______________________________________________________________ An Official Publication of the Philippine Academy of Pediatric Pulmonologists, Inc.

______________________________________________________________

PAPP PERSPECTIVE

Updates

in the

Evaluation and Management of

Pediatric Community-Acquired Pneumonia

PAPP Task Force on pCAP [2008]

Philippine Academy of Pediatric Pulmonologists, Inc. [PAPP, Inc.] 2008 All rights reserved. Publication and request for permission to reproduce can be obtained from the Philippine Academy of Pediatric Pulmonologists, Inc., Room 102 GJ Building, 385 Quezon Avenue Quezon City Telefax No +632 3747201; email: papp_office@yahoo.com. This document is not intended to be a standard of care. The responsibility for its use lies with the reader. In no event shall PAPP, Inc. be liable for damages arising from its use.

PAPP Officers Olivia C. Go, MD FPPS FPAPP.President Arnel Gerald Q. Jiao, MD FPPS FPAPP....Vice-President Cesar M. Ong, MD FPPS FPAPP...Secretary Maria Nerissa A. de Leon, MD FPPS FPAPP....Treasurer Mary Therese M. Leopando, MD FPPS FPAPP.Director Clara R. Rivera, MD FPPS FPAPP.Director Mary Ann F. Aison, MD FPPS FPAPP...Director PAPP Task Force on pCAP Cristan Q. Cabanilla, MD FPPS FPAPP Chair Regina M. Canonizado, MD FPPS FPAPP Anjanette R. de Leon, MD DPPS DPAPP Roslyn Marie K. Dychiao, MD FPPS DPAPP Beatriz Praxedes Apolla I. Mandanas-Paz, MD DPPS DPAPP Anna Marie S. Putulin, MD FPPS FPAPP Emily Dolores G. Resurreccion, MD FPPS FPAPP Ana Maria A. Reyes, MD FPPS FPAPP Marion O. Sanchez, MD DPPS DPAPP Rita Marie Lourdes S. Vergara, MD FPPS FPAPP Rozaida R. Villon, MD FPPS FPAPP Members Gerardo L. Beltran, MD FPCR Guest Radiologist Gladys L. Gillera, MD DPPS DPAPP Secretary

CONTENTS

Foreword

Preface to the Updates and Acknowledgement

2004 Clinical Practice Guideline Clinical Questions with Recommendations, and Update Highlights with Annotations

Appendix

Bibliography

FOREWORD

In the past years, we witnessed a major revolution in the science and practice of pediatric pulmonary medicine, more particularly in our concept and management of pneumonia in children. We are challenged to adopt and apply these newer insights about the disease in dealing with our patients. Despite the inadequate and limited advancement in medical technology among developing countries, we are able to establish the diagnosis of pneumonia and manage it comprehensively largely based on good clinical acumen. Furthermore, our knowledge in clinical epidemiology is imperative to facilitate its holistic management, while the rational use of antimicrobial agents increases our awareness on the emergence of drug resistance in specific localities. This clinical update on pneumonia contains a comprehensive evidence-based review of national as well as international researches that depicts the current clinical practice and management strategies adopted to contain the disease. The Academy maintains its primary purpose to apprise our pediatric practitioners of the many medical investigations on pneumonia and propose practical treatment options to combat the disease. This current issue does not intend to replace the 2004 PPS Clinical Practice Guideline in the Management of Pediatric Community-Acquired Pneumonia. This is simply presented to clarify some gaps in the knowledge stated therein. We look forward that this understanding bridges the small differences in our daily practice to bring forth a worthy clinical outcome. Allow me to take this good opportunity to congratulate the Task Force on PCAP for such an excellent job.

Olivia C. Go, MD President Philippine Academy of Pediatric Pulmonologists, Inc.

PREFACE TO THE UPDATES

One of the issues that was raised regarding the 2004 Clinical Practice Guideline in the Evaluation and Management of Pediatric Community-Acquired Pneumonia is the gap in knowledge underscored in each recommendation. To address this concern, the Task Force on pCAP has reviewed data available from local and foreign literature. As this manuscript is merely an update consisting of recent literature, it is not intended to be a standard of care much more a revision of the current guideline. This update is available in two formats. The abbreviated format consists of update highlights and summary of recent evidence. This is made available as a limited service item in the form of hard copy during the 2008 16th PAPP Annual Convention. The complete version which includes not only similar highlights but detailed description of each update can be downloaded from the Philippine Academy of Pediatric Pulmonologists, Inc. through the website of the Philippine Pediatric Society www.pps.org.ph. The reader is encouraged to access the complete version for a more thorough discussion.

Cristan Q Cabanilla, MD Chair Task Force on pCAP

Acknowledgement

This manuscript is the result of a concerted effort by the Task Force on pCAP under the leadership and guidance of the PAPP officers headed by Olivia C. Go. Special gratitude is due to Luis M. Rivera Sr., Alexander O. Tuazon, Milagros S. Bautista and Agnes R. Mendoza for reviewing the document.

2004 CLINICAL PRACTICE GUIDELINE CLINICAL QUESTIONS WITH RECOMMENDATIONS, AND UPDATE HIGHLIGHTS WITH ANNOTATIONS

Clinical Questions [CQ]

Evaluation 1. 2. 3. 4. Who shall be considered as having community-acquired pneumonia? Who will require admission? What diagnostic aids are initially requested for ambulatory patients? What diagnostic aids are initially requested for in-patients?

Treatment 5. When is antibiotic recommended? 6. What empiric treatment should be administered if a bacterial etiology is strongly considered? 7. What treatment should be initially given if a viral etiology is strongly considered? 8. When can a patient be considered as responding to the current antibiotic? 9. What should be done if a patient is not responding to current antibiotic therapy? 10. When can switch therapy in bacterial pneumonia be started? 11. What ancillary treatment can be given?

Prevention 12. How can pneumonia be prevented?

INTRODUCTION

The world incidence of lower respiratory tract infection that includes pneumonia in developing countries has been recently estimated to be 150.7 million cases, 95% of whom are under five years of age, and 13% severe enough to require hospital admission [Rudan I,2004]. In the Philippines, it continues to be a leading cause of morbidity in children accounting to about 828.8 per 100,000 population [Department of Health Field Health Service Information System, 2006]. Estimates of treatment cost highlight the economic burden that childhood pneumonia places on health care systems. An average cost of treatment for acute respiratory infection per episode from the perspective of developing economies in Asia ranged from USD 1.70 in a primary health care setting to USD 155.30 for hospitalized care [Toan NV,2001; Rattanadilok N,2002]. Outpatient and hospitalized care of a child with pneumonia have been estimated to be USD 13.44 and USD 71.0 per episode, respectively [Hussain H, 2006]. An average parents total household expenses for a childs admission because of pneumonia have been found to be 5 to 11% of an average net income per family in Israel [Shoham Y,2005]. In the local setting as provided by the National Health Insurance Program, the 2006 total payment claims for pneumonia [ICD-10 Code J18.9] below 19 years of age amounted to PhP 324.688 M [Philippine Health Insurance Corporation, Claims Payment Summary for CY 2006 Ages 0-19 for Pneumonia,2007]. One public health strategy to address this continuing concern is the implementation of a clinical practice guideline. In 2004, the Philippine Pediatric Society, the Philippine Academy of Pediatric Pulmonologists and the Pediatric Infectious Disease Society of the Philippines came out with a clinical practice guideline in the evaluation and management of pediatric community-acquired pneumonia. In 2006, the Philippine Health Insurance Corporation has adopted the document as one of the guidelines that can serve as a basis for quality assurance and accreditation [PhilHealth Health Technology Assessment Unit, Quality Assurance Research and Policy Development Group,2006]. Its acceptability and utilization have been subsequently assessed. Of the 166 respondents to a random sampling questionnaire survey conducted during the 2006 43rd PPS Annual Convention, 82% acknowledged applying the recommendation in their practice [Cabanilla C, Santos J, 2006]. In another survey among 61 pediatric consultants and residents from MetroManila, about 96% confirmed that such guideline was being followed [de Jesus-Oabel BA and Atienzade Leon MN, 2007]. This update presents evidences based on recent local and foreign literature dealing with the recognition of community-acquired pneumonia in an immunocompetent patient aged 2 months to 19 years, identification of appropriate and practical diagnostic procedures, and initiation of rational management and preventive measures

CQ 1. Who shall be considered as having community-acquired pneumonia?

2004 Clinical Practice Guideline Recommendation

Predictors of community-acquired pneumonia in a patient with cough 1. for ages 3 months to 5 years are tachypnea and/or chest indrawing [Grade B]. 2. for ages 5 to 12 years are fever, tachypnea, and crackles [Grade D]. 3. beyond 12 years of age are the presence of the following features [Grade D]: a. fever, tachypnea, and tachycardia; and b. at least one abnormal chest findings of diminished breath sounds, rhonchi, crackles or wheezes.

UPDATE HIGHLIGHTS 1. A patient presenting with a history of cough and/or respiratory difficulty should be evaluated for the possible presence of pneumonia. However, the lack of cough does not necessarily imply the absence of the disease as it may not be present as an initial presentation in 24% of cases with radiographic pneumonia. This is particularly true in the younger age group. 2. There are physical signs that are useful to predict the presence of pneumonia using chest x ray as reference standard. In four studies involving children below 5 years old, age-specific tachypnea as defined by the World Health Organization [WHO] remains to be the best single predictor. Another useful single physical sign is the presence of chest indrawing. A combination of tachypnea and chest indrawing provides a higher probability as to the presence of pneumonia. In one study, the combination of tachypnea, low oxygen saturation on admission and nasal flaring gave the highest predictive value among all other signs and symptoms. In two studies dealing with patients older than 5 years, tachypnea alone, or in combination with fever and crackles are reliable predictors. 3. The absence of either age-specific tachypnea as defined by WHO or chest indrawing does not rule out the presence of pneumonia.

Annotation 1A. Background.

