A Randomized Controlled Trial on the Efficacy of Yoga in the Management of Bronchial Asthma

A Research Project of
CENTRAL COUNCIL FOR RESEARCH IN YOGA & NATUROPATHY (Deptt. of AYUSH, Ministry of Health & F. W., Government of India)

61-65, Institutional Area, Janakpuri, New Delhi - 110058 (India)

Central Council for Research in Yoga & Naturopathy

Editor-in-Chief : Prof. Dr. B.T.Chidananda Murthy Director

Compiled by : Dr. Rajiv Rastogi Asstt. Director (Naturopathy) Dr. H.S. Vadiraj B.N.Y.S, Ph.D. Consultant (N & Y) First Edition : 1000 copies, 2010

Published by : CENTRAL COUNCIL FOR RESEARCH IN YOGA & NATUROPATHY

(Deptt. of AYUSH, Ministry of Health & F. W., Government of India) 61-65, Institutional Area, Janakpuri, New Delhi - 110058 (India) Website : www.ccryn.org Email : ccryn.goi@gmail.com Phone : 011-2852 0430, 31, 32 Fax : 011-2852 0435

Produced by :
MAX PRINT SHOP A-110, VIKAS TOWER, VIKASPURI, NEW DELHI-18 PHONE-9971171799

Hkkjr ljdkj
LokLF; lsok egkfunskky; fuekZ.k ou] ubZ fnYyh & 110108
GOVERNMENT OF INDIA
DIRECTORATE GENERAL OF HEALTH SERVICES Nirman Bhawan, New Delhi - 110108 Tel. No.: 91-11-23061438, 23061063 Fax No.: 91-11-23061924 E-mail: dghs@nic.in

Dr. R.K. SRIVASTAVA

M.S. (Ortho) D.N.B. (PMR) Director-General

FOREWORD

The 11th Research Monograph developed by the Central Council for Research in Yoga & Naturopathy (CCRYN) based on the research findings of research project A Randomized Controlled Trial on the Efficacy of Yoga in the Management of Bronchial Asthma underlines the effectiveness of Yoga before the scientific brethren. Bronchial asthma is a global concern in asthma epidemiology and clinical spectrum. An apparent increase has shown in several geographic areas of the world. The condition of India is also not very upbeat where more than 15 million people suffered from this disease. However, Yoga can play a vital role in this direction. The beneficial effects of yoga in bronchial asthma are not difficult to understand. Yogic practices bring about improvement in pulmonary functions. Yoga improves quality of life and reduces need for medication in bronchial asthma more effectively than conventional treatment alone. The finding of this research project will be useful for common people and landmark for the medical fraternity of various disciplines. I accolade the Director, CCRYN for publishing this important monograph. I wish the Council all the very best.

(Dr. R.K. SRIVASTAVA)

(iv)

PREFACE
Bronchial Asthma is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, airflow obstruction, and bronchospasm. Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), and rhonchous lung sounds. Symptoms are often worse at night or in the early morning, or in response to exercise or cold air. During severe attacks, an asthma sufferer can turn blue from lack of oxygen and can experience chest pain or even loss of consciousness. It causes 2.5 lakhs deaths per year worldwide. Public attention in the developed world has increased but the developing hemisphere is still lagging behind. Yoga can make a substantial contribution to the treatment of Bronchial Asthma. It is observed that in chronic airway obstruction, yogic breathing exercises brought about increase in pulmonary functions and exercise capacity. An integrated Yogic intervention decrease in heart rate, sympathetic reactivity and an increase in peak inspiratory flow, breath holding time (BHT) and chest expansion. Among the well known triggers which precipate attacks of bronchial asthma are infections and mental stress? By enhancing immunity, yoga can reduce the frequency of infections and mental stress, which generally consider the main triggers for it Yogic exercises like the poses, Yoga breathing and relaxation techniques control the mind and emotions, making the body more relaxed and thus breathe easier. A comprehensive package of these modalities integrated in a form of yoga based lifestyle management program produce better results for diseases related to psychosomatic in origin including asthma. Yoga improves quality of life and reduces need for medication in bronchial asthma more effectively than conventional treatment alone. To reduce the frequency of bronchial asthma through Yoga , the Central Council for Research in Yoga & Naturopathy (CCRYN) conducted a study on A Randomized Controlled Trial on the Efficacy of Yoga in the Management of Bronchial Asthma at Deptt. of Physiology, All India Institute of Medical Sciences, New Delhi. The important findings of the study have been incorporated in the monograph. It is the 11th Research Monograph in series of research publications of research findings. The earlier Ten research publications were accepted and appreciated by the Medical fraternity, Yoga and Naturopathy practitioners, which promoted the Council to reprint them. Few studies are available on the efficacy of yoga in bronchial asthma and well-controlled randomized trials are still fewer. None of the previous studies has investigated the possible immunological mechanisms through which yoga may influence bronchial asthma. Finally, very few of the previous studies have looked at yoga as comprehensive change in lifestyle: most of them have confined the practice of yoga to a few asanas or breathing exercises. The present study seeks to overcome these limitations.

(Prof. Dr. B.T.Chidananda Murthy) Director

(vi)

Prof. Dr. K.K. Deepak is Professor of Physiology at All India Institute of Medical Sciences, New Delhi, India. He has contributed significantly to research and development (R&D) in autonomic nervous system, its quantification and modification through nonpharmacological means. Dr. Deepak established a Clinical Autonomic Function Lab in 1989 in his Department, which provides facility for autonomic functions testing various health and disease conditions. He also established a Lifestyle Health Clinic in the Department of Physiology at B.P. Koirala Institute of Health Sciences, Dharan, Nepal in the year 1998, which offers therapeutic interventions to the patients based on the principles of Indian Traditional Yoga. His scientific approach is based on non-invasive assessment of physiological signal and attempts to extract information on brain mechanisms from peripheral signals. His emphasis is on applying a reductionistic approach towards the in-depth analysis of physiological signals. Prof. K. K. Deepak has published 35 full-length refereed articles published in indexed journal, also written 9 chapters in the books, 70 abstracts published in indexed journals, and more than 40 scientific communications published. One of his papers has been cited in BRAIN AND MIND BULLETIN OF BREAKTHROUGHS, LA, California, USA and which was published in BIOFEEDBACK AND SELF REGULATION on Meditation and epilepsy. His commendable contribution at international level during recent years is writing a complete chapter on Meditation in a popular and widely circulated book on Complementary and Alternative Therapies for Epilepsy- New York (2004). Dr. Deepak believes and practices the philosophy of 'working together' thus, his group has wide collaborations with several clinical departments for exploring basic mechanisms of autonomic dysregulation. He has been working on various aspects of physiological interventions such as Yoga, Meditation and Biofeedback for the past two decades. His work on Meditation as an interventional strategy in drug resistant epilepsy has been widely acclaimed.

(viii)

CONTENTS
S.No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Page No. Foreword............................................................................................................iv Preface................................................................................................................vi Project Profile...................................................................................................xii Abbreviations...................................................................................................xiv Introduction.........................................................................................................1 Material & Methods............................................................................................3 Data Analysis & Statistics.................................................................................20 Results...............................................................................................................23 Discussion.........................................................................................................44 Conclusion.........................................................................................................63 Bibiliography.....................................................................................................64 Abstract..............................................................................................................74

(x)

PROJECT PROFILE
1. Title of Project:
A Randomized Controlled Trial on the Efficacy of Yoga in the Management of Bronchial Asthma Deptt. of Physiology, All India Institute of Medical Sciences, New Delhi Dr. K.K. Deepak, Professor, Deptt. of Physiology, All India Institute of Medical Sciences, New Delhi Dr. Randeep Guleria, Professor, Department of Medicine, All India Institute of Medical Sciences, New Delhi 4 year (2002 to 2006)

2. Research Centre:

3. Principal Investigator:

4. Co-Investigator:

5. Period: 6. Reviewed by:

I)

Dr. Shibdas Chakrabarti, Sr. Chest Specialist, D/o Respiratory Medicine, Safdarjung Hospital, New Delhi Prof. M. Lal, Director, Mahaprabhu Yog Divya Mandir, Institutional Area, R. K. Puram, Sector-6, New Delhi

ii)

iii) Prof. Asha Gandhi, Head, D/o Physiology, Lady Harding Medical College, New Delhi
(xii)

ABBREVIATIONS
PEFR - Peak Expiratory Flow Rate FEV - Forced Expiratory Volume in 1 second BHT FVC VC PEF ECP EIB - Breath Holding Time - Forced Vital Capacity - Vital Capacity - Peak Expiratory Flow - Eosinophilic Cationic Protein - Exercise Induced Bronchoconstriction

AQLQ - Asthma Quality of Life Questionnaire OD IQR ES ER MID BMI - Optical Density - Inter Quartile Range - Exercise Sensitive - Exercise Resistant - Minimal Important Difference - Body Mass Index

GLM - Generalized Linear Model BLI VIP CRH - Bronchial Liability Index - Vasoactive Intestinal Polypeptide - Cortricotropin Releasing Hormone

(xiv)

AUTONOMIC FUNCTION TESTS IN EPILEPSY : EFFECT OF HATHA YOGA

INTRODUCTION
Bronchial asthma is a common disease, to the treatment of which yoga can make a substantial contribution. A few scientific studies are now available which support the role of yoga in the management of bronchial asthma. Most of the studies have reported subjective improvement along with improvement in some objective parameters like PEFR and FEV1. An important study using both patients and controls was carried out on 53 subjects for a period of 30 months and it was found that there was an improvement in weekly number of attacks, scores of drug treatment, subjective well being and PEFR (Nagarathna and Nagendra 1985). In a still larger trial by the same investigators involving 570 patients given an integrated course on yoga and followed up for 3-54 months, it was found that PEFR moved towards normal and 72%, 69% and 66% of patients could stop or reduce parenteral, oral and steroid medication respectively (Nagendra and Nagarathna 1986). Further, in an effort to see the effects of pranayamic breathing only, Singh (1987) conducted a study on 12 asthmatics by using pink city lung exerciser and found an increase in PEFR. But a subsequent study by Singh et al (1991) using a placebo controlled double-blind cross over design revealed that pranayamic type of breathing using pink city lung exerciser brings about a significant reduction in airway reactivity but no change in PEFR, FEV1, symptom score and inhaler use. Similarly, Tandon (1978) observed that in chronic airway obstruction, yogic breathing exercises brought about increased exercise tolerance without any improvement in pulmonary function. Studies have also been conducted in adolescents with childhood asthma. In 46 young asthmatics with childhood asthma given integrated yoga therapy, it was found that there was an increase in pulmonary functions and exercise capacity. When the subjects were followed up for up to 2 years, there was a reduction in symptom score and drug requirement (Jain et al 1991). In another study, improvement in exercise tolerance was found in 466 indoor adult asthmatic patients given an integrated yoga therapy program with better lung functions and symptom scores (Jain and Talukdar 1993).

Findings of the Research Project

In a recent study, Khanam et al (1996) gave an integrated Yogic intervention to 9 asthmatics for 7 days and found that there was significant decrease in heart rate, sympathetic reactivity and an increase in peak inspiratory flow, breath holding time (BHT) and chest expansion. At the same time, there was no change in other pulmonary functions like FEV1, FVC and PEFR and parasympathetic activity. Another study involving both controls and patients given integrated yoga therapy did not find any improvement in pulmonary functions and drug requirements though there was improvement in subjective parameters (Vedanthan et al 1998). The beneficial effects of yoga in bronchial asthma are not difficult to understand. Yogic practices bring about improvement in pulmonary functions. Nayar and his associates (1975) observed that Yogic practices bring about an increase in VC, BHT and FVC. A 10-week course in Pranayama and Yogasanas resulted in a reduction in resting respiratory rate and an increase in VC, FEV1, BHT and maximum voluntary ventilation (MVV) (Makwana et al 1988). Later on Joshi et al (1992) observed similar effects with a 6-week course in Pranayama. A 12-week course involving asanas for 30 minutes/day led to an increase in BHT and maximum inspiratory and expiratory pressures (Madanmohan et al 1992). Among the well known triggers which precipate attacks of bronchial asthma are infections and mental stress. By enhancing immunity, yoga can reduce the frequency of infections. This may be at least partly due to mental relaxation, which has an immunoenhancing effect through psychoneuroimmunological mechanisms (Walker et al, 1993). Further, asthma being basically a disorder characterized by deranged immunity, improved immunocompetence may get at the root of the disease. Thus there is a strong logic behind the beneficial effects of yoga in bronchial asthma. Very few studies are available on the efficacy of yoga in bronchial asthma. Further, wellcontrolled randomized trials are still fewer. Moreover, none of the previous studies has investigated the possible immunological mechanisms through which yoga may influence bronchial asthma. Further, the previous studies have not investigated the effects of yoga on integrated cardiorespiratory parameters of exercise. Finally, very few of the previous studies have looked at yoga as comprehensive change in lifestyle: most of them have confined the practice of yoga to a few asanas or breathing exercises. This study seeks to overcome these limitations.

Objectives
To investigate the efficacy of yoga in bronchial asthma through a randomized controlled trial as assessed by -

1. Pulmonary function tests. 2. Selected biochemical and immunological indicators known to be indicators of mast cell activation and the course of the disease. 3. Health related quality of life.

Material & Methods

Subjects
Sixty patients (n=60), who were both eligible and willing to participate in the study, were recruited through local newspaper advertisements, posters in the institute and the community at large, and by referral from the consultants in Medical OPD of the institute. There was an initial screening procedure for all the potential participants to assess the degree of reversibility of airway obstruction in response to bronchodilator. The reversal was considered significant if there was 10% increase or 200-mL absolute increase in FEV1 15 minutes after the administration of 2 puffs of a short-acting B2-agonist, salbutamol (Quanjer et al., 1993a). Only those patients who had significant reversal were considered potential patients.

Diagnostic Criteria
The diagnosis of asthma was based on the following criteria: 1. 2. History or presence of episodic symptoms of airflow obstruction (i.e. wheeze, shortness of breath, tightness in the chest, or cough). Airflow obstruction by spirometry: a) FEV1 or PEF < 80 percent predicted; FEV1/FVC < 80 percent or below the lower limit of normal, and/or b) Reversibility: FEV1 increases 10% and at least 200 ml after using a short-acting inhaled beta 2-agonist (e.g. salbutamol)

Inclusion Criteria
The inclusion criteria were age 18 years or older; an established diagnosis of asthma for at least 6 months (American Thorasic Society, 1987); and absence of any yoga practice during at least the 6 months immediately preceding the study. The following criteria were used to classify the patients into mild intermittent, mild persistent and moderate persistent asthma:

Mild Intermittent Asthma Clinical :

Symptoms 2 times a week Asymptomatic and normal PEF between exacerbations Exacerbations brief (from a few hours to a few days); intensity varied Night symptoms 2 times a month

Objective :
PEF or FEV1 80% of predicted values A > 10% increase in FEV1 in response to short-acting inhaled beta2-agonist

Mild Persistent Asthma Clinical :

Symptoms > 2 times a week but < 1 time a day Nocturnal Symptoms > 2 times a month Exacerbations may affect activity

Objective :
PEF or FEV1 80% of predicted values A 12% FEV1 response to short-acting inhaled B2-agonist

Moderate Persistent Asthma Clinical :

Daily symptoms Nocturnal Symptoms > 1 time a week Exacerbations 2 times a week; may last days and affect activity Daily use of inhaled short-acting B2-agonist

Objective :
PEF or FEV1 60-80% of predicted values FEV1/FVC 50-65% absolute values A > 15% FEV1 response to short acting inhaled B2-agonist

Patients having at least two clinical criteria and one objective criterion were included in the study. Although there is a strict criterion for classification of asthma severity, it is applicable only before starting any treatment, but in this study all the patients had already continuing with conventional treatment, therefore the classification was mainly based on their clinical features with only one objective criteria from the above listed.

Exclusion Criteria
Participants were excluded if they had any respiratory tract infection during the past 4 week, were on systemic or oral corticosteroid therapy, were smokers (anyone who had smoked during the last one year was considered a smoker), had any other associated major illness such as coronary heart disease, renal disease or diabetes, or had an unstable medical condition, or had done yoga practice during 6 months preceding the study and who can not attend yoga course for any reason.

Selection of subjects

All patients by either referral or direct approach were screened initially to assess the degree of reversibility of airway obstruction in response to short acting inhaled B2-agonist bronchodilator along with the relevant clinical history. Once the diagnosis is confirmed in accord with American Thorasic Society guidelines (American Thorasic Society, 1987). Patients who had significant reversal ( 10% increase or 200-mL absolute increase in FEV1) were further classified into mild, moderate and severe asthma based on the criteria mentioned elsewhere (NHLBI, 1995; Antonicelli et al., 2004). Patients having at least two clinical criteria and one objective criterion of mild to moderate cases were finally included in the study.

Ethical Clearance
The ethics committee of All India Institute of Medical Sciences (AIIMS) for human studies approved the protocol of the study. The patients were informed about the aims and methods of the study, expected duration of their participation, the benefits that might reasonably be expected from the outcome of research to the subject or to others, and potential risks to the subject associated with the study. Participants were also assured about the maintenance of confidentiality of records, provision of free treatment for research at anytime without penalty or loss of benefits to which the subject would otherwise be entitled. The participants gave their written informed consent before being enlisted for the study.

Research Design
The present study has attempted to understand the efficacy of an integrated comprehensive lifestyle modification program based on principles of yoga at an outpatient clinic by a randomized controlled trial on patients having bronchial asthma. This study also confirms the add on study design, in which both groups have been receiving conventional treatment, but yoga group received yogic intervention in addition to the regular conventional treatment. After making sure that the patients met the selection criteria, eligible participants were randomly divided into either Group I (yoga) or Group II (waitlisted control). After recording the baseline parameters, Group I was given an integrated course on lifestyle based on the principles of yoga for 2 weeks while continuing with the conventional treatment. At the end of the 2-wk training, participants were asked to continue the practice at home for an additional 6 weeks during which parameters were recorded at regular intervals. During the follow-up period, the patients were expected to continue the yoga practice daily. Their compliance was monitored by a diary, which they brought at each visit.

