Characteristics and outcomes of children 2-23 months of age with prolonged diarrhoea: A secondary analysis of data from the 'Antibiotics for Children with Diarrhea' trial.

Background: Approximately 12% of all diarrhoeal episodes last for 7-13 days. As such, they are termed prolonged diarrhoea, and are associated with over two-thirds of all diarrhoeal deaths. Due to a lack of robust data, we aimed to evaluate a comparative background characteristics of young children with acute and prolonged diarrhoea, and their outcomes at day 90 follow-up. Methods: We performed a secondary analysis of data from the Antibiotics for Children with Diarrhea (ABCD) trial. Children aged 2-23 months were enrolled between July 2017 and July 2019 from seven Asian and sub-Saharan African countries. For this analysis, we divide diarrhoea into two categories: acute diarrhoea (duration <7 days) and prolonged diarrhoea (duration ≥7-13 days). We used logistic regression to observe baseline crude and adjusted associations and linear regression to compare post-discharge outcomes. Results: We analysed data on 8266 children, of whom 756 (9%) had prolonged diarrhoea and 7510 (91%) had acute diarrhoea. Pakistan had the highest proportion of children with prolonged diarrhoea (n/N = 178/1132, 16%), while Tanzania had the lowest (n/N = 12/1200, 1%). From an analysis that adjusted for sex, breastfeeding, nutritional status, clinical presentation, housing, water supply, sanitation, and country, we observed that presentation at a health facility with prolonged diarrhoea was associated with low age (2-12 months) (adjusted odds ratio (aOR) = 1.25; 95% confidence interval (CI) = 1.02, 1.53; P = 0.028), presence of three or more under-five children in the family (aOR = 1.54; 95% CI = 1.26, 1.87; P < 0.001), maternal illiteracy (aOR = 1.45; 95% CI = 1.21, 1.74, P < 0.001), moderate underweight (aOR = 1.25; 95% CI = 1.01, 1.55; P = 0.042) and pathogen (Campylobacter) (aOR = 1.27; 95% CI = 1.12, 1.44; P < 0.001). At day 90 follow-up, children with prolonged diarrhoea had significantly lower weight-for-age z-score compared to children with acute diarrhoea (-1.62, standard deviation (SD) = 1.11 vs -1.52, SD = 1.20; P = 0.032), as well as significantly higher frequency of hospital admission (6.1% vs 4.5%; P = 0.042). Conclusions: Prolonged diarrhoea was more common in children of younger age, those who were moderately underweight, those with Campylobacter in stool, those with three or more under-five children in a family, and those with illiterate mothers compared to those who had acute diarrhoea. Children with prolonged diarrhoea more often required hospitalisation during the three-month follow-up period compared to their counterparts.

Safety, reactogenicity, and immunogenicity of ZR-202-CoV and ZR-202a-CoV recombinant vaccines compared with ComirnatyⓇ: A randomized, observer-blind, controlled, phase 1 study.

OBJECTIVES: ZR-202-CoV and ZR-202a-CoV are novel recombinant vaccines containing 25 µg of the prototype (Wuhan strain) or B.1.351 strain (Beta variant) SARS-CoV-2 S-protein expressed in CHO cells, respectively, adjuvanted with Al(OH)3 and CpG-ODN. We assessed their safety and immunogenicity in this Phase I, randomized, observer-blind, controlled study in Mali. DESIGN: Sixty healthy 18-55-year-old adults randomized 1:1:1 received two doses of ZR-202-CoV, ZR-202a-CoV, or ComirnatyⓇ 28 days apart. Primary outcome measures were solicited and unsolicited adverse events (AEs) including AESI (Adverse Events of Special Interest); secondary outcome was immunogenicity measured as SARS-CoV-2 specific neutralizing antibodies. Participants were followed up for 1 year. RESULTS: Injection site pain and headache were the most frequent solicited local and systemic AEs, respectively. No unsolicited AEs or SAEs related to vaccination were reported during the study period. Although most participants had detectable neutralizing antibodies at baseline robust immune responses were observed in all vaccine groups after the first dose with no further increase after the second dose. Cross-neutralizing antibody responses against Beta, Delta, and Omicron BA.5 variants were similar in magnitude after ZR-202-CoV, ZR-202a-CoV and ComirnatyⓇ. CONCLUSIONS: Similar reactogenicity and immunogenicity profiles of ZR-202-CoV, ZR-202a-CoV and ComirnatyⓇ support further clinical investigation in a wider population.