1. The Task Force on pCAP adopted the recommendation as provided by the International Union Against Tuberculosis and Lung Disease that pneumonia should be one of the considerations in a child with acute illness presenting with either cough or difficulty of breathing [Enarson P, 2004]. However, it is important to note that cough may not be necessarily present, as it was noted to be absent as an initial presentation in 24% of radiologic pneumonia [Taina Juven, 2003]. This phenomenom has been observed to be most common in the younger age group.

2. Basis for establishing clinical predictors a. For the purpose of searching relevant literature in determining the clinical predictors for pneumonia, the Task Force on pCAP has agreed to consider radiographic findings as the benchmark in defining the presence or absence of childhood pneumonia. b. Acknowledging inter-observer variability in analyzing chest x-ray studies [Swingler GH, 2001], the World Health Organization has standardized the radiographic interpretation of a child with pneumonia [World Health Organization Pneumonia Vaccine Trial Investigators Group, 2001]. Using this standard, the variability has considerably improved, with a kappa index for the presence of alveolar consolidation at > 0.60 [Cherian T, 2005], and 0.70 (95% CI 0.560.83) [Castro AV, 2006].

Annotation 1B. Clinical presentation predictive of radiographic pneumonia a. There is one [1] study dealing with identifying patients with radiographic pneumonia in the out-patient department

Among 1932 patients aged 2-59 months, cough and tachypnea, and difficulty of breathing and tachypnea had a relative risk [RR] of 1.18 (95% CI 0.41-3.43) and 0.80 (95% CI 0.56-1.13), respectively. [Hazir T, 2006].

b. There is one [1] study dealing with identifying patients with radiographic pneumonia in the combined out-patient department and emergency room Among 181 patients aged 3 months to 5 years, cough of 5 days duration with tachypnea has a + LR [or positive likelihood ratio] of 2.4 (95% CI 1.5-3.8) and LR [or negative likelihood ratio] of 0.27 (95% CI 0.190.39); chest indrawing +LR of 8.7 (95% CI 1.3-62.4) and LR of 0.77 (95% CI 0.70-0.85); fever +LR of 1.3(95% CI 1.1-1.7) and LR of 0.26 (95% CI 0.13-0.51); crackles +LR of 3.1 (95% CI 1.8-5.3) and LR of 9

0.15 (95% CI 0.09-0.25); and combination of tachypnea and chest indrawing +LR of 9.1 (95% CI 1.2-64.1) and LR of 0.76 (95% CI 0.690.84) * [de la Cruz R, 2007]. c. There are five [5] studies dealing with identifying patients with radiographic pneumonia in the Emergency Room Among 207 patients aged 5-12 years old, the combination of cough < 2 weeks duration, fever lasting less than 7 days, RR>30 breaths/minute and crackles has a +LR of 4.95 and LR of 0.36 [Ocbina P, 2006]. Among 165 children aged 6-59 months, a history of previous respiratory distress and persistence of tachypnea after bronchodilator challenge test has a +LR of 1.84 and a LR of 0.6 [Castro AV, 2005]. Among 510 patients aged 2-59 months of age with cough and with any one of the following [Mahabee-Gittens EM, 2005 ]: RR greater than 60 per minute across all ages has +LR of 2.6 (CI 95% 1.6-4.3), and -LR of 0.77 Age > 12 months has +LR of 1.5 (CI 95% 1.2-1.9), and LR of 0.59 Nasal flaring ( among patients aged > 12 months) +LR of 5.2 (CI 95% 2.2-12.2), and LR of 0.71 Combination of RR 50/min, O2 Sat 96% and nasal flaring has + LR of 11.0 (CI 95% 2.4-49.8) Among 570 patients aged 1-16 years of age, tachypnea has +LR of 2.6 and -LR of 0.90; and combination of fever, decreased breath sounds, crackles and tachypnea has +LR of 1.04 and LR of 0.20 [Lynch T, 2004 ]. Among 76 patients from birth to 6 mo of age [de Fatima M, 2005], RR greater than 50 with bacterial etiology has a +LR of 1.2 and a -LR of 0.63; and with a viral etiology +LR of 1.2 and -LR of 0.37 Chest indrawing with bacterial etiology has a +LR 2.3 and a -LR of 0 .70; and with viral etiology +LR of 1.7 and -LR of 0.67 ___________________________________________
*

Likelihood ratio [LR] of around 1 indicate that no useful information for ruling the diagnosis in or out has been produced from the clinical findings. A LR that is further away from 1 increases reliability. A high likelihood ratio (e.g. LR>10) indicate that the sign or symptom [or any diagnostic test] can be used to rule in the disease, while a low likelihood ratios (e.g. LR<0.1) can rule out the disease. Please see Appendix B.

10

CQ 2. Who will require admission? 2004 Clinical Practice Guideline Recommendation 1. A patient who is at moderate to high risk to develop pneumonia-related mortality should be admitted [Grade D]. 2. A patient at minimal to low risk can be managed on an outpatient basis [Grade D].

UPDATE HIGHLIGHTS 1. Single evidence supports the current recommendation on risk classification scheme. 2. A single clinical index that suggests the need for admission because of possible hypoxemia is chest indrawing. 3. Indices that predict mortality include young age, malnutrition, lack of Hib/measles vaccination, and high oxygen requirement on admission. Annotation 2A. Risk classification scheme Among 221 patients with an impression of pCAP, none of the 61 and 80 patients classified as pCAP A and B respectively were admitted within 48 hours. Similarly, none of the 84 patients admitted as pCAP C were discharged or admitted to ICU within 48 hours after admission [Pocsidio C, 2007]. See Appendix C for the table showing the risk classification. Annotation 2B. Individual indices predicting the need for admission 1. Physical examination of the chest in predicting hypoxemia Among 150 patients aged 2-60 months, chest indrawing has a +LR of 5.7 and -LR of 0.39 in predicting the presence and absence respectively of hypoxemia [Basnet S, 2006]. 2. Age and nutrition in predicting mortality Among 30 mortalities because of pneumonia, young age [2-5 months] and weight for age z-score less than -2 SD have an OR of 2.20 (95% CI 1.06-4.54) and 1.86 (95% CI 0.89-3.87), respectively [Lupisan SP, 2007]. 3. Hib/measles vaccination on admission in predicting mortality Among 102 mortalities because of pneumonia, the absence of measles/HIb vaccination has an OR of 15.89 (95% CI 3.473-72.784), and 8.31(95% CI 3.5-19.3), respectively [Sadang-Saguinsin S, 2006]. Annotation 2C. Day care management of pCAP C Among 251 patients aged 2-59 months with severe and very severe pneumonia without any associated co-morbidities, successful management was possible in a day care setting among 93.2% (95% CI, 89-96) of patients [Ashraf H, 2007].

11

CQ 3. What diagnostic aids are initially requested for a patient classified as either PCAP A or PCAP B being managed in an ambulatory setting?

2004 Clinical Practice Guideline Recommendation

No diagnostic aids are initially requested for a patient classified as either PCAP A or PCAP B who is being managed in an ambulatory setting [Grade D].

UPDATE HIGHLIGHT The low risk of bacteremia does not warrant blood culture determination in nonsevere pneumonia.

Annotation 3A. Indication for radiographic and laboratory tests The Task Force on pCAP has not encountered studies investigating the value of WBC, differential count, CRP and ESR in the diagnosis of pCAP patients being managed on an outpatient basis.

Annotation 3B. Blood culture In 540 patients aged 2-24 months, the risk of bacteremia among patients seen as outpatient is 1.6%. (95% CI 0.7-2.9). Streptococcocus pneumoniae was the causative organism in all cases [Shah S 2003].

Annotation 3C. Predictor for bacterial pathogen Serum procalcitonin has been used to differentiate between viral, atypical and bacterial pathogen in 100 patients aged less than 2 years to more than 5 years [74 outpatients and 26 inpatients]. A cut-off limit of > 2.0 ng/ml has a +LR of 1.69 and -LR of 0.73 for Streptococcus pneumoniae, and a +LR of 2.31 and LR of 0.54 for Mycoplasma sp and Chlamydia sp, respectively [Don M 2007]. This test is not currently available locally.

12

CQ 4. What diagnostic aids are initially requested for a patient classified as either PCAP C or PCAP D being managed in a hospital setting?

2004 Clinical Practice Guideline Recommendation

1.The following should be routinely requested: a. Chest x-ray PA-lateral [Grade B] b. White blood cell count [Grade C] c. Culture and sensitivity of Blood for PCAP D [Grade D] Pleural fluid [Grade D] Tracheal aspirate upon initial intubation [Grade D] Blood gas and/or pulse oximetry [Grade D] 2.The following may be requested: Culture and sensitivity of sputum for older children [Grade D] 3. The following should not be routinely requested: a. Erythrocyte sedimentation rate [Grade A] b. C-reactive protein [Grade A]

UPDATE HIGHLIGHTS 1. Chest radiographic evaluation is primarily utilized as an integral part of a clinical prediction rule in identifying the presence of a bacterial pathogen. As an individual tool, it can be used to assess severity and presence of complications, and to predict subsequent course of illness. 2. WBC and CRP have a limited value as an individual test in differentiating bacterial from viral pneumonia. A CRP level [ 12 mg/dl] is associated with necrotizing pneumonia and/or empyema. 3. Single evidence suggests a 63 mm/h value for ESR in predicting the presence of a bacterial pathogen. 4. The microbiologic yield for blood culture ranged from 1.2% to 6.2%. 5. High oxygen requirement on admission is one of the variables associated with mortality.

13

Annotation 4A. Chest x-ray

Radiographic examination offers the following information.

1. Chest x-ray has been used as a tool to predict the type of pathogen Chest x-ray is an integral part of the clinical prediction rule [see Clinical Question 5 and Appendix D] in initiating antibiotic therapy [Moreno L, 2006]. However, its value as an individual tool in differentiating bacterial from other types of infection is insignificant as shown in one report [Michelow IC, 2004]. In this study of 154 patients aged 2 months17 years, the presence of lobar or segmental consolidation with or without effusion can be seen among different pathogens such as bacterial, viral and atypical organisms (p value = 0.06). A compounding variable is the presence of mixed causative agents in about a third of cases of pneumonia in which the radiographic pattern has been shown to be similar to that seen in single pathogen [Tsolia MN, 2004; Taina Juve n, 2004; Michelow IC, 2003; Don M, 2005; Tajima T,2006; Lehtinen P,2006; Huang HH,2006; Chiang WC,2007].

