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Am. J. Trop. Med. Hyg., 77(5), 2007, pp. 795-801
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene

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Invasive Pneumococcal Disease Burden and Implications for Vaccine Policy in Urban Bangladesh

W. Abdullah Brooks*, Robert F. Breiman, Doli Goswami, Anowar Hossain, Khorshed Alam, Samir K. Saha, Kamrun Nahar, Dilruba Nasrin, Noor Ahmed, Shams El Arifeen, Aliya Naheed, David A. Sack, AND Stephen Luby
ICDDR,B (formerly ICDDR,B: Centre for Health and Population Research), Mohakhali, Dhaka, Bangladesh; The Bloomberg School of Public Health, Department of International Health, Johns Hopkins University, Baltimore, Maryland; Dhaka Shishu Hospital, Dhaka, Bangladesh


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We undertook active population-based surveillance in 5,000 urban households among children < 5 years old to determine invasive pneumococcal disease (IPD) incidence, serotype distribution, clinical presentation, and antimicrobial resistance, which have not been previously described in population-based studies from the region. IPD was documented by blood culture isolation. From 01 April 2004 to 31 March 2006, 5,903 blood cultures were collected from 6,167 eligible children. Streptococcus pneumoniae was isolated from 34 pneumococcal patients; IPD was clinically associated with pneumonia (24%), upper respiratory infection (62%), and febrile syndromes (14%). Overall, IPD and 13-valent serotype–related IPD incidences were 447 and 276 episodes/100,000 child-years, respectively. Peak IPD incidence occurred during the cool dry seasons. Penicillin, cotrimoxazole, chloramphenicol, and ciprofloxacin resistances were 2.9%, 82.4%, 14.7%, and 24.1%, respectively. Current conjugate vaccines should substantially reduce IPD, childhood pneumonia, and antimicrobial resistance in Bangladesh.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pneumonia is the primary cause of child mortality, causing 19% of 10.6 million deaths among children < 5 years of age or 2 million deaths per year in 2000–20031; Streptococcus pneumoniae (pneumococcus) contributes substantially to this disease burden.2 Pneumonia is also the primary cause of childhood death in Bangladesh.3,4 Published comparisons of incidence between developing and developed countries indicate that 90%5 to 95%6 of clinical pneumonia occurs in developing countries. Estimated pneumonia incidence among preschool children in Western countries6,7 is strikingly lower than in urban Bangladesh.8 In sub-Saharan Africa and North America, protein–conjugate pneumococcal vaccines showed high degrees of efficacy against pneumococcal disease burden and pneumonia.9–11 However, concerns persist that, despite high pneumonia burden in Bangladesh, current protein–conjugate vaccines offer poor coverage against disease-causing serotypes.12 There are no published incidence data from Bangladesh for invasive pneumococcal disease (IPD). We undertook this study to determine the IPD incidence, clinical presentation, serotype distribution, seasonality, and antimicrobial resistance (AMR) patterns associated with community-acquired disease.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was conducted in Kamalapur, an urban slum in southeast Dhaka, Bangladesh, that the International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B), has used as a field site since 1998. It is an impoverished area comprised of seven communities in four municipal wards with 200,000 residents in an area of 4 km2, with a median household income of US $50.72 (95% CI = 26.09, 144.93) and mean education of 4 years for men and 3 years for women. Pneumonia surveillance in Kamalapur has been described.8 Briefly, ICDDR,B has established a field clinic onsite staffed by project physicians, nurses, and health assistants. The clinic services all studies conducted onsite. Furthermore, Kamalapur is divided into seven geographical strata and 450 geographical clusters, each consisting of ~100 households. Using stratified cluster sampling, we identified ~5,000 households with children < 5 years old. All children < 5 years old residing in selected clusters were kept under active morbidity surveillance, after parents provided informed written consent. Children born or newly immigrated into the surveillance area were also enrolled. Each week, 40 field research assistants (FRAs) visited each household and, using standardized calendar questionnaires, asked about specific illness signs during the previous 7 days. FRAs also measured two major signs at each visit: respiratory rate for 1 minute using a timer and axillary temperature using a digital thermometer. If the respiratory rate was elevated per age,13 the measurement was repeated and the mean reported as the final rate. Clinical signs were divided into major (Category A) or minor (Category B) signs. Major signs included fever (axillary temperature ≥ 38°C), age-specific tachypnea using WHO criteria13 in breaths per minute (0–2 months ≥ 60/min, 2–11 months ≥ 50/min, 12–59 months ≥ 40/min), danger signs (chest indrawing, lethargy, cyanosis, inability to drink, convulsions), difficult breathing, noisy breathing, and ear pain/ discharge. Minor signs included cough, rhinorrhea, sore throat, myalgia/arthralgia, chills, headache, irritability/ decreased activity, and vomiting. Children needed one major or, if absent, two minor signs for clinic referral. Thus, the basis of FRA referrals was identification of standardized key signs and not diagnosis.

