fluid (CSF)
entries type CRS (secondary cardiorenal examination in meningitis, 602–603,
Candidiasis, 661 syndrome), 139 602t
CAP. See Community acquired type I (acute cardiorenal multiple cranial nerve palsy, 361
pneuomonia (CAP) syndrome), 138 study, AES and, 559
Capsid inhibitors, HBV infection and, type II (chronic cardiorenal Cerebrovascular disease, 227–228
466 syndrome), 138 EPCs in, 869
Carbohydrate metabolism, liver role type III (acute renocardiac CETP inhibitors, 214–216
in, 446 syndrome), 138–139
Chandipura virus (CHPV), 556
Cardiac biomarkers, 140, 140t, 152 type IV (chronic renocardiac
Chang sign, 490
syndrome), 139
Cardiac cachexia CHD. See Congenital heart disease
Cardiotoxic drugs, 668
anabolic failure, 80 (CHD)
Cardiovascular diseases (CVD)
catabolic activation, 80 Chest computed tomography, 152–153
dyspnea due to, 482–483, 484f
insulin resistance, 80–81 Chest radiography
NAFLD and, 444
overview, 80 of CAP, 526
OSA and, 497–498
pathophysiology, 80 in dyspnea, 490
Cardiovascular system (CVS), 912–913
skeletal muscle, 81 for pulmonary embolism, 935–936
air pollution effects on, 534
Cardiac chamber catheterization, 123 Chest radiology, SPN diagnosis, 516
GHD, 314, 318
Cardiac CT, 75 Chest wall-related diseases, dyspnea
high altitude systemic hypertension
Cardiac ICU and, 36 and, 485, 486f–487f
hypoglycemia in, 688–689 Cardioversion, immediate and short- Chikungunya fever, 551
Cardiac MRI (CMRI), 76 term outcome of, 166 vaccine for, 551
Cardiac resynchronization therapy Carotid intima-media thickness Chikungunya virus (CHIKV), 551,
(CRT), 148 (CIMT), 75–77 821–824
and arthralgia, 821 complications, 448 CMD. See Coronary microvascular

articular manifestation of, 822, 822t correlation of etiology and dysfunction (CMD)
diagnosis of, 823 severity, 447 CNIs. See Calcineurin inhibitors (CNIs)
inflammatory marker, 823 diagnosis, 448 Coconut oil, 904
and joint pain, 821–822 mechanism of, 446–447 Co-infections. See also Infection(s)
risk factors for, 822–823 medical nutrition therapy and HIV/hepatitis, 469–471
lifestyle modification,
target tissues, 821, 821t epidemiology, 469
448
CHIKV. See Chikungunya virus HIV-HBV coinfection, 470
monitoring, 448
(CHIKV) HIV-HCV coinfection, 470
pharmacotherapy, 448–449
Childhood onset (COGHD), 313. incidence rates, 469
prevalence of, 447
See also Growth Hormone overview, 469
results of study, 449
Deficiency (GHD) pathogenesis, 469–470
risk factors of DM, 447
Childhood phase, growth, 333 treatment, 470
treatment, 448–449
Children, ambulatory blood pressure vaccination, 471
monitoring in, 13 IR in
mechanism of, 446–447 Coin lesion, 514. See also Solitary
Child’s Pugh score/MELD score, 416, pulmonary nodule (SPN)
456 prevalence of, 447
Chronic obstructive pulmonary disease Cold pressed oils, 903
Chlamydia, 528 Colonoscopy, in FMT, 474
(COPD), 505
Chlonorchis, 540
Chronic renocardiac syndrome, 139, Colorectal cancer (CRC)
Chlorofluorocarbons (CFCs), 504 141 gut microbiota in, 438
Chlorthalidone (CTD), 34 CIDP. See Chronic inflammatory NAFLD and, 445
Cholera vaccine, 626 demyelinating Colorimetric redox indicator methods,
Cholesterol, 902–903 polyradiculoneuropathy for TB diagnosis, 578
Cholesterol absorption inhibitor, 77 C1- Inhibitors, 621 Coma
ACE inhibitors and ARB, 77 Circulating tumor DNA (ctDNA), 916 assessment, 733
alirocumab, 77 Cirrhosis of liver, 451, 456–461 brainstem reflexes, 735
anti-inflammatory agents, 77 ACLF, 461 defined, 733
evolocumab, 77 ascites, 456–457 etiology and pathogenesis, 733, 734t
fibrates, 77 hepatic encephalopathy, 457
history, 733
hypertriglyceridemia, 77 HRS, 457, 458t [See also investigations, 735–736
Hepatorenal syndrome
PCSK-9 inhibitors, 77 neurologic examination, 734
(HRS)]
Chronic cardiorenal syndrome, 138, physical examination, 733–734
management, 456
141 prognosis, 736
overview, 456
Chronic hepatitis C (CHC), 446, 448 respiratory patterns, 735
spontaneous bacterial peritonitis
Chronic inflammatory demyelinating Combination therapy, 127
(SBP), 457, 458t, 461
polyradiculoneuropathy
variceal hemorrhage, 456–457, 458t Comet tail sign, SPN, 517
(CIDP), 400–401, 401f, 401t
CKD. See Chronic kidney disease Communicable infections, control of,
Chronic kidney disease (CKD)
(CKD) 911–912
anemia in (See Anemia, in CKD) Community acquired pneuomonia
CLD. See Chronic liver disease (CLD)
in diabetes, 251–253, 251f–253f Clinical malaria, 575 (CAP), 525–532
hypertension and DM, 231–232 Clopidogrel, 419 adjunctive therapies in, 531
NAFLD and, 444 Clopidogrel resistance, 95 antimicrobial therapy
Chronic liver disease (CLD), 446 Clostridium, 437 in inpatients, ICU, 530, 530t
diabetes mellitus (DM) and, 233 Clostridium difficle infection (CDI), in inpatients, nonICU, 530
GMD in 440, 472 international guidelines, 530,
clinical presentation, 447–448 FMT and, 474–275 531t
Index 949
in outpatient setting, 529, 529t Computed tomography (CT) risk factors and pathophysiology,
treatment protocol for, 530–531 CAP diagnosis, 526 100–102, 101f
biomarkers in, 528 in dyspnea, 492 treatment of, 104, 105f
chest radiography, 526 of SPN, 518, 518f Corrosive poisoning, 739–740
clinical features, 526 chest, 516 Corticosteroids, 823
CT of, 526 Congenital heart disease (CHD), 136 Cotton seed oil, 904
defined, 525 antepartum, 136 Covalently closed circular DNA
diagnosis, 525–526, 527f (cccDNA), 464
aortic dissection, 135–136
COX 1 inhibitors, 415
epidemiology, 525 general principles of management,
136 COX 2 inhibitors, 415
etiology, 525, 526t
intrapartum, 136 CPAP therapy, in OSA, 498
general investigations, 528
guidelines, 525 peripartum cardiomyopathy, CPE. See Cardiogenic pulmonary
134–135 edema (CPE)
HRCT findings, 526
preconception, 136 Craniovertebral junction lesions,
immunization in, 531–532, 532t vertigo, 409–410
microbiological investigations prosthetic heart valves, 135
CRB-65, 528, 529t
blood cultures, 526 rheumatic heart disease, 135
CRC. See Colorectal cancer (CRC)
Legionella antigen detection, signs, 135
C-reactive protein (CRP), 528, 697–698
528 symptoms, 135
Creatinine, 141
other pathogens, 528 signs, 135
Crimean Congo hemorrhagic fever
sputum gram stain and cultures, symptoms, 135
virus (CCHFV), 552
526–528 Conjugated linoleic acid (CLA), 437
CRISPR-Cas9, 916
pathogens associated with, 526t Consciousness, 894
Critical care toxicology, 681–683
risk stratification in, 528–529, 529t Continuous positive airway pressure
decontamination, 682
Community-based interventions, (CPAP), 497–498
enhanced elimination, 682–683,
209–210, 209t Conventional anticoagulants, 154
682t
Comorbid illnesses, headache, 357– Cooking oils, 903–904 initial resuscitation and
358, 358t Corn oil, 904 management, 681–682
Comorbidities, heart failure and, 149 Corona radiata, 516, 517f laboratory investigations, 682, 682t
Complex partial seizure (CPS), 376. See Coronary artery bypass grafting Cryptococcosis, 661
also Seizures (CABG), 82 Cryptococcus neoformans infection
automatism, 377–378 duration of DAPT in patients IRIS, 675–676
classifciation of, 377 undergoing, 93 CT. See Computed tomography (CT)
CT vs. MRI, 378, 378f Coronary artery disease (CAD) CT contrast angiography, 492
diagnosis, 378 diabetes mellitus (DM) in India, CT coronary angiography, 76
EEG phenomenon, 378 226–227
ctDNA. See Circulating tumor DNA
etiology, 376 HIV/AIDS and, 668–669 (ctDNA)
features of, 377 secondary prevention of, 116 CT guided needle biopsy, of SPN, 520
management, 379 severity of, 84 CTLA-4-immunoglobulin fusion
pathology, 376 Coronary microvascular dysfunction proteins, 292–293
pathophysiology, 376 (CMD) C-type lectins, 472
prognosis, 379 clinical profile, 102–104 Culture-based methods, TB diagnosis
Comprehensive pulmonary function invasive methods, 103–104 conventional solid media, 576–577
tests, in dyspnea, 492 noninvasive method, 103 liquid culture, 577
Compression ultrasonography (CUS), diagnosis, 102, 102f CURB-65, 528, 529t
931 diagnostic algorithm, 104f CUS. See Compression ultrasonography
for DVT, 936 overview, 100 (CUS)
Cutaneous vasculitis, 826 expanded dengue syndrome (EDS), fundamental mechanism of b-Cell
CVD. See Cardiovascular diseases 565 ER stress and, 194
(CVD) hepatic complications, 587 gestational, 61–62
CV events, prediction of, 8–9 hyperferritinemia (secondary GHD, 318
Cyanobacteria, 436 hemophagocytic- hypertension, 233
Cyclophosphamaide, NMO, 369 lymphohistiocytosis), 587 ideal antihyperglycemic drug, 187
Cyclophosphamide, 827 overview, 586 importance of glycemic control in
Cystatin C (CysC), 453 unusal complications, 586 curbing burden of, 247–251
Cytokine and macrophage phenotypes, usual complications, 586 incidence of DM amongst patients
192 vaccine for, 550–551, 627 with cerebro-vascular
Cytokines clinical pipeline, 550 disease, 229t
as biomarkers in sepsis, 698 current status of, 550 in India, 225–226
NAFLD-related HCC risk and, 444 preclinical pipeline, 550–551 infections, 233
Cytokine Storm, 632–634 Dengue hemorrhagic fever (DHF), 564, inflammation and, 193–194
Cytomegalovirus, 545, 661 586 intraoperative management, 722,
Cytomegalovirus infection IRIS, 674– Dengue shock syndrome (DSS), 565, 723t
675 586 LD in
Dengvaxia®, 550 mechanism of, 447
Depression, 472 prevalence of, 447
D postmenopausal hypertension, 25 long-term complications of, 226f
Daclatasvir, 470 Desensitization, and ABO- macrovascular complications,
Daytime symptoms, of OSA, 497 incompatible KT, 847–848 226–229
D-dimer, 491 DEXA scan-dual energy X-ray management, 300
Death, 890 absorptiometry, 831, 832 measures during surgery, 722–724
Deep vein thrombosis (DVT), 151, 483 Diabetes mellitus (DM), 118–119, 446, metabolic syndrome (MS) and, 229
compression ultrasonography for, 472, 849 metformin, 186, 263
931, 936 air pollution and, 200–201, 200f microvascular complications in
CT venography for, 936 cerebrovascular disease, 227–228 type 2 DM, 229–230
diagnosis of, 935, 935t chronic complications in, 226t mortality rate, 850t
Default mode network (DMN), 922–923 chronic liver disease, 233 noncoronary cardiac complications,
Defective immune response in diabetes complications in, 226, 226t 232–233
mellitus, 288 coronary artery disease, 226–227 other complications in type-2 DM,
Defensins, 472 defective immune response in, 288 232–233
Deferred PCI, 112, 113f diabetic neuropathy and diabetic overview, 225
Delamanid, for M/XDR-TB, 554 foot, 230–232, 231t pancreatic beta cell mass function
Delta hepatitis (HDV), 469 diabetic retinopathy, 230 in, 290–291, 290f
Demographics dipeptidyl pepitidase-4 inhibitors, pathogenesis of, 186–187
age-related, 28 187, 188t brain, 187
sex-related, 28–29 early initiation of insulin therapy in, hyperglucagonemia, 187
Demyelination, vertigo, 409 221–223 incretins, 187
Dengue fever (DF), 550, 564–565, 565f education, 300 insulin resistance, 186
complications, 586 efficacy, 188–189 kidneys, 187
dengue hemorrhagic fever (DHF), in elderly recommendation, 259– lipotoxicity, 187
564 261 progressive beta cell loss,
dengue shock syndrome (DSS), 565 endothelial dysfunction and, 186–187
diagnostics guidelines for HLH- 193–194 perioperative management in,
2004, 587 FMT in, 475 720–724
Index 951
factors causing adverse good tissue distribution of, 249t tolerance, 34–35
outcome, 720–721 hypoglycemia and, 249f torsemide, 35
metabolic response to surgery low free drug concentration and types of, 33–35
and anesthesia, 721 high selectivity favours bendroflurazide, 34
preoperative measures, 721–722, avoidance, 249t CTD, 34
722t–723t Diphtheria vaccine, 624 HCTZ, 33–34
principles and target of, 721 Direct acting vasodilators, 70 indapamide, 34
risk of poor diabetic control, 720 Direct Endoscopic Necrosectomy loop diuretics for HT, 34
peripheral vascular disease, 228– (DEN), 432
DKD. See Diabetic kidney disease
229 Direct sputum smear microscopic (DKD)
pharmacologic therapy for, 175–180 examination, TB, 576
DM. See Diabetes mellitus (DM)
postoperative managemant, 724 Disease-modifying antirheumatic
drugs (DMARDS), 823 DMARDS. See Disease-modifying
prevalence of CAD amongst
antirheumatic drugs
diabetics in India, 228t Disease-modifying therapy (DMT),
(DMARDS)
renal involvement in, 849 392, 393t, 394, 394f
DMN. See Default mode network
risk factors for, 447 Diseases
(DMN)
safety, 189 due to global warming, 505–506
DMT. See Disease-modifying therapy
spectrum of chronic complications gut microbiota and (DMT)
in, 232f future perspectives, 438, 440 DN. See Diabetic nephropathy (DN)
sulfonylureas (SU), 186 relationship between, 438, 439f, DNA (deoxyribonucleic acid), 913–914
uses of EPCs in, 869 472, 473f
circulating tumor, 916
Diabetic amyotrophy, 205 Disseminated intravascular
DNA tools, TB diagnosis, 578–580
Diabetic foot, 230–232, 231t coagulation (DIC), 617–621
GeneXpert (Xpert MTB/RIF), 579
Diabetic kidney disease (DKD), 849– diagnosis, 618–619, 619t
line probe assays, 579
853 differential diagnosis, 619–620
loop-mediated isothermal
biochemical markers, 851 etiology, 617, 617t
amplification test (LAMP),
screening for, 851 ISTH-SSC diagnostic scoring system 579, 580f
treatment of, 851–852 for, 619, 619t
nucleic acid amplification (NAA)
Diabetic muscle infarction, 205 pathogenesis, 617–618, 618f tests, 578–579
Diabetic nephropathy (DN), 849 treatment, 620–621 Donor screening questionnaire, 546
dyslipidemia in, 853 Diuretics, 69 Donor selection
predictors, 850t bendroflurazide, 34 fecal microbiota transplantation,
risk factors for development, 849– combination of diuretic with anti- 472, 474t
850, 850t HT drugs, 35 blood screening, 474
Type I, 851 CTD, 34 history obtained from donor,
diuretic tolerance, 34–35 474
Diabetic neuropathy, 230–232, 231t
effect of low dose diuretic, 33 stool evaluvation, 474
Diabetic retinopathy, 230
HCTZ, 33–34 stool preparation (European
Diagnostic errors, 3–4
indapamide, 34 Consensus 2017), 474
DIC. See Disseminated intravascular
isolated systolic hypertension (ISH), Dorzagliatin, 295
coagulation (DIC)
47 Dosing, GHD, 316t
Diet, 901
loop diuretics for HT, 34 compliance, 317
Digital transcript subtraction (DTS),
542 pharmacodynamics, 34 medications, 317
Dipeptidyl peptidase-4 inhibitors potassium-sparing, 69 obesity and glucose, 317
(DPP4), 293–294 common combination, 35 physiologic factors, 316
comparable efficacy in individual side effects, 69 strategy, 317–318, 317t
trials, 250f thiazides, 69 Doubling time (dt), 518
DPP-4 inhibitors, 449 triple therapy, 96, 96t chest wall-related diseases and, 485,
Drug related fever, 597 variables used to calculate score, 486f–487f
Drugs and toxins, vertigo, 410 91t classification, 482, 483t
Drugs/drug therapy. See also Medical Dulaglutide, 240–241 comprehensive pulmonary function
therapy Dupuytren’s contracture/disease, 204 tests , 492
atherosclerosis, 76–77 Dysbiosis, 446, 475 computed tomography, 492
doses, in CAP, 530t Dyslipidemia, 495 conditions related to, 483t
indirect-acting, HBV infection adenosine triphosphate citrate lyase defined, 481
host-acting pathway, 466 inhibitor, 215 differential diagnosis, 488f
innate and adaptive immune angiopoietin like 3 (ANGPLT-3), 216 diseases of pulmonary vasculature
defense pathways, antisense approach against and, 483
466–467 lipoprotein (a), 215 echocardiography, 492
therapeutic vaccines, 466 antisense oligonucleotide against electrocardiography, 490–491
seizure, 379 apolipoprotein B (Apo B), heart failure and, 482
targeting viral replication cycle, in 214 history taking, 489
HBV infection apolipoprotein A1 (ApoA1) imaging, 492–493
antisense molecules, 466 mimetics, 215
interstitial lung diseases and, 485
capsid inhibitors, 466 approaches for PCSK9 inhibition,
invasive testing , 493
212
entry inhibitors, 465–466 laboratory studies, 490–491
CETP inhibitors, 214–216
HBsAg inhibitors, 466 left heart-related diseases and, 482
in diabetic nephropathy, 853
HBV cccDNA inhibitors, 466 lung parenchyma-related diseases
diagnosis, 497
HBV-DNA polymerase and, 485
inhibitors, 466 microsomal triglyceride transport
magnetic resonance imaging, 492
protein (MTP) inhibitor,
siRNA, 466 213–214, 213t management, 493
Dual antiplatelet therapy (DAPT) overview, 211 mechanism, 481–482, 482f
in ACS, 91 In patients with ASCVD air hunger, 481
aspirin allergy, 95, 95t (atherosclerotic chest tightness, 482
aspirin resistance, 94–95, 95t cardiovascular disease), dyspnea relief, 482
clopidogrel resistance, 95 212–213 work effort, 481–482
debate about, 90 PCSK-9 inhibition (nonmonoclonal neuromuscular diseases and, 485
duration in patients undergoing antibody), 215 other diseases, 485, 487
CABG, 93 PPAR agonists, 216 overview, 481
duration of dual antiplatelet therapy proprotein convertase subtilisin/ pericardium-related diseases and,
in cases of stable CAD after PCI, kexin type 9 (PCSK9) 482–483, 484f
91–92 inhibitors, 212
physical examination, 489–490
in patients with ACS, 92–93 therapies of the future, 215
psychological factors, 485, 487
elective noncardiac surgery in Dyspnea, 481–493
pulse oximetry, 491
patients treated with DAPT ABG analysis, 491
social factors, 485, 487
and PCI, 93–94 advanced studies , 491–493
spirometry, 491
overview, 90 airways-related diseases and, 485
stress testing , 493
risk stratification, 90–91 anemia and, 485
ventilation/perfusion scanning,
shorter duration, 91 assessment of, 487, 489 492–493
short-term vs. long term, 91 blood and serum tests , 491
special circumstances, 94–96 cardiovascular diseases and, 482–
in stable CAD, 91 483, 484f E
switch over between antiplatelets, causes of, 482–487 EARA. See Endothelin A receptor
94 chest radiography , 490 antagonists (EARA)
Index 953
Early diabetes Electroencephalography effect of cardiac drugs on, 868