Group II was a wait-listed control group. For the first 8 weeks, the patients in Group II did not receive any yogic intervention but they continued to receive conventional treatment. The parameters were recorded at regular intervals as in Group I. At the end of 8 weeks, the patients in Group II were also offered yoga intervention as for Group I, i.e. a two-week course. Parameters from both the groups were recorded at regular intervals at 2 wk, 4 wk and 8 wk, although the last time point for recording parameters was not equally separated, taking our patients convenience and continued compliance into consideration, we have kept 4 wk separation for last study visit as indicated in Fig.1 given below. During each study visit two activities were performed, i.e. recording of parameters and individual yoga practice session. Individual yoga practice session was to reinforce patients practice during their follow-up period. In yoga group, the first 2 wk all the patients were given a supervised yoga practice including other associated components such as theory sessions on yoga, meditation, stress management, fundaments on nutrition, and health education. Details of the course are given in Table 1. For the purposes of data collection for the study, the trial was over at 8 wk. The yoga course was offered to the control group at 8 wk because it would be unethical to deny a useful intervention to the control group. However, we could not collect the data after 8 wk of study period from either group. Experimental Design: In-group I (n=30), initial 2 wk yogic intervention course followed by 6 wk of follow-up period whereas in-group II (n=30), the first 8 wk was study period with regular conventional treatment followed by 2 wk yoga course offered to all the patients in that group. Arrows indicate parameters recording points at 0, 2, 4 and 8 wk.
Yogic intervention + Conventional Treatment

Group I

Randomization
Group II Measurements at 0, 2, 4, and 8 wk

Conventional Treatment

4 Time (wk)

Fig.1

Sample size calculation

Sample size was calculated as the minimum number of patients in each group by taking into consideration the most important variable (FEV1) based on the results obtained in previous studies (Jain et al., 1991) and by using an online software (Uitenbroek, 1997) for 80% power at a 2-tailed =.05 to detect a significant difference in FEV1 values at the end of the study period in yoga group.

Randomization
In an intervention trial, randomization refers to the use of a probability device to assign patients to a particular treatment. Randomization improves the chances of the study groups being comparable. This allows us to use statistical methods to make valid statements about the difference between treatments for this set of subjects. Standard software was used (Epistat DOS version, Epistat Services, TX, USA) to generate the random assignment numbers. Based on a randomization table potential eligible participants were allocated/assigned to either the yoga group (Group I) or a wait-listed control group (Group II).

Yogic intervention
Patients assigned to the yoga group underwent a comprehensive yogic intervention. The yogic intervention was mainly included yoga practices and related components such as stress management program for about 3-4 hours a day for 2 weeks. The program consisted of lectures and practical sessions on asanas (physical postures), pranayama (breathing techniques),kriyas (cleansing techniques), meditation and shavasan (relaxation techniques). The lectures were on yoga, its place in daily life, its application to stress management, fundamentals of nutrition, and health education relevant to their illness. Each participant also had at least one session of individualized counseling. The protocol of the course is given in Table 5, and the set of yoga practices included in the course in Table 2.

The physical practices consisted of preliminary breathing exercises and loosening exercises followed by asanas under four categories (standing, sitting, prone and supine), paranayama techniques, kriyas and meditation based on raja yoga. Participants were instructed to follow a specific breathing pattern during each asana and asked to hold each pose in the final position for up to 30 sec without holding their breath. Soothing instrumental music was played while the participants were practicing the yoga techniques to induce relaxation. Participants practiced yoga with awareness focused on their physical movements and breath. Each strenuous posture was followed by an appropriate relaxation posture for a short period. The class concluded with deep relaxation for about 15 minutes as a pre-requisite for guided imagery. Participants were provided printed material and audio cassettes to supplement live instructions. The diet recommended was predominantly vegetarian, consisting of a combination of cereals and pulses, preferably unrefined, as the staple food; moderate amounts of judiciously chosen fat; about 500 g of vegetables and fruits daily, vegetables predominantly of the leafy green variety and at least some eaten raw; moderate amounts of milk and milk products; and spices in moderation (Bijlani, 2003). The patients are also explained why it is not advisable to take tea, coffee, alcohol, and other similar products. Further, the knowledge of nutrition is integrated with Yoga. It is made clear that specific inclusion or exclusion of certain items of the diet does not make a diet yogic. A diet becomes yogic when food is looked upon as sustenance rather than as a source of sensory pleasure. A detached attitude towards sensory pleasures is both a part of the pursuit of yoga and its consequence. The patients are explained how simple food which is good for the body can also be relished, and they are helped in overcoming their previous conditioning about regarding only certain foods such as sweets, fried foods, or meat as worthy of enjoying. Individualized advice session with a doctor for individualized advice, especially about diet, physical activity and behavior modification. During these sessions, the patients also find the doctor to be a patient listener with whom he can in confidence share personal problems. Some counseling is also provided for these problems based on yogic psychology.

10

Control group intervention

Participants assigned to the wait-listed control group received only conventional intervention. They were also encouraged to do any kind of exercise like walking or jogging other than yoga during the study period of 8 weeks. After that, they were offered the same yoga course as the experimental group. The conventional intervention is an established treatment used to prevent and control asthma symptoms, reduce the frequency and severity of asthma exacerbations, and reverse airflow obstruction. Asthma medications are thus categorized into two general classes: long-term-control medications taken daily on a long-term basis to achieve and maintain control of persistent asthma (these medications are also known as long-term preventive, controller, or maintenance medications) and quick-relief of accompanying bronchoconstriction (these medications are also known as reliever or acute rescue medications). Long-term-control medications are those that attenuate inflammation, which included anti-inflammatory agents like inhaled corticosteroids, long-acting bronchodilators like salmeterol. Because many factors contribute to the inflammatory response in asthma, many drugs may be considered anti-inflammatory. It is not yet established, however, which anti-inflammatory actions are responsible for therapeutic effects, such as reduction in symptoms, improvement in expiratory flow, reduction in airway hyperresponsiveness, prevention of exacerbations, or prevention of airway wall remodeling. All the patients were instructed at the beginning of the study either not to change their dosage or type of long-term control medication during the study period, but if any, it should be as per physician's advice. Quick-relief medication or rescue medication which included short-acting beta2-agonists such as salbutamol (asthalin), albuterol and terbutaline, either inhaled puffs or oral tablets and oral syrups (in the absence of inhaled puffs). This was mainly used for relief of acute symptoms by the patients as SOS medication. Details of all medications are listed under Table 5.

11

Follow-up schedule
In yoga group, at the end of the 2-wk yogic intervention course training, participants were asked to continue with the yoga practice at home for an additional 6 weeks. The participant's compliance during the follow up period was monitored by a diary, which they filled in everyday and brought during each visit. An individual yoga practice session was offered to the participants during study follow-up visits. During the follow-up period, telephonic support was also provided for motivation of participants to maintain highest compliance. During follow-up period in addition to the recording of the parameters, patients from yoga group had individual yoga practice sessions. The purpose of follow-up yoga practice sessions was to reinforce the on going yoga practice at home and to increase the motivation levels among patients. In control group, initial 8-wk all the subjects to continue on conventional treatment, but asked them to record everything about medication in a diary provided on every follow-up visit. At the assessments, completed diary (filled out at home during previous weeks) was collected, and blank diaries were furnished.

12

Table 1: PROTOCOL OF THE YOGIC INTERVENTION*

Day 1 2 Week Day Mon/Tue Wed Type of activity Name of activity History taking Introduction to one another Introduction to yoga Shavasana Asanas / Pranayama / Kriyas / Special techniqes Break Meditation Meditation Individualized advice Asanas / Pranayama / Kriyas / Special techniqes Break Fundamentals of nutrition Meditation Individualized advice Asanas / Pranayama / Kriyas / Special techniqes Shavasana Off Asanas / Pranayama / Kriyas / Special techniqes Break Samattvam (Equanimity) Meditation / Shavasana Asanas / Pranayama / Kriyas / Special techniqes Break Stress management Meditation / Shavasana Asanas / Pranayama / Kriyas / Special techniqes Break About your illness Meditation / Shavasana Individualized advice Asanas / Pranayama / Kriyas / Special techniqes Break Yogic attitude in daily life Meditation / Shavasana Individualized advice Asanas / Pranayama / Kriyas / Special techniqes Break Stress management Meditation / Shavasana Asanas / Pranayama / Kriyas / Special techniqes Interactive session on stress management Course feedback Closing session

Thu

Theory Practice Practice Theory Practice Counseling Practice Theory Practice Counseling Practice Practice Practice Film show Practice Practice Film show Practice Practice Film show Practice Counseling Practice Theory Practice Counseling Practice Theory Practice Practice Interaction

Fri

5 6 7

Sat Sun Mon

Tue

Wed

10

Thu

11

Fri

12

Sat

* Description of the yogic practices are given in Table 2.

13

Table 2: LIST OF YOGIC PRACTICES

S.No.

1.

Category Breathing exercises Loosening exercises

2.

Category details Sitting Standing Supine Sukshma Vyayama (Joint movements)

3.

Yogasanas (Postures)

Shithilikarana Vyayama (Warm -ups) Suryanamaskar (Sun - salutation) Standing (6 asanas) Sitting (6 asanas) Prone (4 asanas) Supine (4 asanas) Supine -Shavasan Prone Breathing Water Pranayama

Name of the practice Tiger, Rabbit, Shashankasana Hands-in-out, Hands stretch, Ankle stretch Straight leg raising (single & both) Warm ups starting from the head, working towards the toes: Neck rolls, Shoulder rotation, Arm rotation, Elbow movements, Wrist movements, Finger movements, Waist movements, Knee rotation, Ankle rotation, Toe movements. Forward and backward bending, Side bending, Twisting, Pawana-muktasana Kriya. 12 postures with slow and rhythmic breathing Ardhakatichakrasan, Paarsva Konasan, Padahastasan, Ardhachakrasan,Trikonasan, Parivritta Trikonasan Vajrasan, Vakrasan, Janu-shirasan, Ushtrasan, Shashankasan, Gomukhasan Bhujangasan, Adhomukha-svanasan, Shalabhasan, Dhanurasan Viparitakarani, Matsyasan, Pavanamuktasan, Setubandhasan Quick relaxation, Deep relaxation Makarasan, Balasan Agnisara Jalaneti, Vamandhouti (Kunjal) Sectional breathing, Ujjai, Surya-anuloma viloma (SAV), Nadi -shuddhi (NS) without kumbhak Based on raja yoga (5 step method) Yoga-Chair breathing (Nagarathna et al., 1991 b), practiced once in a week.

4. 5.

6.

Relaxation techniques Kriyas (Cleansing techniques) Breathing Practices

7. 8.

Meditation Raja yoga Assisted yoga Customized techniques practice

14

From the above practices, a few are scheduled to repeat on daily basis and some on weekly basis. All the patients from yoga group are encouraged to follow a standard sequence of practices to maintain homogeneity with similar benefits. Assisted yoga techniques are helpful whenever patients have an acute attack as SOS practice, but advised to practice on weekly basis. Raja yoga meditation based on asana, pranayama, pratyahara, dharana and dhyana.

Parameters measured

The following parameters were measured: a) Indices of ventilatory pulmonary function (FEV1, FVC, PEFR, FEV1/FVC%, FEF 2575). b) Quality of life under four domains i.e. symptoms, activity limitation, emotional function, and reactivity to environmental stimuli; and total quality of life. c) Immunological parameter: Serum Eosinophilic Cationic Protein (ECP) to know the course of the disease activity. d) Exercise induced bronchoconstriction (EIB), i.e. percentage fall in FEV1 with exercise challenge. e) Biochemical parameter: marker of mast cell activation (urinary prostaglandin D2 metabolite, 11-PGF2), i.e. difference in pre-post exercise urinary excretion of 11-PGF2. f) Serum soluble interleukin 2 receptor. g) Frequency of rescue medication use for the 2 weeks preceding the study visit. The parameters were measured at 0 wk (baseline), 2 wk, 4 wk and 8 wk from both groups.

15

Respiratory flows, volumes and capacities

The respiratory flows, volumes and capacities were recorded using K4b2 Spirometry (COSMED, Italy), which was calibrated weekly. K4b measures flow and volume using a bidirectional digital turbine that ensures a great accuracy within a wide flow range (up to 20 lit/sec). The volume resolution (4 mL) together with a very low resistance (<0.7 cm H2O/I/s at 12/I/s) gives accurate measurements within a wide ventilation range (between 0 and 300 liters per minute). The Spirometry program for the K4b2 system is a Windowsbased application that stores the patient's database and generates report with percentage of predicted values. K4b2 has a function to interpret the data automatically by carrying out algorithm referring to ECCS/ERS adjusted standards (Quanjer et al., 1993a). The predicted values are calculated according to the age, height and weight of the patient and compared to the corresponding measured data, customized according to north Indian population with ethnic group correction to measure FEV1, PEFR, FVC, FEV1/FVC% and FEF
25-75 2

. The test

procedure standards confirm to American Thorasic Society norms (American Thorasic Society, 1991), and the reproducibility of the two largest FEV1 and FVC out of at least three acceptable maneuvers was within 200 ml (about + 10%).

Asthma Quality of Life Questionnaire (AQLQ)

The Asthma Quality of Life Questionnaire (AQLQ) is an evaluative instrument that is sensitive to small changes over time and is therefore appropriate for capturing the effect of an intervention in a clinical trial. The AQLQ is a self-administered questionnaire available in bilingual form, i.e. English and Hindi (Juniper et al., 1992). The AQLQ measures quality of life (QOL) under sub-domains; QOL symptoms, QOL activity limitation, QOL emotional function, and QOL environmental stimuli. The AQLQ is a 32-item disease specific questionnaire that has been validated to measure the problems that adult patients with asthma experience in their daily lives (Juniper et al., 1993) and has also been validated on the Indian population (Chhabra & Kaushik, 2005). Patients responded to each item on a 7point scale. The overall score is the mean of all the items (i.e. 7 = no impairment and 1= maximum impairment of quality of life).

16

Serum Eosinophilic Cationic Protein

During every visit, 4 ml of venous blood was collected before exercise challenge from a cubital vein directly into a plain glass tube for serum ECP analysis. The blood was allowed to clot at room temperature (20oC) for 1- hour + 5 minutes and then centrifuged at 1350 g o for 10 minutes. The serum was withdrawn and aliquots were frozen at - 20 C until they were used in the ECP assay. Serum ECP levels assessed by sandwich ELISA kit (MBL ECP ELISA kit, Japan; Code No. 7618E). MBL ECP ELISA Kit measures human ECP by sandwich ELISA. This ELISA detects human ECP with a minimum detection limit of 0.125 ng/ml and does not cross-react with EDN. In the wells coated with anti-human ECP monoclonal antibody, samples to be measured or standards are incubated. After washing, a peroxidase conjugated anti-human ECP polyclonal antibody is added into the microwells and incubated. After another washing, the peroxidase substrate is mixed with the chromogen and allowed to incubate for an additional period. An acid solution is then added to each well to terminate the enzyme reaction and to stabilize the developed color. The optical density (O.D.) of each well is then measured at 450 nm using a microplate reader. The concentration of ECP is calibrated from a standard curve based on reference standards. This ELISA detects human ECP with a minimum detection limit of 0.125 ng/ml and does not cross-react with EDN. Standard curve obtained from OD values using 4-parameter logistic model (Volund, 1978) by MESACUP SYSTEM Version 3.0.9 for Windows software (Medical & Biological laboratories Co., Ltd., Japan).

Serum soluble Interleukin 2 receptor

The receptor of the cytokine interleukin 2 (IL2) plays a crucial role in the regulation of the immune response. Binding of IL-2 to its receptor (IL2R) on the surface of T- lymphocytes triggers a series of intracellular signaling events that result in the activation and proliferation of resting T cells and, ultimately, in the generation of helper, suppressor and cytotoxic T cells, which mediate immune reactions. It has been found that soluble IL2 receptor is present at low levels in serum of healthy individuals and at significantly elevated levels in a broad range of disorders such as neoplastic diseases, autoimmune diseases, organ allograft rejection and different infections. Thus, it appears that sIL2R can serve as a marker for diagnosis, therapeutic evaluation and management of cancer, as well as an indicator of a wide spectrum of disorders involving immune activation. For the quantitative measurement of soluble interleukin 2 receptor (IL2R) IMMULITE 1000 Analyzer was used by solid-phase, two-site chemiluminescent immunometric assay.

17

The serum samples stored at - 20 C were thawed and diluted 1:5 with IL2R sample diluent. The sIL-2R levels of the serum samples were determined by Immulite (Diagnostic Products), a chemiluminescent immunoassay system. The analytical sensitivity of sIL-2R assay was 5 U/ml. the sIL2R results were based on only 43 patients (21 yoga group, 22 control group) at 0 and 2 wk from both the groups.

Exercise Induced Bronchoconstriction (EIB)

All the participants were given standard exercise load for every visit on a stationary bicycle R ergometer (Bodyguard 990, BodyGuard, Sandnes, Norway) for 3 to 7 min at 80-85% of maximum workload. Patients were instructed to pedal at a rate of 60 revolutions per minute (rpm) and they were encouraged to push themselves to the limits of their dyspnoea, without exceeding a heart rate equal to 85% of the predicted maximal heart rate. To indicate the level of physiological strain and intensity during an exercise session, heart rate was monitored continuously through a sensor attached to the patient's chest (Polar Electro Inc., Finland) and the data was displayed on computer via a remote heart frequency receiver and temperature probe plugged to K4b2 machine. The exercise test was performed in an air-conditioned room with an ambient temperature between 20oC and 27oC and relative humidity of 40 to 50%. Immediately before exercise, lung function measured for the baseline value and the measurement was repeated at 3, 8, 15 and 30 min after exercise for post-exercise values. In each case, the best of three FEV1 measurements was considered for purposes of calculation. The bronchoconstriction in response to exercise was determined by the maximum fall in FEV1 among repeated measurements at different time points after cessation of exercise compared to baseline value {FEV1 (baseline) - FEV1 (after EC)/ FEV1 (baseline)}X 100 = percent fall in FEV1.