In the clinic, children were examined as follows. Nurses removed clothing from the torso to inspect for chest-indrawing and count respirations and measured every child’s vital signs (axillary temperature by digital thermometer, respiratory rate for 1 minute, pulse rate, blood pressure). Project physicians used standardized diagnoses to determine whether to collect blood cultures. They diagnosed pneumonia if a child had age-specific tachypnea13 and crepitations on auscultation (fine crackles on inspiration). If the child had pneumonia and chest-indrawing, they diagnosed severe pneumonia. If, besides chest-indrawing, other danger signs13 were present, they diagnosed very severe pneumonia. Children were diagnosed with meningitis if they had fever and nuchal rigidity or a bulging fontanelle. Children were diagnosed with otitis media if the tympanic membrane was inflamed and/or bulging (otoscopes were not equipped to perform insufflation). Children with ear discharge were diagnosed with suppurative otitis media. Children with fever, cough, and rhinorrhea were diagnosed with upper respiratory infection (URI), including those with age-specific tachypnea but no crepitations on auscultation.

All standardized diagnoses were classified as suspected IPD, and a blood culture was obtained. Spinal taps were not done in the field clinic, but in the hospital after referral. We confirmed IPD by culture. Cultures that were negative for S. pneumoniae were defined as non-IPD. Blood cultures required 3 mL of blood, which was injected into pediatric isolator bottles. Blood culture specimens were sent twice daily (within 4 hours of collection) to the Clinical Microbiology Laboratory at ICDDR,B for culture by BactAlert 3D (BioMeriux, France).

Serotyping was done at Shishu Hospital Microbiology Laboratory by the capsular swelling procedure (quellung reaction) with type-specific anti-pneumococcal omni, pool, type, or group, and factor sera (Statens Seruminstitute, Copenhagen, Denmark).14 ATCC strains 6314, 6301, and 10341 and Johns Hopkins University strains 9, 23, and 4 were used as known control strains. Non-typable S. pneumoniae strains were screened out, using omni sera, at the first step of serotyping.

Vaccine serotypes were categorized based on the following vaccine preparations: 7 valent [Wyeth]—(4, 6b, 9v, 14, 18c, 19f, and 23f); 9 valent [Wyeth]—(1, 4, 5, 6b, 9, 14, 18c, 19f, and 23f); 10 valent—[GlaxoSmithKline] (1, 4, 5, 6b, 7f, 9v, 14, 18c, 19f, and 23f); 13 valent—[Wyeth] (1, 3, 4, 5, 6a, 6b, 7f, 9v, 14, 18c, 19a, 19f, and 23f).

Drug susceptibility testing was done by screening S. pneumoniae strains for resistance to oxacillin, cotrimoxazole, chloramphenicol, erythromycin, ampicillin, and ceftriaxone by disk diffusion method.15 Resistant and intermediate strains, based on Clinical and Laboratory Standards Institute guidelines, were subjected to an E-test (AB Biodisk, Solna, Sweden) for determination of minimum inhibitory concentration (MIC). E-tests were performed on Muller-Hinton agar (Oxoid, UK) supplemented with 5% defibrinated sheep blood. Inocula were prepared in Mueller-Hinton broth by direct suspension of pneumococcal colonies grown overnight on sheep blood agar to a density that matched a 0.5 McFar-land opacity standard tube.16 Results were interpreted as susceptible, intermediate, or resistant according to National Committee for Clinical Laboratory Standards–defined break points. Only the penicillin-resistant strains were tested for susceptibility to ampicillin and cephalosporins.15