antidiabetic medicines, 183–184 of AES, 559 in endometriosis, 869
increased CV risk in, 182 seizure, 373–374 fundamental properties of, 866
therapy of, 183–184 Elimination, defined, 607 and growth of tumor, 869
Early Warning Sign (EWS), 426 El Nino event, 505 isolation of, 866
Ebola virus disease (EVD), 636–641 Emergence, of gut microbiota, 436–437, markers, 865t
background, 636 438f in peripheral arterial obstructive
clinical symptoms, 638–639 Emergency neurosurgery, super- disease, 870
diagnosis, 639 refractory status epilepticus, therapeutic uses of, 866
outbreaks in reverse chronological 384 in wound healing, 869–870
order, 636, 637t–638t Emergency surgery, 89 Endothelin 1, high altitude systemic
transmission, 636, 638 Endometriosis, EPCs in, 869 hypertension and, 40–41
treatment and vaccines, 639 Endoplasmic reticulum stress Endothelin A receptor antagonists
theory, 195 (EARA), 853
ECG. See Electrocardiography (ECG)
type 2 diabetes and, 194 Endovascular therapy, 388
Echocardiographic navigation in
management of AF, 158–166 and the unfolded protein response, Enteric fever, 565, 565f
left atrial appendage structureand 194 Environmental factors, NAFLD-related
HCC risk and, 444, 444t
function, 163–166, 164f, Endoscope sphincterotomy (ES), 428
165f Enzymes, acute pancreatitis, 423
Endoscopic retrograde cholangio
left atrial function assessment, pancreaticography (ERCP), EPC. See Endothelial Progenitor Cells
161–162, 161f 428 (EPC)
left atrial/left atrial appendage clot, Endoscopic ultrasound (EUS), 428 EPI. See Expanded Program on
158–159, 158f–159f Immunization (EPI)
Endoscopic ultrasound-guided
transmural drainage (EUS- Episodic ataxia syndromes, vertigo, 410
left atrial size, 159–160, 160f
TD), 432 Epstein Barr Virus (EBV), 540, 545
role of LA function assessment in
clinical decision making, Endoscopic variceal ligation (EVL), 418 ERCP. See Endoscopic retrograde
162–163 Endoscopy cholangio pancreaticography
(ERCP)
Echocardiography, 123, 123f gastrointestinal, 597
Errors
cardiac chamber catheterization, re-bleeding after, 41
123 in examination, 3
for UGI bleeding, 417–418, 417t,
in dyspnea, 492 418t by patients, 4
focussed, 932–933, 932t Erythropoiesis Stimulating Agents
upper GI, in FMT, 474
(ESAs), 855–856
Infective endocarditis (IE), 129, 130t Endothelial dysfunction
hyporesponsiveness, 856, 856t
other routine techniques, 124 diabetes and, 193–194
ES. See Endoscope sphincterotomy
ECMO. See Extracorporeal membrane high altitude systemic (ES)
oxygenation (ECMO) hypertension, 40
ESAs. See Erythropoiesis Stimulating
EEG correlates, status epilepticus (SE), inflammation and, 193–194 Agents (ESAs)
381 postmenopausal hypertension, Esomeprazole, 417
E-governance, 906 25–26
Esophagitis, 833
E-health, 906 Endothelial Progenitor Cells (EPC), 865
Estrogen, and osteoporosis, 831, 833
Eighth Joint National Committee JNC and atherosclerotic cardiovascular
European Male Aging Study (EMAS),
VIII, 21 disease, 867–868
344
Elective noncardiac surgery and cardiovascular risk factors, European Respiratory Society (ERS),
in patients treated with DAPT, 93–94 866–867 525
in patients treated with PCI, 93–94 and cardiovascular trials, 868 European Society of Cardiology (ESC)
Electrocardiography (ECG) in cerebrovascular disease, 869 Hypertension Management
in dyspnea, 490–491 in diabetes mellitus, 869 Guidelines 2016, 21
EUS. See Endoscopic ultrasound (EUS) causes of, 926–927 Feeding vessel sign, SPN, 517
EVD. See Ebola virus disease (EVD) clinical examination, 927 Fever of Unknown Origin (FUO). See
Evidence based medicine (EBM), 911 prevention of, 927–928 Pyrexia of Unknown Origin
recurrent, 926 (PUO)
EVL. See Endoscopic variceal ligation
Fever(s)
(EVL) Family history of short stature (FSS),
334 with acute respiratory distress
Evolocumab, 77
syndrome, 564
Exenatide, 240 Family history of slow growth (CDGP),
with multiorgan dysfunction, 564
Exercise 334, 335
skin lesions associated with, 563t
aerobic, 303 Fats
undifferentiated, 563
anaerobic, 303 composition of, 901–902
Fever with rash, 563, 614–616
flexibility, 303 meaning of, 901
diagnosis, 614–615
gestational diabetes mellitus (GDM) Fatty acids
overview, 614
and, 218 MUFA, 902 viral hemorrhagic fevers, 615–616
as a medicine, 303 omega-3, 902 Fibrates, 77
Expanded dengue syndrome (EDS), omega-6, 902 Fibrinolysis, 92
565 PUFA, 902 Fine needle aspiration cytology
Expanded Program on Immunization saturated, 901 (FNAC), thyroid nodule, 338,
(EPI), 912 trans, 902–903 340
Extensively drug resistant TB (XDR- unsaturated, 901 Firmicutes, 436, 475
TB), 553–555 Febrile-infection related epilepsy 5-alpha reductase inhibitors, nocturia,
anti-TB drugs for, 553 syndrome (FIRES), 381 365
bedaquiline for, 554 Fleischner sign, 490
Fecal enemas, 474
defined, 553 Flexibility exercise, 303
Fecal microbiota transplantation
(FMT), 440, 472–476 Flexor tenosynovitis (FTS) or ‘Trigger
delamanid for, 554
Finger,’ 205, 205f
epidemiology, 553 administration routes, 474
Fluid replacement, SCD and, 611
high dose isoniazid for, 555 Clostridium difficle infection,
Fluid resuscitation, acute pancreatitis,
management, 553 474–475
426
newer drugs options, 554 colonoscopy guided, 474
FMT. See Fecal microbiota
overview, 553 current and future directions, transplantation (FMT)
regimes, 554, 554t 475–476 Focal segmental glomerulosclerosis
shorter duration therapy option, in diabetes, 475 (FSGS), 843
555 donor blood screening, 474 Focussed echocardiography, 932–933,
surgical options, 555 donor selection, 472, 474t 932t
treatment duration, 555 donor stool preparation (European Follow-up imaging, of SPN, 519, 519t
Consensus 2017), 474 Forrest classification,. ulcers, 417, 417t
Extracellular fluid (ECF), 341–342
dysbiosis, 475 4-phenyl butyric acid (PBA), 195
Extracellular matrix (ECM), 447
fecal enemas, 474 Fractional flow reserve (FFR)
Extracorporeal membrane oxygenation
history obtained from donor, 474 assessment of serial lesions, 112–
(ECMO), 512, 683
in inflammatory bowel disease, 475 114, 113f–114f
Extrinsic lesion, 359
characteristics of, 110–111
in irritable bowel syndrome, 475
clinical decisions and, 110–111
in neurological diseases, 475, 476f
F in obesity/insulin resistance, 475
deferred PCI, 112, 113f
defined, 110
Factitious fever, 598 pre- and post-FMT changes, 476f
functional PCI, 111–112, 112f
Faecalibacterium prausnitzii, 475 stool evaluvation, 474 identifying culprit vessel and
Falls, 926–928 techniques, 472, 473f doing appropriate
age related changes and, 926 upper GI endoscopy guidance, 474 revascularization, 111
Index 955
overview, 110 resistant hypertension, 61 health impact, 504

revascularization strategy, 110–111 Gestational diabetes mellitus (GDM) ozone, 505
Fractures cut-off values set to diagnose, 218t surface temperature, rise in, 504–
pathological, 830 diagnosis of, 217–218 505
risk of, 831 one-step strategy, 217–218, 218t Glomerular diseases, 842
vertebral, 831 two-step strategy, 218 characterization and response to
FSGS. See Focal segmental exercise and, 218 treatment, 842t
glomerulosclerosis (FSGS) glycemic targets in, 218 IgA nephropathy, 844
Functional PCI, 111–112, 112f insulin vs. metformin in, 219 membranous nephropathy, 843
Fungal infections, 597 life style modification, 218 and nephrotic syndrome, 843–844
HIV/AIDS and, 670 mechanism of, 217 primary, 843
medical nutrition therapy, 218 secondary, 844
GLP-1RA, 294, 449
G pharmacological treatment, 218–
Glucagon-like peptide-1 (GLP-1)
219, 219t
Gabexate mesylate, 621 analogs
treatment modalities of, 218–219
Gall stone, risk factor, 421 actions of glucagon-like peptide on
types of insulin used during
Gaseous pollutants, 534 pregnancy, 219t various organs, 239t
Gastroenterology/hepatology, 413–476, Gestural, automatism, 377 acute pancreatitis, 243
913 albiglutideis, 241
GHD. See Growth Hormone Deficiency
Gastrointestinal endoscopy, 597 classification, 239t
Ghee, 904
Gastrointestinal system, air pollution dulaglutide, 240–241
effects on, 535 GICs. See Gender Identity Clinics
(GICs) exenatide, 240
Gemigliptin, 188t, 189t extended release exenatide, 240
GINA (Global Initiative for Asthma),
Gender Dysphoric (GD) persons, 872– extra glycemic benefits of, 241–242
500
875, 875f
Glasgow Coma Scale, 734 gastrointestinal effects, 243
Gender Identity Clinics (GICs), 873,
875, 875f, 875t Glimepiride, 255f, 259t glycemic efficacy of, 241
Genetically modified (GM) crops, 915 Gliptins, 186–190 hypoglycemia, 243
Genetic factors cardiovascular safety in, 251–254, liraglutide, 240
253f–254f lixisenatide, 241
NAFLD-related HCC risk and, 444,
444t dipeptidyl peptidase-4 (DPP-4) medullary thyroid carcinoma, 243
postmenopausal hypertension, 26 association-dissociation grid of, overview, 238
249f physiological properties of, 239t
Genetic predisposition, inflammation
and, 192 inhibitor mechanism of action, renal effects, 243
248f
GeneXpert (Xpert MTB/RIF), 579 side effects and associated risks
pharmacological features, 250t GLP-1 receptor agonists,
Genomics, 913–914
Global Alliance for Vaccines and 243
Geriatrics, 861
Immunization (GAVI), 549
anemia in (See Anemia, in elderly) weight loss associated with the use
Global Initiative for Asthma (GINA), of GLP-1 receptor agonists,
falls in, 926–928 500 242–243
immediate need for, 863–864, 864f Global Initiative for Chronic Glucagon like peptide-1 receptor
medical infrastructure, 862 Obstructive Lung Disease agonist (GLP-1RA), 293
medicine, 862–863 (GOLD), 500
Glucose control, lipohypertrophy (LH),
needs of, 862 Global warming 350
services, 862–863 causes, 504 Glucose metabolism, in diseased liver,
teaching, 862 diseases due to, 505–506 446
Gestational diabetes, 61–62 El Nino event, 505 Glucose metabolism disorders (GMD),
older adults, 61–62 future perspectives, 506–507 446–449
in CLD cardiovascular, 314, 318 H

