Urinary arsenic is associated with wasting and underweight status in young children in rural Bangladesh.

BACKGROUND: Deficits in child growth are associated with poor cognitive outcomes and an increased risk for infection and mortality globally. One hundred forty million people are chronically exposed to arsenic from contaminated drinking water worldwide. While arsenic exposure has been associated with cognitive developmental delays in children, there is limited research on the association between arsenic exposure and growth deficits in young children. PURPOSE: The objective of this study was to assess the association between chronic arsenic exposure and deficits in growth among children under 5 years in a rural setting in Bangladesh. METHODS: Urinary arsenic measurements were collected from 465 children between the ages of 28 days-59 months in rural Matlab, Bangladesh, and analyzed by graphite furnace atomic absorption. Height and weight measurements were collected from children according to World Health Organization child growth standards. A z-score cutoff2 standard deviations below the mean was used to define stunting (height-for-age z-score), underweight (weight-for-age z-score), and wasting (weight-for-height z-score). RESULTS: Children under 5 years with urinary arsenic concentrations in the third tertile (greater than 31 µg per liter (µg/L)) had a two times higher odds of being underweight after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (Odds Ratio (OR): 2.29 (95% Confidence Interval (CI): 1.16, 4.52)). Children under 2 years of age had a two times higher odds of being wasted after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (OR: 2.85 (95% CI: 1.18, 6.89)). CONCLUSIONS: These findings suggest that arsenic exposure is associated with an increased odds of being wasted and underweight among young children in rural Bangladesh.

The Predictive Performance of a Pneumonia Severity Score in Human Immunodeficiency Virus-negative Children Presenting to Hospital in 7 Low- and Middle-income Countries.

BACKGROUND: In 2015, pneumonia remained the leading cause of mortality in children aged 1-59 months. METHODS: Data from 1802 human immunodeficiency virus (HIV)-negative children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic. RESULTS: Predictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs). CONCLUSIONS: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.

Mild Respiratory Illness Among Young Children Caused by Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in Dhaka, Bangladesh, 2011.

Background: In March 2011, a multidisciplinary team investigated 2 human cases of highly pathogenic avian influenza A(H5N1) virus infection, detected through population-based active surveillance for influenza in Bangladesh, to assess transmission and contain further spread. Methods: We collected clinical and exposure history of the case patients and monitored persons coming within 1 m of a case patient during their infectious period. Nasopharyngeal wash specimens from case patients and contacts were tested with real-time reverse-transcription polymerase chain reaction, and virus culture and isolates were characterized. Serum samples were tested with microneutralization and hemagglutination inhibition assays. We tested poultry, wild bird, and environmental samples from case patient households and surrounding areas for influenza viruses. Results: Two previously healthy case patients, aged 13 and 31 months, had influenzalike illness and fully recovered. They had contact with poultry 7 and 10 days before illness onset, respectively. None of their 57 contacts were subsequently ill. Clade 2.2.2.1 highly pathogenic avian influenza H5N1 viruses were isolated from the case patients and from chicken fecal samples collected at the live bird markets near the patients' dwellings. Conclusion: Identification of H5N1 cases through population-based surveillance suggests possible additional undetected cases throughout Bangladesh and highlights the importance of surveillance for mild respiratory illness among populations frequently exposed to infected poultry.

Influenza Among Young Children in Bangladesh: Clinical Characteristics and Outcomes From a Randomized Clinical Trial.

BACKGROUND: Influenza causes substantial morbidity in children worldwide, although influenza vaccine is seldom used in low-resource settings. More information on the clinical presentation of influenza and the efficacy of vaccine is needed to inform policy. METHODS: In 2013 we conducted a randomized, placebo-controlled clinical trial of live attenuated influenza vaccine (LAIV) in children aged 24-59 months in Bangladesh (N = 1761). If participants met prespecified specimen collection criteria, we collected nasopharyngeal washes for testing by singleplex reverse-transcription polymerase chain reaction (RT-PCR) for laboratory-confirmed influenza virus infection (LCI). A panel of RT-PCR assays was used to detect noninfluenza respiratory viruses. Primary efficacy results have been reported. In this analysis of prespecified and post hoc objectives from the trial, we compared signs and symptoms between LCI and non-LCI cases and estimated the efficacy of LAIV against moderate-to-severe LCI and other prespecified non-LCI clinical outcomes including all-cause pneumonia and acute otitis media. RESULTS: The most common signs and symptoms of LCI were fever, cough, and runny nose. The combination of subjective fever and cough had a 63% sensitivity for LCI. The combination of measured fever, cough, and runny nose was most specific (90%) but had low sensitivity (32%) for LCI. The efficacy of LAIV against vaccine-strain moderate-to-severe LCI was 56.7% (95% confidence interval, 9.5%-79.2%). No statistically significant vaccine efficacy was found against the non-laboratory-confirmed clinical outcomes. CONCLUSIONS: It was not possible to distinguish LCI from noninfluenza viral infections on clinical evaluations alone in this population of Bangladeshi children. LAIV was efficacious against moderate-to-severe LCI. CLINICAL TRIALS REGISTRATION: NCT01797029.