Children diagnosed with pneumonia (any severity) or otitis media were placed on antibiotics. Those with very severe pneumonia, meningitis, or suspected sepsis were referred to the hospital after an initial antibiotic dose in the field. Outpatient pneumonia was treated with amoxicillin 50 mg/kg ÷ 12 hourly (twice daily) as first-line therapy. If children failed to improve after 72 hours, they were placed on Augmentin (amoxicillin clavulanate) at 50 mg/kg ÷ 12 hourly (twice daily) as second-line therapy. Children failing both first- and second-line antibiotics (after 72 hours) or who were neonates (defined for this study as < 2 months) were referred to hospital and treated with parenteral ampicillin and gentamicin (neonates) or ceftriaxone. Children with URI were provided supportive care and daily home observation.

FRAs followed all suspected IPD patients daily at home until illness resolved. End of illness was defined by a consecutive 7-day disease-free interval, requiring the absence of elevated respiratory rate, danger signs, and fever throughout the interval. Project staff visited hospitalized children daily and continued home follow-up as described above after discharge.

After 7 disease-free days, FRAs referred children to clinic for an exit interview with the physician to document illness resolution, clinical course, and final disposition. Thus, project physicians determined all clinical assessments and outcomes.

The surveillance sample size was based on an expected rate of 0.5 episodes of clinical pneumonia per year among a cohort of 4,400 children under surveillance or 2,200 episodes/yr. Pneumonia was chosen, because it was felt to be an identifiable surrogate for IPD. We predicted a 5.0% isolation rate.17 If pneumococcus caused 10% of pneumonia and had a 5.0% isolation rate, we would need 200 cases of pneumonia to find one isolate.

Statistical analysis was performed using StataSE Release 9.2.18 A child’s observation period began at consent and continued until the child matriculated from the age group or left the cluster. Incidence was calculated as the number of isolates over the person-years of observation. Seasonality was plotted as mean incidence per month.

The Research Review and Ethical Review Committees of ICDDR,B approved the study.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between 01 April 2004 and 31 March 2006, 6,167 children met our criteria for suspected IPD and were blood culture eligible. Of these, 5,949 submitted blood cultures; however, 3 were not tested because of insufficient volume. Thus, 5,946 blood cultures were successfully obtained (96.4%).

There were 315 bacterial isolates from blood during the period for an isolation rate of 5.3%. Of these, 34 (10.9%) were S. pneumoniae. Other isolations included 144 Salmonella typhi (45.7%), 24 Moraxella catarrhalis (7.6%), and 13 Salmonella paratyphi (4.3%). Haemophilus influenzae was not isolated during the study period. The contamination rate, defined as Staphylococcus epidermidis (21), bacillus spp. (27), and coagulase-negative staphylococci (50), was 1.6% and comparable to published outpatient rates.19 There were no CSF isolates of eight CSF specimens cultured. No additional organisms were identified from specimens from which pneumococci were isolated. One child had more than one pneumococcal infection; the first at 14.7 months on 06 January 2005 (serotype 4) and the second at 17.7 months on 05 April 2005 (serotype 18F). Both final diagnoses were febrile bacteremia.

The mean age of children with culture-confirmed IPD was 14.8 ± 9.5 (SD) months compared with 24.4 ± 15.1 months for non-IPD patients (P < 0.001). There were 14 male (41.2%) and 20 female (58.8%) IPD cases compared with 3,041 men (51.4%) and 2,871 women (48.6%) in the non-IPD group, making IPD patients less likely to be male, although not statistically significant (OR = 0.66, 95% CI = 0.31, 1.38). Of the 5,946 blood cultured patients, 1,871 (31.5%) admitted prior medicine exposure, including 407 (6.8%) with prior antibiotic exposure. Of 34 patients with pneumococcal blood isolation, 13 (38.2%) admitted exposure to medications. These were as follows: antibiotics, one (2.9%); antihistamine, two (5.9%); homeopathic remedy, one (2.9%); paracetamol, nine (26.5%).

