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Additional file 3: Annexure 3: MITS Ambulance Set up.

Additional file 8: Annexure 8: Verbal autopsy form for death of people in age group of 16-60 years.

Additional file 1: Annexure 1: Standard operating procedure (SOP) for grief counselling MITS in MAHAN.

Additional file 10: Annexure 10: COD procedure.

Additional file 2: Annexure 2: MITS Ambulance sterilisation SOP.

Additional file 6: Annexure 6: Verbal autopsy form for neonatal deaths (0 to 28 days).

Additional file 9: Annexure 9: Tangerine Software.

Additional file 7: Annexure 7: Verbal autopsy form of post neonatal under 5 children’s deaths.

Additional file 11.

Additional file 4: Annexure 4: Minimally Invasive Tissue Sampling SOP MAHAN.

Supplemental Digital Content is available in the text., Background: HIV-1 infection predisposes to an increased burden of pneumonia caused by community-acquired and opportunistic pathogens. Methods: Within the context of the Pneumonia Etiology Research for Child Health case-control study of under 5 pneumonia, we investigated the etiology of World Health Organization-defined severe/very severe pneumonia requiring hospitalization in South African HIV-infected children. Nasopharyngeal-oropharyngeal swabs and blood, collected from cases and age- and season-matched HIV-infected controls attending outpatient antiretroviral therapy (ART) clinics, were analyzed using molecular diagnostic methods. Cases were also investigated for tuberculosis. Etiologic fractions among cases with radiologically confirmed pneumonia were derived using Bayesian analytic techniques. Results: Of 115 HIV-infected cases, 89 (77.4%) had radiologically confirmed pneumonia. Severe immunosuppression (adjusted odds ratio, 32.60; 95% confidence interval, 7.25–146.64) was significantly associated with radiologically confirmed pneumonia. Cotrimoxazole prophylaxis (46.4% vs. 77.4%) and ART (28.2% vs. 83.1%) coverage were significantly lower in cases compared with ART-clinic controls. An etiologic agent was identified in 99.0% of the radiologically confirmed cases. The ‘top 4’ pathogens associated with radiologically confirmed pneumonia were Pneumocystis jirovecii [23.0%; 95% credible interval (CrI), 12.4%–31.5%], Staphylococcus aureus (10.6%; 95% CrI, 2.2%–20.2%), pneumococcus (9.5%; 95% CrI, 2.2%–18.0%) and respiratory syncytial virus (9.3%; 95% CrI, 2.2%–14.6%). Bacteremia (6.7%) and in-hospital death (10.1%) were frequent among those with radiologically confirmed disease. Conclusions: Pneumocystis jirovecii, S. aureus, pneumococcus and respiratory syncytial virus contribute a considerable burden of radiologically confirmed pneumonia in South African HIV-infected children under 5 years. Expediting access to ART and cotrimoxazole prophylaxis would decrease the burden of pneumonia in these children.

Background: Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. Methods: The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths, Bill and Melinda Gates Foundation, BMGF: OPP1148988.8; Johnson and Johnson, J&J; Merck; Roche; AbbVie, This publication is based on research funded in part by the Bill & Melinda Gates Foundation (grant number OPP1148988.8). ES reports grants from Bill and Melinda Gates Foundation, during the conduct of the study; grants, personal fees and non-financial support from Astra Zeneca Inc, grants, personal fees and non-financial support from Merck & Co., grants, personal fees and non-financial support from Regeneron Inc, grants, personal fees and non-financial support from Pfizer Inc, personal fees, non-financial support and other from Abbvie Inc, personal fees from Alere Inc, grants, personal fees and non-financial support from Roche Inc, other from GSK Inc, grants from Johnson and Johnson, grants and nonfinancial support from Novavax Inc, outside the submitted work; FP reports grants and personal fees from JANSSEN, grants and personal fees from NOVAVAX, INC, personal fees from BAVARIAN NORDIC A/S, personal fees from PFIZER, personal fees from SANOFI, personal fees from REGENERON, personal fees from MERCK, outside the submitted work.