Coronavirus awareness, prevention, and household hardship survey data for the CHAMPS HDSS network: Data collected between August and September of 2022 from the Bamako HDSS, Mali.

Data were gathered through a collaborative initiative to investigate impacts of the COVID-19 pandemic and related lockdowns on child and maternal health, economic hardships, and access to care for children and pregnant women by the Child Health and Mortality Prevention Surveillance (CHAMPS) Network. The data were gathered in Bamako, the capital city of Mali (population ∼2.9 million) between August and September of 2022 through a Health and Demographic Surveillance System (HDSS). Data collectors used a survey instrument specifically designed to measure household awareness, knowledge, and prevalence of COVID-19, as well as hardships that households experienced since the onset of the pandemic in March of 2020. The data are from two neighborhoods of Bamako, Banconi and Djicoroni; the Health and Demographic Surveillance System (HDSS) operating in these neighborhoods tracks the health of approximately 235,000 inhabitants. The data were collected using a stratified random sample of 454 households.

Neurological Symptoms and Cause of Death Among Young Children in Low- and Middle-Income Countries.

Importance: The emergence of acute neurological symptoms in children necessitates immediate intervention. Although low- and middle-income countries (LMICs) bear the highest burden of neurological diseases, there is a scarcity of diagnostic and therapeutic resources. Therefore, current understanding of the etiology of neurological emergencies in LMICs relies mainly on clinical diagnoses and verbal autopsies. Objective: To characterize the association of premortem neurological symptoms and their management with postmortem-confirmed cause of death among children aged younger than 5 years in LMICs and to identify current gaps and improve strategies to enhance child survival. Design, Setting, and Participants: This cross-sectional study was conducted between December 3, 2016, and July 22, 2022, at the 7 participating sites in the Child Health and Mortality Prevention Surveillance (CHAMPS) network (Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa). Minimally invasive tissue sampling was performed at the CHAMPS sites with specimens from deceased children aged younger than 5 years. This study included deceased children who underwent a premortem neurological evaluation and had a postmortem-confirmed cause of death. Data analysis was performed between July 22, 2022, and January 15, 2023. Main Outcomes and Measures: Descriptive analysis was performed using neurological evaluations from premortem clinical records and from postmortem determination of cause of death (based on histopathology, microbiological testing, clinical records, and verbal autopsies). Results: Of the 2127 deaths of children codified during the study period, 1330 (62.5%) had neurological evaluations recorded and were included in this analysis. The 1330 children had a median age of 11 (IQR, 2-324) days; 745 (56.0%) were male and 727 (54.7%) presented with neurological symptoms during illness before death. The most common postmortem-confirmed neurological diagnoses related to death were hypoxic events (308 [23.2%]), meningoencephalitis (135 [10.2%]), and cerebral malaria (68 [5.1%]). There were 12 neonates with overlapping hypoxic events and meningoencephalitis, but there were no patients with overlapping meningoencephalitis and cerebral malaria. Neurological symptoms were similar among diagnoses, and no combination of symptoms was accurate in differentiating them without complementary tools. However, only 25 children (18.5%) with meningitis had a lumbar puncture performed before death. Nearly 90% of deaths (442 of 511 [86.5%]) with neurological diagnoses in the chain of events leading to death were considered preventable. Conclusions and Relevance: In this cross-sectional study of children aged younger than 5 years, neurological symptoms were frequent before death. However, clinical phenotypes were insufficient to differentiate the most common underlying neurological diagnoses. The low rate of lumbar punctures performed was especially worrying, suggesting a challenge in quality of care of children presenting with neurological symptoms. Improved diagnostic management of neurological emergencies is necessary to ultimately reduce mortality in this vulnerable population.