2. Chest x ray has been used as an individual tool to assess severity of pneumonia Presence of necrotizing pneumonia and/or empyema Among 131 patients aged <18 years, the presence of necrotizing pneumonia and/or empyema was significantly more likely to be present in multilobar (2 lobes) involvement (OR 2.83, 95% CI 1.27-6.33) [Lin J,2006].

3. Chest x ray has been used as an individual tool to predict subsequent course a. Predictor of prolonged fever and hospitalization, and pleural effusion Among 167 patients > 12 months of age, left-sided pneumonia was significantly associated with prolonged fever (p=0.02) and hospitalization (p=0.043), and the presence of pleural effusion (OR 2.65; 95% CI 1.096.47; p value=0.031) compared with right-sided pneumonia
[Grafakou O,2004].

14

b. Predictor of mortality Among 102 mortalities because of pneumonia, multilobar (2 lobes) involvement has an OR of 2.55 (95% CI 1.56.5.64) of mortality [Sadang-Saguinsin S, 2006]. In 30 mortalities because of pneumonia, the presence of dense infiltrates has an OR of 3.89 (95% CI 1.75-8.67) [Lupisan SP, 2007]. c. Predictor of treatment failure Among 20% of 218 patients, bilateral consolidation has an OR of 3.10 of having treatment failure on the 72nd hour of admission [Victor R, 2007].

Annotation 4B. WBC Evidence is weak in using white blood count as an individual tool to predict bacterial pathogen a. Among 132 patients <11 months to >5 y old, the +LR and - LR for WBC>13,000 x 109/L are 1.29 and 0.73, and WBC>17,000 x 109/L are 1.89 and 0.80, respectively [Korppi M, 2004]. b. Among 862 patients with proven RSV infection aged 62398 days, WBC > 15,000 x 109/L, the probability of a concurrent serious bacterial infection is 4.7% [Purcell K, 2007]. c. Among 154 patients aged 2 months 17 years, no statistical significance exists among WBCs of bacterial, viral, atypical organisms and mixed infection (p value = 0.76) [Michelow IC, 2004].

Annotation 4C. Acute phase reactants 1. C reactive protein [CRP] Evidence is inconclusive in using CRP to predict the presence of bacterial pathogen a. Among 132 patients aged <11 months to >5 years old, CRP > 146 mg/dl has a +LR of 1.75 and -LR of 0.43. [Korppi M, 2004].

15

b. Among paired serum samples from 265 patients, CRP from 6 to 250 mg/L using latex agglutination test has sensitivity of 100% and specificity of 87% [Requejo H, 2003].

In one study, a CRP level 12 mg/dl has an OR of 3.51 (95% CI 1.717.66) to predict the presence of necrotizing pneumonia and/or empyema [Lin K, 2006].

2. Erythrocyte sedimentation rate [ESR] In one study, there is evidence that ESR can be used to predict the presence of a bacterial pathogen. Among 132 patients aged <11 months to >5 y old, ESR at a value of 63 mm/h has a +LR of 3.50 and -LR 0.84 [Korppi M,2004].

3. Serum procalcitonin In two studies, there is evidence that serum procalcitonin may predict the presence of a bacterial pathogen. This test however is not currently available locally a. Among 132 patients aged <11 months to >5 y old, a procalcitonin level of > 0.84 ng/L has a +LR of 2.05 and a -LR 0.76 [Korppi M, 2004]. b. Among 57 patients less than 15 years old with Streptococcus pneumoniae, procalcitonin > 1 ng/L found in only 14 patients had +LR of 2.40 [Korppi M,2003].

Annotation 4D. Microbiology 1. There are no studies dealing with determining the impact of having to obtain microbiologic examination on the overall outcome of pCAP. 2. Two studies have shown the yield for blood culture as follows: a. 1.2% among 157 patients [Tajima T, 2006]. b. 6.2% among 75 patients [M. N. Tsolia, 2004]. 3. Immunological assay and PCR a. Among 550 paired samples for Streptococcus pneumoniae and Haemophilus influenzae type b polysaccharide antigen, CIE, LA and DotELISA using serum samples had a sensitivity of 91.1% to 100%, and a specificity of 56.4% to 100% [Requejo HI, 2007].

16

b. Among 107 patients, latex particle agglutination test [LPAT] performed in urine samples to detect Streptococcus pneumoniae and Haemophilus influenzae type b polysaccharide antigen, has a +LR of 7.7 and -LR of 0.25 [Nunes A, 2004]. c. Among 389 patients, the sensitivity and specificity using pathogenspecific molecular beacon probes were as follows: 96.2% and 93.2% for Streptococcus pneumoniae, 95.8% and 95.4% for Hemophilus influenzae, 100% and 100% for Streptococcus pyogenes, and 100% and 95.4% for Mycoplasma pneumoniae, respectively [Morozumi M,2006].

Annotation 4E. Oxygen saturation and/or blood gas In addition to the use of determining oxygen saturation and/or blood gas to titrate Fi02 in maintaining adequate oxygenation, it can also be utilized to predict mortality. Among 102 children aged 3 months to 19 years, a high oxygen requirement on admission has an OR of 8.31 (95% CI 3.5-19.3) at risk for mortality [Sadang-Saguinsin S, 2006].

17

CQ 5. When is antibiotic recommended? 2004 Clinical Practice Guideline Recommendation An antibiotic is recommended 1. for a patient classified as either PCAP A or B and is a. beyond 2 years of age [Grade B]; or b. having high grade fever without wheeze [Grade D] 2. for a patient classified as PCAP C and is a. beyond 2 years of age [Grade B]; or b. having high grade fever without wheeze [Grade D]; or c. having alveolar consolidation in the chest x-ray [Grade B]; or d. having white blood cell count >15,000 [Grade C] 3. for a patient classified as PCAP D [Grade D]

UPDATE HIGHLIGHTS 1. Epidemiology a. Recent epidemiologic trend shows that more than 50% of hospitalized cases of pCAP will require antibiotic. b. The importance of mixed infection as causative agents should be clarified as it is responsible for about one-third of all identified causes of hospitalized pCAP. 2. Microbiologic tests The yield in detecting bacteremia in pCAP remains to be low at 1.2% to 26%. 3. Predictors of bacterial pathogen. a. A clinical prediction rule that makes use of a bacterial pneumonia score [BPS] of > 4 can predict the presence of a bacterial pathogen in hospitalized patients aged one month to five years. b. Other individual parameters include the following. Increasing age generally correlates with the presence of antibiotic-requiring pathogen. Identifying a specific age as to when an antibiotic should be started is difficult. There is single evidence in the use of ESR with a value of 63 mm/h in predicting the presence of a bacterial pathogen. There is weak evidence in the use of clinical symptomatology, chest x-ray, WBC and CRP as predictors of bacterial pathogen.

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Annotation 5A. Establishing the etiology

A. Microbiology There are five [5] studies that have looked simultaneously into viral, bacterial, atypical organisms and mixed infection [Michelow I, 2004,; Don M, 2005; Tsolia MN, 2005; Tajima T, 2006; Chang WC, 2007]. Etiology was determined through different methodologies using culture, serology, and pneumolysin-based polymerase chain reaction assays. It is important to note that all patients in these studies are hospitalized [except in one study dealing with both ambulatory and hospitalized patients], and are from developed economies where the rate of vaccination is higher than in the third world. As the table below indicates, organisms requiring antibiotic coverage accounts for more than 50% across all ages. The importance of mixed infection needs to be further studied as there is an observational evidence of a high morbidity from 2% to 35%.

Author Year

Age [Years]

Subjects N

Known Etiology N [%]

Virusa %

Bacteriaa %

Atypical Pathogena %

Mixed Infection %

Chiang 2007 Tajima 2006 Don 2005 Tsolia 2005 Michelow 2004 MEAN

0.1-16

1702

646 [37.9%]

5.5%

10.3%

20.3%

2.0% 18.0% b

0.1-13

157

126 [80.2%]

44.0%

80.1%

25.3%

0.3-16

101

66 [65.3%]

42.0%

30.3%

53.0%

30.0%

5-14

75

58 [77.3%]

65.0%

7.0%

48.2%

35.0%

0.2-17

154

122 [79.2%]

45.0%

60.0%

33.6%

23.0%

23.6% TOTAL
a b

26.5%

26.0%

10.7%

2189

1018 [46.5%]

All cases including mixed infection 28 (17.8%) had viral bacterial infection. 1 (0.6%) had Mycoplasmal-bacterial pneumonia

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B. Establishing the etiology The Task Force on pCAP recognizes the importance of establishing the presence of a bacterial pathogen through culture studies. However, there are limitations to this approach such as invasiveness of the procedure as in lung puncture, low yield (1.2% to 26% in blood culture) [Michelow I, 2004; Tsolia MN, 2005; Tajima T, 2006], and the availability of results at a later time. There are tests that can be used to rapidly detect bacterial pathogens but which are either not readily available locally or expensive. These are immunological assays (CIE, LA and Dot-ELISA in detecting Streptococcus pneumoniae and Haemophilus influenza b antigen with sensitivity of 91.1% to 100% and specificity of 49.5% to100% in 550 paired serum, pleural fluid and urine samples) [Requejo HI, 2007]; PCR (pathogen-specific molecular beacon probes) with the following sensitivity and specificity in 389 patients: 96.2% and 93.2% for Streptococcus pneumoniae, 95.8% and 95.4% for Haemophilus influenzae, 100% and 100% for Streptococcus pyogenes, and 100% and 95.4% for Mycoplasma pneumoniae [Morozumi M, 2006]; and latex particle agglutination test [sensitivity of 77.3% (95% CI, 61.8 - to 88.0) and specificity of 90.3% (95% CI, 79.5 - 96.0) in detecting Streptococcus pneumoniae and Haemophilus influenzae type b polysaccharide antigen in urine samples of 107 patients [Nunes A, 2004].