Urinary Prostaglandin D2 metabolite (11-Prostaglandin F2)

Participants emptied their bladder 5 min before exercise and again at 30 + 5 min after the exercise challenge for collection of urine samples. Urine samples were stored, without the addition of any preservatives, at - 20 C untill analysis. The amount of 11-prostaglandin F2 excretion in non-purified urine was analyzed by using Enzyme Immuno Assay(EIA, Cayman Chemical , Ann Arbor, MI, USA; Catalog No. 516521). This assay is based on the competition between 11-PGF2 and an 11-PGF2 acetylcholinesterase (AChE) conjugate (11-PGF2 tracer) for a limited number of 11-PGF2 specific rabbit antiserum binding sites. Because the concentration of the 11-PGF2 tracer is held
o

18

constant while the concentration of 11-PGF2 varies, the fraction of 11-PGF2 tracer that is able to bind to the rabbit antiserum will be inversely proportional to the concentration of 11-PGF2 in the well. This rabbit antiserum- 11-PGF2 (either free or tracer) complex binds to the rabbit IgG mouse monoclonal antibody that has been previously attached to the well. The plate is washed to remove any unbound reagents and then Ellman's Reagent (which contains the substrate to AChE) is added to the well. The product of this enzymatic reaction has a distinct yellow color and absorbs strongly at 412 nm. The intensity of this color, determined spectrophotometrically, is proportional to the amount of 11-PGF2 tracer bound to the well, which is inversely proportional to the amount of free 11-PGF2 present in the well during the incubation; or Absorbance [Bound 11-PGF2 Tracer] x 1/[11-PGF2]. The Cayman Chemical 11-PGF2 Assay is a competitive assay that provides accurate measurements of 11-PGF2 within the range of 7.8 1000pg/mL, typically with a detection limit (80% B/BO) of 5-10 pg/ml. Inter and intra-assay CV's of less than 15% were achieved at most concentrations of the standard curve. This assay allows sensitive detection of 11-PGF2 in the most common sample matrix, which is urine. Plasma concentrations of 11-PGF2 are generally below the detection limit of the assay. For calculating the assay results by a computer excel workbook spreadsheet program (Cayman Chemical, Ann Arbor, MI) was used by plotting the standard curve (4-parameter logistic or log-logit curve fit) from %B/Bo for standards versus 11PGF2 concentration (in pg/ml). Cross reactivity of the 11-prostaglandin F2 antibody against an array of related compounds are: 2, 3-dinor-11-prostaglandin F2, 10%; PGD2, <0.01%; PGD2, <0.01% and LTB4, <0.01% (Maxey et al., 1992). To correct for the effect of rate of urine formation, creatinine concentrations were measured for all urine samples by a commercially available colorimetric assay (Wipro Biomed, Bangalore, India), using Jaffe' Rate method (Flores et al., 1980). Therefore, the urinary 11-prostaglandin F2 concentrations were expressed as picogram per milligram of creatinine (Misso et al., 2004).

Rescue medication
Rescue medications are a type of medication used by people with asthma to relieve asthma symptoms (such as wheezing, coughing, and shortness of breath) or to treat an asthma flare-up. They are also known as quick-relief or fast-acting medications because they act quickly to stop symptoms, but the effects are not long lasting. They do not treat the underlying inflammation of the airways, this can require daily treatment with other types of medications called controller medications (Moy et al., 2001). The number of rescue

19

puffs use of B-agonist was recorded on a daily basis in the diaries; an average for the 2 wk preceding the study visit was used in the analyses. It was measured as frequency of average use of inhaled bronchodilator or oral bronchodilators (in the absence of inhaled bronchodilators per day.)

Data analysis and Statistics

Categorical variables were analyzed using chi-square analysis. Continuous variables were analyzed using the Mann-Whitney U test or the independent sample t test, depending on the distribution of the data. Data was subjected to computation of differences between mean values of all time intervals with GLM repeated measures, followed by post Hoc analysis (Bonferroni) for each group separately to evaluate the trends. Raw data of pulmonary function indices and AQLQ score, percentage of predicted values of pulmonary function indices and logarithmically transformed ECP values were used for appropriate analysis. Urinary 11-prostaglandin F2 concentrations were not normally distributed; therefore, median (interquartile range, IQR) values are reported, but to normalize the data the percentage change in 11-PGF2 following exercise challenge was used for analysis. Maximum percentage of exercise induced fall in FEV1 values were used for non-parametric test analysis. Sub-group analysis was also done for participants who experienced a decrease of 15% in their FEV1 values following EC at 0 wk (considered as exercise-sensitive, ES) and for those in whom change was < 15% (exercise-resistant, ER). Separate group and sub-group analysis was done for maximum fall in FEV1 and % change in urinary 11-PGF2 values by Mann-Whitney U test to test the differences at individual time points between groups, Friedman test to measure the change with respect to time in each group, if the data distribution was not normal. The results of sIL2R are presented as median values, and the interquartile range (IQR) is provided. Wilcoxon signed rank test to find out distribution of variables compared with baseline values using the exact p values and yoga and control groups were compared with the use of the Mann-Whitney U test. Friedman and Mann-Whitney U test analyzed rescue medication scores as average frequency per day for the 2 wk preceding the study visit.

20

The notion of taking a continuous variable, specifying a threshold that defines an important difference, and examining the proportion of patients who reach that threshold is not a new approach. But what we have done for disease specific asthma quality of life (AQOL) data is to anchor the threshold difference using the smallest difference that patients consider important- the minimal important difference because superficial examination of mean differences can produce very misleading conclusions. When mean differences fall below the minimal important difference, clinicians may intuitively conclude that the treatment has a small, and possibly unimportant effect. Similary, doctors who observe a mean difference that is appreciably greater than the minimal important difference may be ready to assume that each patient benefits. This is not necessarily the case (Gyuatt et al., 1998). This approach does not restrict to health related quality of life or functional status measures, but applies to any clinical variable. Therefore, we have taken a value (0.5) that can be considered clinically meaningful based on previous literature (Juniper et al., 1994), which is usually referred to as the Minimal Important Difference (MID). Based on MID, we calculated the number of patients who experienced clinically meaningful improvement in both the groups. We have categorized all the participants, based on MID, into three categories: improved (>0.5), stayed the same or unchanged (0.5) and deteriorated (<0.5). from this, we calculated the net proportion benefiting from yoga (proportion benefiting from yoga plus conventional treatment minus the proportion benefiting from convention treatment alone). The reciprocal of this value gave us the number of patients needed to be treated with yoga plus conventional treatment for one patient to have a clinically meaningful improvement in quality of life over and above that which he or she would have experienced on conventional treatment alone. However, the concept of estimating NNTs for crossover studies is intuitively quite easy and the calculation is simple. For parallel group studies, the calculations are more complicated and require one to estimate how each patient might have responded when taking the comparator intervention (Gyuatt et al., 1998). In case of parallel group studies, the number needed to treat for one patient to benefit from yoga is calculated from Table 3, by adding up cells of those who improved (bx+cx+cy), subtracting the cells of those who deteriorated (ay+az+bz), and dividing 1 by the result.

21

Table 3: NNT calculation for parallel group studies Yoga Control

Improved (a) Unchanged (b) Deteriorated (c)
NNT = 1 / (bx+cx+cy) (ay+az+bz)

Improved (x) >0.5 ax bx cx

Unchanged (y) 0.5 ay by cy

Deteriorated (z) <0.5 az bz cz

Data was expressed as mean + SD values for baseline characteristics and normally distributed data. Data that is not showing normal distribution was expressed in median with an interquartile range and for statistical comparisons, the same data has been expressed in percentage of change. P values of 2-tailed <.05 were considered statistically significant. Statistical calculations and plots were performed by using validated statistical software packages for personal computers (SPSS for Windows 10.0.1 release; SPSS Inc, Chicago, IL, USA and NCSS/PASS Trial version, Number Cruncher Statistical Systems, Kaysville, Utah).

22

Results
Patients for the Study
The study was carried out on patients having mild to moderate bronchial asthma. The patients were referred from Respiratory Clinic, Department of Medicine or reported directly to the Integral Health Clinic, Department of Physiology, All India Institute of Medical Sciences (AIIMS), New Delhi. Of the 138 patients, 66 did not meet the study eligibility criteria. Out of 72 eligible participants, the 60 patients who agreed to participate in the study were randomized into yoga and control groups. In the yoga group (n = 30) one patient missed his follow-up visits from 4 wk onwards because of being too busy. Hence, in the yoga group only the data on 29 patients were analyzed. One subject, whose data was incomplete, was excluded from the analysis. In control group (n = 30), only 28 patients completed all the visits. Two patients from the control group were lost to followup because one relocated to another city because of his job, and in case of the other, contact was lost completely inspite of all efforts. Hence, in the control group, only the data on 28 patients were analyzed. The two patients, whose data were incomplete, were excluded from analysis. Thus the data from 57 patients was analyzed (yoga group, n = 29; control group, n = 28) since they completed the final follow-up measures up to 8 wk.

Baseline Data Demographics and disease characteristics of the study groups

In yoga group, there were 13 males and 16 females, with mean age of 33.511.4 years. There were 13 mild and 16 moderate asthmatic patients in the group. In yoga group, the average time since they were having asthma was 11.69.6 yr and 13 patients had family history of asthma. In the control group, there were 20 males and 8 females, with mean age 33.411.5 years. There were 11 mild and 17 moderate asthmatic patients in the group. In control group, the chronicity of asthma was 10.511.9 yr and 11 patients had a family history. Other demographic data collected was age, sex, height and weight of the study

23

groups. The Body Mass Index (BMI) was computed using the formula Wt / (Ht) where Wt is weight in kilograms, Ht is height in meters. Both the groups in clinical characteristics and other demographics are comparable as analyzed by chisquare analysis. Table 4. gives the demographics of the study.

Table 4: Demographics and Disease characteristics at baseline

Yoga group (n = 29) Male Female Family history Mild asthma Moderate asthma Asthma duration, yr (mean SD) Body Mass Index (BMI) Age, yr (all patients) - Male - Female 13 (45) 16 (55) 13 (44.8) 13 (44.8) 16 (55) 11.6 9.5 23.4 4.3 33.5 11.4 30.0 12.4 36.4 10.0 Control group (n = 28) 20 (71) 8 (29) 11 (39.3) 11 (39.3) 17 (60.7) 10.5 11.9 22.6 4.0 33.4 11.5 31.9 11.6 37.2 10.9 p-value 0.29 0.19 0.67 0.78 0.82 0.22 0.44 0.96 0.67 0.85

p-value obtained from Chi-square analysis, Mann-Whitney U test, or t test. Values in parenthesis are %

Medication (regular medication) use by study groups

The anti-asthmatic medications being taken by the patients at the beginning of the study have been tabulated in Table 5. As per the study protocol, all the patients in both the groups continued to take medications for asthma as prescribed by their physicians. Patients were given a diary in which the medication use was noted as frequency of medication use on each day. There was no significant difference between yoga and control groups in baseline medication use. Inhaled steroid dose was estimated as mean inhaled steroid use in micrograms per day in the form of inhalers, which have direct impact on airways. The inhaled steroid was calculated as inhaled dose of beclomethasone or its equivalent content of budesonide or fluticasone. These were calculated on the assumption that beclomethasone 2000g = budesonide 1600g = fluticasone 1000g.

24

Table 5: Details of medication at baseline

Type of Medication Yoga group Control group (n = 29) (n = 28) No of patients (%) 22 (75.9) 1 (3.4) 1 (3.4) 1 (3.4) 24 (85.4) 2 (7.1) 5 (17.8) 1 (3.6) p-value

Inhaled bronchodilators: - Salbutamol - Salmeterol - Ipratropium - Tiotropium - Theophylline Oral bronchodilator tablets: - Deriphyllin - Salbutamol - Theophylline Bronchodilator syrups: - Salbutamol - Terbutaline Inhaled corticosteroids: - Beclomethasone - Budesonide - Fluticasone Corticosteroid nasal sprays: - Beclomethasone - Fluticasone Anti-allergics: - Cetrizine - Levocetrizine - Pheniramine maleate - Fexofenadine Other medications: - Ayurveda - Homeopathy

0.34 0.30 0.07 -

10 (34.5) 4 (13.8) 2 (6.8)

14 (50) 2 (7.1) 7 (25)

0.23 0.24 0.05

3 (10.3) 2 (6.8)

2 (7.1) 4 (14.3)

0.32 0.22

3 (10.3) 14 (48.3)

2 (7.1) 2 (7.1) 11 (39.3)

0.32 0.67

1 (3.4) 1 (3.4)

4 (13.8) 2 (6.8) 1 (3.4) -

4 (14.3) 1 (3.6)

0.29 -

4 (13.8) 2 (6.8)

1 (3.6) 2 (6.8)

0.15 0.38

p-value obtained from Chi-square analysis or fisher Exact test. Some patients are using more than one type of bronchodilators.

25

There was no significant difference in baseline medication of oral bronchodilators, inhaled bronchodilators and bronchodilator syrups. There was no significant difference of inhaled corticosteroids per day, ug/day (320.4158.8 vs 360151.4; p=0.48) between groups at the baseline visit (Table 6). Patients taking anti-allergic medication were also not differed significantly between yoga (n = 7) and control groups (n=5) and a few patients were on nonconventional medication such as ayurveda and homeopathy (yoga, 6; control, 3), which is not significantly different between groups.

Table 6: Summary of inhaled corticosteroids and rescue medication dose at baseline in both groups

Type of Medication
Mean inhaled steroid dose, g/day (mean SD) Rescue medication use; (mean SD), times per day, average of l ast 2 wk

Yoga (n = 29) 320.4 158.8 2.27 1.5

Control (n = 28) 360 151.4 1.98 2.09

p - value
0.48 0.19

Daily dose of inhaled steroids in beclomethasone ug equivalents over the past 1-2 wk. These were calculated on the assumption that beclomethasone 2000g = budesonide 1600g = fluticasone 1000g. Rescue medication = Inhaled rescue bronchodilator intake (or) oral rescue bronchodilators in the absence of inhaled bronchodilators per day an average for 2 weeks preceding the study visit. p-value obtained from Chi-square analysis or Mann-Whitney U test.

Baseline rescue medication use

Rescue medication was estimated from filled diaries received from the patients and from personal interviews on every visit. The average rescue medication use per day is frequency of rescue medication use an average for 2 weeks preceding the study visit, measured as average number of inhaled bronchodilator use per day or oral short acting B2bronchodilators (oral tablets or syrups in the absence of inhaled bronchodilators) use per day. The baseline average rescue medication use per day was statistically similar between yoga vs control groups (2.27 1.5 vs 1.98 2.09; p=0.19).

Baseline values of outcome parameters

The yoga and control groups did not differ significantly regarding baseline values of most variables except PEFR of percentage predicted values (p=.031). Although most baseline values were not significantly different, the control group consistently exhibited more disability on all spirometric measurements than the intervention group. As randomization

26

does not necessarily produce comparable groups, there can be minor and some times major differences in the baseline comparisons between groups (Altman & Dore, 1990). The statistical analysis for respiratory function indices were done from both absolute values and predicted values calculated according to the age, height and weight of the patient with ethnic group correction and compared to the corresponding measured data to measure FEV1, PEFR, FEV1/FVC and FEF 25-75%. The post-bronchodilator response in FEV1 before the recruitment of the patients into the study is given in Table 7.

Table 7: Post-bronchodilator response in FEV1 for screening the patients Parameter

Pre FEV1 (L) (mean SD) Post-bronchodilator response in FEV1 (L) Post -bronchodilator response in FEV1 (% change)

Yoga (n = 29)
1.98 0.70 2.36 0.79 21.0 11.2

Control (n = 28)
1.70 0.63 2.10 0.77 24.3 12.1

p-value
0.11 0.19 0.29

FEV1, forced expiratory volume in 1 second; 2 puffs of salbutamol inhaler was used to see postbronchodilator response p-value obtained by unpaired 't' test.

For Asthma Quality of Life Questionnaire (AQLQ), on a 7-point scale (i.e.7=no impairment and 1=maximum impairment) and the symptoms quality of life domain, which is designated here as 'QOL symptoms' is the mean of scores of item numbers 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29 and 30; activity limitation quality of life domain, which is designated as 'QOL activity limitation' is the mean scores of item numbers 1, 2, 3, 4, 5, 11, 19, 25, 28, 31 and 32; emotional function quality of life domain, which is designated as 'QOL emotional function' is the mean of item numbers 7, 13, 15, 21 and 27; response to environmental stimuli quality of life domain, which is designated as 'QOL environmental stimuli' is the mean of item numbers 9, 17, 23 and 26; and the overall score is the mean of all the items. There are no baseline differences between yoga and control groups either in any of the domains of asthma quality of llife or overall quality of life. Baseline values of serum Eosinophilic Cationic Protein (ECP) are not statistically different to each other between yoga and control groups (mean SD, 42.9 59.9 vs 28.7 31.6; p=0.89). At baseline, there are no differences between groups in change in urinary 11-prostaglandin F2 with exercise challenge (i.e. Urinary 11-prostaglandin F2), which means that the exercise induced mast-cell activation levels are not statistically different between groups. These values are expressed in picograms per milligrams of creatinine units of measurement with median and an interquartile range (26.9, 7.4-218 vs 38.4, 3.1-108; p=0.55). however, for

27

analysis purpose the data was converted into percentage of change in excretion of urinary 11--prostaglandin F2 after exercise challenge, which is also not significantly different between yoga vs control groups at baseline (mean SD, 17.6 18.6 vs 16.6 21.0; p=0.97) (Table 8).

Table 8: Baseline values of respiratory function indices, quality of life, serum ECP, 11-prostaglandin F2
Category
Respiratory function indices

Parameter FEV 1 (L), absolute values PEFR (L/sec) FVC (L) FEV 1/FVC% FEF 25 (L/sec) -75 FEV 1, % predicted PEFR FVC FEV 1/FVC% FEF 25 -75 % fall in FEV 1 after exercise challenge QOL overall score QOL symptom score QOL activity limitation QOL emotional function QOL environmental stimuli Serum ECP levels in ng/mL Serum sIL2R, median (IQR) (yoga, n=21; control, n=22) Urinary 11 -prostaglandin F2 (pg/mg of creatinine), median (IQR)

Yoga (n = 29) 1.94 4.36 2.99 66.2 1.38 70.2 68.6 78.7 80.4 0.70 1.44 0.96 10.1 0.65 17.4 18.4 13.3 11.5

Control (n = 28) 1.76 3.94 2.89 60.1 1.21 62.5 57.4 75.2 73.7 0.68 1.73 0.86 12.2 0.69 19.2 19.7 15.0 14.8

p-value 0.12 0.065 0.59 0.006 0.043 0.11 0.03 0.35 0.06 0.31 0.16 0.80 0.70 0.95 0.35 0.14

EIB

38.4 14.5 15.0 14.0 3.72 1.17 3.77 1.34 3.66 1.13 3.94 1.47 3.72 1.17 42.9 59.9 699 (578-813.5) 26.9 (7.4- 218)

33.9 18.3 9.1 10.8 3.64 1.14 3.62 1.42 3.67 1.17 3.59 1.39 4.04 1.42

Quality of Life

IMMU BIO CHEM

28.7 31.6 0.89 785 (5710.34 1025.8) 38.4 (3.1-108) 0.55

Abbreviations: AQOL, Asthma Quality of Life Questionnaire; FEV1, force expiratory volume in 1 second; FEF
25-75

%, forced mid-expiratory flow between 25% and 75%; FVC, forced vital capacity;

PEFR, peak expiratory flow rate; ECP, eosinophilic cationic protein; IQR, inter quartile range; EIB, exercise-induced bronchoconstriction; IMMU, immunological; BIOCHEM, biochemical parameters. p-value obtained by 't' test or Mann-Whitney U test. All values are expressed in mean SD, except 11-PGF2 which is expressed as median with interquartile range.