There were 7,600 observation years for the surveillance period. There were 3,840 clinical pneumonia cases, of which 315 (8.2%) were severe and 65 (1.7%) very severe pneumonia. The overall pneumonia incidence for the period was 50,526 episodes/100,000 child-years (0.51 episodes/child-year). There were eight confirmed meningitis cases during the period for a meningitis incidence of 105 episodes/100,000 child-years.

Ninety-six (2.6%) of all pneumonias had bacteria isolated from blood (excluding contaminants). Bacteremia incidence was 4,118 episodes/100,000 child-years. Adjusting for only focal bacteremias, incidence was 113/7,600 x 100,000 = 1,486 episodes/100,000 child-years.

Overall IPD incidence was 447 episodes/100,000 child-years; vaccine type-specific incidences were 263 episodes/ 100,000 child-years (10-valent) and 276 episodes/100,000 (13-valent). Table 1Go summarizes the vaccine serotype-specific incidence.


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TABLE 1
Total and vaccine-related serotype distribution and incidence
 
IPD incidence ranged from 0 in August–September to 1,150 episodes/100,000 child-years in February (Figure 1Go); it peaked during the drier, cooler months and reached a nadir during the monsoon season.


Figure 1
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  		    FIGURE 1. Seasonality invasive pneumococcal diesase and pneumonia incidence: Kamalapur April 2004 to March 2006.

 
Among children with pneumococcal bacteremia, there was a 2-fold increase in the diagnosis of pneumonia between preliminary and final diagnosis (Table 2Go). Of patients with final pneumonia diagnoses, one was initially diagnosed as fever without localizing signs, two as URI, and one as bronchiolitis. Of eight pneumonia cases, four were severe or very severe. Four of five "other" final diagnoses were febrile bacteremia, and the fifth was otitis media; another was respiratory tract disease. Thus, 29/34 IPD cases (85.3%) had respiratory tract infections.


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TABLE 2
Distribution of preliminary and final diagnoses among children with pneumococcal blood isolates
 
To compare these findings with other published reports, outcomes were recategorized using WHO/IMCI criteria.13 Using respiratory rate cut-offs and history of cough without auscultation findings, 17 (81.0%) of the URI cases and 2 (40.0%) of the "other" cases were recategorized as pneumonia, increasing the pneumonia fraction to 27 (79.4%) of all IPDs. However, for the remainder of this analysis, the term "pneumonia" will be applied to the more restrictive clinical definition, unless specified otherwise.

Table 2Go shows the relationship between diagnoses and serotype distribution. Table 3Go summarizes the same findings using the IMCI definitions. No meningitis cases had pneumococci isolated from their blood or CSF. There were no deaths, although five patients recovered with disability (recurrent wheezing/night-time cough).


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TABLE 3
Distribution of IMCI diagnoses among children with pneumococcal blood isolates
 
Antimicrobial resistance revealed only modest intermediate penicillin resistance (Figure 2Go), because of serotype 14 isolated from an 11.6-month-old girl with febrile bacteremia. Cotrimoxazole resistance was high, involving many vaccine serotypes (1, 4, 5, 6A, 9V, 18C, 19F, and 23F) and seven of eight (including all severe/very severe) pneumonia cases. Chloramphenicol resistance was low. Fluoroquinolone resistance was present, involving vaccine serotypes 1, 14, and 9V. One fluoroquinolone-resistant isolate was also resistant to cotrimoxazole and chloramphenicol.


Figure 2
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  		    FIGURE 2. Streptocococcus pneumoniae antimicrobial resistance pattern: Kamalapur April 2004 to March 2006. AMR pattern for all S. pneumoniae isolates.

 

DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study reported high rates of both bacteremia and invasive pneumococcal disease in a pediatric population with high pneumonia incidence. A distinguishing feature of this study is that its findings are based on active community- and population-based surveillance. Another important feature is that it successfully obtained blood cultures from > 96% of suspected IPD cases. The results therefore represent a comprehensive population-based burden assessment. This likely explains the broader clinical syndrome distribution and total burden estimate than would have been possible with hospital surveillance.