The efficacy and safety of nirsevimab in the treatment of medically attended respiratory syncytial virus (RSV) infections of the lower respiratory tract in otherwise healthy, late preterm and term infants were assessed in the phase 2B1 and phase 3 MELODY2 trials. An ongoing phase 2–3 trial (ClinicalTrials.gov number, NCT03959488. opens in new tab) is evaluating the safety and pharmacokinetics of nirsevimab in infants at risk for severe RSV infection of the lower respiratory tract who are eligible to receive palivizumab. [...]

Summary:\ud Human metapneumovirus (hMPV) is one of several important viruses associated with childhood acute lower respiratory infection (ALRI). However, there are currently no global burden estimates for ALRI associated with hMPV in children, and there are no licenced vaccines or drugs for hMPV infections. We estimated age–stratified global morbidity and mortality burden of hMPV–associated ALRI among children under five years using data on laboratory–confirmed hMPV burden from different geographic regions. \ud Methods: We performed a systematic review of hMPV burden studies published between 1 January 2001 and 31 December 2019 and identified a further 40 high–quality unpublished studies. We assessed the risk of bias using a modified Newcastle–Ottawa Scale. Incidence rates, hospital admission rates, and in–hospital case–fatality ratios (hCFRs) of hMPV–associated ALRI (defined as ALRI with laboratory–confirmed hMPV) were analysed using a generalized linear mixed model. We applied incidence and hospital admission rates of hMPV–associated ALRI to population estimates to yield the morbidity burden estimates. We estimated hMPV–associated ALRI in–hospital deaths by combining hospital admissions and hCFRs of hMPV–associated ALRI. We estimated the overall hMPV–associated ALRI deaths (both in–hospital and out–hospital deaths) using the number of in–hospital deaths, population–based childhood pneumonia mortality, and care–seeking for child pneumonia. We also estimated hMPV–attributable ALRI cases, hospital admissions, and deaths (ALRI burden that are causally attributable to hMPV) by combining hMPV–associated burden estimates and attributable fractions of hMPV in laboratory–confirmed hMPV cases and deaths. \ud Findings: We estimated in 2018 that hMPV could be detected in 14.2 million (UR 10.2–20.1) ALRI cases, 643,000 (UR 425,000–977,000) hospital admissions, 7,700 (UR 2,600–48,800) in–hospital deaths, and 16,100 (UR 5,700–88,000) overall ALRI deaths among children under five years globally. Of these cases and deaths, an estimated 11.1 million (UR 8.0–15.7) ALRI cases, 502,000 (UR 332,000–762,000) ALRI hospital admissions, and 11,300 (UR 4,000–61,600) ALRI deaths could be causally attributable to hMPV. hMPV–associated ALRI incidence rate in the community setting did not vary much by age strata, while about 58% of hospital admissions were in infants less than 12 months; 64% of in–hospital deaths occurred 6 in the first six months of life, of which 80% occurred in low– and lower–middle income countries. \ud Interpretation: Infants younger than one year have disproportionately high risks of severe hMPV infections across settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low– and lower–middle income countries are at greater risk of death from hMPV–associated ALRI compared with other countries. Our mortality estimates, though likely to be conservative and underestimate the true hMPV mortality burden, demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of hMPV–associated ALRI among young infants in low– and lower–middle income countries.