28

Effects of Intervention Pulmonary function based on absolute values

The absolute values of various indices of pulmonary function at different points in time during the study have been given in Table 9. GLM repeated measures with post-hoc analysis was applied individually within each group from data of absolute values. None of the indices measured showed any significant change during the study in the control group. However, in the yoga group, as compared to the baseline (0 wk value), a significant improvement was seen in FVC at 8 wk (p = 0.041) marginally; PEFR at 2 wk (p=0.02), 4 wk (p=0.002) and 8 wk (p=0.000) and FEF25-75 only within group overall significance by considering all time points (p=0.019) but not at any individual time point. We have also done a separate analysis on percentage of predicted values of pulmonary function indices with full factorial model GLM repeated measures followed by post-hoc analysis with Bonferroni correction.

29

Table 9: Pulmonary function indices at different points during the study (based on absolute values) in both groups
Parameter FEV 1 (L) PEFR (I/sec) FVC (L) FEV 1/FVC% (%) FEF 25 (I/sec) -75 Group Yoga Control Yoga Control Yoga Control Yoga Control Yoga Control 0 wk 1.94 0.70 1.76 0.68 4.36 1.44 3.94 1.73 2.99 0.96 2.89 0.86 66.2 10.1 60.1 12.2 1.38 0.65 1.21 0.69 2 wk 2.01 0.71 1.77 0.71 4.87 1.72* 3.97 1.82 2.95 0.91* 2.87 0.90 68.1 11.6 61.0 11.6 1.50 0.77 1.20 0.69 4 wk 2.07 0.73 1.68 0.68 5.18 1.71 3.85 1.98 2.99 0.89 2.81 0.85 69.0 11.8 59.1 12.7 1.61 0.83 1.15 0.67 8 wk 2.12 0.66 1.67 0.64 5.41 1.69 3.77 1.64 3.10 0.87 2.76 0.79 68.4 10.8 59.7 11.4 1.60 0.81 1.11 0.66

*p<.05; p<.01; p<.001 based on GLM repeated measures with post-hoc analysis. Abbreviations: FEV1, forced expiratory volume in 1 second; FEF25-75%, forced mid-expiratory flow between 25% and 75%; FVC, forced vital capacity; PEFR, peak expiratory flow rate. All values are mean SD from absolute values.

Pulmonary function based on percentage of predicted values

The tests for pulmonary function were to test the flow, volumes and capacities of the airways and lung in assessing its functional status. In PEFR, yoga group showed significant linear trend (p=.000) and in post-hoc pair wise comparisons significant change was seen at 2 wk (p=.027), 4 wk (p=.000) and 8 wk (p=.000), but control group did not show any such difference, remained unchanged. In addition, significant group mean difference was observed between yoga and control groups (p=.000). In PEFR, since there is a significant baseline difference, baseline was considered as a constant covariate for between-group comparisons. In FEV1, significant overall liner trend was observed within yoga group (p=.001), but not in control group. In post-hoc analysis, significant difference was observed at 8 wk (p=.013) compared with baseline in yoga group. There is also significant group mean difference observed between yoga and control groups (p=.009).

30

In FVC, yoga group showed only a significant overall change (p=.03). However, in post-hoc pair wise comparisons, none of the follow-up visits was significantly different from baseline values in either group. There is no significant group mean difference also observed between yoga and control groups. In FEV1/FVC%, yoga group showed a significant overall change (p=.027). However, in posthoc pair wise comparisons none of the visits was significantly different from baseline in either group, but significant group mean difference was seen between yoga and control groups (p=.011). In forced mid-expiratory flow (FEF 25-75%), yoga group showed overall significant change (p=.005), but no significant change was observed in post-hoc pair wise comparisons with baseline in either group. However, significant group mean difference was seen between yoga and control groups (p=.035).

Table 10: Effect of 8-wk intervention (yogic/control) on respiratory function indices based on percentage of predicted values
Parameter PEFR % predicted FEV1 % predicted FVC % predicted FEV1 / FVC % predicted FEF25-75 % predicted Group Yoga Control Yoga Control Yoga Control Yoga Control Yoga Control Week 0 68.6 18.4 57.4 19.7 70.2 17.4 62.5 19.2 78.7 13.4 75.0 15.0 80.4 11.5 73.7 14.9 38.4 14.6 34.0 18.3 Week 2 76.5 20.5* 58.2 22.0 73.9 19.6 63.1 20.5 78.0 12.6 74.7 18.3 82.6 13.3 74.8 13.9 42.0 19.4 33.8 17.8 Week 4 81.5 20.9 56.9 26.2 76.1 20.1 60.5 21.6 79.3 13.0 73.4 18.1 83.7 13.4 72.4 15.1 45.0 20.5 32.4 18.1 Week 8 85.3 20.7 56.2 22.0 77.9 17.2* 59.9 19.1 82.2 10.7 72.5 17.5 83.1 12. 2 73.3 13.8 45.0 19.7 31.1 17.1 0.035 0.011 NS 0.009 p -value 0.000

All values are expressed as mean SD. P-value was based on group mean differences between yoga and control groups, NS not significant * p<.05; p<.01; p<.001 based on post-hoc pair wise comparisons with 0 wk values.

31

Results of serum Eosinophilic Cationic Protein

The serum eosinophilic cationic protein (ECP) values are highly variable and since they are not following normal distribution, for analysis purpose the values were converted into logtransformed values with base 10 (Table 11). However, the actual values are represented in box plots with median (horizontal line) and an interquartile range (IQR 25 to 75 percentile in a box) excluding outliers, vertical lines indicate the range. Neither the within subjects nor the between groups was statistically significant. In post-hoc analysis separately, none of the follow-up visits was significantly different from baseline visit in either groups.

Table 11: Log-transformed serum ECP values in both groups (ng/mL)

Group (mean SD) Yoga (n=29) Control (n=28) Week 0 1.32 0.51 1.25 0.43 Week 2 1.23 0.58 1.20 0.49 Week 4 1.29 0.60 1.28 0.49 Week 8 1.19 0.49 1.20 0.44 p-value 0.44 0.73

All values are logarithmically transformed values, mean SD p-value based on GLM repeated measure in each group separately

Results of serum soluble IL2R

The serum soluble interleukin-2 receptor levels were measured only in 43 patients (21 yoga group, 22 control group) from 0 wk samples. There were no significant differences between yoga and control group at baseline values of serum sIL-2R levels. However, yoga group showed significant difference in serum levels of sIL-2R at 2 wk compared with baseline values, U/ml (median, IQR; 699, 578-813.5 vs 607, 551.5-790.5; p<.05), control group did not show any significant difference from baseline values although there is some decrease at 2 wk.

32

Table 12: Serum soluble Intereukin 2 receptor values at 0 and 2 wk

Group Yoga Control Number n = 21 n = 22 0 wk, median (IQR) 699 (578 - 813.5) 785 (571 - 1025.8) 2 wk, median (IQR) 607 (551.5 - 790.5) 734 .5 (564.5 - 980.5) p-value 0.029 0.314

p-value was based on Wilcoxon Signed Ranks test between 0 wk and 2 wk

Asthma Quality of Life Questionnaire (AQLQ)

The Asthma Quality of Life was measured under four sub-domains separately and overall quality of life was computed from total scores of the four sub-domains. There were no significant baseline value differences between yoga and control groups in QOL symptoms, but there was a significant linear improvement seen within yoga group (p =.000) and control group (p =.000). In post-hoc pair-wise comparisons, yoga group shown significant improvements when compared with 0 wk at all follow-up visits i.e. 2, 4 and 8 wk (p =.000) and in control group at 4 wk (p =.004) and 8 wk (p =.001) only. Significant group mean difference also observed between groups (p =.033). Results of AQLQ domains and overall scores are shown in Table 13. In QOL activity limitation, there was a significant linear trend within yoga group (p=.000) and a marginal improvement in control group (p=.048). In post-hoc analysis, yoga group alone showed significant differences at 2, 4 and 8 wk from baseline visit (p=.000). Significant group mean difference was observed between yoga and control groups (p=.003). In QOL emotional function, there is significant linear trend seen within yoga group (p=.000) and in control group (p=.029). However, in post-hoc analysis, yoga group showed significant differences at 2 wk (p=.001), 4 and 8 wk (p=.000) which was not observed in control group at any follow-up visit. Significant group mean difference was observed between yoga and control groups (p=.006). There was a significant linear improvement seen within QOL environmental stimuli (QOL of response to environmental stimuli) within only yoga group (p=.000). In post-hoc pair wise comparisons, yoga group showed significant improvements at all follow-up visits (p=.000)

33

i.e. 2, 4 and 8 wk, but not the control group. In addition, there is no significant group mean difference between groups. Below profile plot shows an interaction, this is clearly displayed as a cross-over interaction between follow-up visits and groups. This means that there is an increase in QOL environmental stimuli scores with time, but with a deviation form this pattern for control group between 0 and 2 wk.

In total quality of life (TQOL), considering scores of all sub-domains the overall quality of life shown a significant linear improvement within yoga group (p=.000) and control group (p=.000). In post-hoc analysis, yoga group showed significant differences at 2, 4 and 8 wk (p=.000) and control group at 4 wk (p=.044) and 8 wk (p=.005) from baseline values. There is also significant group mean difference observed between groups (p=.013). Overall AQLQ scores started from the same point on baseline but there is no cross over interaction between follow-up visits and groups. However, the yoga group showed maximum improvement in initial 2 weeks during yoga training period since then the scope of improvement was not much, whereas control group showed almost a linear improvement over a period of 8 wk.

34

Table 13: Effect of 8-wk intervention (yogic/control) on overall quality of life and its sub-domains
AQLQ domains Symptoms Group Yoga Control Activity limitation Yoga Control Emotional function Yoga Control Response to environmental stimuli Total Quality of Life Yoga Control Yoga Control Week 0 3.77 1.34 3.63 1.42 3.66 1.14 3.67 1.17 3.94 1.47 3.60 1.40 3.46 1.54 4.04 1.43 3.72 1.17 3.64 1.15 Week 2 5.07 1.37 3.96 1.67 4.82 1.29 3.74 1.52 5.10 1.65 4.01 1.64 4.64 1.55 3.83 1.55 4.93 1.31 3.90 1.46 Week 4 5.38 1.11 4.42 1.50 5.21 1.05 3.90 1.36 5.45 1.32 4.15 1.81 5.00 1.43 4.08 1.65 5.28 1.03 4.17 1.40 Week 8 5.42 1.23 4.70 1.67 5.47 1.08 4.20 1.46 5.71 1.29 4.32 1.75 5.30 1.61 4.40 1.76 5.46 1.12 4.50 1.51 p-value (BG) 0.033

0.003

0.006

NS

0.013

All values are expressed as mean SD. P-value was based on group mean differences between yoga and control groups, BG between groups; NS not significant P<.01; p<.001 based on post-hoc (Bonferroni) pair wise comparisons with 0 wk baseline values.

35

Interpreting Asthma Quality of Life data

The Minimal Important Difference (MID) of 0.5 was considered and based on this figure, all the patients were sub divided into improved (>0.5), unchanged (0.5) and deteriorated (<0.5). The average of change occurred between 0 to 2 wk, 2 to 4 wk and 4 to 8 wk was used to detect the number of 'deteriorated', 'unchanged' and 'improved' patients based on MID. The proportion of each sub-category was calculated from the number of patients in each sub-category divided by the total number of patients in each group. Each proportion was obtained from the number of patients in each sub-category divided by the total number of patients in that group. For example, if there are twelve patients in yoga group showed >0.5 (MID) change i.e. improved, the proportion of improvement would be 12/29 = 0.41. The following Table 14 gives the proportion of change in under each sub-category and in both groups.

Table 14: Effect of 8-wk intervention (yogic/control) on the proportion of change in quality of life under sub-categories based on MID in both groups
Yoga Group ( n=29) Improved Unchanged 0.41 0.14 0.48 0.21 0.45 0.21 0.41 0.28 0.45 0.24 Control Group (n=28) 0.25 0.25 0.14 0.14 0.21 0.14 0.18 0.07 0.18 0.29

AQLQ Domain QOL Symptoms QOL Activity limitation QOL Emotional function QOL Environmental stimuli Total Quality of life QOL Symptoms QOL Activity limitation QOL Emotional function QOL Environmental stimuli Total Quality of Life

Deteriorated 0.38 0.31 0.31 0.31 0.31 0.50 0.71 0.64 0.75 0.54

The above proportions were based on average change occurred in QOL sub-domains between 0-2 wk, 2-4 wk and 4-8 wk study periods. MID, 0.5 considered as 'unchanged'; above is 'improved' and below is 'deteriorated.

36

Based on the above proportions who improved, remained the same, and deteriorated relative to their baseline status in both yoga and control groups, we calculated the net proportion benefiting from yoga (proportion benefiting from conventional treatment and yoga minus proportion benefiting from conventional treatment alone) (Table 20). The reciprocal of this value gave us the number-needed-to-treat (NNT). NNT worked out to be as 2.41 in QOL symptoms, 1.66 in QOL activity limitation, 1.91 in QOL emotional function, 1.70 in QOL environmental stimuli and 1.82 in total quality of life which means that between 2 and 3 patients need to be treated with yoga plus conventional treatment for one patient to have a clinically meaningful improvement in sub-domains and total quality of life over and above that which he or she would have experienced on conventional treatment alone. The details of sub-categories based on MID that are clinically significant are shown in Table 15.

Table 15: Comparisons between yoga and control groups under sub-categories based on MID
AQLO domain Symptoms Group Deteriorated < MID (0.5) 0.068 0.22 0.083 0.23 0.132 0.20 0.035 0.27 0.095 0.23 -0.042 0.29 0.109 0.20 -0.087 0.29 0.175 0.16 0.085 0.28 p-value 0.98 0.45 0.18 0.039 0.27 Improved > MID (0.5) 0.944 0.23 0.839 0.26 0.925 0.20 0.830 0.26 1.052 0.33 0.924 0.17 1.010 0.39 0.714 0.17 0.918 0.21 0.820 0.25 p-value 0.24 0.44 0.52 0.047 0.21

Yoga Control Activity limitation Yoga Control Emotional function Yoga Control Response to Yoga environmental stimuli Control Total Quality of Life Yoga Control

All values expressed as mean SD. P<.05 based on Mann-Whitney U test between yoga and control groups. Significant values are under bold. There were no significant proportions of change observed between yoga and control groups except response to environmental stimuli quality of life.

37

Table 16: Calculating the proportion of patients who benefited from receiving yoga in a parallel group trial*
Control Improved (0.18) (a) Unchanged (0.29) (b) Deteriorated (0.54) (c) Improved (0.45) (x) 0.08 (ax) 0.13 (bx) 0.24 (cx) Yoga Unchanged (0.24) (y) 0.04 (ay) 0.07 (by) 0.13 (cy) Deteriorated (0.31) (z) 0.06 (az) 0.09 (bz) 0.17 (cz)

Data from the over all AQLQ scores. The number-needed-to-treat for one patient to benefit from yoga is calculated by adding up cells of those who improved (bx+cx+cy), subtracting the cells of those who ceteriorated (ay+az+bz), and dividing by the result.

Results of Exercise Induced Bronchoconstriction (EIB)

The values of percentage fall in FEV1 in response to exercise challenge did not follow normal distribution, hence non-parametric tests were used such as Friedman group analysis to know the linear trend in each group separately and Mann-Whitney U tests used for testing significant differences between groups at follow-up visits. There was a significant linear decrease in percentage fall in FEV1 observed in yoga group (p=.005), but not in control group. In addition, no significant differences observed between groups at any follow-up visit. In sub-group analysis patients attained 15 percent fall in FEV1 with exercise challenge at 0 wk were considered sensitive to the exercise challenge. There was a significant linear change observed in both yoga (p=.003) and control (p=.015) groups with respect to time. There was also significant difference seen between groups at 4 wk (p=.025).

38

Table 17: Effect of 8-wk intervention (yogic/control) on exercise-induced broncho-constriction (EIB) indicated as percentage fall in FEV1 after exercise challenge in yoga, control groups and ES & ER sub-groups
Category % fall in FEV1 with exercise challenge ES patients (> 15% fall in FEV1) Group Yoga (n = 29) Control (n = 28) Week 0 15.05 14.0 9.13 10.8 26.71 12.7 21.47 6.4 5.58 5.1 3.29 6.6 Week 2 8.81 12.9 9.50 11.1 13.33 16.1 8.83 9.8 5.13 8.4 9.82 11.9 Week 4 5.65 12.9 10.28 10.9 9.90 14.5 18.69 8.2 2.20 10.6 6.31 9.8 Week 8 5.18 11.8 5.81 10.1 7.95 15.1 12.71 9.1 2.93 8.0 2.53 9.0 p-value WG BG 0.005 NS (all NS visits) 0.003 0.015 NS NS NS (all visits) 0.025 (4wk)

Yoga (n = 13) Control (n = 9) ES p atients Yoga (< 15% fall (n = 16) in FEV1) Control (n = 19)

All values are expressed as mean SD. WGwithin group comparison; BGbetween groups comparison; NS not significant; ES exercise sensitive; ER exercise resistant *p - value was based on Friedman test applied on % fall in FEV1 after exercise challenge within each group separately. Between groups comparisons were made by Mann-Whitney U test at

39

Results of urinary Prostaglandin D2 metabolite

The urinary 11-prostaglandin F2 concentrations were not normally distributed and there was a high variability in the data of different visits within same individual. Therefore, the data was reported here in median with interquartile range (IQR). In addition, to normalize the data for analysis, the percentage change with exercise challenge, i.e. percentage change in 11-PGF2 after exercise challenge was considered. Sub-group analysis was also done for participants experienced a decrease of 15% in their FEV1 values following EC considered as exercise-sensitive (ES) and <15% as exerciseresistant (ER) at 0 wk, as separate analysis done on percentage change in urinary 11PGF2 values with EC. Friedman test was used to measures the linear change with respect to time in each group separately and Mann-Whitney U test to test the differences at individual time points between groups. The effects of standard exercise (80-85% of maximum work load) on urinary excretion of 11-PGF2 are given in Table 18. There is no significant linear trend observed in yoga and control groups and no significant difference also seen between groups at any follow-up visits with respect to time. However, if both groups were sub-divided based on their fall in FEV1 in response to exercise challenge at baseline visit, into exercise-sensitive (ES) and exercise-resistant (ER) subjects, no significant linear trend observed in either group. However, in exercisesensitive subjects significant difference was observed between yoga and control groups at 4 wk (p=.03). Whereas in exercise-resistant subjects no significant linear trend observed in either groups or no significant difference between yoga and control groups at individual follow-up visits (Table 19 & 20). Although there is no significant trend seen in either groups and in none of the categories, but exercise-sensitive subjects in yoga group showed an insignificant trend of decline in urinary excretion of 11-PGF2 which means yogic intervention might have some positive influence on preventing mast cell degranulation possibly through reduction in mast cell activation levels. However, it is difficult to make any strong affirmations based on these results.