Annotation 5B. Surrogate predictors of bacterial etiology A. Clinical prediction rule A clinical prediction rule among hospitalized children aged one month to five years has been developed to determine the presence of a bacterial pathogen. An aggregate bacterial pneumonia score [BPS] of > 4 has a sensitivity and specificity of 100% (95% CI 84.6100) and 93.9% (95% CI 87.897.5) respectively. The computed +LR and LR are > 10 and <0.1 respectively. See Appendix D for BPS [Moreno L, 2006]. A limitation of this study is the failure to include mixed causative agents and Mycoplasma infection among its subjects.

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B. Individual clinical predictors 1. Age a. A summary of four [4] epidemiologic reports on all types of organisms that stratifies the occurrence of etiologic agents as to age is shown below. Extracted data are heterogenous making it difficult to come up with a strong conclusion as to what age should antibiotic be likely started. [Michelow I, 2004 ;Don M, 2005; Tajima T 2006;Chang WC 200]. In two studies, increasing age correlates with a higher chance of the presence of bacterial agents. In all four studies, there is a trend in increasing frequency of atypical organism. Virus a [%] Bacteria a [%]

Author Year

Age [Years]

Subjects [N]

Known Etiology [N] 653

Atypical Pathogena [%] 20.3 5.0 16.5 31.0 18.0 3.5 42.8 64.2 34.6 5.7 22.8 71.4 11.0 47.0 d 53.0

Mixed Infection [%] 2.0

Chiang 2007

0.1-16 <2 2-5 >5 0.1-13 <2 2-5 >5 0.3-16 <2 2-5 >5 0.2-17 <2 2-5 >5
a b

1702

5.5 6.6 6.9 0.9 40.0 52.7 47.3 0 18.8a 31.6 57.8 10.5 19.0 55.0c 48.0c 38.0c

10.3 5.2 13.2 8.5 43.0 69.6 32.8 4.2 17.5 22.2 38.8 38.8 26.0 55.0c 68.0c 55.0c

Tajima 2006

157

126

19.0; [2.0b] 83.0 17.0 0 29.7 36.8 22.7 34.2 23.0

Don 2005

101

66

Michelow 2004

154

122

Single and mixed infection Bacterial and Mycoplasma sp c Interpolated data d Percentage data applicable to children below 5 years

21

b. There are five [5] pathogen-directed, across-all-ages studies dealing with atypical organisms [Othman N, 2005; Garcia MC, 2002-2005; Tsai MH,2005; Butun Y,2006; Bamba M, 2006]. Two studies, one of which was done in the local setting, were from developing economies. As shown below, more than half of the total number of cases with atypical organism are children below 5 years of age in three of the five studies. Age with + antibody titer for Mycoplasma sp and/or Chlamydia sp [Years] <5

Author Year

Age [Years]

Prevalence [%]

Butun 2006 Bamba 2006 Othman 2005 Garcia 2005 Tsai 2004

0.3-12

100

53.0

<4-13

141

<4 20.0

0.5-15

76

<5

36.8

1-10

142

<5

63.4

1-14

26

<5

53.8

2. Clinical symptomatology Among 254 inpatients [mean age of 3.8 years] with radiographic pneumonia and proven etiology, the presence of decreased breath sounds is the only single clinical sign noted among patients with bacterial pathogen as compared with viral infection (p<0.05) [Juven T, 2003].

C. Individual ancillary parameters predicting bacterial pathogen 1. Erythrocyte sedimentation rate [ESR] Among 132 patients aged <11 months to >5 years old, ESR of 63 mm/h has a +LR of 3.50 and a -LR of 0.84 [Korppi, 2004].

22

2. White blood cell count [WBC] a. Among 132 patients <11 months to >5 years old, WBC cut-off levels of > 13,000 x 109/L, and > 17,000 x 109/L have +LR of 1.29 and -LR of 0.73, and +LR of 1.89 and -LR of 0.80, respectively [Korppi,2004]. b. Among 862 patients with proven RSV infection aged 6 days8 years and a WBC cut-off level of > 15,000 x 109/L, the probability of a concurrent serious bacterial infection is 4.7% [Purcell K,2007]. c. Among 154 patients aged 2 months 17 years, no statistical difference exists as to the WBC levels among bacterial, viral, atypical and mixed infection (p value = 0.76) [Michelow IC, 2004].

3. C-reactive protein [CRP] a. Among 132 patients aged <11 months to >5 years old, a CRP value of > 146 mg/dl has a +LR of 1.75 and a -LR of 0.43[Korppi, 2004]. b. Among paired serum samples from 265 patients, qualitative determination of CRP has a sensitivity of 100% and specificity of 87.3% in detecting Streptococcus pneumoniae, Haemophilus influenzae b, Staphylococcus aureus and Neisseria meningitidis [Requejo H,2003].

4. Chest x-ray studies a. Among 54 patients aged 2 months to 17 years, no statistical difference exists as to the presence of lobar or segmental consolidation with or without effusion among bacterial, viral, atypical organisms and mixed infection (p value = .06) [Michelow IC, 2004].

23

CQ 6. What empiric treatment should be administered if a bacterial etiology is strongly considered? 2004 Clinical Practice Guideline Recommendation 1. For a patient classified as PCAP A or B without previous antibiotic, oral amoxicillin [40-50 mg/kg/day in 3 divided doses] is the drug of choice [Grade D]. 2. For a patient classified as PCAP C without previous antibiotic and who has completed the primary immunization against Haemophilus influenza type b, penicillin G [100,000 units/kg/day in 4 divided doses] is the drug of choice [Grade D]. If a primary immunization against Hib has not been completed, intravenous ampicillin [100 mg/kg/day in 4 divided doses] should be given [Grade D]. 3. For a patient classified as PCAP D, a specialist should be consulted [Grade D].

UPDATE HIGHLIGHTS 1 Epidemiology a. Epidemiologic trend in developed economies suggests that Streptococcus pneumoniae and Mycoplasma pneumoniae appear to be the most common pathogens causing community-acquired pneumonia across all ages. b. An important emerging pathogen is community-acquired methicillin resistant Staphylococcus aureus [CA-MRSA]. 2. Antibiotic resistance Data on 2006 Antimicrobial Resistance Surveillance Program showed resistance rate of less than 10% for penicillin and chloramphenicol with Streptococcus pneumoniae infection, and for ampicillin with Haemophilus influenzae. 3. Empiric antibiotic therapy a. For pCAP A and B [nonsevere pneumonia], there is evidence for the use of amoxicillin [45 mg/kg/day in three divided doses for a minimum duration of three days]. For those with known hypersensitivity to amoxicillin, a macrolide may be considered. The use of cotrimoxazole is discouraged because of high failure and resistance rates. b. For pCAP C [severe pneumonia], equal efficacies were noted between oral amoxicillin and parenteral penicillin among patients who can tolerate feeding; and between monotherapy and combination therapy for those who cannot tolerate feeding. Among monotherapy available for use, parenteral ampicillin is the best choice considering its cost.

24

Annotation 6A. Causes of pCAP requiring antibiotic coverage A. Predominant pathogen Among patients with known etiology, Streptococcus pneumoniae and atypical organisms generally account for majority of causes of pCAP across all ages [Chang WC, 2007; Huang HH, 2006; Tajima T, 2006; Don M, 2005; Tsolia MN, 2005; Michelow I, 2004] Author Year Age [Years] Streptococcus pneumoniaea [%] 17.4% Haemophilus Mycoplasma Chlamydia sp sp influenazae [%] [%] [%] 0.4% 28.6% 0%

Chiang 2007 Tajima 2006 Huang 2006 Don 2005 Tsolia 2005 Michelow 2004
a

0.1-16

0.1-13

35.7%

26.1%

17.4%

0%

2.0-14

8.9%

1.2%

7.1%

1.8%

0.3-16

17.8%

4.5%

26.7%

7.9%

5.0-14

7.0%

0%

35.0%

3.0%

0.2-17

73.0%

0%

14.0%

9.0%

Streptococcus pneumoniae is more common above 5 years of age[Chiang, 2007; Michelow 2004].

B. Emerging pathogen: Community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA] The epidemiology of community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA] has been recently reviewed. In one study conducted in Driscoll Childrens Hospital, Corpus Christi Texas USA, 93% of a total of 1002 MRSA were identified from 1990 through 2003 as CA-MRSA. Cases ranged from none to nine per year from 1990 through 1999 and then increased exponentially from 36 in 2000 to 459 in 2003 [Purcell K. 2005; Paintsil E,2007]. In the local setting, the Antimicrobial Resistance Surveillance Program reported a hospital rate of MRSA of 31% in 2005 and in 2006 [Carlos CC,2005; Carlos CC,2006].