Data Management and Data Quality in PERCH, a Large International Case-Control Study of Severe Childhood Pneumonia.

The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed comprehensive quality indicator, data query, and monitoring reports. Among the approximately 9000 cases and controls, analyzable laboratory results were available for ≥96% of core specimens collected. Selected approaches to data management in PERCH may be extended to the planning and organization of international studies of similar scope and complexity.

Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites.

BACKGROUND.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. RESULTS.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. CONCLUSIONS.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Density of Upper Respiratory Colonization With Streptococcus pneumoniae and Its Role in the Diagnosis of Pneumococcal Pneumonia Among Children Aged <5 Years in the PERCH Study.

BACKGROUND.: Previous studies suggested an association between upper airway pneumococcal colonization density and pneumococcal pneumonia, but data in children are limited. Using data from the Pneumonia Etiology Research for Child Health (PERCH) study, we assessed this potential association. METHODS.: PERCH is a case-control study in 7 countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. Cases were children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia. Controls were randomly selected from the community. Microbiologically confirmed pneumococcal pneumonia (MCPP) was confirmed by detection of pneumococcus in a relevant normally sterile body fluid. Colonization density was calculated with quantitative polymerase chain reaction analysis of nasopharyngeal/oropharyngeal specimens. RESULTS.: Median colonization density among 56 cases with MCPP (MCPP cases; 17.28 × 106 copies/mL) exceeded that of cases without MCPP (non-MCPP cases; 0.75 × 106) and controls (0.60 × 106) (each P < .001). The optimal density for discriminating MCPP cases from controls using the Youden index was >6.9 log10 copies/mL; overall, the sensitivity was 64% and the specificity 92%, with variable performance by site. The threshold was lower (≥4.4 log10 copies/mL) when MCPP cases were distinguished from controls who received antibiotics before specimen collection. Among the 4035 non-MCPP cases, 500 (12%) had pneumococcal colonization density >6.9 log10 copies/mL; above this cutoff was associated with alveolar consolidation at chest radiography, very severe pneumonia, oxygen saturation <92%, C-reactive protein ≥40 mg/L, and lack of antibiotic pretreatment (all P< .001). CONCLUSIONS.: Pneumococcal colonization density >6.9 log10 copies/mL was strongly associated with MCPP and could be used to improve estimates of pneumococcal pneumonia prevalence in childhood pneumonia studies. Our findings do not support its use for individual diagnosis in a clinical setting.

Is Higher Viral Load in the Upper Respiratory Tract Associated With Severe Pneumonia? Findings From the PERCH Study.

BACKGROUND.: The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of causality of pneumonia, we compared viral load in the URT of children with World Health Organization-defined severe and very severe pneumonia and age-matched community controls. METHODS.: In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine optimal discriminatory viral load cutoffs. Viral load density distributions were plotted. RESULTS.: The mean viral load was higher in cases than controls for 7 viruses. However, there was substantial overlap in viral load distribution of cases and controls for all viruses. ROC curves to determine the optimal viral load cutoff produced an area under the curve of <0.80 for all viruses, suggesting poor to fair discrimination between cases and controls. Fatal and very severe pneumonia cases did not have higher viral load than less severe cases for most viruses. CONCLUSIONS.: Although we found higher viral loads among pneumonia cases than controls for some viruses, the utility in using viral load of URT specimens to define viral pneumonia was equivocal. Our analysis was limited by lack of a gold standard for viral pneumonia.

Pertussis-Associated Pneumonia in Infants and Children From Low- and Middle-Income Countries Participating in the PERCH Study.