40

Table 18: Effect of standard exercise challenge on ? urinary 11-prostaglandin-F2 in both groups

Exercise-Condition Yoga (n=29) 11 Pre-Ex prostaglandinF2 in pg/mg creatinine Post-Ex (median, IQR) Control (n=28) 11 prostaglandinF2 in pg/mg creatinine (median, IQR) Pre-Ex

Week 0 455.4 (107.2-1098.1) 474.0 (127.4-1318.7) 223.7 (98.8-562.7) 264.6 (119.5-698.6)

Week 2 293.5 (112.1-844.1) 324.0 (130.4-976.9) 247.4 (142.8-853.9) 261.4 (136.2-975.5)

Week 4 456.4 (141.6-947.4) 461.4 (147.7-1132) 365.3 (100.9-662.6) 452.2 (116.9-858.4)

Week 8 476.1 (135.5-997.6) 506.5 (137.5-1117.7) 305.1 (100.4-725.9) 371.7 (106.8-848.1)

Post-Ex

All values are expressed as median with interquartile range (IQR). The above values are pre and post exercise condition values of 11-prostaglandin-F2 in pg/mg creatinine. The exercise load was kept constant on every timepoint as 80-85% of maximum work load. The urine samples were collected at before exercise and 30 min after exercise.

Table 19: Effect of 8-wk intervention (yogic/control) on urinary 11-prostaglandin-F2 with exercise challenge (absolute values) in both groups
11 prostaglandinF2 in pg/mg creatinine (median, IQR) ES patients (median, IQR) Group Yoga (n = 29) Control (n = 28) Yoga (n = 13) Control (n = 9) Yoga (n = 16) Control (n = 19) Week 0 26.9 (7.4 -217.4) 34.5 (3.0-73.5) 37.2 (7.7-251.9) 39.7 (11.5-110.5) 24.3 (3.9-205.9) 11.6 (1.9-73.6) Week 2 24.9 (6.0-173.7) 19.1 (5.9-158.5) 27.5 (5.4-177.3) 10.3 ( -4.8-234.2) 20.9 (6.5-203.7) 20.6 (5.5-94.4) Week 4 19.2 (1.7-229.1) 39.6 (2.2-142.7) 19.2 (4.6 -274.8) 143.4 (21.9-323.9) 22.5 (-4.0-153.8) 20.1 ( -2.8-109.8) Week 8 24.0 (3.2-140.5) 26.8 (4.0-148.0) 30.3 (5.4-140.4) 59.1 (11.0-210.9) 17.0 (1.64 -179.4) 9.9 (-3.0-2.0)

ES patients (median, IQR)

All values are expressed as median with interquartile range (IQR). ES exercise sensitive; ER exercise resistant patients.

41

Table 20: Percentage values of urinary 11 -prostaglandin-F2 with exercise challenge in both groups
Group 11 prostaglandin F2 (mean SD) ES patients (mean SD) Yoga (n = 29) Control (n = 28) Yoga (n = 13) Control (n = 9) Yoga (n = 16) Control (n = 19) Week 0 17.6 18.6 16.6 21.0 18.3 22.2 15.5 21.2 17.1 15.9 17.0 21.5 Week 2 19.7 24.7 18.6 22.0 20.4 29.5 13.3 18.1 19.0 21.0 21.1 23.6 Week 4 14.7 16.5 16.3 22.3 13.8 16.8 28.5 16.3 * 15.4 16.8 10.6 22.8 Week 8 16.8 19.7 20.7 23.5 12.3 16.9 18.9 8.2 20.4 21.5 21.6 28.2 pvalue 0.49 (NS) 0.84 (NS) 0.63 (NS) 0.11 (NS) 0.79 (NS) 0.08 (NS)

ES patients (mean SD)

All values are expressed as percentage change of 11-prostaglandin-F2 with exercise challenge. *P value was based on Friedman test in each group separately from % change in 11-PG-F2. p<.05 based on Mann-Whitney U test at 4 wk between two groups. ES exercise sensitive; ER exercise resistant patients; NS not significant.

Results of rescue medication

Rescue medications are a type of medication used by people with asthma to relieve asthma symptoms (such as wheezing, coughing, and shortness of breath) or to treat an asthma flare-up. It was measured as frequency of average use of inhaled bronchodilator or oral bronchodilator (in the absence of inhaled bronchodilators) per day. The frequency of rescue medication use in the previous 2 weeks was not significantly different at baseline, which is predominantly, inhaled short acting 2-adrenoceptor agonists (salbutamol) in yoga (n=22) and control (n=24) groups, but a few were on oral short acting 2-adrenoceptor agonists such as oral salbutamol tablets (yoga, 4; control, 2) and remaining patients were on bronchodilator syrups (salbutamol). There was no significant difference between yoga and control groups in frequency use of rescue medication per day (2.27 1.5 vs 1.98 2.09; p=0.19) at a baseline. However, with respect to time there is a linear decrease in the frequency use of rescue medication in yoga (p<.001) and control groups (p<.05) over 8 wk period. In addition, there is a significant difference observed between groups at 2 wk (p<.05) and 4 wk (p<.01).

42

Table 21: Results of average rescue medication use

Parameter Average rescue medication use per day Group Yoga Control 0 wk 2.27 1.49 1.98 2.09 2 wk 1.12 1.33 a 2.19 2.04 4 wk 0.62 0.84 1.89 1.94 6 wk 0.83 0.99 1.56 2.12 8 wk 0.80 0.99 1.57 2.09 p-value* 0.000 0.013

All value are mean SD. *p-value was based on Friedman test for overall group significance. a p<.05; p<.01 based on Mann-Whitney U test at individual time points between two groups.

Summary of the results

The baseline characteristics of the yoga and control groups were similar, although the control groups was slightly more severely affected by the disease process than the yoga group. The PEFR expressed as % of predicted, FEV1/FVC and FEF 25-75 absolute values were slightly lower in the control group at 0 wk. This happened inspite of randomization. All indices of pulmonary function showed a clear, steady and progressive trend towards improvement in the yoga group whereas these indices remained same in the control group over the 8-wk, and that in PEFR at 2, 4 and 8 wk, FEV1 at 8 wk in the yoga group. None of the changes in pulmonary function in the control group was statistically significant. Since both groups received conventional treatment, improvement in pulmonary function in the yoga group may be attributed to yoga. There was no significant change in serum eosinophilic cationic protein (ECP) levels over the 8-wk steady period in either group. However, there was a significant decrese of serum IL 2R after 2 wk of yogic intervention, but not in control group after 2 wk. There was a significant decrease in exercise-induced fall in FEV1 in the yoga group, but not in control group. Further, the patients were divided based on the 0 wk response to exercise into exercise-sensitive ( 15% fall in FEV1) and exercise-resistant (< 15% fall in FEV1). Separate sub group analysis revealed a significant decrease in the % fall in FEV1 in response to exercise in the exercise-sensitive patients in the yoga group. Where as exercise-sensitive patients in control group also showed a significant decrease in the % fall in FEV1 in response to exercise. However, in exercise-sensitive patients, % fall in FEV1 in yoga group was much higher than control group and that is significant at 4 wk. Since exercise-induced bronchoconstriction is associated with mast cell activation, the mast cell

43

activity marker (urinary prostaglandin D2 metabolite 11-PGF2) was also measured before and after exercise. The urinary concentrations of 11-PGF2 showed a trend similar to % fall in FEV1 but again the changes were statistically not significant in either group except a significant difference observed between groups at 4 wk in exercise-sensitive patients. The overall quality of life as well individual domains of quality were significantly better at 2 wk as compared to the baseline in the yoga groups but not in the control group. Further improvement was also seen in the yoga group up to 8 wk. the control group also showed improvement at 4 wk and 8 wk. The number needed to treat (NNT) worked out to be 1.82 for total quality of life. In other words, only two patients need to be treated with yoga and conventional treatment, alone. Although the need for rescue medication decreased over the 8-wk study period in both groups, the decline was greater in the yoga group than in the control group.

Discussion The experimental design

The study is a randomized controlled unmasked trial with two parallel limbs. Doing a randomized controlled trial (RCT) on yoga involves some inevitable compromises. There is no placebo for yoga, and the subject can not be blinded. Further, neither the control nor the experimental group can be denied the conventional treatment, if available. Therefore, we decided, as is a common practice in RCTs on yoga, to give only the conventional treatment to the control group, and to add the yogic treatment to the conventional treatment in the study group (yoga group). Thus, any difference in the efficacy of intervention in the two groups may be attributed to yogic intervention. Since considerable evidence for the efficacy of yoga in bronchial asthma already exists, it is unethical to deny yoga even to the control group. Therefore, the control group was only a wait-listed control. At the end of the 8-wk RCT, the yogic intervention was available also to the control group. The 8-wk duration of the intervention was an arbitrary compromise. It is long enough to demonstrate the effect, but the ideal would be a much longer study. However, in practice, the drop-outs increase steeply as the duration of the study increases.

44

A yogic intervention may be on an out-patient or residential basis, may be supervised or unsupervised. We chose, keeping the patients convenience and our infrastructure in mind, a 2-wk supervised in-hospital intervention at Integral Health Clinic followed by 6 wk of closely monitored intervention at home. The 2-wk training period was adequate to make the patients reasonably proficient in physical postures, breathing exercises and relaxation techniques, and to acquaint them with principles of stress management and a healthy yoga-based lifestyle. Leaving the patient to continue with these practices on his own and apply the principles learnt to everyday situations for 6 wk was reasonably long to test the feasibility of the intervention in real life, and to assess how far the gains achieved in 2 wk of supervised training were sustained during follow-up. Not only could the patients continue with the intervention, the gains of the first 2 wk were improved upon during the 6 wk of follow up. From the scientific point of view, it might be argued that the uniformly prescribed pattern of the intervention might have been diluted during the follow-up, making it more heterogeneous and individual. However, since the value of the intervention has to be ultimately judged in real life situations, the 6-wk of intervention in free-living conditions would improve the external validity of the conclusions. The allocation of the patients to the two groups was randomized, but the selection of patients from the patient population was not random. Every patient who made it to our clinic to volunteer for the trial was already convinced in his mind about the beneficial effects of yoga. This is an inherent flow of such trials, and limits the extrapolation of results to the entire patient population. However, this limitation does not reduce the external validity of the study because in practice only those patients opt for a particular modality of treatment who have faith in its efficacy.

The intervention
The various interventions administered under the omnibus title 'yoga' cover a very wide spectrum. This is inevitable because yoga is not a system of medicine; it is a way of life, the implications of which go beyond health and disease (Bijlani, 1998) employed for prevention or management of disease, some convenient and highly visible elements of yoga are used selectively. The selection can vary enormously depending on the inclinations of the yoga therapist. Our intervention was based on the following considerations:

45

a) the intervention showed be used as an opportunity to familiarize the subject with a comprehensive view of yoga, even if some aspects may not be immediately relevant to his needs, b) the mind-body complex is a continuum, and therefore yogic techniques which act predominantly on the mind or the body should both be used even in 'physical' disorders like bronchial asthma, and c) the acceptability and responsiveness to the predominantly physical or psychological approach varies a lot with the individual patient. Therefore, we should offer a comprehensive intervention so that at least some component of it would be useful for each patient. In short, our intervention has used yoga as a tool in mind-body medicine (Smith et al., 2005). This approach now has a strong scientific foundation in psychoneuroimmunology, and is particularly relevant to a disorder like bronchial asthma which is characterized by deranged immune function.

Analysis of data
Data was analyzed by Generalized Linear Model (GLM) repeated measures analysis by SPSS statistical software. Repeated measure analysis was done to evaluate the effect of intervention over two months for the same variables overall intra-group analysis and also inter-group analysis to compare the same variables taking all time points into consideration, between yoga and control groups. In addition to the linear trend that was observed in both groups separately, post-hoc comparisons were also done with respect to baseline visit to know the level of improvement at individual follow-up visits. The profile plots created through repeated measures depicts the linear trend in a simple graphical representation, in which the estimated marginal means were considered to interpret the data scientifically and comprehensively. Data that was not following the normal distribution was analyzed by non-parametric tests where the comparisons between groups at individual time points were measured. Such data which did not show the normal distribution was expressed in terms of median and interquartile range or 95% confidence interval. For interpreting asthma quality of life data, a special statistical analysis was done for estimating number-needed-to-treat which added statistical relevance to the analysis and interpretation of clinical data.

46

Baseline differences between groups

Although the patients had, a wide range of symptoms and the severity of the disease from mild intermittent to moderate persistent, all these patients were distributed equally in both groups. However, randomization does not necessarily produce comparable groups, and there can be minor and sometimes major differences in the baseline comparisons between groups (Altman & Dore, 1990). In the present study, there are significant baseline differences between the control and experimental groups in PEFR percentage of predicted values. However, other pulmonary function indices are not significantly different between groups. Statistically the baseline differences were corrected by fixing the baseline visit as covariate in full-factorial model of repeated measures.

47

Summary of Results
In pulmonary function indices, yoga group has shown a significant overall improvement in PEFR, FEV1, FVC, FEV1/FVC%, FEF25-75% over a steady period. However, in post-hoc comparisons PEFR, FEV1, and marginally FVC only showed significant improvement from baseline. Where as control group remain unchanged and no such significant changes observed in any one of the pulmonary function indices. In exercise-induced bronchoconstriction (EIB) as depicted by percentage of fall in FEV1, yoga group showed a significant reduction in EIB with 8-wk yogic intervention. In addition, exercise-sensitive patients in both groups showed a significant decrease in EIB, but yoga group showed higher magnitude of reduction than control group and it was also significant at 4 wk. The urinary concentrations of 11-PGF2 showed a trend similar to % fall in FEV1 but again the changes were statistically not significant in either group except a significant difference observed between groups at 4 wk in exercise-sensitive patients.

In asthma quality of life domains such as symptoms, activity limitation, emotional function, response to environmental stimuli and overall quality of life, yoga group showed a significant improvement in within group comparisons from baseline. Control group also showed a significant improvement in only in symptoms, emotional function and overall quality of life. However, yoga group showed better improvement than control group in QOL symptoms, QOL emotional function, overall quality of life and a marginal improvement in QOL activity limitation. In rescue medication use, both yoga and control groups showed a significant reduction in use of rescue medication. However, rescue medication use in yoga group had higher reduction than control group which is also significant at 2 wk and 4 wk. For better understanding, the summary of the significant results are tabulated in the Table 21.

48

Discussion of the Results

Pulmonary function indices

Indices of pulmonary function showed a steady, progressive significant improvement over the 8-wk period of the study in the yoga group, whereas these indices remained the same at the baseline level in the control group. Thus, the conventional treatment is able to keep the symptoms in check but does not improve pulmonary function. On the other hand, adding yoga to the conventional treatment improves pulmonary function which would translate into improvement in physical work capacity. Based on the above results it may be questioned as to which component of yoga-based intervention is responsible for the improvement observed. The most important benefit of yoga is physical and mental therapy. Although individual components of yoga produce the desirable benefits, to get the maximum benefits of yoga one has to combine the practices of yogasanas, pranayama, kriyas, relaxation and meditation. For example the deep relaxation reduces the panic element or anxiety in an attack so that one can turn the mind inwards to relax their airways through deep awareness. Some simple techniques in yoga such as 'yoga chair breathing' which is a combination of breathing, physical movements and relaxation reverse the bronchospasm as it was showed in previous studies (Nagarathna et al., 1991a). Combination of yogic postures interspersed with relaxation reduces arousal more than relaxation alone does (Telles et al., 2000), similarly in our yoga protocol we have used integrated approach of yoga to reduce the anxiety levels and enhance relaxation response in day-to-day life of patients having asthma. Previous indications also provide evidence of significant increase in PEFR after modified Jacobson's systemic relaxation training in asthmatics (Alexander et al., 1972). The practice of yoga generally helps not through the poses but through the general lifestyle change involved in it. Yoga encourages a lifestyle that includes a healthy diet which can help build your resistance against cold, allergies and other environmental causes and triggers of asthma. Yogic exercises including the poses, yoga breathing and relaxation techniques also put you in control of your mind and emotions, making you more relaxed and breathe easier. This will also help in the better functioning of lungs, and help asthma patients by enhancing airflow during asthma attacks (Nagarathna & Nagendra, 1985; Nagendra & Nagarathna, 1986). Although some of these interventions individually also can produce health benefits in individuals with asthma (Singh et al., 1990; Hockemeyer & Smyth, 2002), a comprehensive package of these modalities integrated in a form of yoga based lifestyle management program for 2 wk produce better results for diseases related to psychosomatic in origin including asthma.