clinical presentation, 447–448 COGHD vs. AOGHD, 314
HAARTs. See Highly active
complications, 448 diabetes mellitus, 318 antiretroviral therapies
correlation of etiology and diagnosis of, 315–316 (HAARTs)
severity, 447
dosing, 316–318, 316f Haemophilus influenzae vaccine, 626
diagnosis, 448
etiology, 313, 313t HAI. See Hospital acquired infections
mechanism of, 446–447 (HAI)
metabolic complications, 314
medical nutrition therapy and Halo sign, SPN, 517
lifestyle modification, osteopenia/osteoporosis, 314–315
Hampton hump, 490
448 quality of life, 315
HAPS. See Harmless Acute Pancreatitis
monitoring, 448 symptoms and signs, 314t
Score (HAPS)
pharmacotherapy, 448–449 treatment, 315 Harmless Acute Pancreatitis Score
prevalence of, 447 tumor regrowth/recurrence, 318 (HAPS), 424, 425t
results of study, 449 uses of, 319 Harry Benjamin International Gender
risk factors of DM, 447 Growth parameters, 335 Dysphoria Association
treatment, 448–449 (HBIGDA), 873
Growth pattern, of SPN, 518–519
Glycemic control HbA1C, 851, 852
Gut associated lymphoid tissues
diabetes and, 247–251 (GALT), 438 HBIGDA. See Harry Benjamin
goals for, 247 International Gender
Gut microbiota (gut flora), 436–440.
Glycemic oscillations, lipohypertrophy Dysphoria Association
See also Fecal microbiota (HBIGDA)
(LH), 348, 349t transplantation (FMT)
GM crops. See Genetically modified HBsAg. See Hepatitis B surface antigen
as an organ (HBsAg)
(GM) crops
as immunomodulator, 438, 439f HBsAg inhibitors, 466
GMD. See Glucose metabolism
disorders (GMD) metabolic functions, 437 HBV. See Hepatitis B virus (HBV)
God, 898–899 prevention of infection, 437–438 HBV cccDNA inhibitors
God men, 898–899 changes in, 438 HBV infection and, 466
GOLD (Global Initiative for Chronic colorectal cancer, 438 HBV-DNA polymerase inhibitors
Obstructive Lung Disease), hepatic encephalopathy, 438 HBV infection and, 466
500 inflammatory bowel disease, HCTZ, 33–34
Gold Standard Test, 576 438 HCV NS 5A protein, 446
Goris multiple organ failure score, 424 irritable bowel syndrome, 438 HDL. See High density lipoprotein
Gram-negative organisms, 717 obesity, 438 (HDL)
Gram-positive organisms, 717 Parkinson disease, 438 Headache, 355
Granulocyte Colony Stimulating factors challenges in, 355
type 2 diabetes mellitus, 438
(G-CSF), 461 with comorbidities, 357–358, 358t
composition, 436, 436f
Ground-glass opacity (GGO), 517 in elderly, 357
Ground nut oil, 904 described, 472
evaluation, 355
Growth (short stature) and diseases, relationship between,
438, 439f, 472, 473f investigations, 356
approach to, 336f menstrual migraine, 357
causes of, 334t emergence of, 436–437, 438f
in pregnancy, 356–357
defined, 334 future perspectives, 438, 440
status migranosus, 357
diagnosis, 334–335 humans as microbial depots, 436,
Head impulse test (HIT), 404–405
patterns of, 333–334, 335t 437f
HEALING (Healthy Endothelial
physiology of, 333 infants, 436–437
Accelerated Lining Inhibits
Growth Hormone Deficiency (GHD), overview, 436 Neointimal Growth)
313 role in homeostasis, 472 programme, 869
Index 957
Health care expenditure, 913 Heart failure with reduced ejection siRNA, 466
Health impact, of global warming, 504. fraction (HFrEF), 482 epidemiology in India, 463–464
See also Global warming Heart transplantation, 149 HIV-HBV coinfection, 470
Heart failure (HF), 97–99, 117–118 Heavy metals, air pollution due to, 534 immunopathogenesis, 464
arrhythmias and conductance Helicobacter pylori, 540 incidence, 463
disturbances, 149 Hematochezia, 416 indirect-acting drugs
biomarkers in, 97–99 Hematology/oncology, 757–808 host-acting pathway, 46
biomarkers of HFpEF, 98–99 Hematopoietic stem cell innate and adaptive immune
cardiac troponin, 98 transplantation (HSCT), 759– defense pathways,
classification, 144–145, 145t 761, 763–766 466–467
comorbidities, 149 allogeneic, 760, 764–766 therapeutic vaccines, 466
and comorbidities, 149 autologous, 760, 763–764 management of, 465
definition of, 145t indications, 759 natural history of infection, 464–465
diagnosis, 97–98, 145–147 5 phases of, 760 HBeAg-negative chronic HBV
clinical, 145 principles, 763–766, 763t infection (phase 3), 465
investigations, 145–147 sources, 759 HBeAg-negative chronic
dyspnea and, 482 Hemolysis, 878 hepatitis B (phase 4),
Hemolytic anemia, 877 465
EPCs and, 868
treatment of, 880 HBeAg-positive chronic HBV
heart transplantation, 149
Hemopoietic Stem Cells (HSC), 865 infection (phase 1), 464
Infective endocarditis (IE), 130
Hemotransfusion therapy, 784–787 HBeAg-positive chronic hepatitis
mechanical circulatory support B (phase 2), 464–465
(MCS) systems, 148–149 Henoch–Schönlein purpura, 768–769
HBsAg-negative phase (phase
monitoring, 149 Hepatic complications, of dengue fever,
5), 465
587
nonsurgical device treatment, pathogenesis, 469–470
147–148 Hepatic encephalopathy, 457
gut microbiota in, 438 and polyarteritis nodosa, 817,
cardiac resynchronization 819–820
therapy (CRT), 148 Hepatic steatosis, 447
prevalence of, 463
implantable cardioverter- Hepatic stellate activation, 444, 444b
treatments, 465, 470
defibrillator, 147–148 Hepatic stellate cells (HSC), 447
Hepatitis C virus (HCV), 469, 540, 544
implantable electrical devices, Hepatitis A vaccine, 624
148 HIV-HCV coinfection, 470
Hepatitis A virus, 544
overview, 97 pathogenesis, 470
Hepatitis B surface antigen (HBsAg),
pathophysiology of, 80f 463, 464 and polyarteritis nodosa, 817
pharmacologic treatment, 147 Hepatitis B vaccine, 622–624 Hepatitis E vaccine, 627
prognostic value of NP, 98 Hepatitis B virus (HBV), 463–467, 469, Hepatitis E virus, 544
role of natriuretic peptides in 540, 544 Hepatocellular carcinoma (HCC),
diagnosis of, 97–98 cure in, 465 791–794
urinary volume, 363–364 described, 464 NAFLD and, 442
Heart failure with mid-range ejection drugs targeting viral replication Hepatorenal syndrome (HRS), 451–454,
fraction (HFmrEF), 482 cycle 457
Heart failure with preserved ejection antisense molecules, 466 biomarkers in, 453
fraction (HFpEF), 482 capsid inhibitors, 466 classification, 451
in acute setting, 99 entry inhibitors, 465–466 defined, 451
galectin 3 and ST 2, 99 HBsAg inhibitors, 466 diagnosis, 453
natriuretic peptides (NP) in, 98–99 HBV cccDNA inhibitors, 466 diagnostic criteria, 453
prognostic value of plasma HBV-DNA polymerase epidemiology, 451
biomarkers in, 99 inhibitors, 466 overview, 451
pathophysiology, 451–452 High density lipoprotein (HDL), 903 opportunistic infections (OI)
precipitating factors, 452, 452f Higher PEEP, ARDS and, 512, 512t affecting CNS, 664–665,
preventive measures, 453 Highly active antiretroviral therapy 665f, 666t
treatment, 453–454 (HAART), 469, 671 peripheral neuropathy, 664
albumin with vasoconstrictors, High resolution computed tomography primary CNS lymphoma, 666,
454 (HRCT) imaging, 514, 519 666f
liver replacement therapy, 454 CAP diagnosis, 526 progressive multifocal
leukoencephalopathy
liver transplant, 454 History taking, dyspnea assessment,
(PML), 666
renal replacement therapy, 454 489
opportunistic infections in, 660–662
High altitude (HA) HIV/AIDS, 464, 469, 543–544, 643–677
candidiasis, 661
BP behaving with aging in people antiretroviral therapy (ART), 652–
658 cryptococcosis, 661
chronically exposed to, 42
antiretroviral drug toxicity, 657, cytomegalovirus, 661
defined, 36
658t Mycobacterium avium complex
High altitude systemic hypertension
considerations before initiation (MAC), 662
(HASH)
ageing, high altitude and blood of, 654–656, 655f Pneumocystis carinii
pressure, 41 first line regimen selection, 656, pneumonia (PCP), 660
ageing and, 41 656t TB, 661–662
blood pressure changes with aging, goals, 652, 652t toxoplasmosis, 660–661
41–42 integrase inhibitors, 653, 654t 90-90-90 strategy in HIV epidemic,
BP behaving with aging in people 645–650, 646f, 647f
non-nucleoside reverse
chronically exposed to high transcriptase inhibitors, vaccine, 627
altitude, 42 653 HIV Associated Neurocognitive
carry home messages, 43 nucleoside/nucleotide reverse Disorder (HAND), 663, 664t
with deletion allele of ACE gene, transcriptase inhibitors, HIV-HBV coinfection, 470
40–41 653 HIV-HCV coinfection, 470
diagnosis of, 42 patient monitoring, 656–657, HIV/hepatitis co-infections, 469–471
effects of high altitude on 657t epidemiology, 469
cardiovascular system, 36 principles, 653, 653t incidence rates, 469
endothelin 1 level, 40–41 protease inhibitors, 653 overview, 469
association of HASH with regimens, 656 pathogenesis, 469–470
deletion allele of ACE treatment failure, 658 treatment
gene, 40–41 cardiopulmonary manifestations of, HIV-HBV coinfection, 470
importance of recognizing, 42 667–670 HIV-HCV coinfection, 470
need for definition of HASH -and its bacterial infections, 669–670 vaccination, 471
prevalence, 36–38
cardiotoxic drugs, 668 HIV/TB co-infection, 658, 918, 919f
overview, 36
coronary artery disease, 668–669 HIV-VL coinfection, 608
pathophysiology of, 38–40
fungal infections, 670 HLH-2004, diagnostics guidelines for,
endothelial dysfunction, role
malignant neoplasms, 670 587
of, 40
pericardial disease, 667–668 H1N1 influenza, 629–634
increased erythropoiesis and
raised hematocrit, role pulmonary manifestations, 669 antigenic shift/drift, 629–630, 630f
of, 39–40 neurological manifestations of, Cytokine Storm, 632–634
sympathetic activation, role of, 663–666 government of India guidelines
38–39 acute seroconversion illness, 663 category A, 630
treatment of, 42–43 ART and, 666 category B1, 630
antihypertensives, 42–43 direct viral invasion, 663 category B2, 630–631
beta blockers, 42 myelopathy due to, 663–664 category C, 631–632
Index 959
history, 629–630 HSC. See Hemopoietic Stem Cells diuretics, 69

influenza trivalent vaccine, 633 (HSC) grey areas in diagnosis and
overview, 629 HSCT. See Hematopoietic stem cell management of, 67–71
pandemic cases, 632t transplantation (HSCT) Indian guidelines of, 21
HOLD (Hypertension, Obesity, Lipid HSCT-peripheral blood stem cell, 760 lifestyle modification, 68
abnormality and Diabetes) Human being management
behavioral modification, 208–209, birth of, 890 diagnostic errors, 3–4
208f body functions, 890–894 errors by patients, 4
cardiovascular risk with, 207 as contribution of universe, 889 errors in examination, 3
community-based interventions, death of, 890 treatment errors, 4
209–210, 209t defined, 890 masked, 8
dietary modifications, 208–209, 208f as holistic, 889–890 and menopause
evidence-based diet priorities to internal and external happiness, 891 role of oxidative stress and
hold, 209f life energies, 894–895 vasoconstrictors, 24–26
getting rid of persistent organic arterial stiffness, 26
mind of (See Mind)
pollutants, 209–210, 209t
as miniature of universe, 889 depression and anxiety, 25
holding the, 208, 208f
part of universal energy in, 895–896 endothelial dysfunction,
mechanistic characteristics, 208 25–26
personal identity, 896
peculiarities in India, 207–208 genetic factors, 26
and religions, 896–897
pharmacological interventions, 210 renin-angiotensin system
soul, 895–897
physical activity, 209 (RAS), 26
universal awareness and oneness,
prevalence of, 207, 207t 896 role of obesity and fat
Homeostasis, gut microbiota role in, Human immunodeficiency virus (HIV) distribution, 25
472 infection. See HIV/AIDS salt sensitivity, 26
HOPE trial, 116–117 sympathetic overactivity, 25
Human life, purpose of, 891
Horizontal transmission, 717 OSA and, 495, 497–498
Human papilloma virus (HPV), 540
Hormone therapy, 874 physicians’ bias in, 68–70
Humans
Hospital acquired infections (HAI), prescribed drugs, 68
gut microbiota [See Gut microbiota
725–729
(gut flora)] resistant, 61
catheter related blood stream
as microbial depots, 436, 437f as risk-factor during menopause,
infection, 728
Human T-lymphotropic virus type I/II, 26–27
causative organisms, 726
540, 544–545 rule of halves, 67–70
diagnosis, 726
Hypercholesterolemia, 867 white-coat, 7–8
management, 729
Hyperferritinemia, 587 Hypertension in diabetes
nosocomial pneumonia, 725–726,
Hyperglucagonemia, 187 blood pressure and, 56–57
725t
Hyperglycemia, 869 complications, 56
nosocomial surgical site and soft
tissue infection, 728–729 Hyperostosis, 204 deadly combination, 55–56
nosocomial urinary tract infection Hypertension (HTN) gestational diabetes, 61–62
(UTI), 727 ABPM guiding management of, older adults, 61–62
preventive measures, 727 9–10 overview, 55
treatment, 726–728 Beta adrenergic blocking agents, 70 pharmacologic treatment, 58–61
Host-acting pathway, HBV infection blood pressure instruments, 70–71 antihypertensive medications,
and, 467 calcium channel blockers, 69 59–61
HPV vaccine, 626 diabetes mellitus (DM) in India, 233 bed time dose, 61
H. pylori infection, 415 diagnosis, 497 monitoring, 61
HRS. See Hepatorenal syndrome (HRS) direct acting vasodilators, 70 resistant hypertension, 61
status of control, 57 prevalence of, 685, 686f defined, 671–672