25

Annotation 6B. Antibiotic resistance

A. Antibiotic resistance surveillance reports

1. Local data : Antimicrobial Resistance Surveillance Program Of 24 112, 23 749, 29 782 and 25 768 isolates for 2003, 2004, 2005 and 2006 respectively as reported by the Research Institute of Tropical Medicine, the resistance rates of hospital infection involving Streptococcus pneumoniae and Hemophilus influenzae to different antibiotics are shown below [Carlos CC,2003; Carlos CC, 2004; Carlos CC,2005; Carlos CC,2006]:

Penicillin a
2003 04 05 06

Chloramphenicol
2003 04 05 06 2003

Cotrimoxazole
04 05 06 2003

Ampicillin
04 05 06

Streptococcus Pneumoniae

9%

5%

11%

6%

3%

5%

4%

5%

9%

15%

16%

14%

No data
13%

No data

No data

No data

Haemophilus Influenzae
a

No data

No data

No data

No data

13%

10%

20%

14%

18%

36%

15%

16%

10%

10%

9%

Screening with 1 ug oxacillin disc

2. Asian data: Asian Network for Surveillance of Resistant Pathogens Of 555 isolates of Streptococcus pneumoniae from ten Asian countries (Korea, China, Hong Kong, Thailand, Taiwan, India, Sri Lanka, Singapore, Malaysia and Vietnam) as reported by the Asian Network for Surveillance of Resistant Pathogens (ANSORP), 329 (59.3%) were resistant to erythromycin [Jae-Hoon Song, 2004]. 3. Individual country data : Japan Among 2,462 clinical specimens collected between April 2002 and March 2004 from pediatric outpatients with respiratory tract infections, about 10 macrolideresistant Mycoplasma pneumoniae (MICs of >1ug/m) out of a total of 195 isolated strains have been reported. Resistance rate in this study is 1.9% [Morozumi M,2005]. . 26

Annotation 6C. Antibiotic regimen for PCAP A or B [non severe pneumonia]

A. Oral Amoxicillin

1. Comparative trial

a. In a Cochrane systematic review using failure rate as an outcome measure, the rate was higher in cotrimoxazole compared to amoxicillin (OR 1.33; 95% CI 1.05 - 1.67) [Kabra SK;2006].

b. In a Cochrane systematic review using failure rate as an outcome measure, the rate was lower in the amoxicillin group compared to chloramphenicol (OR 0.64; 95% CI 0.41 - 1.00) [Kabra SK;2006]. c. There are two [2] studies comparing amoxicillin with either azithromycin or erythromycin. Amoxicillin versus azithromycin using end-of-treatment chest x-ray and clinical parameters as outcome measures Among 47 patients aged 1 month - 14 years, using chest xray on day 7 as outcome measure showed improvement greater than 75% compared with baseline in the azithromycin group versus those who received amoxicillin [81.0% vs. 60.9%, p value = 0.09]. No difference exists between the two groups in other parameters such as fever, crackles and use of accessory muscles on day 7 and 14 of treatment [Kogan R;2003]. Amoxicillin versus erythromycin using cure rate as outcome measure Among 85 patients aged 4 months-19 years, there was no difference between amoxicillin and erythromycin as to cure rate (p value = 0.274) [Romulo AC, 2006]. d. For those with known hypersensivity to amoxicillin, a macrolide antibiotic can be considered.

27

2. Treatment regimen

a. Standard dose versus double dose using treatment failure as outcome measure Among 876 patients aged 2-59 months, the standard dose of amoxicillin at 45 mg/kg/day did not show any statistically significant difference compared with double dose amoxicillin at 90 mg/kg/day using treatment failure by day 5 (4.5% in the standard and 5.7% in the double dose, p value = 0.55), and cumulative treatment failure including relapses (5.9% in the standard and 7.9% in the double dose, p value=0.29) as outcome measures [Hazir T,2007].

b. TID dosing frequency versus BID using pharmacokinetic studies as outcome measure Among 266 patients aged 3-59 months in whom amoxicillin was given orally either at 25 mg/kg/dose BID or 15 mg/kg/dose TID, all but two children had plasma amoxicillin concentrations above 0.5 ug/ml for >50% of the dose interval [Fonseca W, 2003]. There are no studies comparing the clinical outcome of patients with pneumonia on TID regimen versus BID.

c. Three-day versus five-day duration using clinical cure rate and relapse rate as outcome measures Among 2188 patients aged 2-59 months, clinical cure rates with three days and five days treatment were 89.5% and 89.9%, respectively (absolute difference 0.4, 95% CI 2.1-3.0). There was no difference in relapse rate between the two groups after 5 days (RR = 1.22; absolute difference 1.0, 95% CI 1-3). Limitations such as the study was performed in patients with clinical suspicion of pneumonia without radiographic evidence and insufficient detailing of patients history were noted [Agarwal, 2004].

28

B. Other antibiotic options

1. Cotrimoxazole a. Comparative trial using cure rate as outcome measure There is one Cochrane systematic review dealing with antibiotic treatment of pCAP showing procaine penicillin having better cure rate compared with co-trimoxazole (OR 2.64; 95% CI 1.57 - 4.45) [Kabra SK;2006]. b. Treatment regimen using treatment failure rate as an outcome measure Among 1134 patients aged 2-59 months, treatment failure occurred in 112 (19.4%) on standard dose [4 mg trimethoprim plus 20 mg sulfamethoxazole/kg of body weight] group and in 118 (21.2%) on double-dose (RR 1.10; 95% CI 0.871.37) [Zeba A,2005].

2. Azithromycin, erythromycin and co-amoxyclavulanic acid using cure rate as an outcome measure In a Cochrane systematic review dealing with antibiotic treatment of pCAP, there was no difference between azithromycin and erythromycin (OR 1.17; 95% CI 0.70 - 1.95); or azithromycin and co-amoxyclavulanic acid (OR 1.02; 95% CI 0.54 - 1.95) [Kabra SK;2006].

3. Clarithromycin extended release using cure rate as an outcome measure Among 21 patients aged 6 to 16 years, there is no difference as to cure rate between extended release clarithromycin once a day and the standard clarithromycin twice a day (90% vs 90.1%) [Block SL,2006].

4. Antibiotics for community acquired lower respiratory tract infections (LRTI) secondary to Mycoplasma pneumoniae [Gavranich JB,2005]. A Cochrane systematic review dealing with antibiotics for community acquired lower respiratory tract infections (LRTI) failed to find any randomised controlled trial which specifically looked at the effectiveness of antibiotics for LRTI secondary to M. pneumoniae. In the subgroup of children with LRTI secondary toM. pneumoniae the intervention was a macrolide antibiotic versus a non-macrolide antibiotic, usually amoxicillin-clavulanate. This subgroup identified only 38 children with M. pneumoniae infection and there were insufficient data to analyse the efficacy of macrolide antibiotics in this group.

29

ANNOTATION 6D. PCAP C or severe pneumonia

A. Monotherapy Parenteral penicillin vs oral amoxicillin A Cochrane systematic review using failure rate as an outcome measure showed no difference between injectable penicillin and oral amoxicillin (OR 1.03; 95% CI 0.81 to 1.31) [Kabra SK;2006]. Included in this review is a study among 1702 patients aged 3-59 months who received either oral amoxicillin or parenteral penicillin. Results showed that treatment failure was 19% in either group (risk difference 0.4%, 95% CI -4.2 - 3.3) [Addo-Yobo, 2004]. Among 246 patients aged 6 months to 16 years with radiologically confirmed pneumonia, no significant difference exists between the group on oral amoxicillin versus IV benzylpenicillin using time for temperature to settle <38C for 24 continuous hours (p value = 0.001) as the outcome measure. Using another outcome measure, the median time to complete resolution of symptoms was 9 days in both groups [Atkinson M, 2007].

B. Combination therapy 1. Parenteral penicillin plus chloramphenicol versus ampicillin using cure rate and duration of hospitalization as outcome measures In a Cochrane systematic review, the cure rates (OR 0.48; 95% CI 0.15 to 1.51), and duration of hospitalization were similar in the two groups (weighted mean difference (WMD) 0.1; 95% CI -1.13 to 0.93) [Kabra SK; 2006]. 2. Parenteral penicillin plus chloramphenicol versus ceftriaxone using cure rate as outcome measure In a Cochrane systematic review using cure rate as outcome measure, the use of parenteral penicillin plus chloramphenicol was as efficacious compared with ceftriaxone alone (OR 1.36; 95% CI 0.47 to 3.93) [Kabra SK; 2006].

30

3. Parenteral penicillin plus chloramphenicol versus cefuroxime using clinical parameters as outcome measures Using clinical parameters as outcome measures among 88 patients aged 2 months-18 years, early defervescence (p value=0.006), absence of tachypnea (p value=0.024), absence of chest retractions (p value=0.001), and shorter hospital stay (p value=0.029) were noted among patients treated with penicillin G/Chloramphenicol compared with cefuroxime [Carlos GP,2006].

4. Parenteral penicillin plus gentamicin versus chloramphenicol using re-hospitalization rate, death rates and adverse events as outcome measures In a Cochrane systematic review using re-hospitalization rate before 30 days as outcome measure, the use of parenteral penicillin plus gentamycin was better than chloramphenicol alone (OR 1.61; 95% CI 1.02 to 2.55). Death rates and adverse events were similar in both groups [Kabra SK;2006].

5. Parenteral penicillin plus gentamicin versus amoxicillin/clavulanate using clinical parameters as outcome measures Using clinical parameters as outcome measures among 71 patients aged 2-59 months, the mean time taken for normalization of tachypnea, hypoxia, chest wall indrawing and inability to feed was similar for both groups receiving penicillin plus gentamicin versus amoxicillin/clavulanate (p value > 0.05) [Bansal A,2006]

6. Parenteral ampicillin plus gentamicin versus parenteral ampicillin alone using clinical parameters as outcome measures Using clinical parameters as outcome parameters among 40 patients aged 2 months to 5 years who received either combination therapy of IV ampicillin and gentamicin versus IV ampicillin alone, fever clearance time, improvement of respiratory rate, improvement of chest indrawing and resolution of rhonchi were comparable between the two groups (p value <0.05) [Hasali A 2005].

31

7. Other treatment regimens

a. Amoxicillin/sulbactam versus cefuroxime using defervescence as outcome measure Using defervesecence as an outcome measure among 62 patients aged 3 months-15 years who received either amoxicillin/sulbactam or cefuroxime, both treatment arms were comparable (97% for amoxicillin/sulbactam vs 100% for cefuroxime) [Lovera D,2005].

b. Chloramphenicol Among 250 children treated with chloramphenicol, 98% had a favorable treatment outcome [Ayap J, 2006]

C. Community-acquired MRSA For suspected cases of community-acquired MRSA, immediate referral to an appropriate specialist is necessary. The following information serves to provide basic knowledge in the therapeutic options dealing with MRSA [Strategies for Clinical Management of MRSA in the
community: Summary of an Experts meeting,2006; Shelburne S, 2004].

a. Antibiotic susceptibility based on culture studies should be followed. b. Vancomycin remains to be the first line therapy for severe infections possibly caused by MRSA. c. Community-associated MRSA were more likely to be synergistically inhibited by combinations of vancomycin and gentamicin (p value =0.025) versus vancomycin alone.

32

CQ 7. What treatment should be initially given if a viral etiology is strongly considered?