This study underscores how surveillance methodology affects clinical syndrome distribution estimates. First, using a standardized but strict set of clinical criteria, 24% of the IPD cases were categorized as pneumonia and 62% as URI. The proportion of pneumonia is comparable or greater than that from recent studies of similar age groups.9,20–23 Using standard WHO definitions,24 nearly 80% of IPD cases in this study were classified as pneumonia, and 29% were classified as severe or very severe pneumonia. The rationale for using the sensu stricto pneumonia definition is that fast-breathing with or without chest indrawing may represent non-pneumonia illness,25 whereas ascertainment of fluid in the lungs (as identified by crepitations during auscultation) may reflect vaccine-preventable pneumonia that will present to a health facility. The more generous definition may overestimate potential vaccine pneumonia impact and underestimate empirical efficacy against clinical pneumonia through misclassification.

Second, as shown by the different definitions of pneumonia and URI, disease severity is subject to interpretation, which influences health-seeking behavior,26 including hospitalization. Many of these cases of pneumonia and URI would not have presented to hospitals. Active surveillance resulted in early case detection, in which most IPD cases with respiratory disease (including those with tachypnea) had no documented fluid in the lungs. Four URI patients subsequently progressed to clinical pneumonia. Whether this indicates that the bacteremic phase of IPD is largely pre-pneumonic is uncertain. It does indicate that surveillance of only more severe infections would underestimate IPD. This is consistent with a study in Kenya that obtained blood cultures from 10% of children presenting to an outpatient clinic.21 Clinically significant bacteremia was twice as high and pneumococcal bacteremia four times as high as estimated from hospital surveillance of more severe cases.

These additional cases identified through active surveillance are important, not only because they expand burden estimates, but because these cases are exposed to outpatient antimicrobial agents. This broader base of antibiotic use is also associated with antimicrobial resistance10,27–29 and should be factored into a decision to introduce vaccine.

This study showed total and vaccine serotype-specific invasive pneumococcal disease incidence nearly identical to that in the Gambian vaccine trial9 and comparable to total and non-occult bacteremia incidences in Kenya.21

Our serotype distribution data differ notably from previous IPD reports in Bangladesh, which indicated poor vaccine coverage. Earlier reported studies were either clinic-30 or hospital-based,12,14,31 and only one included pneumonia patients.14 Thus, blood isolate data for respiratory diseases were under-represented. In contrast, 85% of the Kamalapur isolates (97% using IMCI criteria) were associated with respiratory tract infections. The difference in syndromic distribution and sample collection practices between the hospital and population-based studies likely explains the difference in serotype distribution32 and vaccine coverage estimates.

IPD burden in this study is likely underestimated. Blood cultures are insensitive. In the Gambian study, which reported identical IPD rates to ours by blood culture, the 9-valent pneumococcal conjugate vaccine reduced radiographic pneumonia by 37% and radiographic severe pneumonia by 35% (per protocol analysis),9 showing that the preventable pneumococcal disease burden is likely orders of magnitude greater than what is microbiologically detectable. Hib vaccine studies also show blood culture is insensitive,33–35 resulting in substantial disease burden underestimation.36 Although a vaccine probe study might better establish disease burden, factors related to pneumococcal disease incidence, such as serotype replacement, would require additional observation and cautious interpretation,37 which would be facilitated by ongoing surveillance.

The absence of meningitis isolates may be caused by several factors. First, lumbar punctures are all referred to hospitals. A blood culture is drawn, and following IMCI guidelines, children are given an antibiotic dose and referred.13 This prior antibiotic exposure may compromise the CSF culture.38 Second, of 18 children referred to hospitals for suspected meningitis, only 8 (44%) had CSF collected. Local physicians are commonly reluctant to perform lumbar punctures on ill children and frequently diagnose them as sepsis, thus under-diagnosing childhood meningitis. Another factor is that isolation is related to the type of CSF specimen. Among hospitalized children < 5 years of age with meningitis, one study reported pneumococci associated from 94 of 412 pyogenic CSF samples (22.8%).14 It is not known what proportion of the cases from Kamalapur had pyogenic CSF, but if even one in five had it, we would have required at least 22 meningitis cases to have 90% power to detect a single pneumococcal isolate. Active surveillance, with early case detection and intervention, may halt progression to meningitis in some cases. Finally, meningitis may simply be relatively uncommon in IPD for this population.