BACKGROUND: Few data exist describing pertussis epidemiology among infants and children in low- and middle-income countries to guide preventive strategies. METHODS: Children 1-59 months of age hospitalized with World Health Organization-defined severe or very severe pneumonia in 7 African and Asian countries and similarly aged community controls were enrolled in the Pneumonia Etiology Research for Child Health study. They underwent a standardized clinical evaluation and provided nasopharyngeal and oropharyngeal swabs and induced sputum (cases only) for Bordetella pertussis polymerase chain reaction. Risk factors and pertussis-associated clinical findings were identified. RESULTS: Bordetella pertussis was detected in 53 of 4200 (1.3%) cases and 11 of 5196 (0.2%) controls. In the age stratum 1-5 months, 40 (2.3% of 1721) cases were positive, all from African sites, as were 8 (0.5% of 1617) controls. Pertussis-positive African cases 1-5 months old, compared to controls, were more often human immunodeficiency virus (HIV) uninfected-exposed (adjusted odds ratio [aOR], 2.2), unvaccinated (aOR, 3.7), underweight (aOR, 6.3), and too young to be immunized (aOR, 16.1) (all P ≤ .05). Compared with pertussis-negative African cases in this age group, pertussis-positive cases were younger, more likely to vomit (aOR, 2.6), to cough ≥14 days (aOR, 6.3), to have leukocyte counts >20 000 cells/µL (aOR, 4.6), and to have lymphocyte counts >10 000 cells/µL (aOR, 7.2) (all P ≤ .05). The case fatality ratio of pertussis-infected pneumonia cases 1-5 months of age was 12.5% (95% confidence interval, 4.2%-26.8%; 5/40); pertussis was identified in 3.7% of 137 in-hospital deaths among African cases in this age group. CONCLUSIONS: In the postneonatal period, pertussis causes a small fraction of hospitalized pneumonia cases and deaths; however, case fatality is substantial. The propensity to infect unvaccinated infants and those at risk for insufficient immunity (too young to be vaccinated, premature, HIV-infected/exposed) suggests that the role for maternal vaccination should be considered along with efforts to reduce exposure to risk factors and to optimize childhood pertussis vaccination coverage.

Household-level risk factors for influenza among young children in Dhaka, Bangladesh: a case-control study.

OBJECTIVES: To identify household-level factors associated with influenza among young children in a crowded community in Dhaka, Bangladesh. METHODS: We conducted a case-control study using existing active surveillance for respiratory illness. Cases were children aged 12-59 months with laboratory-confirmed influenza. Controls were children frequency-matched by age group with no respiratory illness in the prior 6 months. We interviewed caregivers and observed household handwashing behaviour. Soap consumption was estimated by summing weight differences of three bars of soap sequentially left in each household. We measured concentrations of airborne particulate matter <2.5 µg in diameter (PM2.5) in a subset of households. We used logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI). RESULTS: We enrolled 145 cases and 341 controls between March 2009 and April 2010. Case and control household members were observed to wash hands with similar frequency during a 5-h period (mean, 0.64 events vs. 0.63, P = 0.87), and similar daily soap consumption per capita (mean 2.92 grams vs. 2.93, P = 0.92). Case households were more likely than controls to have crowded (≥4 persons) sleeping areas (aOR = 1.67, CI: 1.06-2.63) and cross-ventilated cooking spaces (aOR = 1.75, CI: 1.16-2.63). Case and control households had similar median 24-h geometric mean PM2.5 concentrations in the cooking (69.2 vs. 69.6 µg/m(3), P = 0.45) and sleeping (65.4 vs. 67.4 µg/m(3), P = 0.19) spaces. CONCLUSIONS: Handwashing with soap was practiced infrequently and was not associated with paediatric influenza in this community. Interventions aimed at crowded households may reduce influenza incidence in young children.

Arsenic exposure is associated with pediatric pneumonia in rural Bangladesh: a case control study.