Benefits of school reopening must be weighed against the morbidity and mortality risks and the impact of enhancing spread of coronavirus disease 2019 (COVID-19). We investigated the effects of school reopening and easing of social-distancing restrictions on dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Israel between March and July 2020.We examined the nationwide age-wise weekly incidence, prevalence, SARS-CoV-2 polymerase chain reaction tests, their positivity, COVID-19 hospitalizations, and associated mortality. Temporal differences in these parameters following school reopening, school ending, and following easing of restrictions such as permission of large-scale gatherings were examined.Incidence of SARS-CoV-2 infections gradually increased following school reopening in all age groups, with a significantly higher increase in adults than children. Higher rate ratios (RRs) of sample positivity rates 21-27 days following school reopening relative to positivity rates prior to openings were found for the age groups 40-59 (RR, 4.72; 95% CI, 3.26-6.83) and 20-39 (RR, 3.37 [2.51-4.53]) years, but not for children aged 0-9 (RR, 1.46 [.85-2.51]) and 10-19 (RR, .93 [.65-1.34]) years. No increase was observed in COVID-19-associated hospitalizations and deaths following school reopening. In contrast, permission of large-scale gatherings was accompanied by increases in incidence and positivity rates of samples for all age groups, and increased hospitalizations and mortality.This analysis does not support a major role of school reopening in the resurgence of COVID-19 in Israel. Easing restrictions on large-scale gatherings was the major influence on this resurgence.

Summary Influenza vaccination during pregnancy decreased the incidence of acute lower respiratory tract infection hospitalizations in infants born to vaccinated mothers. The benefits of protecting against influenza virus infection during early infancy might extend beyond protecting only against influenza-confirmed illness., Background Influenza immunization of pregnant women protects their young infants against laboratory-confirmed influenza infection. Influenza infection might predispose to subsequent bacterial infections that cause severe pneumonia. In a secondary analysis of a randomized clinical trial (RCT), we evaluated the effect of maternal vaccination on infant hospitalizations for all-cause acute lower respiratory tract infection (ALRI). Methods Infants born to women who participated in a double-blind placebo-controlled RCT in 2011 and 2012 on the efficacy of trivalent inactivated influenza vaccine (IIV) during pregnancy were followed during the first 6 months of life. Results The study included 1026 infants born to IIV recipients and 1023 born to placebo recipients. There were 52 ALRI hospitalizations (median age, 72 days). The incidence (per 1000 infant-months) of ALRI hospitalizations was lower in infants born to IIV recipients (3.4 [95% confidence interval {CI}, 2.2–5.4]; 19 cases) compared with placebo recipients (6.0 [95% CI, 4.3–8.5]; 33 cases) with a vaccine efficacy of 43.1% (P = .050). Thirty of the ALRI hospitalizations occurred during the first 90 days of life, 9 in the IIV group (3.0 [95% CI, 1.6–5.9]) and 21 in the placebo group (7.2 [95% CI, 4.7–11.0]) (incidence rate ratio, 0.43 [95% CI, .19–.93]) for a vaccine efficacy of 57.5% (P = .032). The incidence of ALRI hospitalizations was similar in the IIV and placebo group for infants >3 months of age. Forty-four of the hospitalized infants were tested for influenza virus infection and 1 tested positive. Conclusions Using an RCT as a vaccine probe, influenza vaccination during pregnancy decreased all-cause ALRI hospitalization during the first 3 months of life, suggesting possible protection against subsequent bacterial infections that influenza infection might predispose to. Clinical Trial Registration NCT01306669.

Summary Serology provided a more detailed evaluation of exposure to seasonal influenza virus. Vaccine efficacy was similar when measured for polymerase chain reaction–confirmed influenza illness (PCR-CI) or serologically diagnosed influenza infection (SDI) in pregnant women; however, vaccination prevented a greater number of SDIs than PCR-CIs., Background. The utility of serologic testing to evaluate vaccine efficacy of seasonal inactivated influenza vaccine (IIV) is controversial. We aimed to evaluate the efficacy of IIV against serologically diagnosed influenza infection (SDI) and reverse-transcription polymerase chain reaction–confirmed influenza illness (PCR-CI) in women vaccinated during pregnancy. Methods. We undertook a post hoc analysis of 2 randomized clinical trials evaluating IIV efficacy among human immunodeficiency virus (HIV)–uninfected and HIV-infected pregnant women. SDI was defined as ≥4-fold increase in paired hemagglutinin antibody inhibition titers from 1 month postvaccination until end-of-study participation. PCR-CI was defined as molecular diagnostic evidence of influenza virus in pharyngeal specimens collected during clinical illness. Results. Among placebo recipients, the respective incidence of PCR-CI and SDI was 5.6% and 35.0% in HIV-uninfected women and 20.5% and 43.6% among HIV-infected women. Vaccine efficacy in HIV-uninfected women was similar for PCR-CI (66.9%; 95% confidence interval [CI], –20.1% to 90.9%) and SDI (59.2%; 95% CI, 37.0%–73.5%); however, fewer women required vaccination to prevent 1 episode of SDI (5; 95% CI, 3–9) than PCR-CI (27; 95% CI, 12–∞). Also, vaccine efficacy was similar for PCR-CI (61.2%; 95% CI, 10.7%–83.2%) and SDI (60.9%; 95% CI, 33.9%–76.9%) in HIV-infected women, with 2-fold fewer women needing to be vaccinated to prevent SDI (4; 95% CI, 3–8) than PCR-CI (8; 95% CI, 4–52). Conclusions. Although vaccine efficacy was similar when measured for PCR-CI or SDI, IIV vaccination prevented a greater number of SDI than PCR-CI; the clinical relevance of the former warrants interrogation.Clinical Trials Registration. NCT01306669 and NCT01306682