treatment strategies, 57–58, 58t reason for death and, 688 Mycobacterium tuberculosis (TB),
Hypertension trials, 115–116 recognition of, 685–686, 686t 673–674
Hypertriglyceridemia, 77 Hypogonadism, 345 varicella zoster virus infection IRIS,
Hyperuricemia Hypomagnesemia, vitamin D 675
deficiency, 330 Immunity
asymptomatic (See Asymptomatic
hyperuricemia) Hypoparathyroidism. See Primary in the pathogenesisof diabetes
hypoparathyroidism mellitus, 286–288
causes of, 811–812, 812t
Hypothermia, super-refractory status type 1 diabetes mellitus, 286–287
classification of, 811
epilepticus, 382–383 type 2 diabetes mellitus, 287–288
clinical consequences of, 812–813
Hypovolemia Immunization. See also Adult
definition of, 811
focussed echocardiography for immunization
epidemiology, 811
assessment of, 933 role in CAP, 531–532, 532t
Hypnoanalysis, 925
in HRS, 453 Immunological therapy, super-
Hypnosis, 922 refractory status epilepticus,
Hypoxemia, 485
brain areas affected by, 922–923 Hysterical (pseudo seizures), 378 384
factors affecting therapeutic Immunomodulator, gut microbiota as,
response, 923 438, 439f
levels of, 923 I Immunomodulatory therapies, for HBV
physiological effects of, 923 IARC. See International Agency for infection, 465
types of, 923–924 Research on Cancer (IARC) Immunotherapy, 801–803
Hypnotherapy, 924–925, 924t Ibandronate, 833 adoptive cell therapy (ACT), 802
Hypnotic trance, induction of, 923 IBD. See Inflammatory bowel disease immune check point blockade,
Hypoglycemia, 243 (IBD) 802–803, 803t
DPP4 inhibitors and, 249f IBS. See Irritable bowel syndrome (IBS) oncolytic viruses in, 801–802
in ICU, 684–694 ICU. See Intensive care unit (ICU) vaccines in, 802
acute coronary syndrome, 689– Idiopathic CD4 lymphocytopenia, Implantable cardioverter-defibrillator,
694, 689t, 690t 788–790 147–148
brain and, 688f IDSA/ATS consensus guidelines, 530, Implantable electrical devices, 148
in cardiac ICU, 688–689 531t Incretins
IgA nephropathy (IgAN), 844 DM and, 187
classification, 684
Imaging. See also specific types effect, 247f, 248
clinical mimics, 687
acute pancreatitis, 423, 424f Indapamide, 34
complications and
consequences, 687–688, AES, 558–559, 559f India
687f, 687t dyspnea, 492–493 AES vaccination, 561 [See also
defined, 684 of SPN, 516, 518–520, 518f, 519t Acute encephalitis
syndrome (AES)]
ECG changes, 689 follow-up, 519, 519t
air pollution, 533
hemodynamic changes, 689 Imeglimin, 294–295
antibiotic resistance threat in, 718
induced mortality, 688, 689t, Immune reconstitution inflammatory
690t syndrome (IRIS), 671–676 CAD amongst diabetics in, 228t
management challenges, 688, atypical mycobacterial IRIS, 674 CAP epidemiology in, 525
689t background, 671 diabetes in, 225–226
myocardial effects, 689 clinical factors, 672–673, 672t diabetic neuropathy in, 231t
neuroglycopenic signs and Cryptococcus neoformans diabetic retinopathy in, 231t
symptoms, 686 infection IRIS, 675–676 HBV epidemiology in, 463–464
overview, 684 cytomegalovirus infection IRIS, insulin pumps in, 270–272
pathogenesis, 684–689, 685f 674–675 JE vaccination in, 561
Index 961
kala-azar elimination in, 607–608 Epstein Barr Virus, 540 clinical benefits based on
asymptomatic carrier, 607–608 HBV, 540 inflammatory theory,
HIV-VL coinfection, 608 HCV, 540 195
treatment of post-kala-azar Helicobacter pylori, 540 clinical implications of
dermal leishmaniasis, inflammation in type-2
human papilloma virus, 540
608 diabetes, 195
human T-lymphotropic virus
uninterrupted supply of drugs, drugs related to the
type 1, 540
608 endoplasmic reticulum
IARC classification, 539–540, stress theory, 195
vector control, 608 540t
VL, treatment of, 608 genetic predisposition, 192
incidence, 539
malaria prevalence, 570–571, 571f innate immune system
Kaposi Sarcoma-Associated activation, 191
metabolic syndrome in, 207t Herpes Virus, 540
insulin, 195
peculiarities of HOLD in, 207–208 opisthorchis, 540
link between, 191–194
PUO in, 592–593, 593t pathogenesis, 539
scope of stem cell therapy in, overview, 191
Schistosoma Hematobium, 540 stress and, 191–192
761–762
diabetes mellitus (DM) in India, 233 Toll-like Receptors (TLRs) and,
snake bite management, 742–754
infective endocarditis (IE), 130–131 191
Indian Guidelines of Hypertension, 21
prevention of, gut microbiota and, type-2 diabetes and innate
Indirect-acting drugs, HBV infection
437–438 immune system, 192
host-acting pathway, 46
uncontrolled, 130–131 endothelial dysfunction and,
innate and adaptive immune
Infectious diseases, control of, 911–912 193–194
defense pathways, 466–467
Infectious Disease Society of America Inflammatory bowel disease (IBD), 472
therapeutic vaccines, 466
(IDSA), 525 dysbiosis, 475
Individualization of diabetes care
Infective endocarditis (IE) FMT in, 475
antihyperglycemic therapy, 284
acute renal failure, 131 gut microbiota in, 438
implementation strategies, 284
antimicrobial therapy, 129–130, Inflammatory pathways to insulin
individualized goals, 283–284
130t resistance, 193
key points, 285
changing epidemiological profile, Inflammatory response inhibitor, 853
other considerations, 284–285
129 Inflammatory theory, clinical benefits
patient-centered approach, 284
common pathogens and based on, 195
therapeutic patient education, 285 antimicrobial therapy in, Influenza vaccine, 626
therapy in newly diagnosed T2DM 131t
patients, 281–283, 282f, Inhalational corticosteroids (ICS), 502
complications, 130–131
282t In-hospital prophylaxis, 155
diagnostic issues, 129
treatment approaches for T2 Initial resuscitation and management,
echocardiography, 129, 130t 681–682
diabetes, 281–284
embolic events, 131 Innate immune system
Industrial chemicals, 199
Infants heart failure, 130 activation, 191
growth phase, 333 indications for surgery, 131–132 HBV infection and, 466–467
gut microbiota, 436–437 endocarditis team, 132 Innocent mind, 891
Infection(s), 537–641. See also Co- follow-up after antimicrobial Inpatients, antimicrobial therapy for
infections; specific entries therapy, 131–132 CAP in
associated cancer, 539–542 pathological criteria and blood ICU, 530, 530t
agents, 540, 541t culture, 129 nonICU, 530
chlonorchis, 540 prevention, 132 Institute for Health Metrics and
detection and proving uncontrolled infection, 130–131 Evaluation (IHME), 481
association of agents, Inflammation Insulin injection technique,
540, 541t–542t, 542 diabetes and, 193–194 lipohypertrophy, 350, 350f
Insulin pump Integrase inhibitors, for HIV infections, Interleukin 2 (IL-2), 293
components of, 270 653, 654t Interleukin (IL)-6, 444
current scenario of, 272 Integrons, 717 Intermediate-acting insulin, 274
in India, 270–272 Intensive care unit (ICU), 679–679 Intermediate (savannah) cycle, of
indications for, 271 antibiotic resistance in yellow fever virus, 583–584
medtronic, 270f defined, 716 Intermediate syndrome, 361
superiority of, 271 judicial use of antibiotics and, Internal pancreatic fistulas (IPF),
718 430–431
types, 271
mechanisms, 716–717 International Agency for Research on
Insulin resistance (IR), 80–81
newer interventions, 718 Cancer (IARC), 539
in CLD
threat in India, 718 classification of infection associated
mechanism of, 446–447
critical care toxicology, 681–683 cancers, 539–540, 540t
prevalence of, 447
decontamination, 682 International Club of Ascites (ICA), 453
DM and, 186
enhanced elimination, 682–683, International League Against Epilepsy
FMT in, 475 682t (ILAE), 380
inflammatory pathways to, 193 initial resuscitation and Interstitial lung diseases, 485
NAFLD-related HCC risk and, 444 management, 681–682 Intraarterial tPA, 388
obesity and, 192–193 laboratory investigations, 682, Intracranial pressure, increased, 560
OSA and, 495, 498 682t Intrauterine growth phase, 333
Insulins, 301 hypoglycemia in, 684–694 Intravascular ultrasound (IVUS), 76
gestational diabetes mellitus acute coronary syndrome, 689– Intravenous fat emulsion (IFE) therapy,
(GDM), 219 694, 689t, 690t 683
inflammation and, 195 brain and, 688f Intravenous immunoglobulins (IVIgs),
intermediate-acting insulin, 274 in cardiac ICU, 688–689 848
long-acting insulins, 274–275 classification, 684 Intravenous steroids, NMO, 369
premixed insulin, 275 clinical mimics, 687 Intrinsic lesion, 359
rapid-acting insulin, 274 complications and Intrinsic short stature, 335
short-acting insulin, 274 consequences, 687–688,
Invasive testing , in dyspnea, 493
687f, 687t
Insulin therapy, 221–223 IPT. See Isoniazid preventive therapy
defined, 684
barriers to basal insulin in type 2 (IPT)
ECG changes, 689
diabetes mellitus, 222–223 IR. See Insulin resistance (IR)
hemodynamic changes, 689
basal insulin, 221–222 IRIS. See Immune reconstitution
induced mortality, 688, 689t,
benefits of, 222 inflammatory syndrome (IRIS)
690t
early vs late use, 222 Iron deficiency anemia
management challenges, 688,
fine-tuning, 277 689t evaluation of, 879
GMD in CLD, 449 myocardial effects, 689 management of, 880
hospitalized patients, 275–276 neuroglycopenic signs and oral therapy treatment of, 880
initiating, 275–277 symptoms, 686 Iron therapy, 854–855, 854t
need for, 273–274 overview, 684 Irritable bowel syndrome (IBS), 472
overcoming the psychological pathogenesis, 684–689, 685f FMT in, 475
barriers to, 277–279, 278t prevalence of, 685, 686f gut microbiota in, 438
overview, 221 reason for death and, 688 Isolated systolic hypertension (ISH)
role of insulin in treatment of type 2 recognition of, 685–686, 686t angiotensin converting enzyme
diabetes mellitus, 222 nosocomial pathogens seen in, 717 inhibitors, 47
starting insulin, 223 Intensive insulin therapy (IIT), 292, 293 angiotensin 2 receptor blockers,
type 1 diabetes patients, 276 Interferon gamma (IFN-γ) release 47–48
type 2 diabetes patients, 276–277 assays, 580–581 antihypertensives, useful in, 47–48
Index 963
benefits of treatment of, 48 vaccination, 549–550 Latent tuberculous infection diagnosis

calcium channel blockers, 47 in India, 561 interferon gamma (IFN-γ) release
classification of, 45 Japanese encephalitis vaccine, 626 assays, 580–581
clinical presentation, 45 Japanese encephalitis virus (JEV), 556 serological diagnosis, 581
diuretics, 47 Jnana Yoga, 897 tuberculin skin test, 580
in elderly, 44 Joint pain, chikungunya virus and, LDL. See Low density lipoprotein (LDL)
etiology, 45 821–822 Ledipasvir, 470
evaluation of, 45 Left atrial (LA)
clinical decision making, 162–163
interventional trial concerning, 48 K function assessment, 161–162, 161f
management of hypertension,
45–48 Kala-azar, elimination in India, 607–608 size, 159–160, 160f
asymptomatic carrier, 607–608 Left atrial appendage (LAA)
corollary recommendation, 46,
46t HIV-VL coinfection, 608 assessment of function of, 163–166
JNC8 recommendations, 45 treatment of post-kala-azar dermal dysfunction, 165
leishmaniasis, 608 flow pattern, 165f
pathophysiology, 45
uninterrupted supply of drugs, 608 multilobed anatomy of, 164f
prevalence and risk factor, 44–45
vector control, 608 structure, 163–166
smaller studies on, 48
VL, treatment of, 608 structureand function, 163–166,
treatment of, 46–47
Kaposi Sarcoma-Associated Herpes 164f, 165f
nonpharmacological treatment,
Virus (KSHV), 540, 542 structure and function in clinical
46–47
Karma Yoga, 897–898 practice, 164
in young, 44 stunning, 166
Karyotype, short stature, 335
Isoniazid, high dose, for M/XDR-TB, thrombus, 164–165
555 Kernig’s sign, 602
Kerosene oil ingestion, 740 Left ventricular (LV) function
Isoniazid preventive therapy (IPT),
Ketogenic diet, super-refractory status focussed echocardiography for, 932
919–920
epilepticus, 384 Legionella antigen, detection, CAP
in children, 919
Kidney Disease Outcomes Quality investigation and, 528
drug resistance with, 921
Initiative (KDOQI) Guidelines Leishmania donovani complex, 607
in HIV, 919–920 Leptin, 444
for Treatment of Hypertension
INH for, 920 Associated with Chronic Leptospirosis, 566, 566f, 604–606
in noncomplaint cases, 920 Kidney Disease, 21–22 clinical presentation, 605
in pregnant woman, 920 Kidneys, DM and, 187 diagnosis, 605–606
Isotope scan, 338 Kidney transplantation (KT), 846. See epidemiology, 604–605
IT solutions, 906 also Renal transplant (RT) incidence, 604
IVIgs. See Intravenous ABO-incompatible (See ABO- overview, 604
immunoglobulins (IVIgs) incompatible (ABOi) KT) treatment and prevention, 606
Knuckle sign, 490 Licensed vaccines, Japanese
Kyasanur forest disease, 551–552 encephalitis, 549–550
J
clinical features, 551 Lifestyle diseases, 302
Japanese encephalitis (JE), 549, 556– mode of transmission, 551 aerobic exercise and, 303
557 anaerobic exercise and, 303
vaccination, 551–552
and AES, differentiation of, 558 Asian Indians and, 303
Kyphoscoliosis, 485
epidemiology, 556–557 exercise as a medicine, 303
licensed vaccines, 549–550 L
flexibility exercise like yoga, 303
and non-JE, differentiation of, 558 Lactobacillus, 440 Lifestyle modifications
pipeline vaccines, 550 Large vessel vasculitis, 826–827 gestational diabetes mellitus
treatment of, 560, 560t Large volume ascites, 457 (GDM), 218
GMD in CLD and, 448 Long-acting insulins, 274–275 global scenario, 570, 570f
OSA and Long-acting muscarinic antagonists history, 570
antiplatelets and statins therapy, (LAMA), 502 Indian scenario, 570–571, 571f
498 Loop diuretics for HT, 34 lab diagnosis, 573–574
behavioral methods, 498 Loop-mediated isothermal malignant behavior of Plasmodium
blood pressure, 498 amplification test (LAMP), vivax, 572–573, 572t
insulin resistance, 498 579, 580f
management, 574, 574t
Likert scale, 489 Low density lipoprotein (LDL), 903
parasite, 571
Limited joint mobility, 203–204 Low grade-inflammation, obesity and,
pathophysiology, 573
Linagliptin, 187, 188t, 189, 189t 192–193
second line treatment, 574
albuminuria lowering associated Low tidal volume ventilation (LTVV),
508, 510t, 511 severe malaria, 573, 573t
with, 252f
Low volume ascites, 457 treatment in pregnancy, 574–575
CV risk inot increased with, 253f
Low-volume voids, nocturia, 364 vaccine, 627
CV safety meta-analysis, 254f
Vivax malaria, 571–572
Line probe assays, 579 LT. See Liver transplantation (LT)
Malignancy, vertigo, 409
Lipase, 423 Lung Injury Prediction Score (LIPS),
508 Malignant neoplasms, HIV/AIDS and,
Lipid metabolism, gut microbiota and, 670
437 Lung mass, 514. See also Solitary
pulmonary nodule (SPN) Malnutrition, vitamin D deficiency, 330
Lipid profile, metformin, 263
Lung parenchyma-related diseases, Mannitol, 560
Lipohypertrophy (LH)
dyspnea and, 485 Mantoux test, 580
bruising, 348, 350
Lung transplantation, 128 Marshal organ dysfunction score, 424
causes of, 347–348
Lung ultrasonography, 929–930, 930t MAS. See Macrophage activation
definition of, 347
Lupus nephritis (LN), 844 syndrome (MAS)
diagnosis, 348
Lymphoma, 598 Masked hypertension, 8
glucose control, 350
MCD. See Minimal change disease
glycemic oscillations, 348, 349t (MCD)
management, 350–351 M MDR-TB. See Multidrug-resistant
prevalence of, 347 tuberculosis (MDR–TB)
Macitentan, pulmonary arterial
Lipotoxicity, DM and, 187 hypertension (PAH), 126 Mean arterial pressure (MAP), 452
Liquid biopsies, 916 Macroalbuminuria, 849–850 Mean corpuscular volume (MCV),
Liquid culture, TB diagnosis and, 577 Macroangiopathy, 447–448 NMO, 369
Liraglutide, 240 Macrophage activation syndrome Measles, mumps and rubella vaccine,
Liver, role in carbohydrate metabolism, (MAS), 778–782 624
446 Macrophage infiltration in white Mechanical circulatory support (MCS)
Liver disease (LD), 446 adipose tissue, 192–193 systems, 148–149
in DM Magnesium and pyridoxine infusions, Medical ethics, 885–887
mechanism of, 447 super-refractory status governing bodies and rules, 887
prevalence of, 447 epilepticus, 383–384 important points, 886–887
glucose metabolism in, 446 Magnetic resonance imaging (MRI), theories of, 885–887 (See also
in T2DM, 251 492 specific theories)
Liver replacement therapy, for HRS Malaria fever, 544, 564, 564f Medical management, RVHT, 30–31
treatment, 454 clinical classifications, 573–574 Medical nutrition therapy
Liver transplantation (LT), 451 clinical features, 573 gestational diabetes mellitus
for HRS treatment, 454 clinical malaria, 575 (GDM), 218
Lixisenatide, 241 epidemiology, 570–571 for GMD in CLD, 448
LN. See Lupus nephritis (LN) global mortality, 572f Medical research pyramid, 268f
Index 965
Medical therapy clinical presentation, 600–601, 601f additional therapeutic potential,