BACKGROUND: Pneumonia is the leading cause of death for children under 5 years of age globally, making research on modifiable risk factors for childhood pneumonia important for reducing this disease burden. Millions of children globally are exposed to elevated levels of arsenic in drinking water. However, there is limited data on the association between arsenic exposure and respiratory infections, particularly among pediatric populations. METHODS: This case control study of 153 pneumonia cases and 296 controls 28 days to 59 months of age in rural Bangladesh is the first to assess whether arsenic exposure is a risk factor for pneumonia in a pediatric population. Cases had physician diagnosed World Health Organization defined severe or very severe pneumonia. Urine collected during hospitalization (hospital admission time point) and 30 days later (convalescent time point) from cases and a single specimen from community controls was tested for urinary arsenic by graphite furnace atomic absorption. RESULTS: The odds for pneumonia was nearly double for children with urinary arsenic concentrations higher than the first quartile (≥6 µg/L) at the hospital admission time point (Odd Ratio (OR):1.88 (95% Confidence Interval (CI): 1.01, 3.53)), after adjustment for urinary creatinine, weight for height, breastfeeding, paternal education, age, and number of people in the household. This was consistent with findings at the convalescent time point where the adjusted OR for children with urinary arsenic concentrations greater than the first quartile (≥6 µg/L) was 2.32 (95% CI: 1.33, 4.02). CONCLUSION: We observed a nearly two times higher odds of pneumonia for children with creatinine adjusted urinary arsenic concentrations greater than the first quartile (≥6 µg/L) at the hospital admission time point. This novel finding suggests that low to moderate arsenic exposure may be a risk factor for pneumonia in children under 5 years of age.

Early detection of pandemic (H1N1) 2009, Bangladesh.

To explore Bangladesh's ability to detect novel influenza, we examined a series of laboratory-confirmed pandemic (H1N1) 2009 cases. During June-July 2009, event-based surveillance identified 30 case-patients (57% travelers); starting July 29, sentinel sites identified 252 case-patients (1% travelers). Surveillance facilitated response weeks before the spread of pandemic (H1N1) 2009 infection to the general population.

Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis.

BACKGROUND: The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. METHODS: We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. FINDINGS: We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49-162 million) new cases of influenza (data from nine studies), 20 million (13-32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1-2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28,000-111,500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. INTERPRETATION: Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. FUNDING: WHO; Bill & Melinda Gates Foundation.

Pre COVID-19 molecular epidemiology of respiratory syncytial virus (RSV) among children in Bangladesh.

Epidemiological data of specific respiratory pathogens from the pre-COVID-19 period are essential to determine the effects of the COVID-19 pandemic on other respiratory infections. In this study, we revealed the pre-COVID-19 molecular epidemiology of respiratory syncytial virus (RSV) among children in Bangladesh. We tested 3170 samples collected from 2008 to 2012 for a panel of respiratory viruses; RSV, human metapneumovirus (hMPV), human parainfluenza viruses (hPIV) 1, 2, 3, and adenovirus. Five hundred fifty-five samples (17.5 %) were positive for RSV, including 2.5% having co-infections with other viruses. Genotypic characterization of RSV showed that RSV-A (82%) contributed more acute respiratory infections than RSV-B (18%). Clinical features were similar with RSV-A and RSV-B infections. However, children with RSV-B were more likely to have upper respiratory infections (URI) (10% vs. 29%, p = 0.03). Among RSV-A cases, hospitalization was higher for ON1 cases (25%, ON1 vs. 8%, NA1, p = 0.04), whereas the recovery without a disability was higher among the NA1 cases (56%, ON1 vs. 88%, NA1, p = 0.02). The time to the most recent common ancestor (TMRCA) for RSV in Bangladesh was 1949 for RSV-A and 1944 for RSV-B. This study revealed the genotypic diversity and evolutionary relatedness of RSV strains in Bangladesh and provided pre-COVID molecular epidemiology data to understand better the COVID-19 impact on upcoming RSV epidemiology in Bangladesh.

Associations between ambient fine particulate matter and child respiratory infection: The role of particulate matter source composition in Dhaka, Bangladesh.