Background: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. Methods: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms “RSV”, “respiratory syncytial virus”, or “respiratory syncytial viral” combined with “mortality”, “fatality”, “death”, “died”, “deaths”, or “CFR” for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. Findings: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3–11·0) in low-income or lower middle-income countries, 4·0 months (2·0–10·0) in upper middle-income countries, and 7·0 months (3·6–16·8) in high-income countries. Interpretation: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries. Funding: Bill & Melinda Gates Foundation. Sin financiación 18.705 JCR (2017) Q1, 1/180 Public, Environmental and Occupational Health UEM

Background: A model to predict hospitalization due to respiratory syncytial virus (RSV) of infants born at 33-35 weeks' gestation was developed using seven risk factors from the Spanish FLIP study "birth ± 10 weeks from the beginning of the RSV season", "birth weight", "breast fed ≤2 months", "number of siblings ≥2 years", "number of family members with atopy", "number of family members with wheezing", and "gender". The aim of this study was to validate the model using French data. Methods: The FLIP model [predictive accuracy 71%, receiver operating characteristic (ROC) 0.791] was tested against the French data (77 hospitalized infants with RSV born at 33-35 weeks and 154 age-matched controls) using discriminatory function analysis by applying the FLIP coefficients to the French data and by generating the seven variable model from the French data. Results: Applying the FLIP coefficients to the French dataset, the model correctly classified 69% of cases (ROC 0.627). The predictive power increased to 73% (ROC 0.654) when "number of siblings ≥ 2 years" was substituted for "number of children at school". The number needed to treat (NNT) in order to prevent 70% of hospitalizations was 18. The model derived using French data could correctly classify 62% of cases in the French data (ROC 0.658). Conclusions: The model was successfully validated and may potentially optimize immunoprophylaxis in French infants born at 33-35 week's gestation.

OBJECTIVES: A model for predicting respiratory syncytial virus hospitalization in infants born 33-35 weeks' gestational age (wGA) has been developed from the Spanish FLIP study risk factors. The model correctly classified 71% of cases and the area under the receiver operating characteristic (ROC) curve was 0.791. To assess its applicability in Italy, the model was validated against data from the Osservatorio VRS study. METHODS: Discriminant function analysis was used to validate the model by (a) using the predictive variables identified in FLIP to generate a function from the Italian data and (b) applying the coefficients from the FLIP calculations to the Italian data. RESULTS: The function calculated from the Italian data provided 77% accurate classification (ROC: 0.773). Applying the FLIP coefficients to the Italian data resulted in correctly classifying 68% of cases and a ROC of 0.760. The number needed to treat to prevent hospitalization of 80% of at risk infants was 13.4, based on a hospitalization rate of 5% and 80% treatment efficacy. CONCLUSIONS: The Italian data confirm the predictive ability of the model, which could be used to target palivizumab prophylaxis in Italian infants born 33-35 wGA.