2004 Clinical Practice Guideline Recommendation

1.Ancillary treatment should only be given [Grade D]. 2.Oseltamivir [2 mg/kg/dose BID for 5 days] or amantadine [4.4-8.8 mg/kg/day for 3-5 days] may be given for influenza that is either confirmed by laboratory [Grade B] or occurring as an outbreak [Grade D].

UPDATE HIGHLIGHT Oseltamivir remains to be the drug of choice for laboratory confirmed cases of influenza.

Annotation 7A. Definite treatment

Influenza In a Cochrane systematic review, oseltamivir reduced the median duration of illness by 26% (or 36 hours) in healthy children with laboratory-confirmed influenza (p value < 0.001) [Matheson NJ,2007]. In proven influenza illness among adolescents, oseltamivir reduced the incidence of influenza-related lower respiratory tract complications resulting in antibiotic therapy by 5.5% (4.6% vs 10.3% with placebo; p value < 0.001) [Kaiser L,2003]. The computed number need to treat for oseltamivir is 20. In influenza-like illness without confirmed influenza infection, no significant difference exist between oseltamivir and placebo[Kaiser L,2003].

Annotation 7B. Ancillary treatment Please refer to CQ 11. What ancillary treatment can be given? for recommendations pertaining to ancillary treatment.

33

CQ 8. When can a patient be considered as responding to the current antibiotic? 2004 Clinical Practice Guideline Recommendation

1. Decrease in respiratory signs [particularly tachypnea] and defervescence within 72 hours after initiation of antibiotic are predictors of favorable therapeutic response [Grade D]. 2. Persistence of symptoms beyond 72 hours after initiation of antibiotics requires re-evaluation [Grade B]. 3. End of treatment chest x-ray [Grade B], WBC, ESR or CRP should not be done to assess therapeutic response to antibiotic [Grade D].

UPDATE HIGHLIGHTS 1. In children with nonsevere pneumonia, clinical index suggestive of good therapeutic response is a respiratory rate >5 breaths/min slower than baseline recording at the 72nd hour. 2. In children with severe pneumonia, clinical indices suggestive of good therapeutic response are defervescense, decrease in tachypnea and chest indrawing, increase in oxygen saturation, and ability to feed within 48 hours.

Annotation 8A. Treatment response A. Background The clinical outcome definition of improved provided by the World Health Organization in 1990 is a respiratory rate < age-specific range without lower chest indrawing or danger signs (central cyanosis, inability to drink, abnormally sleepy, and convulsions) [WHO 1990].

34

B. Response to treatment

1. Ambulatory patients Respiratory rate Among 876 patients aged 2-59 months with nonsevere pneumonia, clinical improvement on the 72nd hour is respiratory rate >5 breaths/min slower than baseline recording [Hazir T,2006].

2. Hospitalized patients Duration of fever Among 153 children aged 1 month to 16 years, 91% became afebrile within 48 hours. Children with bacteremic pneumococcal pneumonia have become afebrile within an average of 22 hours after onset of antimicrobial therapy [Juve n T, 2006]. Respiratory rate Average time of recovery from tachypnea among 71 children aged 2-59 months is 38-40 hours [Bansal A, 2006]. Oxygen saturation Average time of recovery from SpO2 (<90%) among 71 children aged 2-59 months is 32-33 hours [Bansal A,2006]. Chest indrawing Average time of recovery from chest indrawing among 71 children aged 2-59 months is 33-36 hours [Bansal A,2006]. Inability to feed Average time of recovery from inability to feed among 71 children aged 2-59 months is 33-36 hours [Bansal A,2006].

35

CQ 9. What should be done if a patient is not responding to current antibiotic therapy?

2004 Clinical Practice Guideline Recommendation

1. If an outpatient classified as either PCAP A or PCAP B is not responding to the current antibiotic within 72 hours, consider any one of the following [Grade D]: a. change the initial antibiotic; or b. start an oral macrolide; or c. reevaluate diagnosis. 2. If an inpatient classified as PCAP C is not responding to the current antibiotic within 72 hours, consider consultation with a specialist because of the following possibilities [Grade D]: a. penicillin resistant Streptococcus pneumoniae; or b. presence of complications [pulmonary or extrapulmonary]; or c. other diagnosis 3. If an inpatient classified as PCAP D is not responding to the current antibiotic within 72 hours, consider immediate re-consultation with a specialist [Grade D].

UPDATE HIGHLIGHTS 1. There are no studies dealing with therapeutic interventions following treatment failure among children having community-acquired pneumonia. 2. A definition of treatment failure for nonsevere pneumonia is as follows: a. Same status. This is defined as respiratory rate > age-specific range but + 5 breaths/min to the baseline reading and without lower chest indrawing or any danger signs; b. Worse status. This is defined as developing lower chest indrawing or with any of the danger signs. 3. The causes of treatment failure include coinfection with respiratory syncytial virus or mixed infection, non-adherence to treatment for nonsevere pneumonia, resistance to antibiotics, clinical sepsis, and progressive pneumonia. 36

Annotation 9A. Course of action in treatment failure There are no comparative trials specifically dealing with therapeutic interventions following treatment failure among children having community-acquired pneumonia.

Annotation 9B. Definition of treatment failure

A. Background The clinical outcome definitions of same and worse status provided by the World Health Organization in 1990 are as follows [WHO 1990] : Same : Respiratory rate > age-specific range without lower chest indrawing or any danger signs (central cyanosis, inability to drink, abnormally sleepy or convulsions) Worse : Developed lower chest indrawing or any of the danger signs (central cyanosis, inability to drink, abnormally sleepy, or convulsions)

B. Treatment failure 1. pCAP A and B [Nonsevere pneumonia] Among 876 patients aged 2-59 months with nonsevere pneumonia, treatment failure has been redefined on the 72nd hour after initiating antibiotic as either [a] same status : respiratory rate > age-specific range but + 5 breaths/min to the baseline reading without lower chest indrawing or danger signs (central cyanosis, inability to drink, abnormally sleepy or convulsions), or [b] worse status : developed lower chest indrawing or any of the danger signs (central cyanosis, inability to drink, abnormally sleepy or convulsions) [Hazir T,2006]. 2. pCAP C [Severe pneumonia] There are no studies in hospitalized patients.

37

Annotation 9C. Causes of failure in the treatment of bacterial pneumonia

A. Causes of treatment failure are as follows:

1. pCAP A and B [nonsevere pneumonia] Among 2188 patients aged 2-59 months, 10.3% were reported to be cases of treatment failure. Causes include an association with isolation of respiratory syncytial virus (an adjusted OR 1.95; 95% CI 1.0-3.8), and non-adherence with treatment (OR 11.57; 95% CI 7.4-18.0) [Agarwal, 2004].

2. pCAP C [severe pneumonia]

a. Among 71 patients aged 2-59 months, 2.8% were reported to be cases of treatment failure. Causes include resistance to antibiotics and worsening clinical condition [Bansal A, 2006].

b. Among 218 patients aged 3 months to 19 years, 20% were reported to be cases of treatment failure. Causes include clinical sepsis and progressive pneumonia [Victor R, 2007].

c. Among 60 patients aged 3 months to five years, 23% was reported to be treatment failure. Progressive pneumonia has been cited as the most common cause at 57%. [Prada C, 2007]

d. Among 153 patients aged 1 month to 16 years, 9% was reported to be treatment failure. Of these, 50% had evidence of mixed infection. [Juven T,2004]

38

CQ 10. When can switch therapy in bacterial pneumonia be started?

2004 Clinical Practice Guideline Recommendation

Switch from intravenous antibiotic administration to oral form 2-3 days after I nitiation of antibiotic is recommended in a patient [Grade D] who [a] is responding to the initial antibiotic therapy, [b] is able to feed with intact gastrointestinal absorption; and [c] does not have any pulmonary or extrapulmonary complications.

UPDATE HIGHLIGHTS Switch therapy from three [3] days of IV ampicillin to four [4] days of either amoxicillin or cotrimoxazole may be used among patients admitted because of community-acquired pneumonia. Amoxicillin is preferred because of high failure and resistance rates reported in the use of cotrimoxazole.

Annotation 10A. Comparative trial Using clinical cure up to day 14 as the outcome measure among 21 patients aged 3 months to 5 years, no significant statistical difference exists between that with 7 days of IV ampicillin versus 3 days IV ampicillin plus 4 days oral amoxicillin (p value > 0.05) [Ochoa-Ragaza S,2004]. Using clinical cure up to day 7 as the outcome measure among 26 patients aged 3 months to 5 years on 3 days of IV ampicillin, no significant statistical difference exists (p value = 0.6) between that with cotrimoxazole versus oral amoxicillin as step down therapy (p value > 0.05) [Marquez W,2007]. The use of cotrimoxazole however is discouraged because of high failure and resistance rates [Carlos CC,2003; Carlos CC, 2004; Carlos CC,2005; Carlos CC,200;6 Kabra SK;2006].

39

CQ 11. What ancillary treatment can be given?

2004 Clinical Practice Guideline Recommendation

1. Among inpatients, oxygen and hydration should be given if needed [Grade D]. 2. Cough preparations, chest physiotherapy, bronchial hygiene, nebulization using normal saline solution, steam inhalation, topical solution, bronchodilators and herbal medicines are not routinely given in community-acquired pneumonia
[Grade D].

3. In the presence of wheezing, a bronchodilator may be administered [Grade D].

UPDATE HIGHLIGHTS 1. There is no evidence to support the use of hydration or fluid restriction and cough preparation in the management of pneumonia. 2. The value of elemental zinc or vitamin A is inconclusive. 3. Single study demonstrated benefit for either virgin coconut oil or probiotic as adjunct therapy in pneumonia. Annotation 11A. Fluid management A. Increase fluid intake In a Cochrane systematic review among ambulatory patients with acute respiratory infection, no randomized controlled trials assessing the effect of increasing fluid intake in acute respiratory infections were found [Guppy MPB,2005]. B. Fluid restriction There are no controlled studies assessing the effect of restricting fluid intake among patients hospitalized with pneumonia. In a Cochrane systematic review among hospitalized patients, the rate of hyponatremia has been reported to be 31%-45% for nondehydrated children with moderate to severe pneumonia [Guppy MPB, 2005]. Among 50 children aged 259 months with severe, and very severe pneumonia, extracellular water [ECW] and plasma volume [PV] were moderately increased [ECW 318 (45) vs 308 (49) ml/kg, PV 53.2 (2.3) vs 52.1 (2.3) ml/kg, p,0.05]. The SpO2 showed a significant linear relationship with ECW and PV (0.46 and 0.42 respectively, p =0.05) [Singhi S, 2005].