Air pollution in the form of fine particulate matter (PM2.5) has been linked to adverse respiratory outcomes in children. However, the magnitude of this association in South Asia and sources of PM2.5 that drive adverse health effects are largely unknown. This study evaluates associations between short-term variation in ambient PM2.5 and incidence of pneumonia and upper respiratory infections among children in Dhaka, Bangladesh. We also perform an exploratory analysis of the PM2.5 source composition that is most strongly associated with health endpoints. We leveraged data from health surveillance of children less than five years of age between 2005 and 2014 in Kamalapur, Bangladesh, including daily physician-confirmed diagnoses of pneumonia and upper respiratory infection. Twice-weekly source-apportioned ambient PM2.5 measurements were obtained for the same period, and Poisson regression adjusted for time-varying covariates was used to estimate lagged associations between ambient PM2.5 and respiratory infection. We use complementary matching and stratification approaches to evaluate whether these associations vary across PM2.5 source composition. Total PM2.5 mass was associated with a modest increase in incidence of pneumonia, with a peak effect size two days after exposure (rate ratio = 1.032; 95% confidence interval = 1.008-1.056). We did not identify a significant association between PM2.5 and upper respiratory infection. Stratified and matching analyses suggested this association was stronger among days when ambient PM2.5 had a higher mass percent associated with brick kiln and fugitive lead emissions.: This study suggests that elevated ambient PM2.5 contributes to increased incidence of child pneumonia in urban Dhaka, and that this relationship varies among days with different source composition of PM2.5.

The Etiology of Childhood Pneumonia in Bangladesh: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: Pneumonia remains the leading infectious cause of death among children <5 years, but its cause in most children is unknown. We estimated etiology for each child in 2 Bangladesh sites that represent rural and urban South Asian settings with moderate child mortality. METHODS: As part of the Pneumonia Etiology Research for Child Health study, we enrolled children 1-59 months of age with World Health Organization-defined severe and very severe pneumonia, plus age-frequency-matched controls, in Matlab and Dhaka, Bangladesh. We applied microbiologic methods to nasopharyngeal/oropharyngeal swabs, blood, induced sputum, gastric and lung aspirates. Etiology was estimated using Bayesian methods that integrated case and control data and accounted for imperfect sensitivity and specificity of the measurements. RESULTS: We enrolled 525 cases and 772 controls over 24 months. Of the cases, 9.1% had very severe pneumonia and 42.0% (N = 219) had infiltrates on chest radiograph. Three cases (1.5%) had positive blood cultures (2 Salmonella typhi, 1 Escherichia coli and Klebsiella pneumoniae). All 4 lung aspirates were negative. The etiology among chest radiograph-positive cases was predominantly viral [77.7%, 95% credible interval (CrI): 65.3-88.6], primarily respiratory syncytial virus (31.2%, 95% CrI: 24.7-39.3). Influenza virus had very low estimated etiology (0.6%, 95% CrI: 0.0-2.3). Mycobacterium tuberculosis (3.6%, 95% CrI: 0.5-11.0), Enterobacteriaceae (3.0%, 95% CrI: 0.5-10.0) and Streptococcus pneumoniae (1.8%, 95% CrI: 0.0-5.9) were the only nonviral pathogens in the top 10 etiologies. CONCLUSIONS: Childhood severe and very severe pneumonia in young children in Bangladesh is predominantly viral, notably respiratory syncytial virus.

Global burden of acute lower respiratory infection associated with human parainfluenza virus in children younger than 5 years for 2018: a systematic review and meta-analysis.