49

Similarly, our yogic intervention protocol was also based on the same principles. Hence, it is difficult to dissect the contribution of individual component but as a result of lifestyle intervention based on the principles of yoga that combines daily practice of asanas (postures), pranayama (breathing practices), kriyas (cleansing practices), relaxation techniques (shavasana), meditation, and advice about diet, stress management, and other aspects of lifestyle contributed to the results of our study. However, like previous studies (Nagarathna & Nagendra, 1985; Singh et al., 1990), the present study also found statistically significant differences between the yoga and control groups and an improvement from baseline in yoga group (Jain et al., 1991; Sabina et al., 2005) on pulmonary function indices. As yoga has several components in which physical component is most widely used as dynamic postures where different stretching exercises are involved along with a particular breathing pattern. It is hypothesized that yogic exercises that follows a similar pattern like exercise training where there is a gradual improvement of aerobic capacity/conditioning like suryanamaskar (Sinha et al., 2004) and slow breathing exercises that would improve lung functions over a period. While a number of studies on exercise training in asthmatic children have reported an improvement in lung function, aerobic capacity/conditioning, psychosocial behavior (Olivia, 1990; Engstrom et al., 1991; Thio et al., 1996). This further confirms the role of yoga in physical training in bronchial asthma to improve both physical and psychological aspects in bronchial asthma. In addition to the improvement observed in regular parameters like PEFR, FEV1, there is also a significant linear trend observed in other parameters like FVC and FEF25-75. The beneficial change in FVC and FEF25-75 could be attributed to inhaled corticosteroids (Sheikh et al., 1999) and yoga similar to previous studies (Nayar et al., 1975). This study has successfully demonstrated the efficacy of yoga intervention as an adjunct to conventional medical treatment for adults with mild-to-moderate asthma.

50

Serum Eosinophilic Cationic Protein (ECP)

Although there are no significant changes observed in either group in 8 wk study period, there is an insignificant trend towards reduction in serum ECP levels in yoga group, which is not evident in control groups (Table 11). The significant level might have reached in yoga group with more number of subjects. The changes occurred in serum ECP may be due to regular use of inhaled corticosteroids (Wever et al., 1997; Bacci et al., 2002; Basyigit et al., 2004) and long acting 2-agonists (Pinto Pereira et al., 2003) but could have achieved significant level, if the medication dose is being taken by all participants in right proportions. Because low-medium doses of inhaled corticosteroids may be more beneficial in addition to salmeterol (NAEPP, 1991). It is also possible that the number of participants using inhaled corticosteroids, which contains beclomethasone and fluticasone, are not sufficient to bring a significant change in serum ECP levels in either group (Table 10). Although, the decrease was seen in only yoga group, it is speculative to attribute these changes to yogic intervention because there is no significant trend. Since serum ECP, is only a surrogate marker for airway inflammatory status, recommendations based on our results are only supportive to definite results observed in other pertinent parameters. To suppress disease activity completely at a significant level, repeated long-term treatment is important, but clear conclusions can not be drawn based on our present results.

Serum soluble Interleukin 2 receptor

As studies have suggested that soluble interleukin-2 receptor (sIL-2R) levels offer a rapid, reliable, and noninvasive measure of inflammatory disease activity associated with T-cell immune activation (Robb et al., 1981; Rubin et al., 1985). The inflammatory response in asthma can be precipitated initially through either an IgE-dependent or an IgEindependent mechanism leading principally to mast cell degranulation and resultant acute bronchospasm. The driving force behind this inflammatory response is T-cell activation, which produce key cytokines in alleric inflammation and asthma. Previous studies suggest that T-lymphocyte activation occurs in asthma patients and becomes more prominent during moderate and severe acute attacks, which is depicted as increased in serum sIL-2R (Motojima et al., 1995). The data demonstrated that of yoga intervention in addition to conventional treatment results in reduction of T-cell activation as reflected in significant fall in serum sIL-2R levels in mild-to-moderate asthmatic patients. Although the exact mechanism that is responsible for the significant decrease of serum sIl-2R in yoga group after 2 wk is not known, but it could be attributed partially to the use of inhaled

51

corticosteroids along with salmeterol. Because inhaled salmeterol along with inhaled corticosteroids are potential for clinical improvement associated with reduced T-cell activation and Th2 type cytokine mRNA expression in bronchial asthma patients (Lai et al., 1995; Gemou-Engesaeth et al., 1997). Since the eosinophilic cationic protein in yoga group also showed a trend, but with a non-significant decrease in ECP levels, yogic intervention for 2 wk along with conventional treatment may be responsible for it. Control group also showed a non-significant reduction in serum sIl2R levels without any major clinical improvements. Brown et al, reported elevated levels of soluble IL-2R in patients with asthma, independent of severity of the disease and of the presence of acute symptoms (Brown et al., 1991). It is speculative to understand the plausible mechanisms for the reduction of serum sIL2R with 2 wk yogic intervention on selected patients. Further investigations might be needed to explain completely the role of yoga on soluble IL-2R in patients with asthma and allergic disorders.

Asthma Quality of Life Questionnaire (AQLQ)

The present study has demonstrated the efficacy of yoga as an adjunct to conventional medical treatment for adults with mild-to-moderate asthma. It shows that measurable improvement in quality of life indices occurs within 8 weeks as a result of lifestyle intervention based on the principles of yoga that combines daily practice of asanas (postures), pranayama (breathing practices), kriyas (cleansing practices) relaxation techniques (shavasana), meditation, and advice about diet, stress management, and other aspects of lifestyle. Our study results demonstrated the improvement of overall quality of life and its individual components such as QOL reactivity to environmental stimuli in yoga group with 8 wk intervention, however, control group also shown improvement in QOL activity limitation (Table 13). The changes in control group could be attributed to the effect of conventional treatment. Because, the inhaled long-acting 2-agonists, the symptom controllers of asthma, are playing an important role in the management of persistent asthma, particularly even when it is moderate and severe (Donohue, 2000). Significant improvements in overall asthma quality of life and its individual components in yoga group and also significant differences between yoga and control groups confirm a comparable improvement in yoga group.

52

Previous studies (Singh et al., 1990; Cooper et al., 2003) also investigating yoga for asthma obtained similar results (although not significant) for symptom score and respiratory function, but such results were only apparent in yoga group. Further to confirm the effect of yoga on overall quality of life, there is a strong improvement observed in yoga group for the initial 2 week which is primarily due to effect of yoga training which is also in consistent with previous study (Manocha et al., 2002). After 2 weeks, the improvement was not as strong as before because the maximum improvement that is possible in quality of life was already achieved in the initial 2 weeks and there was no much scope available for further improvement. In control group, the improvement was almost steady and linear because of regular medication. However, to understand the contribution of yoga for the improvement observed in quality of life sub-domains a separate analysis was done on the basis of 'minimal important difference', which is the smallest difference in score in the domain of interest which patients perceive as beneficial and would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient's management (Jaeschke et al., 1989). Based on recent trials on Asthma Quality of Life Questionnaire (AQLQ), it is realized that just comparing the mean differences between treatment groups with the MID is very inadequate and may lead to erroneous conclusions, because patients are very heterogeneous in their responses to interventions and by only looking at the mean one ignores the distribution about the mean (Juniper et al., 1995). Therefore, we calculated the number of patients who experienced clinically meaningful improvements (>0.5) on yoga plus conventional treatment than the effect of conventional treatment alone, the proportion falling into the three categories of 'improved', 'unchanged', 'deteriorated' are shown else where in Table 19. From overall quality of life scores in yoga group, 13 patients had improved and 9 patients did not reach 0.5 change, whereas in control group, only 5 patients had improved and 15 did not reach MID (Fig.19 & 20) which means addition of yoga not only produce improvement but also minimize the deterioration. From this, we calculated the number needed to treat (NNT) for one patient to benefit from yoga is calculated by adding up cells of those who improved, subtracting the cells of those who deteriorated, and dividing 1 by the result (Table 16). In this case the NNT worked out to be 3.41 in QOL symptoms, 1.66 in QOL activity limitation, 1.91 in QOL emotional function, 1.70 in QOL environmental stimuli and 1.82 in total quality of life which means that between 2 and 3 patients need to be treated with yoga plus conventional treatment for one patient to have a clinically meaningful improvement in sub-domains and total quality of life over and above that which he or she would have experienced on conventional

53

treatment alone. Our results are comparable to the previous results on quality of life with conventional treatment (Juniper et al., 1995). However, in previous studies, there was a comparison between long and short acting B2-agonists; in this case, it is the yoga that is contributing in addition to the conventional treatment, hence the NNT is comparatively less by one number, which is highly effective. Our results on AQLQ are in partial agreement with a previous double blind, randomized controlled trial on sahaja yoga, a traditional system of meditation based on yogic principles (Manocha et al., 2002) in which yoga intervention group (sahaja yoga plus conventional treatment) had improvement than control group (conventional treatment plus relaxation methods and cognitive behavior therapy-like exercises) but there was no between group difference in the change in AQLQ scores 2 months after the intervention was completed. Another recent randomized, controlled, double-masked clinical trial did not have any agreement with our study. Because they found no significant differences between the yoga and control groups in asthma-related quality-of-life scores (Sabina et al., 2005). The reasons for our results not having complete agreement with the previous studies could be due to lack of integrative approach of yoga intervention in both previous trials. Both these trials have attempted to assess the efficacy of two individual yoga systems (sahaja yoga and iyenger yoga) in which one focuses on meditation and other on physical postures respectively, but the strength of our study is that we have used an integrated yoga program which included meditation, yoga postures, pranayama, kriyas, relaxation techniques, imagery techniques, stress management, nutritional and behavioral counseling and health education. Alternatively, the control intervention also has a benefit of its own. In the previous studies on quality of life, it is claimed that the regular use of inhaled corticosteroids in addition to long acting 2-adrenoceptor agonist (salmeterol) which is associated with improvements in asthma quality of life including symptoms (Juniper et al., 1995; Kemp et al., 1998). In previous studies (Bowler et al., 1998; Manocha et al., 2002), although using different quality-of-life scales, did not report significant differences between yoga and control groups; however, they observed positive trends in the mood subscale of the quality-oflife measure and observed positive over all quality-of-life trends, respectively. Previous studies (Bowler et al., 1998; Cooper et al., 2003) in yogic breathing techniques were successful in producing a significant reduction in symptoms and decrease in bronchodilator use. However, yoga group in our study also achieved the similar results but with a higher magnitude of improvement than control group in all quality of life sub-domains. Hence, yoga intervention has contributed to the results as an additional treatment to the existing conventional treatment.

54

Exercise-Induced-Bronchoconstriction (EIB)
A significant decline in percentage fall in FEV1 after exercise was evident in only yoga group (over all group) which means that there is a blunting effect on exercise induced bronchoconstriction over a period of 8 wk. This is similar to the results obtained in previous studies in which yoga group showed a better exercise tolerance (Vedanthan et al., 1998) and a decrease in exercise-induced bronchial liability index (BLI) in adolescents with mild to severe asthma (Jain et al., 1991) and exercise capacity in moderate to severe chronic asthma patients (Jain & Talukdar, 1993). In previous studies, the exercise challenge for provocation test was introduced by using various tests like 12 min walk test (12-md), modified Harvard step test, and free range running was used (Jain et al., 1991; Jain & Talukdar, 1993) whereas in our study we have improved the procedure for provocation test by using bicycle ergometer with a standard protocol, because cycling exercise can be used effectively and it is a satisfactory alternative with easy safety measures (Wasserman et al., 1999). We have also maintained ambient room temperature and relative humidity constant during exercise and used a standard work load. Therefore, the improvement observed after yoga in EIB is reliable. Because exercise-induced bronchoconstriction varies with the site of exercise, exercise work load, breathing pattern and respiratory heat and water loss (Solway et al., 1985) as conditioning of the inspired air apparently reduces the magnitude of the stimulus and its penetration into the lung periphery. While airway cooling during exercise and airway rewarming after exercise are important determinants of the magnitude of response in adults (McFadden, 1987), they are not prerequisites for EIB (Anderson & Daviskas, 1992). Although the high exercise work load (95% calculated maximum) seemed better correlated with exercise-induced bronchoconstriction than low work load (85%) (Carlsen et al., 2000), for safety and ethical reasons, we have kept our limit only 85% of calculated maximum work load. The same level of work load was maintained for all patients and in all recordings. Although exercise-induced bronchoconstriction is a common manifestation of asthma and occurs in 70-80% of untreated asthmatics (Lee & Anderson, 1985), not all patients in our study responded to exercise provocation test. Since there is a heterogeneity of patients' response to exercise stimuli, we did a subset analysis by arbitrarily dividing all the patients from both groups into exercise-sensitive patients (who attained 15% fall in FEV1 after EC) and exercise-resistant patients (<15% fall in FEV1 after EC) at baseline visit. However, some patients (yoga, 2; control, 6) in exercise-resistant category in their follow-up visits. Still for analysis purpose, we have put them into resistant category. Although it is difficult to explain, it may be because these patients might have had repeated bouts of exertion or hyperpnoea on their baseline visit. Individuals who exhibit a refractory period experience

55

less obstruction in response to repetitive challenge (Edmunds et al., 1978). The presence of a refractory period appears to be independent of the magnitude of obstruction provoked by the first challenge (Ben-Dov et al., 1982). It is also important to note that refractoriness is expressed in about half of the asthmatic patients that exhibit EIB (Anderson & Schoeffell, 1982; Rakotosihanaka et al., 1986; Belcher et al., 1987). Another plausible explanation for this same drop in PEFR, following strenuous exercise capable of increasing heart rate to 170-180/min with an increase of oxygen uptake of 60-85% of maximum (Anderson, 1985; Spector, 1993). But we have considered 15% of fall in FEV1 based on previous studies to have a similar approach for subset analysis on urinary 11-PGF2 data (O'Sullivan et al., 1998) for better comparison. Hence, some of the patients who attained fall in FEV1 from 10-15% on their baseline visit were considered as resistant group but they could have come under sensitive category using a different criterion. However, for comparing the results with previous studies, we chose the 15% criterion. Exercise-sensitive patients from both groups exhibited a significant reduction in exerciseinduced bronchoconstriction over a period of 8 wk, but with a higher magnitude of reduction in yoga group. There was also a significant mean difference between yoga and control groups at 4 wk that means exercise-sensitive subjects in yoga group exhibited higher reduction in EIB over a period of 8 wk which is steady and consistent and control group did show similar trend but with a deviation from this pattern between 2 and 4 wk. However, there is an overall reduction in EIB observed in control group which may be an associated effect of prolonged use of inhaled salmeterol (Kemp et al., 1994; Villaran et al., 1999; Coreno et al., 2005) and regular inhaled corticosteroids (Freezer et al., 1995) against EIB. Our study results on EIB are similar to the results obtained in previous studies by Jain et al. (1991) in which they successfully demonstrated a significant increase in exercise tolerance by showing a decrease in exercise-induced bronchial liability index (BLI) with yoga practice for 40 days in adolescents with mild to severe asthma and in another study by the same authors in moderate to severe chronic asthma patients (Jain & Talukdar, 1993). However, neither of these studies attempted to explain the mechanisms involved in the prevention of EIB, but we have attempted to understand this lacunae through mast cell activation. Since exercise-induced bronchoconstriction is associated with mast cell activation, the mast cell activity marker (urinary prostaglandin D2 metabolite) was measured before and after exercise and the same has been discussed below.

56

In recent years, physical training is considered useful for chronic asthmatics (Bundgaard, 1985) and rehabilitation programs including drug treatment, exercise training, patient education, breathing retraining, evacuation of mucus, relaxation techniques, and recreational activities for asthmatic patients and with chronic obstructive pulmonary disease (Cambach et al., 1997) which improves their exercise tolerance and quality of life. Yoga involves integration of techniques of cleansing respiratory tract (mucus evacuation techniques) (Singh, 1987), physical conditioning (Muralidhara & Ranganathan, 1982) and breathing exercises (Singh et al., 1990) and has been reported to have good response in the management of asthma (Bramchari et al., 1980; Goyeche et al., 1982; Nagarathna & Nagendra, 1985). It is hypothesized that yogic kriyas (cleansing techniques) and certain yogic postures help in removal of secretions and allows postural drainage from airways including small airways (Bake, 1981; Singh, 1987; Jain & Talukdar, 1993) which is also demonstrated by significant improvement in forced mid-expiratory flow in pulmonary function indices (small airways obstruction ) and yogic breathing exercises provide training in the efficient use of abdominal and diaphragmatic muscle in breathing (Renne & Creer, 1976). Yogic postures reduce psychological over activity (Tandon, 1978) in asthmatics and also induce an increase in muscle efficiency (Ray et al., 1986). In recent years, some studies have indicated the possible application of yoga for management of asthmatic patients. Yoga is being applied as an adjunct therapy for patients with mild to moderate airways obstruction (Manocha et al., 2002; Sabina et al,. 2005). The present study has successfully demonstrated the efficacy of yoga as an adjunct intervention in reducing exercise-induced bronchoconstriction in mild to moderate asthma.

Mast cell activation levels

Most of the previous studies showing beneficial effects of yoga in asthma have been restricted to pulmonary functions and a few components of quality of life (Nagarathna & Nagendra, 1985; Manocha et al., 2002). Secondly, none of the previous studies has attempted to explain the plausible mechanisms involved in the efficacy of yoga for the management of asthma. Measurement of urinary LTE4 and 11-PGF2 is potentially useful in assessing chronic inflammation associated with eosinophil and mast cell activation in the airways of asthmatic patients (Dahlen & Kumlin, 1998). The present study has attempted to explain the speculative mechanisms of prevention of EIB with yoga intervention through the indicators of mast cell activation i.e. urinary 11-PGF2, which is associated to increase with exercise stimuli in patients having asthma, also who are sensitive to exercise (O'Sullivan et al., 1998).

57

The present study results show a trend of reduction over 8-wk period in yoga group and significant difference between the groups in secretion of exercise induced urinary prostaglandin D2 metabolite in exercise-sensitive subjects. Although yoga group exhibited no significant reduction in the levels of post-exercise urinary 11-PGF2 with respect to time, there is an obvious linear trend of decrease was observed. (Table 19). This means that there is a decrease of mast cell activation for the same exercise stimuli in subsequent weeks of study period in exercise-sensitive patients. Lack of statistical significance in the changes observed may be due to indequate sample size and marked inter-subject variation. However, the mean differences between groups reached significance at 4 wk. Some patients from exercise-resistant category being responded to exercise during their follow-up visits which can be attributed to the refractoriness on their baseline visit due to less obstruction in response to repetitive challenge. Other studies of asthmatic patients indicate that exercise or hyperpnoea induced refractoriness is associated with a leukotriene-induced release of inhibitory prostaglandins, resulting in exercise refractoriness (Manning et al., 1993). Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise i.e. PGE2 which markedly attenuates exercise bronchoconstriction in asthmatic patients and suggest that this effect is not occurring through functional antagonism of airway smooth muscle (Melillo et al., 1994). In our study, patients who might have experienced refractoriness did not show any significant difference during their follow-up visits with baseline comparisons in post-exercise excretion of the urinary level of PGD2 metabolite, 11-PGF2 which means that the level of 11-PGF2 was unaltered during follow-up visits despite their experience of EIB. However, our results are in excellent agreement with the results of the previous studies (Nagakura et al., 1998; O'Sullivan et al., 1998) who found an increase of similar magnitude in urinary 11-PGF2 following exercise in exercise-sensitive and resistant patients.