for diabetes, 175–180 CSF examination, 602–603, 602t 263
GMD in CLD, 448–449 examination, 601–602 adverse drug reactions and
acarbose, 449 incidence, 600 contraindications, 264–265
DPP-4 inhibitors, 449 investigation, 602 and body weight, 263–264
GLP-1RA, 449 laboratory studies, 603 cancer biology, 264
insulin, 449 neuroimaging, 603 diabetes prevention, 263
meglitinides, 449 overview, 600 gestational diabetes mellitus
(GDM), 219
metformin, 448 recurrent bacterial, 600
glycemic control, 263
pioglitazone, 449 subacute, 600
history, 262
SGLT-2 inhibitors, 449 treatment, 603
sulfonylureas, 448 lipid profile, 263
tuberculosis and, 600
heart failure (HF), 147 mechanism of action, 262–263, 262t
Meningococcal vaccine, 625
hypertension in diabetes, 58–61 microvascular and
Menstrual migraine, headache, 357
macrovascularrisk
nocturia, 365 Mepolizumab, 828 reduction, 264
for OSA, 498 Metabolic functions, of gut microbiota,
newer antihyperglycemic agents,
for UGI bleeding, 417 437
265
Medicine Metabolic risk factors
nonalcoholic fatty liver disease, 264
in Ancient Egyptian Civilization, NAFLD and
overview, 262
909–910 cytokine/adipocytokine
polycystic ovarian syndrome
in Ancient Greek Civilization, 910 signaling pathways, 444
(PCOS), 264
in Ancient India, 910–911 in disease progression, 443
in T2DM, 263
robot in, 915 genetic and environmental
Methotrexate, 828
before 20th Century, 909–911 factors, 444, 444t
Metronomic chemotherapy
trends in, 909–916 insulin resistance, 444
activation of immunity, 806
in 20th Century, 911–913 oxidative stress (and hepatic
stellate activation), 444, in adult cancers, 807
in 21st Century, 913–915 angiogenesis–chemotherapy
444b
Meditation, 898 model, 806
pathophysiologic link with HCC,
Medium vessel vasculitis, 826 443–444, 444b in metastatic malignancies, 805–807
Medtronic insulin pump, 270f Metabolic syndrome (MS), 229 rational of various drugs used in,
Medullary thyroid carcinoma, 243 NAFLD and, 442 806–807
Megabloblastic anemia, treatment of, Metabolic syndrome X, 495 toxicity of, 807
880 vs. conventional chemotherapy,
OSA with (See Syndrome Z)
Mega trials in cardiology, 115–120 805–806
Metabolism, GHD, 314
arrhythmia, 117 Microalbuminuria, 849–850
Metastatic malignancies, metronomic
diabetes mellitus (DM), 118–119 diagnosis of, 850
chemotherapy in, 805–807
heart failure, 117–118 management of, 851
activation of immunity, 806
HOPE trial, 116–117 Microarchitectural disruption, 830
in adult cancers, 807
hypertension trials, 115–116 Microbiological investigations
angiogenesis–chemotherapy
overview, 115 model, 806 in CAP
SCD-HeFT, 117 rational of various drugs used in, blood cultures, 526
secondary prevention of CAD, 116 806–807 Legionella antigen detection,
Meglitinides, 449 toxicity of, 807 528
Ménière’s disease, 408 vs. conventional chemotherapy, other pathogens, 528
Meningitis, 600–603 805–806 sputum gram stain and cultures,
aseptic, 600 Metformin, 186, 255f, 300, 448 526–528
Microbiology laboratory, 718 MOG. See Myelin oligodendrocyte investigations in, 361
Microbiota, gut. See Gut microbiota glycoprotein sites of lesion, 360–361, 360t
(gut flora) Molecular adsorbent recirculating Multiple sclerosis (MS), 389, 472
Microscopic observation drug system (MARS), 454
ADEM vs., 397t
susceptibility (MODS) assay, Monosodium urate (MSU) crystals, 811
577–578 disease-modifying immunotherapy
deposition of, 813
for, 392, 393t, 394, 394f
Microscopic polyangiitis (MPA), 816 Monounsaturated fatty acids (MUFA),
Microsomal triglyceride transport 901, 902 relapses
protein (MTP) inhibitor, 213– Montreal Protocol of 1987, 504 immunotherapy for, 389, 391–
214, 213t 392, 391f
Moral objectivism, 885
Microvascular and macrovascularrisk Multiple seizure, 371. See also Seizure
Moral pluralism, 885
reduction, 264 Musculoskeletal manifestationsof
Moral relativism, 885
Midodrine, with octreotide, 454 diabetes mellitus
Morphine, 611
Mind adhesive capsulitis of the shoulder
MPA. See Microscopic polyangiitis
conditioning of, 891–892 (ACS), 204
(MPA)
innocent, 891 carpal tunnel syndrome (CTS),
MRI. See Magnetic resonance imaging
spiritual culturing of, 892–893 204–205
(MRI)
unscientific, 892 diabetic amyotrophy, 205
MS. See Multiple sclerosis (MS)
Minimal change disease (MCD), 843 diabetic muscle infarction, 205
MSU crystals. See Monosodium urate
Minimally invasive surgery (MIS), 915 Flexor tenosynovitis (FTS) or
(MSU) crystals
Ministry of New and Renewable Energy ‘Trigger Finger,’ 205, 205f
MUFA. See Monounsaturated fatty
(MNRE), 535
acids (MUFA) hyperostosis, 204
Ministry of Petroleum and Natural Gas
Multidrug resistant (MDR) pathogens, limited joint mobility, 203–204
(MoPNG), 535
701 neuroarthropathy (charcot’s joints),
MIS. See Minimally invasive surgery
Multidrug-resistant tuberculosis 205, 206f
(MIS)
(MDR–TB), 553–555
Mitoxantrone, NMO, 369 osteoporosis, 205
anti-TB drugs for, 553
Mitral stenosis, 122 overview, 203
bedaquiline for, 554
with close-upon mitral valve, 122– reflex sympathetic dystrophy (RSD),
defined, 553
124, 122f 206
pathophysiology, 122 delamanid for, 554
Rosenbloom syndrome (RS),
physical examination, 122–123 epidemiology, 553
203–204
signs and symptoms, 122 high dose isoniazid for, 555
Mustard oil, 903
severity of, 123f, 123t management, 553
Myasthenia gravis (MG), 402, 402t
Mitral valvuloplasty, 124, 124f newer drugs options, 554
Mycobacterium avium complex
MMN. See Multifocal motor overview, 553
(MAC), 662
neuropathy regimes, 554, 554t
Mycobacterium tuberculosis (TB) IRIS,
Modafinil, 498 shorter duration therapy option,
673–674
Model for end-stage liver disease 555
surgical options, 555 Mycophenolate, 828
(MELD) score, 456
treatment duration, 555 Mycophenolate mofetil, NMO, 369
Moderate volume ascites, 457
Modes of insulin delivery Multifocal motor neuropathy (MMN), Mycoplasma, 528
pen, 274 401–402, 401f Myelin oligodendrocyte glycoprotein
pump, 274 Multiorgan dysfunction, fever with, 564 (MOG), 394–395
syringe, 274 Multiple cranial nerve palsy, 359 Myeloperoxidase (MPO), 501
Modified Borg dyspnea scale, 489 causes of, 359–360 Myocardium-related diseases, dyspnea
Modified Medical Research Council diagnosis, 361 and, 482
(MMRC) scale, 489 intermediate syndrome, 361 Myrcludex B, 466
Index 967
N MOG, 394–395 renal failure, 87t, 88

multiple sclerosis, 389, 391f vitamin K antagonists (VKAs) vs.,
NACO (National Aids Control
Neurological manifestations, of HIV/ 86–89
Organization), 543
AIDS, 663–666 New-onset refractory status epilepticus
Nadolol, 456
acute seroconversion illness, 663 (NORSE), 381
NAFLD. See Nonalcoholic fatty liver
ART and, 666 Night-time blood pressure, 8, 8t
disease (NAFLD)
direct viral invasion, 663 90-90-90 strategy in HIV epidemic,
NASH. See Nonalcoholic
myelopathy due to, 663–664 645–650, 646f, 647f
steatohepatitis (NASH)
opportunistic infections (OI) Nitrate reductase assay (NRA), 578
Nasogastric tube (NG)
affecting CNS, 664–665, NMOSD. See Neuromyelitis optica
in UGI bleed, 416
665f, 666t spectrum disorders
National Confidential Enquiry into peripheral neuropathy, 664 Nocturia
Patient Outcome and Death
primary CNS lymphoma, 666, 666f assessment of, 364f
(NCEPOD), 432
progressive multifocal clinical presentation, 363
National Pneumonia Guidelines, 527,
leukoencephalopathy defined, 363
528, 529, 530, 531, 532
(PML), 666
National Vector Borne Disease Control evaluation, 364–365
Neuromuscular diseases, dyspnea due
Programme (NVBDCP), 556 low-volume voids, 364
to, 485
Natriuretic peptides (NP), 97–98, 140 multidisciplinary management, 366
Neuromyelitis optica (NMO), 367
in HFpEF, 98–99 night time urinary volume, 363–364
acute case, 369
NCEPOD. See National Confidential obesity, 364
AQP4-IgGs, 368
Enquiry into Patient Outcome sleep disorders, 364
clinical presentation and diagnosis,
and Death (NCEPOD) treatment, 365–366
367–368
Nephrotic syndrome, glomerular Nocturnal symptoms, of OSA, 497
diagnosis, 368, 368f, 369f
disease and, 843–844
features, 370t Nodular goiter. See Thyroid nodule
Nervous system, air pollution effects
maintenance therapy, 369 Nonalcoholic fatty liver disease
on, 535
treatment, 368 (NAFLD), 264, 442–445, 446
Neuroarthropathy (charcot’s joints),
Neuromyelitis optica spectrum CKD and, 444
205, 206f
disorders (NMOSD), 392, 394, colorectal cancers and, 445
Neurohormonal activation, cardiorenal
syndrome (CRS), 139 395t CV risk and, 444
clinical presentation and diagnosis, extrahepatic complications, 444–
Neuroimaging
367–368 445
meningitis, 603
Neuronal antibody mediated super- incidence, 442
seizure, 374 refractory SE, 382 metabolic risk factors
Neurological disorders, 389 Neurosurgical therapy, seizure, 379 cytokine/adipocytokine
ADEM, 395–396, 396f, 397t, 398, Neutrophil Gelatinase Associated signaling pathways, 444
398t, 399f Lipocalin (NGAL), 453, 457, in disease progression, 443
AIDP, 398–400, 399f, 400t 501
genetic and environmental
CIDP, 400–401, 401f, 401t Newer oral anticoagulants (NOAC), 154 factors, 444, 444t
CNS, 398 age/fraility, 88 insulin resistance, 444
DMT, 392, 393t, 394, 394f bleeding complications/antidote, oxidative stress (and hepatic
FMT in, 475, 476f 88–89 stellate activation), 444,
immunomodulatory agents in, 390t change from VKAs to, 89 444b
immunotherapy MS relapses, 389, defined, 86 pathophysiologic link with HCC,
391–392, 391f emergency surgery, 89 443–444, 444b
MG, 402, 402t extreme weight, 88 metabolic syndrome and, 442
MMN, 401–402, 401f patient education, 87–88 obesity and, 447
prevalence of, 447 NSSB. See Non-selective beta-blockers behavioral methods, 498
progression of, 442–443, 443f, 443t (NSSB) blood pressure, 498
risk factors, 442–443, 443f, 443t Nucleic acid amplification (NAA) tests, insulin resistance, 498
type 2 diabetes mellitus and, 442 578–579
with metabolic syndrome X (See
Nonalcoholic steatohepatitis (NASH), Nucleoside/nucleotide reverse Syndrome Z)
442 transcriptase inhibitors
nocturnal symptoms, 497
Noncommunicable diseases, for HIV infections, 653
obesity and, 495
management of, 912–913 Nucleoside reverse transcriptase
occurrences, 495
Noncoronary cardiac complications inhibitor (NRTI), 470
physical examination, 497
in diabetes mellitus (DM), 232–233 Nutrition
treatment, 497–498
Non-high-density lipoprotein acute pancreatitis, 427
type 2 diabetes mellitus and, 498
cholesterol (non-HDL-C), GMD in CLD, 448
305–309 vascular effects of, 496, 496f
Nutritional anemia, 877, 877t, 878, 879f
advantages of, 307–309 Octreotide, 417
as an indicator of ASCVD risk, midodrine with, 454
305–307 O Oils, 901
Non-nucleoside reverse transcriptase Obesity, 472, 495 blending, 905
inhibitors ambulatory blood pressure cold pressed, 903
for HIV infections, 653 monitoring in, 13 cooking, 903–904
Nonosmotic release of antidiuretic central, 497 refined, 903
hormone (AVP/ADH), 452 diagnosis, 497 selection of, 904–905
Nonpalpable purpura, 767–768 FMT in, 475 unrefined, 903
Nonpeptidomimetics, 187 gut microbiota in, 438
Older adults
Non-selective beta-blockers (NSSB), insulin resistance and, 192–193
ambulatory blood pressure
456 low grade-inflammation and,
monitoring in, 13–15
Nonspecific bacterial infections at 192–193
gestational diabetes, 61–62
different sites, 593 NAFLD and, 447
hypertension in diabetes, 61–62
Nonsteroidal anti-inflammatory drugs nocturia, 364
(NSAIDs), 419, 823 OSA and, 495 Olive oil, 903
risk of UGI bleeding and, 415 postmenopausal hypertension, 25 Omega-3 fatty acids (alpha-linolenic
acid N-3), 902
Nonstructural, vertigo, 408, 410 related breathlessnss, 485
type-2 diabetes and, 192–193 Omega-6 fatty acids (linoleic acid N-6),
Nonsurgical device treatment, 147–148
902
cardiac resynchronization therapy Obstructive sleep apnea (OSA)
Oncolytic viruses, in immunotherapy,
(CRT), 148 apnea hypopnea index (AHI), 497
801–802
implantable cardioverter- cardiovascular diseases and,
defibrillator, 147–148 497–498 ONSD. See Optic nerve sheath
diameter (ONSD)
implantable electrical devices, 148 characteristics, 495–497
clinical features, 497 Opisthorchis, 540
Noradrenaline, with albumin, 454
CPAP therapy, 497–498 Optical coherence tomography (OCT),
Normal growth. See Growth (short
76
stature) daytime symptoms, 497
defined, 495 Optic nerve sheath diameter (ONSD),
Nosocomial pathogens, in ICU, 717
931
Nosocomial pneumonia, 725–726, 725t diagnosis, 497
Oral antidiabetic drugs, 300–301, 448
Nosocomial surgical site and soft tissue drug therapy of, 498
infection, 728–729 hypertension and, 495, 497–498 insulin, 301
Nosocomial urinary tract infection insulin resistance and, 495 Metformin, 300
(UTI), 727 lifestyle modifications pioglitazone, 301
NRTI. See Nucleoside reverse antiplatelets and statins therapy, sulfonylurea, 300–301
transcriptase inhibitor (NRTI) 498 Organophosphate poisoning, 738–739
Index 969
Organ therapy, 914 Abatacept, 292–293 Parvovirus B19, 545, 823