BACKGROUND: Human parainfluenza virus (hPIV) is a common virus in childhood acute lower respiratory infections (ALRI). However, no estimates have been made to quantify the global burden of hPIV in childhood ALRI. We aimed to estimate the global and regional hPIV-associated and hPIV-attributable ALRI incidence, hospital admissions, and mortality for children younger than 5 years and stratified by 0-5 months, 6-11 months, and 12-59 months of age. METHODS: We did a systematic review of hPIV-associated ALRI burden studies published between Jan 1, 1995, and Dec 31, 2020, found in MEDLINE, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Global Health Library, three Chinese databases, and Google search, and also identified a further 41 high-quality unpublished studies through an international research network. We included studies reporting community incidence of ALRI with laboratory-confirmed hPIV; hospital admission rates of ALRI or ALRI with hypoxaemia in children with laboratory-confirmed hPIV; proportions of patients with ALRI admitted to hospital with laboratory-confirmed hPIV; or in-hospital case-fatality ratios (hCFRs) of ALRI with laboratory-confirmed hPIV. We used a modified Newcastle-Ottawa Scale to assess risk of bias. We analysed incidence, hospital admission rates, and hCFRs of hPIV-associated ALRI using a generalised linear mixed model. Adjustment was made to account for the non-detection of hPIV-4. We estimated hPIV-associated ALRI cases, hospital admissions, and in-hospital deaths using adjusted incidence, hospital admission rates, and hCFRs. We estimated the overall hPIV-associated ALRI mortality (both in-hospital and out-hospital mortality) on the basis of the number of in-hospital deaths and care-seeking for child pneumonia. We estimated hPIV-attributable ALRI burden by accounting for attributable fractions for hPIV in laboratory-confirmed hPIV cases and deaths. Sensitivity analyses were done to validate the estimates of overall hPIV-associated ALRI mortality and hPIV-attributable ALRI mortality. The systematic review protocol was registered on PROSPERO (CRD42019148570). FINDINGS: 203 studies were identified, including 162 hPIV-associated ALRI burden studies and a further 41 high-quality unpublished studies. Globally in 2018, an estimated 18·8 million (uncertainty range 12·8-28·9) ALRI cases, 725 000 (433 000-1 260 000) ALRI hospital admissions, and 34 400 (16 400-73 800) ALRI deaths were attributable to hPIVs among children younger than 5 years. The age-stratified and region-stratified analyses suggested that about 61% (35% for infants aged 0-5 months and 26% for 6-11 months) of the hospital admissions and 66% (42% for infants aged 0-5 months and 24% for 6-11 months) of the in-hospital deaths were in infants, and 70% of the in-hospital deaths were in low-income and lower-middle-income countries. Between 73% and 100% (varying by outcome) of the data had a low risk in study design; the proportion was 46-65% for the adjustment for health-care use, 59-77% for patient groups excluded, 54-93% for case definition, 42-93% for sampling strategy, and 67-77% for test methods. Heterogeneity in estimates was found between studies for each outcome. INTERPRETATION: We report the first global burden estimates of hPIV-associated and hPIV-attributable ALRI in young children. Globally, approximately 13% of ALRI cases, 4-14% of ALRI hospital admissions, and 4% of childhood ALRI mortality were attributable to hPIV. These numbers indicate a potentially notable burden of hPIV in ALRI morbidity and mortality in young children. These estimates should encourage and inform investment to accelerate the development of targeted interventions. FUNDING: Bill & Melinda Gates Foundation.

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

BACKGROUND: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. METHODS: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. FINDINGS: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. INTERPRETATION: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

Avian influenza virus A (H5N1), detected through routine surveillance, in child, Bangladesh.

We identified avian influenza virus A (H5N1) infection in a child in Bangladesh in 2008 by routine influenza surveillance. The virus was of the same clade and phylogenetic subgroup as that circulating among poultry during the period. This case illustrates the value of routine surveillance for detection of novel influenza virus.

Population-based Incidence of Childhood Pneumonia Associated With Viral Infections in Bangladesh.

BACKGROUND: The contribution of respiratory viruses to childhood pneumonia in tropical low- and middle-income countries is poorly understood. We used population-based respiratory illness surveillance in children 5 years of age or younger in Dhaka, Bangladesh, to characterize these illnesses. METHODS: We conducted weekly home visits to children who were referred to clinic for fever or respiratory symptoms. Standardized clinical data were collected. Nasopharyngeal washes were collected for one fifth of children diagnosed with a febrile or respiratory syndrome, with virus isolation testing for influenza and reverse transcription polymerase chain reaction testing for other viruses. Pneumonia was defined as age-specific tachypnea and crepitations on chest auscultation by study physicians. RESULTS: From April 2004 to February 2008, 17,584 children were followed for 17,644 child-years; 6335 children had 12,499 clinic visits with eligible illnesses, including 6345 pneumonia episodes (incidence of 36 episodes/100 child-years). Annual incidence of pneumonia/100 child-years ranged from 88.3 for children 0-6 months of age to 13.1 for those 36-60 months of age. Of 1248 pneumonia visits with laboratory testing, 803 (64%) had detection of viral pathogens, including 274 respiratory syncytial virus (22% of pneumonia visits with laboratory testing; incidence 7.9/100 child-years), 244 adenovirus (19%; 7.0/100 child-years), 198 human metapneumovirus (16%; 5.7/100 child-years), 174 parainfluenza (14.0%; 5.0/100 child-years), and 81 influenza (6.5%; 2.3/100 child years). CONCLUSIONS: Viral pathogens contribute to a majority of childhood pneumonia episodes in Bangladesh, a setting with high pneumonia rates, especially in children 2 years of age or younger. Developing effective prevention strategies targeting these children is a high priority. Given less sensitive laboratory method used for influenza detection, influenza rates may be underestimated.