Mast cell activation and emotional stress

Mast cells are activated independently of FcRI, by substances such as several neuropeptides including substance P, vasoactive intestinal polypeptide (VIP) and somatostatin (Church et al., 1989; Schierhorn et al., 1995) and emotional stress in asthma (Bienenstock et al., 1988; Bienenstock et al., 1991). Moreover, recent reports have indicated that stress can induce asthma exacerbations (Bienenstock, 2002; Laube et al.,

58

Olness et al., (1999) demonstrated successfully an inhibition of mast cell activation, if conditioned relaxation techniques such as relaxation-imagery was applied to children with migraine and suggested that stress may activate mast cells which could be involved in the pathophysiology of migraine (Olness et al., 1999). Our study is the first of its kind and the first documentation on yoga and mast cell activation levels in asthma. In the present context, it is hypothesized that since yoga is an established intervention to reduce stress levels, and mast cells also get degranulated during stress conditions, the reduction in release of urinary 11-PGF2 with exercise stimuli could be due to yoga effect though stress reduction. Because it is a well established fact that yoga reduces psychological stress (Vempati & Telles, 2002) and enhances immune function (Xu, 1994). Mast cells could act as a link between the immune and the nervous systems and are the immune gate to the brain (Stead et al., 1990; Theoharides, 1990) because neuropeptides can augment hypersensitivity (Foreman, 1987) and inflammatory reactions (Theoharides, 1996). The possibility is made more likely because psychological or emotional stress triggers dura mast cell secretion via release of corticotropin-releasing hormone, CRH (Theoharides et al., 1995), which was recently shown to be a potent mast cell secretagogue (Theoharides et al., 1998). Another study also indicated that acute psychological stress could lead to cardiac mast cell degranulation through CRH acting directly or through neurotensin (Pang et al., 1998). However, any association with pulmonary mast cells is yet to be made (Theoharides & Cochrane, 2004). The mind-body interventions such as yoga, relaxation, imagery sessions and breathing exercises are beneficial for stress reduction in general (Jaber, 2002; Lehrer et al., 2002) and may be helpful in further controlling asthma through inhibiting mast cell activation.

Mast cell activation and airway frictional stress

Another plausible explanation for reduction in 11-PGF2 in yoga group, frictional stress from air flowing through narrowed airways may damage the airway mucosa and thereby perpetuates airway inflammation and airway obstruction. Because higher flow rates, high values of the frictional stress could lead to damage the airway wall, especially during episodes of cough, and particularly when the mucosa is inflammed and friable as it is in asthmatic patients (Chowdhary et al., 1999), whereas pranayama in yoga may reverse the process (Singh et al., 2000) by reducing the frictional stress thereby stabilizing the mast cell activation. In our yoga protocol, we have used slow breathing which was also incorporated into practices like breathing exercises, loosening exercises, yogasanas,

59

relaxation techniques and pranayama (Table 2). Therefore, enough emphasis was laid on slow and deep breathing which might be responsible for reducing frictional stress thereby airway inflammation and airway obstruction. It has been proposed that airway wall shear stresses, created by peak expiratory flow-rates during coughing episodes in asthmatics, are responsible for airway inflammation, which was also confirmed by a previous study using a computational fluid dynamics technique to model peak expiratory flow in the trachea and major lung bronchi (Green, 2004). Engorged vessels due to airway inflammation can also leak due to frictional stress of rapid breathing, leading to mediator release from inflammatory cells including mast cells and bronchospasm (storms, 1999). Therefore, slow and deep breathing in yoga is having a major role in the management of asthma (Anil Kumar et al., 1985; Behera & Jindal, 1990; Greenfield, 1998) possibly by reducing the frictional stress and thereby mast cell degranulation. It may be pointed out that long acting B2-adrenoceptors are effective inhibitors of mast cells (Kay & Peachell, 2005) and inhaled glucocorticosteroids reduce the number and activation of mast cells (Laitinen et al., 1992; Yates et al., 1998) along with inhibition of the early response to allergen (De Baets et al., 1990). Previous studies observed low doses of budesonide for 12 weeks significantly reduced the severity of EIB (Jonasson et al., 2000). Hence, the decrease in post-exercise excretion of urinary 11-prostaglandin F2 in exercise-sensitive subjects in yoga group could be a combined effect of conventional treatment plus yogic intervention. However, control group did not show any such trend which could be attributed to the small sample size (exercise-sensitive subjects, n=9) or not all the subjects are on inhaled conrticosteroids along with long acting 2-adrenoceptors (Table 5). In addition, exercise is a much less vigorous stimulus for provocation of airways and activate the mast cells than allergen provocation in which approximately 200-300% increases seen in levels of urinary 11-PGF2 with an allergen challenge (O'Sullivan et al., 1996). In our study, the patients in exercise-sensitive group achieved maximum of 28.5% increase on average levels of urinary 11-PGF2 that is comparable with the previous study results at 30 min post exercise sampling (-32%) whereas exercise-resistant patients achieved 21.6% maximum increase on average levels of urinary 11-PGF2 which is not comparable with previous study results (O'Sullivan et al., 1998). The reason for exerciseresistant patients to have higher levels of urinary 11-PGF2 in our study could be more severity of the disease than previous study population in which all the patients were having only mild asthma. This is also confirmed by the baseline variations in pre-exercise

60

levels of urinary 11-PGF2, but it is not clear why basal urinary 11-PGF2 levels vary so widely between patients of varied severity of disease. The possible contributing factors may be variation in the numbers and activation of 11-PGF2 producing cells especially mast cells for producing PGD2 or physiological variations in metabolism and urinary excretion (Misso et al., 2004). However, baseline urinary 11-PGF2 concentrations may not be useful in discriminating between asthmatic patients with differing severity of disease, possibly because small changes consequent to airway inflammation may be obscured by inter-subject variation and the dilution of PGD2 mediator produced in the lungs (Dworski & Sheller, 1998). Therefore, we did subset analysis based on % fall in FEV1 after exercise challenge. We found no baseline differences in percentage of 11-PGF2 between yoga and control groups in either subset (Table 19). Inspite of having so many influences responsible for variations in the baseline values of 11-PGF2 including progesterone levels that precedes menstruation in female patients (Baird et al., 1996; Critchely et al., 2001), there is an insignificant steady decrease of 11-PGF2 which means a decrease of mast cell activation levels or prevention of mast cell degranulation. Based on the above results it may be questioned as why yoga influences only exercise sensitive patients for reducing mast cell activation levels? It may be because these patients are exercise-sensitive and their mast cells are activated sufficiently by exercise for there to be scope for reduction in activation. In our study, we used exercise as a stimuli for activating the mast cells. However, not all asthmatics are sensitive to exercise for activating mast cells; hence, exercise-resistant patients did not show any trend. Therefore, based on our study results no firm conclusions be made that yoga could decrease mast cell activation levels in only exercise-sensitive asthmatics.

Rescue medication
Although there was no significant difference at baseline, there was a significant difference in rescue medication use per day between groups at 2 wk and 4 wk, the medication in the yoga group being less than in the control group (Table 20). Previous studies (Singh et al., 1990; Bowler et al., 1998; Cooper et al., 2003) successfully demonstrated encouraging

61

results on yogic breathing techniques in producing a significant decrease in rescue inhaler use. Our study also observed the similar results. Although control group also showed similar trend, the magnitude is very less than in the yoga group, possibly because the control group consistently exhibited more disability at baseline and required moderate to high doses of medication regularly. Significant reduction of rescue medication after 2 wk is obvious because of significant improvement in QOL symptoms with higher magnitude from 2 wk was apparent in yoga group alone. Vedanthan et al. (1998) who studied yoga intervention, observed reduced rescue inhaler use in the yoga group, although it was not significantly different from that in the control group. It is hypothesized that owing to the regular use of inhaled corticosteroids in which long acting B2-adrenoceptor agonist (salmeterol) which is also a component of each inhaled corticosteroid dose, responsible for improvements in asthma quality of life including symptoms (Juniper et al., 1995; Kemp et al, 1998), hence the significant decrease in rescue medication use (short acting B2-adrenoceptor agonists) in control group.

It is also possible that lack of statistically difference between the yoga and control groups on some of outcome measures is attributable to the similar kind of intervention for both the groups but additionally yoga intervention was applied to yoga group as an adjuvant to conventional treatment. Therefore, it is not so easy to achieve significant differences between yoga and control groups, which may require a large sample size to demonstrate statistically significant change over and above the conventional treatment.

In conclusion, this study finds evidence of benefit specifically attributable to yogic intervention in mild-to-moderate asthma. The results indicate that yoga, as an additional treatment to the conventional treatment in mild or moderate asthma results in significant improvement as compared to conventional treatment alone. Yoga may also be useful in preventing exercise-induced bronchoconstriction, possibly by stabilizing mast cell activation in patients having mild to moderate bronchial asthma.

62

Conclusions
a) Indices of pulmonary function showed a steady, progressive significant improvement over the 8-wk period of the study in the yoga group, whereas these indices did not show any significant trend from the baseline level in the control group. Therefore, adding yoga to the conventional treatment improves pulmonary function which could be a factor in improving physical work capacity. b) No significant changes observed in serum eosinophil cationic protein (ECP) in either group and no correlations were found in either group with any other pertinent parameters. The high variability in ECP levels suggests the need for much larger number of subjects for arriving at definitive conclusions. c) There is a significant trend observed in yoga group that 2 wk yogic intervention reduces T-cell activation in patients with mild to moderate asthma by showing decrease in serum sIL2R levels. d) There is a significant trend suggesting a decrease in broncho-constriction and a similar trend of insignificant reduction in mast cell activation in response to exercise challenge in the yoga group, particularly in the exercise-sensitive patients. Once again, in view of high variability in response, a much larger number of exercisesensitive subjects are required for definitive conclusions. e) Yoga improves quality of life and reduces need for medication in bronchial asthma more effectively than conventional treatment alone. f) Since conventional treatment alone keeps symptoms in check and improves quality of life without improving pulmonary function, its benefit may be considered primarily symptomatic. Addition of yoga to the treatment potentiates the benefits of conventional treatment, and in addition improves pulmonary function. Thus, only yoga brings about a genuine improvement in physical capabilities of the patient. g) The trial supports for the efficacy of yoga in the management of bronchial asthma. However, inspite of preliminary efforts it has failed to throw much light on the mechanism by which yoga works in bronchial asthma.

63

Bibiliography

1.

Alexander A, Miklich D & Hershkoff H. (1972). The immediate effects of systematic relaxation training on peak expiratory flow rates in asthmatic children. Psychol Med 34, 388. Altman DG & Dore CJ. (1990). Baseline comparisons in clinical trials. Lancet 335, 1476. American Thoracic Society. (1987). Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 136, 225-244. American Thoracic Society. (1991). Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 144, 1202-1218. Anderson SD. (1985). Issues in exercise-induced asthma. J Allergy Clin Immunol 76, 763-772. Anderson SD & Daviskas E. (1992). The airway microvasculature and exercise induced asthma. Thorax 47, 748-752. Anderson SD & Schoeffel RE. (1982). Respiratory heat and water loss during exercise in patients with asthma. Effect of repeated exercise challenge. Eur J Respair Dis 63, 472-480. Anil Kumar K, Gnana Kumari K, Girija Kumari D, Sahay BK & Murthy KJR. (1985). Immediate effects of pranayama in airways obstruction. Lung India 3, 77-81. Antonicelli L, Bucca C, Neri M, De Benedetto F, Sabbatani P, Bonifazi F, Eichler HG, Zhang Q, & Yin DD. (2004). Asthma severity and medical resource utilization. Eur Respir J 23, 723-729.

2. 3.

4.

5.

6.

7.

8.

9.

10. Bacci E, Di Franco A, Bartoli ML, Carnevali S, Cianchetti S, Dente FL, Giannini D, Vagaggini B, Ruocco L & Paggiaro PL. (2002). Comparison of anti-inflammatory and clinical effects of beclomethasone dipropionate and salmeterol in moderate asthma. Eur Respir J 20, 66-72. 11. Baird DT, Cameron ST, Critchley HO, Drudy TA Howe A, Jones RL, Lea RG & Kelly RW. (1996). Prostaglandins and menstruation. Eur J Obset Gynecol Reprod Biol 70,15-17.

64

12. Bake B. (1981). Is maximum mid-expiratory flow rate sensitive to small airways obstruction? Eur Respir J 62, 150-151. 13. Basyigit I, Yildiz F, Kacar Ozkara S, Boyaci H, Ilgazli A & Ozkarakas O. (2004). Effects of different anti-asthmatic agents on induced sputum and eosinophil cationic protein in mild asthmatics. Respirology 9, 514-520 14. Behera D & Jindal SK. (1990). Effect of yogic exercises on bronchial asthma. Lung India 8, 187-190. 15. Belcher NG, Rees PJ, Clark TJ & Lee TH. (1987). A comparison of the refractory periods induced by hypertonic airway challenge and exercise in bronchial asthma. Am Rev Respir Dis 135, 822-825. 16. Ben-Dov I, Bar-Yishay E & Godfrey S. (1982). Refractory period after exercise-induced asthma unexplained by respiratory heat loss. Am Rev Respir Dis 125, 530-534. 17. Bhole MV. (1967). Treatment of Bronchial Asthma by Yogic Methods. Yoga Mimansa 9, 33-41.

18. Bienenstock J. (2002). Stress and asthma: the plot thickens. Am J Respir Crit Care Med 165, 1034-1035. 19. Bienenstock J, Macqueen G, Sestini P, Marshall JS, Stead RH & Perdue MH. (1991). Mast cell/nerve interactions in vitro and in vivo. Am Rev Respir Dis 143, S55-58. 20. B ienenstock J, Perdue MH, Blennerhassett M, Stead R, Kakuta N, Sestini P, Vancheri C &Marshall J.(1988). Inflammatory cells and the epithelium. Mast cell/nerve interactions in the lung in vitro and in vivo. Am Rev Respir Dis 138, S31-34. 21. Bijlani R. (2003). Scientific Medicine Shows Signs Of A Paradigm Shift. New Approaches to Medicine and Health (NAMAH) 11, 28-40. 22. Bijlani RL.(1998). Is yoga system of medicine? New Approaches to Medicine and Health 6, 27-36 23 Bijlani RL,Vempati RP, Yadav RK, Ray RB, Gupta V, Sharma R, Mehta N & Mahapatra SC. (2005). A brief but comprehensive lifestyle education program based on yoga reduces risk factors for cardiovascular disease and diabetes mellitus. J Altern Complement Med 11, 267-274.

24. Bonferroni CE. (1935). II calcolo delle assicurazioni su gruppi di teste. In Study In Onore del Professore Salvatore Ortu Carboni, pp. 13-60, Rome: Itlay.

65

25. Bowler SD, Green A & Mitchell CA. (1998). Buteyko breathing techniques in asthma a blinded randomized controlled trial. Med J Aust 169, 575-578. 26. Bramchari D, Bahuguna JM & Jain SC. (1980). Therapeutic value of yoga in treatment of bronchial asthma (abstract). Indian J Physiol Pharmacol 24, 135. 27. Brown PH, Crompton GK & Greening AP. (1991). Proinflammatory cytokines in acute asthma. Lancet 338, 590-593. 28. Bundgaard A. (1985). Exercise and the asthmatic. Sports Med 2, 254-266. 29. Cambach W, Chadwick-Straver RV, Wagenaar RC, Van Keimpema AR & Kemper HC. (1997). The effects of a community-based pulmonary rehabilitation programme on exercise tolerance and quality of life: a randomized controlled trial. Eur Respir J 10,104-113. 30. Carlsen KH, Engh G & Mork M. (2000). Exercise-induced bronchoconstriction depends on exercise load. Respir Med 94, 750-755. 31. Chhabra S & Kaushik S (2005). Validation of the asthma quality of life questionnaire (AQLQ-UK English version) in Indian asthmatic subjects. Indian J Chest Dis Allied Sci 47, 167-173. 32. Chowdhary R, Singh V, Tattersfield AE, Sharma SD, Kar S & Gupta AB.(1999). Relationship of flow and cross-sectional area to frictional stress in airway models of asthma. J Asthma 36, 419-426. 33. Church MK, Lowman MA, Robinson C, Holgate ST & Benyon RC. (1989). Interaction of neuropeptides with human mast cells. Int Arch Allergy Appl Immunol 88, 70-78. 34. Cooper S, Oborne J, Newton S, Harrison V, Thomson Coon J, Lewis S & Tattersfield A. (2003). Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomized controlled trial. Thorax 58, 674-679. 35. Coreno A, Skowronski M, West E, El-Ekiaby A & Mcfadden Er, JR. (2005). Bronchoprotective effects of single doses of salmeterol combined with montelukast in thermally induced bronchospasm. Chest 127, 1572-1578. 36. Critchley HO, Kelly RW, Brenner RM & Baird DT. (2001). The endocrinology of menstruationa role for the immune system. Clin Endocrinol (Oxf) 55, 701-710.

37. Dahlen SE & Kumlin M. (1998). Can Asthma be studied in the urine? Clin Exp Allergy 28, 129-133.

66

38. Debaets FM, Goeteyn M & Kerrebijn KF. (1990). The effect of two months of treatment with inhaled budesonide on bronchial responsiveness to histamine and house-dust mite antigen in asthmatic children. Am Rev Respir Dis 142, 581-586. 39. Donohue J. (2000). The expanding role of long-acting beta agonists. Chest 118, 283285. 40. Dworski R & Sheller JR. (1998). Urinary mediators and asthma. Clin Exp Allergy 28, 1309-1312. 41. Edmunds AT, Tooley M & Godfrey S.(1978). The refractory period after exerciseinduced asthma. : its duration and relation to the severity of exercise. Am Rev Respir Dis 117, 247-254. Engstrom I, Fallstrom K, Karlberg E, Sten G & Bjure J.(1991). Psychological and respiratory physiological effects of a physical exercise programme on boys with severe asthma. Acta Paediatr Scand 80, 1058-1065.