Prevalence of group B Streptococcus colonisation in mother-newborn dyads in low-income and middle-income south Asian and African countries: a prospective, observational study.

BACKGROUND: Rectovaginal group B Streptococcus (GBS) colonisation in pregnant individuals at the time of labour is a major risk factor for invasive GBS disease by age 7 days (early-onset disease). We aimed to investigate the prevalence of rectovaginal GBS colonisation at the time of labour among pregnant women and vertical transmission to their newborns across selected low-income and middle-income African and south Asian countries. METHODS: This prospective, observational study was undertaken at 11 maternity and obstetric care facilities based in Ethiopia, Kenya, Mozambique, Nigeria, Mali, South Africa, Bangladesh, India, and Bhutan. HIV-negative pregnant women aged 18-45 years who were in the early stages of labour and at least 37 weeks' gestation were eligible for inclusion. Lower vaginal and rectal swabs and urine were collected from the women, and swabs of the umbilicus, outer ear, axillary fold, rectum, and throat were obtained from their newborns, for GBS culture. Standardised sampling and culture using direct plating and selective media broth for detection of GBS colonisation was undertaken at the sites. Serotyping of GBS isolates was done in South Africa. The primary outcome was the prevalence of rectovaginal GBS among pregnant women, analysed in participants with available data. This study is registered with the South African National Clinical Trials Register, number DOH-27-0418-4989. FINDINGS: 6922 pregnant women were enrolled from Jan 10, 2016, to Dec 11, 2018, of whom 6514 (94·1%; 759-892 per country) were included in the analysis; data from Bhutan were not included in the study due to issues with specimen collection and processing. Overall, the prevalence of maternal GBS colonisation was 24·1% (95% CI 23·1-25·2; 1572 of 6514); it was highest in Mali (41·1% [37·7-44·6]; 314 of 764) and lowest in Ethiopia (11·6% [9·5-14·1]; 88 of 759). The overall rate of vertical transmission of GBS from women with rectovaginal GBS colonisation was 72·3% (70·0-74·4; 1132 of 1566); it was highest in Mozambique (79·2% [73·3-84·2]; 168 of 212) and lowest in Bangladesh (55·8%, 47·5-63·8; 77 of 138). The five most common GBS colonising serotypes were Ia (37·3% [34·9-39·7]; 586 of 1572), V (28·5% [26·3-30·8]; 448 of 1572), III (25·1% [23·0-27·3]; 394 of 1572), II (9·2% [7·8-10·7]; 144 of 1572), and Ib (6·5% [5·4-7·8]; 102 of 1572). There was geographical variability in serotype proportion distribution; serotype VII was the third most common serotype in India (8·6% [5·3-13·7]; 15 of 174) and serotype VI was mainly identified in Bangladesh (5·8% [3·0-11·0]; eight of 138) and India (5·7% [3·2-10·3]; ten of 174). INTERPRETATION: Our study reported a high prevalence of GBS colonisation in most settings, with some geographical variability even within African countries. Our findings suggest that serotypes not included in current multivalent capsular-polysaccharide GBS vaccines prevail in some regions, so vaccine efficacy and post-licensure effectiveness studies should assess the effect of vaccination on maternal GBS colonisation given the potential for replacement by non-vaccine serotypes. FUNDING: Bill & Melinda Gates Foundation.

Comparison of causes of stillbirth and child deaths as determined by verbal autopsy and minimally invasive tissue sampling.