Organ transplantation, 837 anakinra, 295 Pathogen inactivation technology, 546
Orientia tsutsugamushi, 588 anti-CD20, 292 Pathological fracture, 830
OSA. See Obstructive sleep apnea anti-CD3 antibodies, 292 Patient education
(OSA) AS1842856 (forkhead transcription ‘newer oral anticoagulants’
Oseltamivir, 632 factor), 295 (NOACs), 87–88
Osler, Sir William, 181 B-lymphocytes, 292 therapeutic, 285
Osteoblasts, 830 CTLA-4-immunoglobulin fusion PCR studies, multiple cranial nerve
Osteoclasts, 830 proteins, 292–293 palsy, 361
Osteocytes, 830 dipeptidyl peptidase-4 inhibitors PCSK-9 inhibition (nonmonoclonal
(DPP4i), 293–294 antibody), 215
Osteomyelitis, 598
dorzagliatin, 295 PCSK-9 inhibitors, 77
Osteopenia, 314–315, 830–833
GLP-1RA, 294 PD. See Parkinson disease (PD)
Osteoporosis, 205, 314–315, 830–833
glucagon like peptide-1 receptor PDD. See Pancreatic ductal disruption
bisphosphonates for, 832–833
agonist (GLP-1RA), 293 (PDD)
calcitonin and, 833
imeglimin, 294–295 PDGF. See Platelet-derived growth
characteristics of, 830 factor (PDGF)
intensive insulin therapy (IIT), 293
diagnosis of, 831–832 PE. See Plasma exchanges (PE);
Interleukin 2 (IL-2), 293
estrogen and, 831, 833 otelixizumab, 292 Pulmonary embolism (PE)
osteopenia and, 830–833 rituximab, 292 Peptic ulcer disease, UGI bleed and,
risk factors, 831 sinogliatin, 295 415
screening for, 831–832 sodium-glucose cotransporter 2 Peptides, gut microbiota in metabolism
SERMs for, 833 Inhibitors (SGLT2i), 294 of, 437
teriparatide and, 833 teplizumab, 292 Peptidomimetics, 187
treatment of, 832 therapeutic approaches to preserve, Percutaneous coronary intervention
Otelixizumab, 292 291–293, 293–295 (PCI)
Outpatient setting, antimicrobial thiazolidinediones (TZDs), 294 deferred, 112, 113f
therapy for CAP in, 529, 529t T-lymphocytes, 292 duration of dual antiplatelet therapy
Oxidative stress in cases of stable CAD after,
tumor necrosis factor-α (TNF-α)
91–92
cardiorenal syndrome (CRS), agonist, 293
elective noncardiac surgery in
139–140 vitamin D supplementation, 291–
patients treated with, 93–94
NAFLD-related HCC risk and, 444, 292
functional, 111–112, 112f
444b Pancreatic ductal disruption (PDD),
430–431, 431f improvement in survival with, 83
Oxygen cost diagram (OCD), 489
management of, 431–432 indications for, 83
Ozone, 505, 534
Pancytopenia, etiological spectrum of, Pericardial disease, HIV/AIDS and,
876, 876t 667–668
P Pantoprazole, 417 Pericardial effusion, focussed
echocardiography for
Painful ophthalmoplegia, 360 Parathyroid hormone (PTH) deficiency
diagnosis, 932–933
Pain management, acute pancreatitis, exocytosis of, 341–342
Pericardium-related diseases, dyspnea
426 primary hypoparathyroidism and, 482–483, 484f
Palla sign, 490 (See primary Perioperative management, in
Palm oil, 904 hypoparathyroidism) diabetes, 720–724
Palpable purpura, 768 Parkinson disease (PD), 472 factors causing adverse outcome,
PAN. See Polyarteritis nodosa (PAN) gut microbiota in, 438 720–721
Pancreatic beta cell mass function in Partial seizure, 372 metabolic response to surgery and
diabetes, 290–291, 290f Particulate matter (PM), 533, 534 anesthesia, 721
preoperative measures, 721–722, Platelet-derived growth factor (PDGF), laboratory investigations, 797
722t–723t 452 mechanisms, 795–796
principles and target of, 721 Pneumococcal antigen detection, physical examination, 797
risk of poor diabetic control, 720 527–528 relative, 795
Peripartum cardiomyopathy, 134–135 Pneumococcal conjugate vaccine secondary, 800
Peripheral arterial obstructive disease, (PCV), 532
systemic examination, 797
870 Pneumococcal vaccine, 625
Polycythemia vera, 798–800
Peripheral vascular disease, 228–229 Pneumocystis carinii pneumonia Polymerase chain reaction (PCR) assay,
Persistent organic pollutants (POP), (PCP), 660
578
198–200, 199f Pneumonia severity index (PSI), 528 Polyunsaturated fatty acids (PUFA),
by-products, 199 Poisoning 901, 902
HOLD, 209–210, 209t aluminium phosphide poisoning Polyvalent polysaccharide vaccine
industrial chemicals, 199 (celphos poisoning), 737 (PPV), 531–532
pesticides, 199 anticoagulants, 740 Positron emission tomography (PET),
some evidences, 199–200 benzodiazepines, 740–741 492, 922
Pertussis vaccine, 624 clinical features, 737–738 of SPN, 519–520
Pesticides, 199 corrosive poisoning, 739–740 Post-kala-azar dermal leishmaniasis
PET. See Positron emission tomography kerosene oil, 740 (PKDL), treatment of, 608
(PET) mechanism of toxicity, 737 Postmenopausal hypertension
Pharmacodynamics, 34 organophosphate poisoning, arterial stiffness, 26
Pharmacogenomics, 914 738–739 depression and anxiety, 25
Pharmacological interventions rodenticides, 740 endothelial dysfunction, 25–26
gestational diabetes mellitus zinc phosphide, 740 genetic factors, 26
(GDM), 218–219, 219t Pollution and diabetes obesity and fat distribution, 25
HOLD, 210 air pollutants sources, 200–201 preventable, 25
Pharmacologic therapy. See Medical human studies, 201 renin-angiotensin system (RAS), 26
therapy persistent organic pollutants salt sensitivity, 26
Physical activity (POPs), 198–200, 199f sympathetic overactivity, 25
and EPC, 866–867 Polyarteritis nodosa (PAN), 815–820, treatment of, 27
HOLD, 209 816f Postnatal growth, 333
nocturia, 366 case study, 815–816, 815f, 816f Postoperative managemant, in
Physical examination classification of, 816 diabetes, 724
in dyspnea, 489–490 clinical features, 817–818 Potassium-sparing common
obstructive sleep apnea, 497 definition of, 816 combination diuretics, 35
Pioglitazone, 301, 449 epidemiology, 817 Pott’s shunt, 128
Pipeline vaccines, Japanese laboratory evaluation, 818 PPAR agonists, 216
encephalitis, 550 management of, 819–820 Pranayama, 898
Plaque morphology, 76 prevalence of, 817 Pratyahara, 898
Plasma exchanges (PE), 820, 827 prognosis, 818–819 Prebiotics, 440
NMO, 369 Polycystic ovarian syndrome (PCOS), defined, 440
Plasmids, 717 264 Prediabetes
Plasmodium falciparum, 572–573 Polycythemia antidiabetic medicines, 183–184
uncomplicated, 575 absolute, 795 increased CV risk in, 182
Plasmodium vivax, 571 causes, 796, 796t Indian epidemiology, 181–182
malignant behavior of, 572–573, combined, 795 screening for, 183
572f, 572t idiopathic, 795 therapy of, 183–184
uncomplicated, 574–575 initial evaluation, 796 when should be intervene, 182
Index 971
Prediction Prostacycline (PGI2), 125 Pulmonary embolism (PE), 935

of atrial fibrillation, 162 Prosthetic heart valves, 135 acute, 936t, 937f
of stroke risk, 162 Protease inhibitors, for HIV infections, cardiac biomarkers, 152
of thromboembolism, 165 653 catheter angiography for, 937
Prednisolone, 827 Proteins, gut microbiota in metabolism chest computed tomography,
Pre-existing respiratory illness, ACOS of, 437 152–153
incidence and, 501 Proteobacteria, 436 chest radiograph for, 935–936
Pregnancy Proteonomics, 913–914 Classic Well’s criteria to assess
air pollution effects on, 535 Protozoa. See also specific names clinical likelihood of, 152t
ambulatory blood pressure TTIs of, 543 classification based on early
monitoring in, 13–15 mortality risk, 153t
Provoked seizure, 372, 372t. See also
GHD, 316 Seizure clinical presentations, 151–152
headache, 356–357 CT angiography for, 936–937
Pseudocysts, in acute pancreatitis, 431
malaria treatment in, 574–575 diagnosis, 152–153
Pseudohypoparathyroidism (PHP), 341
uncomplicated P. falciparum, cardiac biomarkers, 152
Psychiatry, air pollution and, 535
575 chest computed tomography,
Psycho-neuro-endo-immuno-cellular
152–153
uncomplicated P. vivax, 574– axis, 899
575 diagnosis of, 935, 935t
Puberty, GHD, 316
physiological changes in, 133–134 diagnostic algorithm in, 939, 939f
PUFA. See Polyunsaturated fatty acids
snake bite in, 750 in-hospital prophylaxis, 155
(PUFA)
types of insulin used during, 219t key factors and a vicious cycle of
Pulmonary arterial hypertension (PAH)
cardiogenic shock in, 152f
Premixed insulin, 275 AMBITION trial, 127
management of acute, 153–155,
Pre-XDR-TB, 553 atrial septostomy, 128 153t
Primary CNS lymphoma, 666, 666f combination therapy, 127 MR angiography for, 937
Primary hypoparathyroidism, 341 defined, 125 original and simplified PESI, 153t
epidemiology, 341 endothelin (ET-1) pathway, 126 overview, 151
measurement, 342 epidemiology, 125 pathophysiology, 151
pathophysiology, 341–342 incidence of, 125 reperfusion therapies, 154–155
signs and symptoms, 342 lung transplantation, 128 catheter based reperfusion, 155
treatment, 342–343 macitentan, 126 surgical embolectomy, 155
Probiotics, 438, 440 management of, 125–126 thrombolysis, 154–155
Procalcitonin (PCT), 528, 697
newly approved medications for, severity and prognostication, 937–
Programmatic Management of Drug 126–127 938, 939f
Resistant TB (PMDT), 554
nitric oxide (NO) pathway, 126 Skiagram signs in, 490
Progressive beta cell loss, 186–187
nonpharmacological options, 128 treatment of acute phase, 154–155,
Progressive multifocal 155t
overview, 125
leukoencephalopathy (PML),
Pott’s shunt, 128 anticoagulations, 154
666
prostacycline (PGI2) pathway, 125 aspirin, 154
Projected height (PH), 335
pulmonary artery denervation, 128 conventional anticoagulants,
Prone positioning, ARDS and, 511 154
Prophylaxis, 132 riociguat, 126
newer oral anticoagulants
Propionic acid, 437 selexipag, 127
(NOAC), 154
Propranolol, 456 stem cell therapy, 128
ventilation-perfusion scintigraphy
Proprotein convertase subtilisin/kexin Treprostinil, 126–127 for, 936
type 9 (PCSK9) inhibitors, 212 Treprostinil diolamine, 126–127 Pulmonary embolism severity index
PRORATA trial, 701 Pulmonary artery denervation, 128 (PESI), 153t
Pulmonary functional status and sarcoidosis, 598 RAS. See Renin angiotensin system
dyspnea questionnaire vasculitis, 597 (RAS)
(PFSDQ), 489 infections, 593 Rash. See Fever with rash
Pulmonary function tests malignancies, 593 Reactive oxygen species (ROS), 444
comprehensive, in dyspnea, 492 management, 597 Re-bleeding
Pulmonary hypertension, 483 miscellaneous, 593–596, 594f–596f after endoscopy therapy, 419
categories, 483 nonspecific bacterial infections at prevention in UGI bleeding, 419,
Pulmonary thromboembolic disease, different sites, 593 419f
483 serological tests, 596 in UGI bleeding, 417
Pulmonary vasculature diseases, systemic autoimmune disorders, Receiver-operator characteristic (ROC)
dyspnea and, 483 593 curves, 696, 696f
Pulmonary vasculitis, 483 systemic lupus erythematosus, 598 Receptor for advanced glycation
Pulse oximetry, in dyspnea, 491 temporal/giant cell arteritis, 597 endproduct (RAGE), 447
PUO. See Pyrexia of Unknown Origin uncommon manifestations, 598 Recombinant human erythropoietin
(PUO) (rHuEPO), 855
vasculitis, 593
Purpura Recruitment maneuvers (RMs), 512
case studies, 768 Recurrent bacterial meningitis, 600
defined, 767 Q Recurrent falls (RF), 926
Henoch–Schönlein purpura, Quality of life, GHD, 315 Red Blood Cells
768–769 hemolytic anemia due to, 877
management, 769–770 impaired production, 877, 877t
nonpalpable, causes of, 767–768
R Reduced left ventricular systolic
palpable, causes of, 768 Radiological scoring systems, 426 function, 84
pathophysiology, 767 Radon, 505 Refined oils, 903
purpuric spots, 768 Raja Yoga, 898 Reflex sympathetic dystrophy (RSD),
Rajiv Gandhi Grameen Vidyutikaran 206
Purpura fulminans, 769
Yojana, 535 Refractory status epilepticus, 381
Pyretics, 821
Raloxifene, 833 Relapses, multiple sclerosis, 389, 391–
Pyrexia of Unknown Origin (PUO),
Ramadan, 261 392, 391f. See also Multiple
592–598
Randomized controlled clinical trials sclerosis
bronchoscopy and bronchoalveolar
(RCTs) Relaxed-circular (rc) DNA, 464
lavage, 597
centrality of, 267–268 Relief of angina, 83–84
classification, 592t
DCCT/EDIC, 266 Religions, human beings and, 896–897
defined, 592
in diabetes helped clinical practice Remote symptomatic seizure, 372
epidemiology, 592, 593t
in last decade, 269 Remote Village Electrification
Indian perspective, 592–593
factors which influence physician Programme, 535
etiology, 593
practice, 268 Renal biomarkers, 140–141, 140t
etymology, 592
impact of recent Cvot in diabetes on Renal failure, 87t, 88
factors defining, 598 practice, 267 Renal percutaneous transluminal
gastrointestinal endoscopy, 597 importance of clinical practice angioplasty (RPTA), 31
history, 592 guidelines, 268 Renal replacement therapy (RRT), for
important conditions in medical research pyramid, 268f HRS treatment, 454
drug related fever, 597 prelude, 266 Renal transplant (RT), 837
factitious fever, 598 tighter glucose control, 266–267 advantages of, 837
fungal infections, 597 UKPDS, 266 contraindications of, 837
lymphoma, 598 Rapeseed oil, 903 donor evaluation, 839–841
osteomyelitis, 598 Rapid-acting insulin, 274 recipient evaluation, 837–839
Index 973
Renin angiotensin aldosterone system other routine techniques, 124 Saturated fatty acids (SFAs), 901
(RAAS), 452 medical treatment, 124 Saxagliptin, 187, 188, 188t, 189t
Renin-angiotensin system (RAS), 852 mitral stenosis, 122–124, 122f SBP. See Spontaneous bacterial
postmenopausal hypertension, 26 pathophysiology, 122 peritonitis (SBP)
Renovascular hypertension (RVHT) physical examination, 122–123 SCD. See Sickle cell disease (SCD)
angioplasty, 31 signs and symptoms, 122 SCFA. See Short chain fatty acids
causes of, 28–29 mitral valvuloplasty, 124, 124f (SCFA)
age-related demographics, 28 signs and symptoms, 121, 121t, 135 Schistosoma Hematobium, 540
clinical clues, 29 surgical treatment, 124 Scoring systems. See also specific
clinical presentation, 29 symptoms, 135 entries
epidemiology, 28 Rheumatic valvular heart disease. See acute pancreatitis, 424–426,
sex-related demographics, 28–29 Rheumatic heart disease 425t–426t
diagnosis, 29–30 rHuEPO. See Recombinant human Scrub typhus, 565, 566f, 588–591
medical management, 30–31 erythropoietin (rHuEPO) clinical manifestations, 589–590,
Ribavarin therapy, HIV/HCV co- 589f, 590t
pathogenesis, 28
infection, 470 diagnosis, 590
points favoring expected
positive response post Rice bran oil (RBO), 904 differential diagnosis, 590
revascularization, 30 Rifampicin resistant TB (RR-TB), 553 epidemiology, 588
points not favoring positive Rifaximin, 457 etiology, 588
response post Right ventricular (RV) function incidence, 588
revascularization, 30 focussed echocardiography for, 932 overview, 588
summary of current thinking on, 31 Riociguat, 126 prevention, 591
surgical revascularization, 31 Risedronate, 833 transmission, 588
treatment of, 29–30 Risk stratification, in CAP, 528–529, 529t treatment, 590–591
REPAIR-AMI Trial, 868 Rituximab (RTX), 292, 369, 827, 842 Secondary cardiorenal syndrome, 139,
Reperfusion therapies, 154–155 142
adverse effects of, 844–845
catheter based reperfusion, 155 Secondary prevention of CAD, 116
and lupus nephritis, 844
surgical embolectomy, 155 and membranous nephropathy, 843 Seizures, 371, 601. See also Complex
thrombolysis, 154–155 partial seizure (CPS)
Robot, in medicine, 915
Resistant hypertension, 61 AED, 371, 372
Rockall and Glasgow Blatchford scoring
gestational diabetes, 61 (GBS) systems, 416 approach to, 373–374
Resistin, 444 Rodenticides, poisoning, 740 diagnosis of, 373t
Respiratory system, 479–535 Rosenbloom syndrome (RS), 203–204 management, 374
air pollution effects on, 534 multiple, 371
RRT. See Renal replacement therapy
Restrictive transfusion strategy, UGI (RRT) phenomena, 377–378
bleed and, 416 RT. See Renal transplant (RT) provoked vs. unprovoked, 372t
Resuscitation, UGI bleed and, 416 Rule of halves, 67–70 recurrence, 372–373, 373t
Revascularization strategy, 110–111 Ruminococcus, 437 types of, 372
Reverse halo sign, SPN, 517 Selexipag, 127
Revised Atlanta Classification (2012), Sepsis
423, 429t S biomarkers in, 695–698
RF. See Recurrent falls (RF) Safflower oil, 904 applications, 695, 695t
Rheumatic heart disease, 135 Salt sensitivity, postmenopausal combinations, 698
echocardiography, 123, 123f hypertension, 26 C-reactive protein (CRP),
cardiac chamber Samadhi, 898 697–698
catheterization, 123 Sarcoidosis, 598 diagnostic criteria, 695–696, 696t
examples, 697t patterns of, 333–334, 335t reactions, 750–751