40

Annotation 11B. Cough preparation A. In a Cochrane systematic review, one study performed exclusively in children using three different mucolytics (bromhexine, ambroxol, neltenexine) demonstrated no significant difference for the primary outcome of not cured or not improved (OR 0.40, 95% CI 0.10-1.62), and secondary outcome of no improvement (OR 0.34, 95% CI 0.09 to 1.36) [Chang CC, 2007]. B. Among ambulatory 62 children aged 3 month 19 years, there was no statistical difference in improving cough using verbal category Descriptive Scoring System between the group on ambroxol and the group without treatment (p value > 0.05) [Alquiza G,2006] C. Among hospitalized 70 children aged 3 months 19 years, there was no statistical difference in decreasing respiratory rate and intercostal retractions between salbutamol, normal saline solution and no treatment (p>0.05) [Gotos L,2004 ].

Annotation 11C. Micronutrients A. In a Cochrane systematic review, five trials involving 1453 patients younger than 15 years old with non-measles pneumonia did not demonstrate significant difference between those treated with adjunctive vitamin A and placebo as to mortality, measures of morbidity, nor an effect on the clinical course of pneumonia (pooled odds ratio OR 1.49; 95% CI 0.66 to 3.35) [Ni J,2005]. B. In a systematic review of five double-blinded, randomized, controlled intervention studies involving 2177 children aged 2-59 months children stratified according to basal serum retinol concentration (<200 and >200 ug/L), the time to remission of 3 respiratory signs was significantly lower in children with higher basal serum retinol concentrations in the vitamin A group than in their counterparts in the placebo group [69.9+49.9 h compared with 131.3+143.9 h; p value=0.049) [Brown N, 2004].

41

C. In a randomized controlled trial involving 287 children aged 259 months, with pneumonia, no overall differences were observed between the group who received vitamin A 50 000 IU (aged 212 mo) or 100 000 IU (aged 1259 mo) and those who received placebo [Rodriguez A,2005].

D. Among 187 children aged < 11 years hospitalized with 215 ALRI episodes, there was no clinical benefit of supplementation with vitamin A, elemental zinc or the two combined, compared with placebo in time to resolution of fever or tachypnea, or duration of hospitalization. Children given elemental zinc had an increased risk of readmission for ALRI within 120 days (relative risk [RR] 2.4; 95% CI 1.0036.1) [Chang AB, 2006].

E. In a randomized controlled trial of patients aged 2-35 months admitted with severe LRI, there is no difference between the groups who receive alpha-tocopherol 200 mg and ascorbic acid 100 mg twice daily or placebo for 5 days as to time taken to recover from a very ill status, fever, tachypnoea, and feeding difficulty [Mahalanabis D, 2006].

F. In a randomized trial of 299 patients aged 2-23 months, there were no clinical or statistically significant differences in the duration of tachypnea, hypoxia, chest indrawing, inability to feed, lethargy, severe illness, or hospitalization between those who received 10-mg tablets of zinc sulfate versus placebo twice a day (p value = 0.015) [Bose A, 2006].

G. In a randomized controlled trial 153 children aged 224 months who were hospitalized with severe ALRI, recovery rates from very ill status and from fever in zinc treated boys were 2.6 times (p= 0.004) and 3 times (p= 0.003) those in non-zinc-treated children; feeding difficulty and tachypnea were not significantly different between groups after an adjusted analysis. Recovery rates were not significantly different between groups on the basis of vitamin A treatment [Mahalanabis D,2004].

H. In a randomized double-blind placebo-controlled clinical trial of 270 children aged 2-23 months, the group receiving elemental zinc (20 mg per day) had reduced duration of severe pneumonia (relative hazard [RH]=0.70, 95% CI 0.51-0.98), including duration of chest indrawing (95% CI 0.80, 0.61-1.05), respiratory rate more than 50 per min (95% CI 0.74, 0.57-0.98), and hypoxia (95% CI 0.79, 0.61-1.04), and overall hospital duration (95% CI 0.75, 0.57-0.99). The mean reduction is equivalent to 1 hospital day for both severe pneumonia and time in hospital [Brooks WA,2004].

42

Annotation 11D. Chest Physiotherapy Summary of three [3] studies did not demonstrate any statistically significant difference between the group who have undergone chest physiotherapy and the control group as to time to improvement in chest xray, and the duration of the following parameters, namely fever, cough and hospital stay (p value < 0.05) [Gilchris FJ,2007].

Annotation 11E. Alternative medicine A. Virgin coconut oil In a single blinded randomized controlled trial conducted to 40 children, the group who received 2 ml/kg/day of virgin coconut oil orally taken for a maximum period of three days had a respiratory rate normalizing earlier than the control group (32.6 hrs (SD=21.73) versus 48.2 hrs (SD 17.62); p value = 0.017) [Erquiza,2007].

B. Probiotic Among 76 infants, probiotic OMX capsules had shorter duration of cough and hospital stay with mean 2.4 + 1 days compared to control mean 4.3 + 1 day (p value <0.007); resolution of tachypnea and retractions 1.5 + 0.5 days compared to control 4.3+ 1 days (p value < 0.001); and tachypnea on day 3 as outcome measure (RR 0.11; NNT 2) [Bayer-Mulsid,2006].

43

CQ 12. How can pneumonia be prevented? 2004 Clinical Practice Guideline Recommendation

1. Vaccines recommended by the Philippine Pediatric Society should be routinely administered to prevent pneumonia [Grade B]. 2. Zinc supplementation [10 mg for infants and 20 mg for children beyond two years of age given for a total of 4 to 6 months] may be administered to prevent pneumonia [Grade A]. 3. Vitamin A [Grade A], immunomodulators [Grade D] and vitamin C [Grade D] should not be routinely administered as a preventive strategy.

UPDATE HIGHLIGHTS 1. A meta-analysis on immunomodulators showed a general reduction of rates in acute respiratory tract infection through the use of immunostimulants. 2. There are evidences to suggest that handwashing using antibacterial soaps, pneumococcal and Hib vaccination, elemental zinc, and breastfeeding are effective in preventing pneumonia. 3. Single study showed that patients on gastric acid inhibitors are at an increase risk to have pneumonia

Annotation 12A. Immunomodulators In a Cochrane systematic review involving thirty-four placebo-controlled trials (3877 participants) aged less than 18 years old, the use of immunostimulants was shown to reduce rates of acute respiratory infection by 40% (Weighted Mean Difference 39.68%; 95% CI -47.27% to 32.09%). Caution should be exercised in interpreting the possible advantage of immunostimulant because the quality of trials that were included in the meta-analysis was generally poor, and a high level of statistical heterogeneity was evident [Del-Rio-Navarro,2006]. The number needed to prevent is 3.

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Annotation 12B. Handwashing Among 600 households who received handwashing promotion with either antibacterial soap [plain soap with 1.2% triclocarban] or plain soap versus 306 households as controls [without handwashing promotion], children younger than 5 years in households that received handwashing promotion and soap had a 50% lower mean incidence of pneumonia than controls ( -45% 95% CI -64% to -26% for antibacterial soap, and -50% 95%CI =65% to -34% for plain soap) [Luby SP,2005]. The number needed to prevent is 2.

Annotation 12C. Vaccine A. Pneumococcal vaccine In a Cochrane systematic review, the pooled relative risk [RR] for x-ray confirmed pneumonia with consolidation (of unspecified etiology) and clinical pneumonia with or without x-ray confirmation from two articles were 0.78 (95% CI 0.69 - 0.89) and vaccine efficacy [VE] for x-ray confirmed pneumonia of 22% (95% CI 11% - 31%) [Lucero MG, 2004]. Comparing the rates in 2004 with those in the baseline period of 1997 to 1999 among children younger than 2 years, hospitalizations due to all-cause pneumonia declined from 11.5 to 5.5 per 1000 children (52.4% decline; p<.001); and ambulatory visits due to all-cause pneumonia declined from 99.3 to 58.5 per 1000 children (41.1% decline; p<.001). Rates of hospitalizations due to pneumococcal pneumonia declined from 0.6 to 0.3 per 1000 children (57.6% decline; p<.001) and rates of ambulatory visits declined from 1.7 to 0.9 per 000 children (46.9% decline; p<.001) [Zhou F, 2007]. Among 1,555 patients aged 75105 days (median 82 days), PCV-7 (n = 819) at 3, 5 and 11 months of age. radiologic pneumonia is less in the PCV-7 group than in the control group (RR: 0.35; 95% CI: 0.220.53; p <0.0001) within 24 months [Esposito S, 2007].

B. Hib vaccine In 1293 children (431 cases, 862 controls) below 2 years, the risk for radiologic pneumonia is OR 0.69; 95% CI 0.43 to 1.09 [Sampaio AL,2004]

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Annotation 12 D. Micronutrients In a randomized controlled trial of 1665 children aged 60 days to 12 months old, 70 mg elemental zinc given orally once a week for 1 year compared with placebo led to a significantly lower incidence of pneumonia in the zinc group than in the placebo group (RR 0.83 95% CI 0.73-0.95) [Brooks WA,2005].

Annotation 12 E. Breastfeeding 15,890 infants who were exclusively breastfed had a large and statistically significant reduction in risk for hospitalization for lower respiratory tract infection (adjusted OR: 0.66; 95% CI: 0.470.92) compared with those who were not breastfed [Quigley MA, 2007].