The ratio of pneumococcal pneumonia to meningitis has implications for vaccine impact on IPD: the larger the proportion of pneumonia, the larger the impact on IPD. Given the Bangladesh population of 140 million, if 11.5% are children < 5 years of age, if the mean national childhood pneumonia incidence is one half of the Kamalapur rate (i.e., 0.26 episodes/child/yr), and if vaccine efficacy of any valence is at least 25% against pneumonia, it should prevent > 1 million cases of pediatric pneumonia per year in Bangladesh. Data from regions with similar burden suggest that this is a reasonable effect size estimate.9,10 Furthermore, the Gambian study reported a vaccine-related 16% reduction in all-cause mortality, despite only a 6% reduction in clinical pneumonia (intention-to-treat analysis), indicating that pneumonia and community-acquired bacteremia may contribute more to childhood mortality than previously recognized from direct assessments,9 a finding that our data support, and suggesting a potentially substantial impact on overall childhood mortality in this population.

Antimicrobial resistance data indicate low penicillin resistance, similar to hospital findings,12,14,31 that is seen only in vaccine serotype (14), an association previously reported from Bangladesh12,31 and elsewhere.39–44 Of note, fluoroquinolone resistance has risen from 3.9% and 0% high and intermediate resistance, respectively, in early 2005 to 6.9% and 17.2%, respectively, in 2006, and should be monitored. A possible explanation is that ciprofloxacin, which is manufactured locally, is often provided to young children for febrile and respiratory illnesses. The introduction of an efficacious pneumococcal vaccine should lower the overall prevalence of antimicrobial-resistant IPD.10,45

Limitations to this study include reliance on blood isolation and lack of access to non-pretreated CSF specimens, both of which combine to underestimate burden; limited 2-year duration of data collection, which may have missed important serotype distribution and AMR trends; and the number of culture-confirmed cases, potentially limiting the power to detect serotype and syndrome-specific trends.

IPD in urban Bangladesh seems to be primarily associated with respiratory illnesses and contributes to the pneumonia disease burden in the community. The high IPD rates indicate that introduction of a protein conjugate pneumococcal vaccine would substantially reduce both childhood illness and related antimicrobial resistance.

Received January 21, 2007. Accepted for publication July 19, 2007.

Acknowledgments: The authors are grateful for the support of the PneumoADIP Project at the Bloomberg School of Public Health at Johns Hopkins University, and in particular, the advice and feedback from Maria Deloria Knoll, Farzana Muhib, and Jennifer Moisi from PneumoADIP on our surveillance and data collection methodology, Marie Diener-West in the Biostatistics Department of the Bloomberg School of Public Health, Johns Hopkins University, Amanatullah Khan and team for assistance with GIS mapping, and the assistance of Anjali Bilkis Ara and team for outstanding assistance with data management.

Disclaimer: This publication was supported by a subcontract from The Johns Hopkins University with funds provided by The Boards of the Global Alliance for Vaccines and Immunizations and the Vaccine Fund (GAVI) ("Agency"). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Agency. GAVI had no role in the data analysis, interpretation, or decision to publish.

* Address correspondence to W. Abdullah Brooks, GPO Box 128 Mohakhali, Centre for Health & Pop Research, ICDDR, B, Mohakhali, Dhaka 1000. E-mail: abrooks{at}icddrb.org or abrooks{at}jhsph.edu Back

Authors’ addresses: W. Abdullah Brooks, Robert Breiman, Doli Goswami, Anowar Hossain, Khorshed Alam, Kamrun Nahar, Dilruba Nasrin, Noor Ahmed, Shams El Arifeen, Aliya Naheed, David Sack, and Stephen Luby, ICDDR,B, 68 Shaheed Tajuddin Ahmed Sharani, Mohakhali, Dhaka 1212, Bangladesh. E-mails: abrooks{at}icddrb.org, abrooks{at}jhsph.edu. Samir K. Saha, Dhaka Shishu Hospital, Dhaka, Bangladesh.


REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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