ROC curves, 696, 696f physiology of, 333 severe current local
described, 700 Sickle cell disease (SCD), 610–613 envenoming, 749
early and empiric antibiotics in, acute chest syndrome systemic envenoming, 748
700–703 aplastic crisis, 612 complicated and uncomplicated
de-escalation, 701 hydroxyurea, role of, 612–613 cases, 742–743, 742f
duration of therapy and dosing, hyperhemolytic crisis, 612 diagnosis phase, 744, 745f–746f
701–702 initial management, 611–612 20 minute whole blood clotting
first dose administration time, test (20 WBCT), 747
priapism, 612
700–701 first aid treatment protocol, 743
sequestration crisis, 612
monotherapy vs combination late-onset envenoming, 747
stroke, 612
therapy, 701 neurotoxic envenomation, 751
transfusions, role of, 613
regimen selection, 702–703, pain, 747–748
702t–703t analgesia, 611
in pregnancy, 750
Sequential organ failure assessment described, 610
preventative measures, 744
(SOFA) score, 424 diagnosis, 610
fluid replacement, 611 prevention and occupational risk,
SERMs (selective estrogen receptor 744
modulators), 833 management, 610–611
recommended method, 743
Serological diagnosis, of TB, 581 vaccination, 613
recovery phase, 751–752
Serology, AES, 559 “Silencing” RNA (SiRNA), HBV
infection and, 466 signs and symptoms
Serum calcitonin, 338
Simeprevir, 470 of elapid envenomation, 747
Serum testosterone. See Testosterone
Single photon emission computed of viperine envenomation, 744,
therapy
tomography (SPECT), 492 747
Serum tests, in dyspnea, 491
Sinogliatin, 295 tourniquets, handling
Serum uric acid level, 811
SIRS. See Systemic inflammatory antisnake venom, 748
Severe malaria, 573, 573t
response syndrome score tourniquets use, 743
management of, 574
(SIRS) traditional methods to be
Severity assessment discarded, 743–744
Sitagliptin, 187, 188, 188t, 189t, 449
acute pancreatitis, 424–426, Sodium-glucose cotransporter 2
Skeletal muscle, 81
425t–426t Inhibitors (SGLT2i), 294
Skiagram signs in pulmonary
scoring systems, 424–426, 425t–426t SOFA score. See Sequential organ
embolism, 490
Severity of coronary artery disease, 84 failure assessment (SOFA)
Sleep disorders, nocturia, 364, 366
Sex, ACOS incidence and, 501 score
SMART-COP, 528, 529t
Sex hormone binding globulin (SHBG), Sofosbuvir, 470
Smoking
344 Solitary pulmonary nodule (SPN),
and EPC, 866
Sex reassignment surgery (SRS), 874 514–522
status, ACOS incidence and, 501
Sex-related demographics, 28–29 bronchus sign, 517
SMRT-CO, 528, 529t
SFAs. See Saturated fatty acids (SFAs) causes, 514–515, 515t
Snake bite management, in India,
SGLT-2 inhibitors, 449 742–754 comet tail sign, 517
Short-acting insulin, 274 antihemostatic maximum ASV ‘corona radiata,’ 516, 517f
Short chain fatty acids (SCFA), 437 dosage guidance, 752–7514 defined, 514
Short stature (growth) ASV (hyperimmune diagnosis, 515–521
approach to, 336f immunoglobulin) associated findings, 517
causes of, 334t administration, 749–750 bronchoscopy, 520–521
defined, 334 administration criteria, 748–749 calcification, 517–518, 518f
diagnosis, 334–335 prevention of reactions, 749–751 cavitation, 518
Index 975
chest radiology, 516 SPN. See Solitary pulmonary nodule Section 12: Children and
clinical evaluation, 515–516 (SPN) Adolescents, 178–179
contrast enhancement, 518 Spontaneous bacterial peritonitis Section 13: Management of
CT scan of chest, 516 (SBP), 451, 457, 458t, 461 Diabetes in Pregnancy, 179
Sputum Gram stain and cultures, CAP Section 14: Diabetes Care in the
density, 517
investigation and, 526–528 Hospital, 180
distribution, 516–517
SRS. See Sex reassignment surgery Staphylococcus, 360
follow-up imaging, 519, 519t (SRS) Staphylococcus aureus, 129
growth pattern, 518–519 Stable coronary artery disease (CAD) Statins/statins therapy, 76–77, 76t, 868
margin, 516, 517f duration of dual antiplatelet therapy in OSA, 498
PET imaging, 519–520 after PCI, 91–92
Status epilepticus (SE), 380
size, 516 improvement in survival with PCI,
age, 381
surgical biospsy, 521 83
EEG correlates, 381
tissue diagnosis, 520 indications for PCI, 83
management of, 82 etiology, 380–381
transthoracic needle aspiration/
overview, 82 FIRES, 381
CT guided needle
biopsy, 520 patient preference, 84 NORSE, 381
doubling time (dt), 518 patients without clear indications refractory, 381
feeding vessel sign, 517 for intervention, 84 semiology, 380, 381t
halo sign, 517 reduced left ventricular systolic super-refractory (See Super-
function, 84 refractory status
malignant conditions, 515–516
relief of angina, 83–84 epilepticus)
management, 521–522
severity of coronary artery disease, Status migranosus, headache, 357
overview, 514
84 Steatohepatitis, 442
prevalence, 515
Standards of Care (ADA), 173–180 Steeple sign (wine bottle sign), 490
reverse halo sign, 517
Section 1: Promoting Health Stem cells, 914
satellite lesions, 517 andReducing Disparities in classes, 759
Soluble receptor for advanced glycation Populations, 173 defined, 759
end products (sRAGE), 501 Section 2: Classification and transplantation methods, 759
Solute diuresis, urinary volume, 363 Diagnosis of Diabetes, 174
Stem cell therapy, 128, 759–762. See
Somatostatin, 417 Section 3: Comprehensive Medical
also Hematopoietic stem cell
Sonothrombolysis, 387 Evaluation and Assessment
transplantation (HSCT)
Soul, 895–897 of Comorbidities, 174
ethical issues, 761
Section 4: Lifestyle Management,
defined, 896 important trials in, 761
174
part of universal energy, 895–896 recent advances, 761
Section 5: Prevention or Delay of
Soya bean oil, 903–904 Type 2 Diabetes, 174–175 risks, 761
Spiritual energy, 894 Section 6: Glycemic Targets, 175 scope in India, 761–762
centers, 895, 895t Section 7: Obesity Management for uses of, 760–761
effects of, 894–895 the Treatment of Type 2 Stigmata of recent hemorrhage (SRH),
ways of acquiring, 897–898 Diabetes, 175 417
Spiritual health, 888 Section 8: Pharmacologic Stool evaluvation, for FMT, 474
defined, 899 Approaches to Glycemic Stool preparation, for FMT, 474
Treatment, 175
diagnosis of, 899–900 Stress
Section 9: Cardiovascular Disease
effect of, 899 diabetes and, 191–192
and Risk Management, 176
Spirituality, 893–894 Section 10: Microvascular inflammation and, 191–192
Spiritual knowledge, 893 Complications and Foot Stress testing , in dyspnea, 493
Spirometry, in dyspnea, 491 Care, 176–178 Stroke risk, prediction of, 162
Structural causes, vertigo, 408–410 diagnosis, 497 effects, 344–345

