Increased Childhood Mortality and Arsenic in Drinking Water in Matlab, Bangladesh: A Population-Based Cohort Study

Background: Arsenic in drinking water was associated with increased risk of all-cause, cancer, and cardiovascular death in adults. However, the extent to which exposure is related to all-cause and deaths from cancer and cardiovascular condition in young age is unknown. Therefore, we prospectively assessed whether long-term and recent arsenic exposures are associated with all-cause and cancer and cardiovascular mortalities in Bangladeshi childhood population. Methods and Findings: We assembled a cohort of 58406 children aged 5–18 years from the Health and Demographic Surveillance System of icddrb in Bangladesh and followed during 2003–2010. There were 185 non-accidental deaths registered in-about 0.4 million person-years of observation. We calculated hazard ratios for cause-specific death in relation to exposure at baseline (µg/L), time-weighted lifetime average (µg/L) and cumulative concentration (µg-years/L). After adjusting covariates, hazard ratios (HRs) for all-cause childhood deaths comparing lifetime average exposure 10–50.0, 50.1–150.0, 150.1–300.0 and ≥300.1µg/L were 1.37 (95% confidence interval [CI], 0.74–2.57), 1.44 (95% CI, 0.88–2.38), 1.22 (95% CI, 0.75–1.98) and 1.88 (95% CI, 1.14–3.10) respectively. Significant increased risk was also observed for baseline (P for trend = 0.023) and cumulative exposure categories (P for trend = 0.036). Girls had higher mortality risk compared to boys (HR for girls 1.79, 1.21, 1.64, 2.31; HR for boys 0.52, 0.53, 1.14, 0.99) in relation to baseline exposure. For all cancers and cardiovascular deaths combined, multivariable adjusted HRs amounted to 1.53 (95% CI 0.51–4.57); 1.29 (95% CI 0.43–3.87); 2.18 (95%CI 1.15–4.16) for 10.0–50.0, 50.1–150.0, and ≥150.1, comparing lowest exposure as reference (P for trend = 0.009). Adolescents had higher mortality risk compared to children (HRs = 1.53, 95% CI 1.03–2.28 vs. HRs = 1.30, 95% CI 0.78–2.17). Conclusions: Arsenic exposure was associated with substantial increased risk of deaths at young age from all-cause, and cancers and cardiovascular conditions. Girls and adolescents (12–18 years) had higher risk compared to boys and child

Unmasking herd protection by an oral cholera vaccine in a cluster-randomized trial.

BACKGROUND: Several studies have shown that inactivated, whole-cell oral cholera vaccines (OCVs) confer both direct protection on vaccinees and herd protection on populations. Because our earlier cluster-randomized effectiveness trial (CRT) in urban Bangladesh failed to detect OCV herd protection, we reanalysed the trial to assess whether herd effects were masked in our original analysis. METHODS: A total of 267 270 persons were randomized to 90 approximately equal-sized clusters. In 60 clusters persons aged 1 year and older were eligible to receive OCV and in 30 clusters persons received no intervention and served as controls. We analysed OCV protection against severely dehydrating cholera for the entire clusters, as in our original analysis, and for subclusters consisting of residents of innermost households. We hypothesized that if OCV herd protection was attenuated by cholera transmission into the clusters from the outside in this densely populated setting, herd protection would be most evident in the innermost households. RESULTS: During 2 years of follow-up of all residents of the clusters, total protection (protection of OCV recipients relative to control residents) was 58% [95% confidence interval (CI): 43%, 70%; P<0.0001], indirect protection (protection of non-OCV recipients in OCV clusters relative to control participants) was 16% (95% CI: -20%, 41%; P=0.35) and overall OCV protection (protection of all residents in the OCV clusters relative to control residents) was 46% (95% CI: 30%, 59%; P<0.0001). Analyses of the inner 75% and 50% households of the clusters showed similar findings. However, total protection was 75% (95% CI: 50%, 87%, P<0.0001), indirect protection 52% (95% CI: -9%, 79%; P=0.08) and overall protection 72% (95% CI: 49%, 84%; P<0.0001) for the innermost 25% households. CONCLUSION: Consistent with past studies, substantial OCV herd protective effects were identified, but were unmasked only by analysing innermost households of the clusters. Caution is needed in defining clusters for analysis of vaccine herd effects in CRTs of vaccines

Spatial and temporal clustering of typhoid fever in an urban slum of Dhaka City: Implications for targeted typhoid vaccination

Background: Salmonella enterica serotype Typhi (Salmonella Typhi) causes severe and occasionally life-threatening disease, transmitted through contaminated food and water. Humans are the only reservoir, inadequate water, sanitation, and hygiene infrastructure increases risk of typhoid. High-quality data to assess spatial and temporal relationships in disease dynamics are scarce. Methods: We analyzed data from a prospective cohort conducted in an urban slum area of Dhaka City, Bangladesh. Passive surveillance at study centers identified typhoid cases by microbiological culture. Each incident case (index case) was matched to two randomly selected index controls, and we measured typhoid incidence in the population residing in a geographically defined region surrounding each case and control. Spatial clustering was evaluated by comparing the typhoid incidence in residents of geometric rings of increasing radii surrounding the index cases and controls over 28 days. Temporal clustering was evaluated by separately measuring incidence in the first and second 14-day periods following selection. Incidence rate ratios (IRRs) were calculated using Poisson regression models. Results: We evaluated 141 typhoid index cases. The overall typhoid incidence was 0.44 per 100,000 person-days (PDs) (95% CI: 0.40, 0.49). In the 28 days following selection, the highest typhoid incidence (1.2 per 100,000 PDs [95% CI: 0.8, 1.6]) was in the innermost cluster surrounding index cases. The IRR in this innermost cluster was 4.9 (95% CI: 2.4, 10.3) relative to the innermost control clusters. Neither typhoid incidence rates nor relative IRR between index case and control populations showed substantive differences in the first and second 14-day periods after selection. Conclusion: In the absence of routine immunization programs, geographic clustering of typhoid cases suggests a higher intensity of typhoid risk in the population immediately surrounding identified cases. Further studies are needed to understand spatial and temporal trends and to evaluate the effectiveness of targeted vaccination in disrupting typhoid transmission