Annotation 12F. Gastric acid inhibitors Among 186 GERD patients aged 8-16 months old on gastric acid inhibitors (10 mg/kg ranitidine per day divided twice daily or 1 mg/kg omeprazole once a day) during 4 month follow-up period, the risk to develop pneumonia is higher among those who are on gastric acid inhibitors) than controls ( OR 6.39; 95% CI: 1.3829.70) [Canani RB,2006].

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Appendix A Development Process

Task Force on pCAP. The Task Force on pCAP are as follows: Cristan Q. Cabanilla as the chair of the Task Force, Gladys L. Gillera as the secretary, and Regina M. Canonizado, Anjanette R. de Leon, Roslyn Marie K. Dychiao, Beatriz Praxedes I. Apolla Mandanas-Paz, Anna Marie S. Putulin, Emily Dolores G. Resurreccion, Ana Maria A. Reyes, Marion O. Sanchez, Rita Marie Lourdes S. Vergara and Rozaida R. Villon as members. A pediatric radiologist, Dr Gerado L. Beltran has been invited to provide insight to radiologic concerns. There are no competing interests for any member of the pCAP Task Force except as guest lecturers or reactors in a pharmaceutical industry sponsored scientific meeting dealing with therapy.

Identification and appraisal of evidence. Search strategies have included MeSH on each of the 12 clinical questions run on online database [PubMed], the Philippine Pediatric Society publication and researches from each of the six Philippine Academy of Pediatric Pulmonologists, Inc. accredited training program in pediatric pulmonology. Literature search is limited to the following: [1] articles published from January 2003 to December 2007; [2] English language; [3] 3 months to 19 years of age; [4] and immunocompetent host. Inclusion of an article was assessed by each subgroup to be adequate for appraisal.

External Review. The update has been reviewed by pediatric pulmonologists who are not involved in the development process, and subsequently approved by the PAPP Board of Directors.

Funding. PAPP has exclusively funded the formulation of this update.

Disclaimer. As the update merely serves to inform the physician of recent evidence, it is not intended to be a standard of care. Due to specific requirements imposed by individual children, the physician is advised to exercise personal clinical judgment to the best interest of the patient.

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Appendix B. Definition of terms

Absolute risk (AR) The probability that an individual will experience the specified outcome during a specified period. It lies in the range 0 to 1, or is expressed as a percentage. In contrast to common usage, the word "risk" may refer to adverse events or desirable events. Absolute risk increase (ARI) The absolute difference in risk between the experimental and control groups in a trial. It is used when the risk in the experimental group exceeds the risk in the control group, and is calculated by subtracting the AR in the control group from the AR in the experimental group. Absolute risk reduction (ARR) The absolute difference in risk between the experimental and control groups in a trial. It is used when the risk in the control group exceeds the risk in the experimental group, and is calculated by subtracting the AR in the experimental group from the AR in the control group. Baseline risk The risk of the event occurring without the active treatment. It is estimated by the baseline risk in the control group. Confidence interval (CI) The 95% confidence interval (or 95% confidence limits) would include 95% of results from studies of the same size and design in the same population. This is close but not identical to saying that the true size of the effect (never exactly known) has a 95% chance of falling within the confidence interval. If the 95% confidence interval for a relative risk (RR) or an odds ratio (OR) crosses 1, then this is taken as no evidence of an effect. Hazard ratio (HR) Broadly equivalent to relative risk (RR); useful when the risk is not constant with respect to time. It uses information collected at different times. The term is typically used in the context of survival over time. If the HR is 0.5 then the relative risk of dying in one group is half the risk of dying in the other group. Likelihood ratio The ratio of the probability that an individual with the target condition has a specified test result to the probability that an individual without the target condition has the same specified test result. Meta-analysis A statistical technique that summarises the results of several studies in a single weighted estimate, in which more weight is given to results of studies with more events and sometimes to studies of higher quality. Negative likelihood ratio (- LR) The ratio of the probability that an individual with the target condition has a negative test result to the probability that an individual without the target condition has a negative test result. This is the same as the ratio (1-sensitivity/specificity). Negative predictive value (NPV) The chance of not having a disease given a negative test result. Number needed to harm (NNH) One measure of treatment harm. It is the average number of people from a defined population you would need to treat with a specific intervention for a given period of time to cause one additional adverse outcome. NNH can be calculated as 1/ARI. Number needed to treat (NNT) One measure of treatment effectiveness. It is the average number of people who need to be treated with a specific intervention for a given period of time to prevent one additional adverse outcome or achieve one additional beneficial outcome. NNT can be calculated as 1/ARR .

48

Odds ratio (OR) One measure of treatment effectiveness. It is the odds of an event happening in the experimental group expressed as a proportion of the odds of an event happening in the control group. The closer the OR is to one, the smaller the difference in effect between the experimental intervention and the control intervention. If the OR is greater (or less) than one, then the effects of the treatment are more (or less) than those of the control treatment. Note that the effects being measured may be adverse (e.g. death or disability) or desirable (e.g. survival). When events are rare the OR is analagous to the relative risk (RR), but as event rates increase the OR and RR diverge. Positive likelihood ratio (+LR) The ratio of the probability that an individual with the target condition has a positive test result to the probability that an individual without the target condition has a positive test result. This is the same as the ratio (sensitivity/1-specificity). Positive predictive value (PPV) The chance of having a disease given a positive test result P value The probability that an observed or greater difference occurred by chance, if it is assumed that there is in fact no real difference between the effects of the interventions. If this probability is less than 1/20 (which is when the P value is less than 0.05), then the result is conventionally regarded as being "statistically significant". Relative risk (RR) The number of times more likely (RR > 1) or less likely (RR < 1) an event is to happen in one group compared with another. It is the ratio of the absolute risk (AR) for each group. It is analogous to the odds ratio (OR) when events are rare. Relative risk is the absolute risk (AR) in the intervention group divided by the AR in the control group. It is to be distinguished from odds ratio (OR) which is the ratio of events over non-events in the intervention group over the ratio of events over non-events in the control group. Relative risk increase (RRI) The proportional increase in risk between experimental and control participants in a trial. Relative risk reduction (RRR) The proportional reduction in risk between experimental and control participants in a trial. It is the complement of the relative risk (1-RR). Sensitivity The chance of having a positive test result given that you have a disease Specificity The chance of having a negative test result given that you do not have a disease Statistically significant Means that the findings of a study are unlikely to have arisen because of chance. Significance at the commonly cited 5% level (P < 0.05) means that the observed difference or greater difference would occur by chance in only 1/20 similar cases. Weighted mean difference (WMD) A measure of effect size used when outcomes are continuous (such as symptom scores) rather than dichotomous (such as death). The mean differences in outcome between the groups being studied are weighted to account for different sample sizes and differing precision between studies. The WMD is an absolute figure and so takes the units of the original outcome measure.

For more of glossary of EBM terms, please log on to http://cebm.net/toolbox.asp

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Appendix C. Risk Classification for Pneumonia-Related Mortalitya

PCAP A
Minimal risk

PCAP B
Low risk

PCAP C
Moderate risk

PCAP D
High risk

VARIABLES 1. Co-morbid illnessb 2. Compliant caregiverc 3. Ability to follow-upc 4 Presence of dehydrationd 5. Ability to feed 6. Age 7. Respiratory ratee 2-12 months 1-5 years > 5 years 8. Signs of resp failure a. Retraction b. Head bobbing c. Cyanosis d. Grunting e. Apnea f. Sensorium 9. Complications
[effusion, pneumothorax] OPDf Follow-up at end of treatment OPDf Follow-up after 3 days

None Yes Possible None Able >11 mo >50/min >40/min >30/min

Present Yes Possible Mild Able >11 mo >50/min >40/min >30/min

Present No Not possible Moderate Unable <11 mo >60/min >50/min >35/min

Present No Not possible Severe Unable < 11 mo >70/min >50/min >35/min

None None None None None Awake None

None None None None None Awake None

Intercostal / subcostal Present Present None None Irritable Present

Supraclavicular/ intercostal/subcostal Present Present Present Present Lethargic/stuporous/ comatose Present

ACTION PLAN

Admit to regular ward

Admit to a critical care unit Refer to specialist

In the presence of overlapping parameters, assume the next severe classification even with only one parameter present. Comorbid illness includes malnutrition, asthma, congenital heart disease and other clinical conditions that can directly affect respiratory function.

Nonavailability of these external factors necessitates admission even if accompanied by less severe parameters Grading of dehydration adapted from Nelsons Textbook of Pediatrics1: MILD [thirsty, normal or increased pulse rate, decreased urine output and normal physical examination]; MODERATE [tachycardia, little or no urine output, irritable/lethargic, sunken eyes and fontanel, decreased tears, dry mucus membranes, mild tenting of the skin, delayed capillary refill, cool and pale]; SEVERE [rapid and weak pulse, decreased blood pressure, no urine output, very sunken eyes and fontanel, no tears, parched mucous membranes, tenting of the skin, very delayed capillary refill, cold and mottled]

e f

World Health Organization age specific criteria for tachypnea2

Parents should be advised that if patient is rapidly deteriorating, immediate follow-up is necessary

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Appendix D. Bacterial Pneumonia Score

Predictor

Points 3

Axillary temp >39c 2 Age > 9 months 2 Absolute neutrophil count >8,000/mm3 1 Bands > 5% -3 to 7 Chest x ray Infiltrate Well-defined, lobular, segmental, subsegmental [rounded] Poorly defined, patchy Interstitial, peribronchial Single lobe Multiple lobes in one or both lungs, but well-defined infiltrates as in above Multiple sites, perihilar, poorly defined: Minimal blunting of angle Obvious fluid Equivocal Obvious Subsegmental [usually multiple sites] Lobar, involving RML or RUL Lobar, involving other lobes

2 points 1 point -1 point 1 point

Location

1 point -1 point 1 point 2 points 1 point 2 points -1 point -1 point 0 point

Fluid in pleural space

Abscess, bullae or pneumotocoele Atelectasis

Moreno L, Krishnan JA, Duran P, and Ferrero F: Development and Validation of a Clinical Prediction Rule to Distinguish Bacterial From Viral Pneumonia in Children. Pediatr Pulmonol 2006; 41:331-337

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