42.

43. Flores O, Sun L, Vaziri N & Miyada D.(1980). Colorimetric rate method for the determination of creatinine as implemented by the Beckman Creatinine Analyzer 2. Am J Med Technol 46, 792-798. 44. Foreman JC. (1987). Neuropeptides and the pathogenesis of allergy. Allergy 42, 1-11. 45. Freezer NJ, Croasdell H, Doull IJ, & Holgate ST. (1995). Effect of regular inhaled beclomethasone on exercise and methacholine airway responses in school children with recurrent wheeze. Eur Respir J 8,1488-1493. 46. Gemou-Engesaeth V, Bush A, Kay AB, Hamid Q & Corrigan CJ.(1997). Inhaled Glucocorticoid Therapy of Childhood Asthma Is Associated With Reduced Peripheral Blood T Cell Activation and 'Th2-Type' Cytokine mRNA Expression.Pediatrics 99, 695703. 47. Goyeche JR, Abo Y & Ikemi Y. (1982). Asthma: the yoga perspective. Part II: Yoga therapy in the treatment of asthma. J Asthma 19, 189-201. 48. Green AS. (2004). Modeling of peak-flow wall shear stress in major airways of the lung. J Biomech 37, 661-667. 49. Greenfield RH. (1998). Yoga as an adjunct in the long-term relief of asthma. Alternative Medicine Alert 1, 127-130. 50. Gyuatt G, Juniper E, Walter S, Griffith I & Goldstein R. (1998). Interpreting treatment effects in randomized trials. Br Med J 101, 163-170.

67

51. Hockemeyer J & Smyth J. (2002). Evaluating the feasibility and efficacy of a self administered manual-based stress management intervention for individuals with asthma: results from a controlled study. Behav Med 27, 161-172. 52. Jaber R. (2002). Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Prim Care 29, 231-261.

53. Jaeschke R, Singer J & Guyatt G. (1989). Measurement of health status ascertaining the minimal important difference. Controlled Clin Trials 10, 407-415. 54. Jain SC, Rai L, Valecha A, Jha UK, Bhatnagar SO & Ram K. (1991). Effect of yoga training on exercise tolerance in adolescents with childhood asthma. J. Asthma 28, 437-442. 55. Jain SC & Talukdar B. (1993). Evaluation of yoga therapy programme for patients of bronchial asthma. Singapore Med J 34, 306-308. 56. Jonasson G, Carlsen KH & Hultquist C. (2000). Low-dose budesonide improves exercise-induced bronchospasm in school children. Pediatr Allergy Immunol 11, 120125.

57. Juniper E, Guyatt G, Willan A & Al E. (1994). Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol 47, 81-87. 58. Juniper E, Guyatt G, Ferrie P & Al E. (1993). Measuring quality of life in asthma. Am Rev Respir Dis 147, 832-838. 59. Juniper EF, Guyatt GH, Epstein RS & Al E. (1992). Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax 47, 76-83. 60. Juniper EF, Johnston PR, Borkhoff CM, Guyatt G H, Boulet LP & Haukioja A. (1995). Quality of life in asthma clinical trials: comparison of salmeterol and salbutamol. Am J Respir Crit Care Med 151, 66-70. 61. LJ & Peachell PT. (2005).Mast cell beta2-adrenoceptors. Chem Immunol Kay Energy 87, 145-153.

62. Kemp JP, Cook DA, Cox FM & Al E. (1998). Salmeterol improves quality of life in patients with asthma requiring inhaled corticosteroids. J Allergy Clin Immunol 101, 188-195. 63. Kemp JP, Dockhorn RJ, Busse WW, Bleecker ER & Van As A. (1994). Prolonged effect of inhaled salmeterol against exercise-induced bronchospasm. Am J Respir Crit Care Med 150, 1612-1615.

68

64.

Khalsa SB. (2004). Yoga as a therapeutic intervention: a bibliometric analysis of published research studies. Indian J Physiol Pharmacol 48, 269-285.

65. Lal CK, Chan CH, Ho SS, Hui AC & Lal KN. (1995). Inhaled salmeterol and albuterol in asthmatic patients receiving high-dose inhaled corticosteroids. Chest 108, 36-40.

66. Laitinen LA, Laitinen A & Haahtela T. (1992). A comparative study of the effects of an
inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double- blind, parallelgroup controlled trial. J Allergy Clin Immunol 90, 32-42. 67. Laube BL, Curbow BA, Costello RW & Fitzgerald ST. (2002). A pilot study examining the relationship between stress and serum cortisol concentrations in women with asthma. Respir Med 96, 823-828.

68. Laupacis A, Sacektt D & Roberts R. (1988). An assessment of clinically useful measures
of the consequences of treatment. N Eng J Med 318, 1728-1733. 69. Lee TH & Anderson SD. (1985). Heterogeneity of mechanisms in exercise induced asthma. Thorax 40, 481-487. 70. Lehrer P, Feldman J, Giardino N, Song HS & Schmaling K. (2002). Psychological aspects of asthma. J Consult Clin Psychol 70, 691-711. 71. Madanmohan Jatiya L, Udupa K & Bhavanani AB. (2003). Effect of yoga training on handgrip, respiratory pressures and pulmonary function. Indian J Physiol Pharmacol 47, 387-392. 72. Manning PJ, Watson RM & O'byrne PM. (1993). Exercise-induced refractoriness in asthmatic subjects involves leukotriene and prostaglandin interdependent mechanisms. Am Rev Respir Dis 148, 950-954. 73. Manocha R, Marks GB, Kenchington P, Peters D & Salome CM. (2002). Sahaja yoga in the management of moderate to severe asthma: a randomized controlled trial. Thorax 57, 110-115. Maxey KM, Maddipati KR & Birkmeier J. (1992). immunoassays. J clin. Immunoassay 15, 116-120. Interference in enzyme

74.

75. Mcfadden ER, JR. (1987). Exercise- induced asthma. Assessment of current etiologic concepts. Chest 91, 151S-157S. 76. Melillo E, Woolley KL, Manning PJ, Watson RM & O'byrne P. (1994). Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects. Am J Respir Crit Care Med 149, 1138-1141.

69

77. Misso N, Aggarwal S, Phelps S & Al E.(2004). Urinary leukotriene E4 and 9 alpha, 11 beta-prostaglandin F2 concentrations in mild, moderate and severe asthma, and in healthy subjects. Clin Exp Allergy 34, 624-631. 78. Motojima S, Hirata A, Kushima A, Tateishi K, Numao T, Fukuda T & Makino S. (1995). Serum levels of soluble interleukin-2 receptor in asthma patients. J Asthma 32, 151158. 79. Moy ML, Israel E, Weiss ST, Juniper EF, Dube L & Drazen JM. (2001). Clinical predictors of health-related quality of life depend on asthma severity. Am J Respir Crit Care Med 163, 924-929. 80. Muralidhara DV & Ranganathan KV. (1982). Effect of yoga practice on Cardiac Recovery Index. Indian J Physiol Pharmacol 26, 279-283. 81. Naepp, N.A.E.A.P.P. (1991). Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health, pub no 91-3642. Bethesda, MD. 82. Nagakura T, Obata T, Shichijo K, Matsuda S, Sigimoto H, Yamashita K, Masaki T & Maekawa K. (1998). GC/MS analysis of urinary excretion of 9alpha, 11 beta-PGF2 in acute and exercise-induced asthma in children. Clin Exp Allergy 28, 181-186. 83. Nagarathna R & Nagendra HR. (1985). Yoga for bronchial asthma: a controlled study. Br Med J (Clin Res Ed) 291, 1077-1079. 84. Nagarathna R, Nagendra HR & Seethalakshmi R. (1991a). Yoga-chair breathing for acute episodes of bronchial asthma. Lung India 9, 141-144. 85. Nagarathna R, Nagendra HR & Seethalakshmi R. (1991b). Yoga-chair breathing for acute episodes of bronchial asthma. Lung India 9, 141-144. 86. Nagendra HR & Nagarathna R. (1986). An integrated approach of yoga therapy for bronchial asthma: a 3-54-month prospective study. J Asthma 23, 123-137. 87. Nayar H, Mathur R & Sampathkumar R. (1975). Effects of yogic exercises on human physical efficiency. Indian J Med Res 63, 1369-1376.

88. NHLBI, N. H. L. A. B. I. (1995). Global Initiative for asthma: global strategy for asthma management and prevention; NHLBI/WHO workshop report. National Heart Lung and Blood Institute, Bethesda, MD. 89. Olivia CK. (1990). Physical conditioning programme for children with bronchial asthma. Acta Paediatr Jpn 32, 173-175.

70

90. Rubin LA, Kurman CC, Fritz ME, Biddison WE, Boutin B, Yarchoan R & Nelson DL. (1985). Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol 135, 3172-3177. 91. Sabina AB, Williams AL, Wall HK, Bansal S, Chupp G & Katz DL. (2005). Yoga intervention for adults with mild-to-moderate asthma: a pilot study. Ann Allergy Asthma Immunol 94, 543-548.

92. Schierhorn K, Brunnee T, Schultz KD, Jahnke V & Kunkel G. (1995). Substance-PInduced histamine release from human nasal mucosa in vitro. Int Arch Allergy Immunol 107, 109-114. 93. Sheikh S, Goldsmith LJ, Howell L & Eid N. (1999). Comparison of the efficacy of inhaled fluticasone propionate, 880 microg/ day, with flunisolide, 1500 microg/day, in moderate-to-severe persistent asthma. Ann Allergy Asthma Immunol 83, 300-304. 94. Singh V. (1987). Kunjal: a nonspecific protective factor in management of bronchial asthma. J Asthma 24, 183-186. 95. Singh V, Chowdhary R & Chowdhary N. (2000). The role of cough and hyperventilation in perpetuating airway inflammation in asthma. J Assoc Physicians India 48, 343-345. 96. Singh V, Wisniewski A, Britton J & Tattersfield A. (1990). Effect of yoga breathing exercises (pranayama) on airway reactivity in subjects with asthma. Lancet 335, 1381-1383. 97. Sinha B, Ray US, Pathak A & Selvamurthy W. (2004). Energy cost and cardiorespiratory changes during the practice of Surya Namaskar. Indian J Physiol Pharmacol 48, 184190. 98. Smith JE, Richardson J, Hoffman C & Pilkington K. (2005). Mindfulness-Based Stress Reduction as supportive therapy in cancer care: systematic review. J Adv Nurs 52, 315-327.

99. SolwayJ, Pichurko BM, Ingenito EP, Mcfadden ER, Jr, Fanta CH, Ingram RH, Jr, & Drazen JM. (1985). Breathing pattern affects airway wall temperature during cold air hyperpnea in humans. Am Rev Respir Dis 132, 853-857. 100. Spector SL. (1993). Update on exercise induced asthma. Sports Med 25, 1-6. 101. Stead RH, Bienenstock J, Burger MM & Al., E. (1990). Cellular interactions between the immune and peripheral nervous system. A normal role for mast cells? In Cell to Cell Interaction, pp. 170-187. Karger, Basel.

71

102. Storms WW. (1999). Exercise-induced asthma: diagnosis and treatment for the recreational or elite athlete. Med Sci Sports Exerc 31, S33-38. 103. Tandon M. (1978). Adjunct treatment with yoga in chronic severe airway obstruction. Thorax 33, 514-517. 104. Telles S, Reddy SK & Nagendra HR. (2000). Oxygen consumption and respiration following two yoga relaxation techniques. Appl Psychophysiol Biofeedback 25, 221227. 105. Theoharides TC. (1990). Mast cells: the immune gate to the brain. Life Sci 46, 607617. 106. Theoharides TC. (1996). The mast cell: a neuroimmunoendocrine master player. Int J Tissue React 18, 1-21. 107. Theoharides TC & Cochrane DE. (2004). Critical role of mast cells in inflammatory diseases and the effect of acute stress. J Neuroimmunol 146, 1-12. 108. Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E & Chrousos G. (1998). Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology 139, 403-413. 109. Theoharides TC, Spanos C, Pang X, Alferes L, Ligris K, Letourneau R, Rozniecki JJ, Webster E & Chrousos GP. (1995). Stress induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect. Endocrinology 136, 5745-5750. 110. Thio BJ. Nagelkerke AF, Ketel AG, Van Keeken BL & Dankert-Roelse JE. (1996). Exercise-induced asthma and cardiovascular fitness in asthmatic children. Thorax 51, 207-209. 111. Uitenbroek D. (1997). Sample Size, vol. 2003. SISA. 112. Vedanthan PK, Kesavalu LN, Murthy KC, Duvall K, Hall MJ, Baker S & Nagarathna S. (1998). Clinical study of yoga techniques in university students with asthma: a controlled study. Allergy Asthma Proc 19, 3-9. 113. Vempati RP & Telles S. (2002). Yoga-based guided relaxation reduces sympathetic activity judged from baseline levels. Psychol Rep 90, 487-494.

72

114. Villaran C, O'neill SJ, Helbling A, Vannoord JA, Lee TH, Chuchalin AG, Langley SJ, Gunawardena KA, Suskovic S, Laurenzi M, Jasan J, Menten J & Leff JA. (1999). Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group. J Allergy Clin Immunol 104, 547-553. 115. Volund A. (1978). Application of the four-parameter logistic model to bioassay: comparison with slope ratio and parallel line models. Biometrics 34, 357-365. 116. Wardlaw AJ, Dunnette S, Gleich GJ, Collins JV & Kay AB. (1988). Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am Rev Respir Dis 137, 62-69. 117. Wasserman K, Hansen JE, Sue DY, Whipp BJ & Casaburi R. (1999). Principles of Exercise Testing and Interpretation, pp. 115-142. Lea & Febiger, Philadelphia.

118. Wever A, Hess J & Hermans J. (1997). The use of serum eosinophil cationic protein
(ECP) in the management of steroid therapy in chronic asthma. Clin Exp Allergy 27,519529. 119. Xu SH. (1994). Psychophysiological reactions associated with qigong therapy. Chin Med J (Engl) 107,230233. 120. Yates DH, Wordsdell M & Barnes PJ. (1998). Effect of an inhaled glucocorticosteroid on mast cell and smooth muscle beta 2 adrenergic tolerance in mild asthma. Thorax 53, 110-113.

73

The efficacy of a comprehensive lifestyle modification programme based on yoga in the management of bronchial asthma: a randomized controlled trial. Vempati R, Bijlani RL, Deepak KK. BMC Pulm Med. 2009 Jul 30; 9:37.

Abstract
BACKGROUND: There is a substantial body of evidence on the efficacy of yoga in the management of bronchial asthma. Many studies have reported, as the effects of yoga on bronchial asthma, significant improvements in pulmonary functions, quality of life and reduction in airway hyper-reactivity, frequency of attacks and medication use. In addition, a few studies have attempted to understand the effects of yoga on exercise-induced bronchoconstriction (EIB) or exercise tolerance capacity. However, none of these studies has investigated any immunological mechanisms by which yoga improves these variables in bronchial asthma. METHODS: The present randomized controlled trial (RCT) was conducted on 57 adult subjects with mild or moderate bronchial asthma who were allocated randomly to either the yoga (intervention) group (n = 29) or the wait-listed control group (n = 28). The control group received only conventional care and the yoga group received an intervention based on yoga, in addition to the conventional care. The intervention consisted of 2-wk supervised training in lifestyle modification and stress management based on yoga followed by closely monitored continuation of the practices at home for 6-wk. The outcome measures were assessed in both the groups at 0 wk (baseline), 2, 4 and 8 wk by using Generalized Linear Model (GLM) repeated measures followed by post-hoc analysis. RESULTS: In the yoga group, there was a steady and progressive improvement in pulmonary function, the change being statistically significant in case of the first second of forced expiratory volume (FEV1) at 8 wk, and peak expiratory flow rate (PEFR) at 2, 4 and 8 wk as compared to the corresponding baseline values. There was a significant reduction in EIB in the yoga group. However, there was no corresponding reduction in the urinary prostaglandin D2 metabolite (11beta prostaglandin F2alpha) levels in response to the exercise challenge. There was also no significant change in serum eosinophilic cationic protein levels during the 8-wk study period in either group. There was a significant improvement in Asthma Quality of Life (AQOL) scores in both groups over the 8-wk study period. But the improvement was achieved earlier and was more complete in the yoga group. The number-needed-to-treat worked out to be 1.82 for the total AQOL score. An improvement in total AQOL score was greater than the minimal important difference and the same outcome was achieved for the sub-domains of the AQOL. The frequency of rescue medication use showed a significant decrease over the study period in both the groups. However, the decrease was achieved relatively earlier and was more marked in the yoga group than in the control group. CONCLUSION: The present RCT has demonstrated that adding the mind-body approach of yoga to the predominantly physical approach of conventional care results in measurable improvement in subjective as well as objective outcomes in bronchial asthma. The trial supports the efficacy of yoga in the management of bronchial asthma. However, the preliminary efforts made towards working out the mechanism of action of the intervention have not thrown much light on how yoga works in bronchial asthma.

74

COUNCIL'S PUBLICATIONS HIGHLY SUBSIDISED AND DISCOUNT UPTO 25%

HINDI 1. Sadharan Rogon ki Yogic evam Prakritik Chikitsa 2. Aadi Urja Prana 3. Vyavaharik Prakritik Chikitsa 4. Vidyarthiyon ki liye Swasthya Shiksha 5. Vaidic Vangmaya mei Prakritik Chikitsa (Vol.I) 6. Vaidic Vangmaya mei Prakritik Chikitsa (Vol.II) 7. Prakritik Chikitsa ki Avashyak Upchar Vidhiyan 8. Patanjal Yog Sutra Bhashya Vivaranam 9. Manushya mein Prana ke Aayam 10. Prakritik Chikitsa Darshan evam Vyavahar 11. Yoga Therapy and Naturopathy (CD) 12. Research Activities of Council (CD) ENGLISH 1. 2. 3. 4. Yogic and Naturopathic Treatment for Common Ailments Health Education for Students Important Therapeutic Modalities used in Naturopathy Yoga Therapy and Naturopathy (CD) TAMIL 1. Yoga Therapy and Naturopathy (CD) 50/30/5/20/50/PRICE (RS) 30/100/120/5/175/175/20/150/180/160/50/50/-

Note: 25% discount is given on purchase of 10 copies or more and 10% on less than 10 copies of books. The publications may be purchased by remitting the cost through DD/ Cash in favour of Director, CCRYN, New Delhi.