Pulmonary Tuberculosis and Drug Resistance in Dhaka Central Jail, the Largest Prison in Bangladesh

There are limited data on TB among prison inmates in Bangladesh. The aim of the study was to determine the prevalence of pulmonary tuberculosis (TB), its drug resistance and risk factors in Dhaka Central Jail, the largest prison in Bangladesh.Cross sectional survey with, active screening of a total number of 11,001 inmates over a period of 2 years. Sputum samples from TB suspects were taken for acid- fast bacilli (AFB) microscopy, culture and drug susceptibility testing. (5.37, 4.02–7.16).The study results revealed a very high prevalence of TB in the prison population in Dhaka Central Jail. Entry examinations and active symptom screening among inmates are important to control TB transmission inside the prison. Identifying undiagnosed smear-negative TB cases remains a challenge to combat this deadly disease in this difficult 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

Estimating the contribution of subclinical tuberculosis disease to transmission: An individual patient data analysis from prevalence surveys.

BACKGROUND: Individuals with bacteriologically confirmed pulmonary tuberculosis (TB) disease who do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at the time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. METHODS: We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual-level data on representative populations for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high-burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission. RESULTS: We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, the Philippines, and Viet Nam) and one case-finding trial in Viet Nam. The odds ratio for infection in a household with a clinical versus subclinical index case (irrespective of sputum smear status) was 1.2 (0.6-2.3, 95% confidence interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% prediction interval [PrI]). Fourteen countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB. CONCLUSIONS: Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination. FUNDING: JCE, KCH, ASR, NS, and RH have received funding from the European Research Council (ERC) under the Horizon 2020 research and innovation programme (ERC Starting Grant No. 757699) KCH is also supported by UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to KCH); however, the views expressed do not necessarily reflect the UK government's official policies. PJD was supported by a fellowship from the UK Medical Research Council (MR/P022081/1); this UK-funded award is part of the EDCTP2 programme supported by the European Union. RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 and INV-001754), and the WHO (2020/985800-0)

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

Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study

Background Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. Methods We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1–59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. Findings Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6–97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3–65·6) of causes, whereas bacteria accounted for 27·3% (23·3–31·6) and Mycobacterium tuberculosis for 5·9% (3·9–8·3). Viruses were less common (54·5%, 95% CrI 47·4–61·5 vs 68·0%, 62·7–72·7) and bacteria more common (33·7%, 27·2–40·8 vs 22·8%, 18·3–27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4–34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus–enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. Interpretation In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes

Incidence of respiratory syncytial virus-associated lower respiratory tract illness in infants in low- and middle-income regions during the Coronavirus disease 2019 pandemic

DATA AVAILABILITY : Study data and documents can be requested for further research from www.clinicalstudydatarequest.com.BACKGROUND : Incidence data of respiratory syncytial virus–associated lower respiratory tract illness (RSV-LRTI) are sparse in low- and middle-income countries (LMICs). We estimated RSV-LRTI incidence rates (IRs) in infants in LMICs using World Health Organization case definitions. METHODS : This prospective cohort study, conducted in 10 LMICs from May 2019 to October 2021 (largely overlapping with the coronavirus disease 2019 [COVID-19] pandemic), followed infants born to women with low-risk pregnancies for 1 year from birth using active and passive surveillance to detect potential LRTIs, and quantitative reverse-transcription polymerase chain reaction on nasal swabs to detect RSV. RESULTS : Among 2094 infants, 32 (1.5%) experienced an RSV-LRTI (8 during their first 6 months of life, 24 thereafter). Seventeen (0.8%) infants had severe RSV-LRTI and 168 (8.0%) had all-cause LRTI. IRs (95% confidence intervals [CIs]) of first RSV-LRTI episode were 1.0 (.3–2.3), 0.8 (.3–1.5), and 1.6 (1.1–2.2) per 100 person-years for infants aged 0–2, 0–5, and 0–11 months, respectively. IRs (95% CIs) of the first all-cause LRTI episode were 10.7 (8.1–14.0), 11.7 (9.6–14.0), and 8.7 (7.5–10.2) per 100 person-years, respectively. IRs varied by country (RSV-LRTI: 0.0–8.3, all-cause LRTI: 0.0–49.6 per 100 person-years for 0- to 11-month-olds). CONCLUSIONS : RSV-LRTI IRs in infants in this study were relatively low, likely due to reduced viral circulation caused by COVID-19–related nonpharmaceutical interventions. CLINICAL TRIALS REGISTRATION : NCT03614676.https://academic.oup.com/ofidhj2024Medical MicrobiologySDG-03:Good heatlh and well-bein

Association of C-reactive protein with bacterial and respiratory syncytial virus-associated pneumonia among children aged <5 years in the PERCH study

Background. Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods. We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for "confirmed" bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to "RSV pneumonia" (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Results. Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIVnegative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity. Conclusions. Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study