Subacute meningitis, 600 lifestyle modifications, 498 measurement, 345
Subconsciousness, 894 antiplatelets and statins therapy, reproductive hormones, changes
Succinic acid, 437 498 in, 344
Sudden Cardiac Death in Heart Failure behavioral methods, 498 Tetanus vaccine, 624
Trial (SCD-HeFT), 117 blood pressure, 498 TFAs. See Trans fatty acids (TFAs)
Sulfonylureas, 186, 259–261, 300–301, insulin resistance, 498 Therapeutic patient education, 285
448 pathophysiology, 495–497, 496f Therapeutic vaccines. See also
Sulphonylureas, 254–255, 254t treatment, 497–498 Vaccines/vaccination
ADA-2017 renewed interest in, 261 Synergistes, 436 HBV infection and, 466
cardiovascular mortality and, 261 Syphilis, 544 Thiazides, 69
IDF recommended, 256–259 Systemic autoimmune disorders, 593 Thiazolidinediones (TZD), 195, 294
negative is not absolutely negative Systemic inflammatory response Thoracotomy, 521
in usage, 261 syndrome score (SIRS), 424, Thrombocytopenia, fever with, 563
points in favor of, 261 425t, 426 Thrombocytosis, 772–776
Sunflower oil, 904 Systemic lupus erythematosus, 598 Thromboembolism, 165
Superconsciousness, 894–895 Systolic blood pressure, 867 Thrombolysis, 154–155
Superior semicircular canal Systolic diastolic hypertension in for acute ischemic stroke, 386
dehiscence, 408 middle age, 44 complications, 387–388
Super-refractory status epilepticus, 381, Systolic hypertension dosage, 387
382. See also Status epilepticus isolated systolic hypertension in intraarterial tPA, 388
(SE) elderly, 44
outcomes, 386–387
algorithm for, 383f isolated systolic hypertension in
rates of, 386
treatment of, 382–385 young (ISHY), 44
sonothrombolysis, 387
Surface temperature, rise in, global systolic diastolic hypertension in
middle age, 44 telestroke, 387
warming and, 504–505
tenecteplase, 387
Surfactant protein-A (SP-A), 501
thrombolysis and endovascular
Surgical biopsy, of SPN, 521 T therapy, 388
Surgical embolectomy, 155 Thrombus, 164–165
Tachypnea, 489
Surgical revascularization, 31 Thumb sign, 490
Target height (TH), 334–335
Survival Sepsis Campaign (SSC), 700t Thyroid nodule, 337
Tauroursodeoxycholic acid (TUDCA),
Suspected white-coat HTN, 7–8 195 clinical diagnosis, 338
Sustained viral response (SVR), 470 Technitium scan, 492 malignancy, 337–338
Sutsugamushi triangle, 588 Telemedicine, 915 management, 338, 339f, 340
Sylvatic (jungle) cycle, yellow fever Telestroke, 387 Tissue biopsy, 827
virus, 583
Temporal/giant cell arteritis, 597 Tissue diagnosis, in SPN, 520
Sympathetic nervous system (SNS),
Tenecteplase, 387 Tissue plasminogen activator (tPA), 386
HRS and, 452
Teneligliptin, 188t, 189, 189t dosage of, 387
Sympathetic overactivity,
postmenopausal Teplizumab, 292 T-lymphocytes, 292
hypertension, 25 Teratogen information system (TERIS), Tocilizumab, 828
Symptomatic treatment, vertigo, 356 Tolerability, azilsartan, 18–19
410–411 Teriparatide Toll-like Receptors (TLRs), 191
Syndrome Z, 495–498. See also and osteoporosis, 833 Tolvaptan, 456
Obstructive sleep apnea (OSA) Terlipressin, 417, 454 TOPCARE-AMI Study, 868
components, 497 with albumin, 454 Torsemide, 35
defined, 495 Testosterone therapy Total lung capacity (TLC), 485
Index 977
Tourniquets use, 743 sylvatic (jungle) cycle, 583 culture-based methods for
Toxicology, 731–755 urban cycle, 584, 584f diagnosis
Toxoplasmosis, 660–661 Transposons, 717 conventional solid media,
Trans fatty acids (TFAs), 902–903 Trans-sexuals, 872, 873 576–577
Transfusion transmitted bacterial liquid culture, 577
Transthoracic needle aspiration, of
infection (TTBI), 545 SPN, 520 described, 576
Transfusion transmitted infections Transwomen (MTF), 872–873 direct sputum smear microscopic
(TTI), 543–546 examination, 576
Trauma, ultrasonography in, 933–934
arboviruses, 545 DNA tools, diagnosis based on,
Treatment protocol, for antimicrobial
bacteria, 543 578–580
therapy in CAP, 530–531
bacterial infections, 545 GeneXpert (Xpert MTB/RIF),
Trelagliptin, 188t, 189t
579
cytomegalovirus, 545 Treprostinil, 126–127 line probe assays, 579
donor screening questionnaire, 546 Treprostinil diolamine, 126–127 loop-mediated isothermal
Epstein–Barr Virus, 545 Triage-Titrate approach, 405–406, 406f amplification test
hepatitis A virus, 544 Triggering receptor expressed on (LAMP), 579, 580f
hepatitis B virus, 544 myeloid (TREM), 697–698 nucleic acid amplification
hepatitis C virus, 544 Triglycerides, 901, 903 (NAA) tests, 578–579
hepatitis E virus, 544 Triple therapy, 96, 96t epidemiology of, 918t
human immunodeficiency virus, Tropical fevers, 562–568 extensively drug resistant (See
543–544 acute febrile encephalopathy/acute Extensively drug resistant
human T-lymphotropic virus I and encephalitic syndrome, 564 TB (XDR-TB))
II, 544–545 latent tuberculous infection
with acute respiratory distress
malaria, 544 syndrome, 564 diagnosis
other agents, 546 clinical approach to, 562–563, 563t interferon gamma (IFN-γ)
Parvovirus B19, 545 release assays, 580–581
defined, 562
pathogen inactivation technology, serological diagnosis, 581
dengue fever, 564–565, 565f
546 tuberculin skin test, 580
enteric fever, 565, 565f
prion disease, 543 and meningitis, 600
investigation strategy, 566
protozoa, 543 multidrug-resistant [See Multidrug-
leptospirosis, 566, 566f
syphilis, 544 resistant tuberculosis
malaria fever, 564, 564f (MDR–TB)]
virus, 543
with multiorgan dysfunction, 564 newer modalities in diagnosis of,
West Nile Virus, 545
overview, 562 576–581
Transgenders, 872
with rash/thrombocytopenia, 563 nitrate reductase assay (NRA), 578
Transient ischemic attack (TIA), 378,
408–409 scrub typhus, 565, 566f rapid detection of drug resistance
Transjugular intrahepatic skin lesions associated with, 563t MODS Assay, 577–578
portosystemic shunt (TIPS), treatment strategy, 566–567, Tumor, role of EPCs in growth of, 869
418 567f–568f Tumor necrosis factor (TNF)-α, 444
Transmen (FTM), 872–873 undifferentiated fever, 563 25 hydroxy vitamin D3, 327, 328t. See
Transmission Trypsinogen, 423 also Vitamin D deficiency
AES, 557 TTI. See Transfusion transmitted 20 minute whole blood clotting test (20
arboviruses, 547–548, 548f infections (TTI) WBCT), 747
horizontal, 717 Tuberculin skin test (TST), 580 Type 1 diabetes mellitus
scrub typhus, 588 Tuberculosis (TB), 553, 661–662, 918 immunity, 286–287
of yellow fever virus, 583–584 annual incidence of, 918 staging of, 174
intermediate (savannah) cycle, colorimetric redox indicator Type 2 diabetes mellitus (T2DM)
583–584 methods, 578 barriers to basal insulin in, 222–223
clinical implications of Unexplained anemia, 880 HIV/hepatitis co-infections, 471

inflammation in, 195 treatment of, 881 in immunotherapy, 802
diagnosis, 497 United Nations Environmental Japanese encephalitis (JE), 549–550,
gut microbiota in, 438 Program (UNEP), 504 561
and innate immune system, 192 United Nations Inter-governmental Kyasanur forest disease, 551–552
Life Style Modifications and Panel on Climate Change SCD, 613
Metformin, 195 (IPCC), 504 therapeutic, HBV infection and, 466
liver disorder in, 251 Universal Immunization program Vanaspati ghee, 904
(UIP), 912
microvascular complications in, VARD. See Video-assisted
229–230 Universe retroperitoneal debridement
NAFLD and, 442 human being and (See Human (VARD)
being) Variant Creutzfeldt-Jakob disease
obesity and, 192–193
human life, purpose of, 891 (vCJD), 543
OSA and, 498
natural principles of, 888–889 Variceal bleed
other complications in, 232–233
origin and evolution of, 888 endoscopic therapy and, 418
role of endoplasmic reticulum
stress in, 194 Unprovoked seizure, 371, 372t. See also endoscopic variceal ligation (EVL)
Seizure for, 418
role of insulin in treatment of, 222
Unrefined oils, 903 risk factors for, 416
unfolded protein response in, 194
Unsaturated fatty acids (USFAs), 901 UGI bleed and, 415
Type 1 HRS, 451, 457
Upper GI bleeding (UGIB), 451 Variceal hemorrhage, 456–457, 458t
Type 2 HRS, 451, 457
Upper GI endoscopy, in FMT, 474 Varicella and zoster (shingles) vaccines,
Type 3 HRS, 451 624–625
Urate lowering therapy (ULT), 813, 814
Type 4 HRS, 451 Varicella zoster virus infection IRIS, 675
Urban cycle, of yellow fever virus, 584,
Typhoid vaccine, 626–627 584f Vascular endothelial growth factor
Urinary system, air pollution effects (VEGF), 452
Vasculitides, 825
U on, 535
Urinary tract infection (UTI) Vasculitis, 593, 597, 825–828
UGI bleeding. See Acute upper classification of, 825, 826f
nosocomial, 727
gastrointestinal (UGI) bleeding
Urinary volume, 363–364. See also constitutional features, 825–826
UIP. See Universal Immunization
Nocturia cutaneous, 826
program (UIP)
USFAs. See Unsaturated fatty acids diagnosis of, 827, 827t
Ulcers
(USFAs) frequency distribution of disorders,
Forrest classification, 417, 417t 826t
USG neck, 338
UGI bleeding [See Acute upper Utilitarianism, 885 large vessel, 826–827
gastrointestinal (UGI)
management of, 827–828
bleeding]
medium vessel, 826
ULT. See Urate lowering therapy (ULT) V pathogenesis, 825
Ultrasonography (USG), 813, 929–934 Vaccines/vaccination. See also Adult Vasoactive agents, UGI bleed and, 417
abdominal, 933 immunization Vasoconstrictors
advantages, 934 arboviral infections, 548–549 albumin with, for HRS treatment,
bedsideocular ultrasound, 931 CAP, 531–532, 532t 454
compression, 931 chikungunya fever, 551 midodrine with octreotide, 454
equipment, 929 dengue, 550–551 noradrenaline, 454
limitations, 934 clinical pipeline, 550 terlipressin, 454
lung, 929–930, 930t current status of, 550 VEGF. See Vascular endothelial growth
in trauma, 933–934 preclinical pipeline, 550–551 factor (VEGF)
Undifferentiated fever, 563 EVD, 639 Velpatasvir, 470
Index 979
Venous thromboembolism (VTE), 151 TTIs of, 543 World Meteorological Organization
Ventilation/perfusion (V/Q) scan, in Visceral leishmaniasis (VL), 607 (WMO), 504
dyspnea, 492–493 HIV-VL coinfection, 608 World Professional Association for
Ventilation-perfusion scintigraphy, for treatment of, 608 Transgender Health (WPATH),
pulmonary embolism, 936 Visual analogue dyspnea scale (VADS), 873
Ventilator induced lung injury (VILI), 489 WPATH. See World Professional
508, 511 Vital capacity (VC), 485 Association for Transgender
Verrucomicrobia, 436 Vitamin D, 326 Health (WPATH)
Vertebral fractures, 831 deficiency, 326–327, 331
Vertebro basilar stroke/transient
ischemic attack (TIA), 408–409
relation to lifestyle, 329–330 X
social relevance, 330–331
Vertigo, 404 XDR-TB. See Extensively drug resistant
supplementation, 291–292
approach to, 404, 405t, 406t TB (XDR-TB)
Vitamin K antagonists (VKAs)
BPPV, 406–407
‘newer oral anticoagulants’
classification of, 404 (NOACs) vs., 86–89 Y
Ménière’s disease, 408 Vivax malaria, 571–572 Yellow fever (YF)
nonstructural, 408, 410 Volatile organic compounds (VOCs),
clinical presentation, 584
peripheral vs. central vestibular 534
disorders, 404–405, 406t described, 583
structural causes, 408–410 differential diagnosis, 585
superior semicircular canal
W laboratory finding, 584
dehiscence, 408 Walled-off necrosis (WON), 428, 430 pathogenesis, 584
treatment of, 407t, 410–411 management of, 431–432 prognosis, 585
Triage-Titrate approach, 405–406, Wegener’s granulomatosis, 825 resurgence of, 583–585
406f Weight, ‘newer oral anticoagulants’ treatment and prevention, 585
vestibular neuritis, 407–408 (NOACs), 88
Yellow fever vaccine, 549, 626
Vestibular disorders Weight loss, GLP-1 receptor agonists
and, 242–243 contraindication of, 549
peripheral vs. central vestibular international certificate of, 549
disorders, 404–405 Westermark sign, 490
West Nile Virus (WNV), 545 Yellow fever virus
Vestibular migraine, vertigo, 410
White-coat HTN, 7–8 transmission of, 583–584
Vestibular neuritis, 407–408
WHO. See World Health Organization intermediate (savannah) cycle,
Vestibular rehabilitation therapy,
(WHO) 583–584
vertigo, 411
Wisconsin Sleep Cohort Study, 495, 497 sylvatic (jungle) cycle, 583
Vestibular schwannoma, vertigo, 409
Women urban cycle, 584, 584f
Video-assisted retroperitoneal
GHD (See also Growth Hormone Yoga, 303, 897
debridement (VARD), 431, 432
Deficiency (GHD))
Video-Assisted Thoracic Surgery components of, 897–898
oral estrogen, 317
(VATS), 521
puberty and pregnancy, 316
Vildagliptin, 187, 188, 188t, 189t
Village Energy Security Programme,
World Health Organization (WHO), Z
463, 481, 483, 585
535 Zanamavir, 632
case definition of AES, 556
Viral hemorrhagic fevers, 615–616 Expanded Program on Zinc phosphide, poisoning, 740
Virtue ethics, 885 Immunization, 912 Zoledronate, 833
Virus(es). See also specific names report on air pollution, 533 Z-score, 831

Medicine Update (Vol 28) 2018 PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Medicine Update (Vol 28) 2018 PDF

Uploaded by

Copyright:

Available Formats

Medicine Update 2018

© Copyright API 2018

Pritam Gupta MBBS MD (Gen Med) FICP FAMS

New Delhi, India

Making me so proud of them

Aakash Aggarwal AKP Singh Anil Kumar Gupta

Ajay Aggarwal Amar R Pazare Anshul Kumar Jain

A Pandey Asha N Shah BB Thakur

DC Sharma Dipankar M Bhowmik G Prakash

Deepak Sharma Gurleen Wander

Devendra Prasad Singh Gurpreet Singh Wander

Harpreet Singh Kashinath Padhiary Laxmi Kant Goyal

Mathew Thomas Munish Prabhakar Niteen D Karnik

Mayank Gupta NK Singh

Piyush Jain Prashasti Gupta Punit L Jain

Rajesh Kumar Jha Ravindra Kumar Das R Sajith Kumar

Sanjay Kumar Agarwal Shaurya Mehta Sidhartha Das

Santosh Kumar Swain Shipra Kunwar SN Narasingan

SS Lakshmanan Sunil Gupta TP Singh

Sunita Aggarwal Tuhin Santra

SV Ramana Murty Umashankar US

Suhas Erande Rajahmundry, Andhra Pradesh, India

Vijay Negalur Viplav N Deogaonkar VK Katyal

Yash Pal Munjal

Pritam Gupta MBBS MD (Gen Med) FICP FAMS

2. Ambulatory Blood Pressure Monitoring in Clinical Practice.....................................................................6

3. Azilsartan: A New Baby in Old Horizon...................................................................................................... 17

4. Hypertension and Menopause.................................................................................................................... 24

5. Renovascular Hypertension: Current Status............................................................................................. 28

6. Diuretics for Hypertension: Review and Update...................................................................................... 33

7. High Altitude Systemic Hypertension: Unraveling the Mystery........................................................... 36

8. Management of Isolated Systolic Hypertension: Current Concepts.................................................... 44

9. Blood Pressure Control with Changing Time............................................................................................ 50

10. Management of Hypertension in Diabetes............................................................................................... 55

11. Grey Areas in Diagnosis and Management of Hypertension................................................................. 67

13. Cardiac Cachexia............................................................................................................................................ 80

14. Is Intervention Still Relevant in Stable CAD?............................................................................................ 82

15. Newer Oral Anticoagulants in Clinical Practice........................................................................................ 86

16. Dual Antiplatelet Therapy: How Long?...................................................................................................... 90

17. Newer Biomarkers in Heart Failure............................................................................................................. 97

18. Coronary Microvascular Dysfunction: An Update................................................................................. 100

20. Mega Trials in Cardiology........................................................................................................................... 115

Heart Failure 117

21. Rheumatic Valvular Heart Disease............................................................................................................ 121

22. Advances in Management of Pulmonary Arterial Hypertension........................................................ 125

23. Infective Endocarditis: An Update............................................................................................................ 129

24. Pregnancy and Heart Disease.................................................................................................................... 133

25. A Review of Cardiorenal Syndrome.......................................................................................................... 138

27. Pulmonary Embolism: Focus on New Drugs........................................................................................... 151

28. Echocardiographic Navigation of AF from Irregular Pulse to Slurring of the Speech:

32. Diabetes and Inflammation ....................................................................................................................... 191

33. Pollution and Diabetes: Is there a Link?................................................................................................... 198

34. Musculoskeletal Manifestations of Diabetes Mellitus.......................................................................... 203

35. How to Hold the HOLD?.............................................................................................................................. 207

Behavioral Modification 208

36. Dyslipidemia Management: Newer Avenues.......................................................................................... 211

37. Metformin versus Insulin in Treatment of Gestational Diabetes Mellitus......................................... 217

38. Early Initiation of Insulin Therapy in Diabetes Mellitus........................................................................ 221

39. Diabetic Complications in Indian Scenario: An Update........................................................................ 225

40. GLP-1 Analogs: Benefits Beyond Glycemic Control............................................................................... 238

Extra Glycemic Benefits of GLP-1 Analogs 241

41. Gliptins versus Sulfonylureas: Which is Better?...................................................................................... 247

42. Metformin—the Molecule of the Decade: Old is Gold.......................................................................... 262