In resource-limited settings where vital registration and medical death certificates are unavailable or incomplete, verbal autopsy (VA) is often used to attribute causes of death (CoD) and prioritize resource allocation and interventions. We aimed to determine the CoD concordance between InterVA and CHAMPS's method. The causes of death (CoDs) of children <5 were determined by two methods using data from seven low- and middle-income countries (LMICs) enrolled in the Child Health and Mortality Prevention Surveillance (CHAMPS) network. The first CoD method was from the DeCoDe panel using data from Minimally Invasive Tissue Sampling (MITS), whereas the second method used Verbal Autopsy (VA), which utilizes the InterVA software. This analysis evaluated the agreement between the two using Lin's concordance correlation coefficient. The overall concordance of InterVA4 and DeCoDe in assigning causes of death across surveillance sites, age groups, and causes of death was poor (0.75 with 95% CI: 0.73-0.76) and lacked precision. We found substantial differences in agreement by surveillance site, with Mali showing the lowest and Mozambique and Ethiopia the highest concordance. The InterVA4 assigned CoD agrees poorly in assigning causes of death for U5s and stillbirths. Because VA methods are relatively easy to implement, such systems could be more useful if algorithms were improved to more accurately reflect causes of death, for example, by calibrating algorithms to information from programs that used detailed diagnostic testing to improve the accuracy of COD determination.

Clinicopathological discrepancies in the diagnoses of childhood causes of death in the CHAMPS network: An analysis of antemortem diagnostic inaccuracies.

INTRODUCTION: Determining aetiology of severe illness can be difficult, especially in settings with limited diagnostic resources, yet critical for providing life-saving care. Our objective was to describe the accuracy of antemortem clinical diagnoses in young children in high-mortality settings, compared with results of specific postmortem diagnoses obtained from Child Health and Mortality Prevention Surveillance (CHAMPS). METHODS: We analysed data collected during 2016-2022 from seven sites in Africa and South Asia. We compared antemortem clinical diagnoses from clinical records to a reference standard of postmortem diagnoses determined by expert panels at each site who reviewed the results of histopathological and microbiological testing of tissue, blood, and cerebrospinal fluid. We calculated test characteristics and 95% CIs of antemortem clinical diagnostic accuracy for the 10 most common causes of death. We classified diagnostic discrepancies as major and minor, per Goldman criteria later modified by Battle. RESULTS: CHAMPS enrolled 1454 deceased young children aged 1-59 months during the study period; 881 had available clinical records and were analysed. The median age at death was 11 months (IQR 4-21 months) and 47.3% (n=417) were female. We identified a clinicopathological discrepancy in 39.5% (n=348) of deaths; 82.3% of diagnostic errors were major. The sensitivity of clinician antemortem diagnosis ranged from 26% (95% CI 14.6% to 40.3%) for non-infectious respiratory diseases (eg, aspiration pneumonia, interstitial lung disease, etc) to 82.2% (95% CI 72.7% to 89.5%) for diarrhoeal diseases. Antemortem clinical diagnostic specificity ranged from 75.2% (95% CI 72.1% to 78.2%) for diarrhoeal diseases to 99.0% (95% CI 98.1% to 99.6%) for HIV. CONCLUSIONS: Antemortem clinical diagnostic errors were common for young children who died in areas with high childhood mortality rates. To further reduce childhood mortality in resource-limited settings, there is an urgent need to improve antemortem diagnostic capability through advances in the availability of diagnostic testing and clinical skills.

Safety and immunogenicity of a single dose of Tdap compared to Td in pregnant women in Mali and 3 its effect on infant immune responses: a single-centre, randomised, double-blind, active-controlled phase 2 study.

Background: While maternal pertussis vaccination is a strategy to reduce infant morbidity, safety and immunogenicity data are limited in sub-Saharan Africa. We aimed to evaluate the safety of a single dose of tetanus, diphtheria and acellular pertussis vaccine (Tdap) vaccine compared to tetanus and diphtheria vaccine (Td) vaccine in pregnant women in Bamako, Mali and to assess the pertussis toxin (PT) antibody response at birth. Methods: In this phase 2, single-centre, randomised, double-blind, active-controlled study, from 23 January 2019 to 10 July 2019, healthy 18-39 year old women in the second trimester of a singleton pregnancy were randomised 2:1 to receive Tdap or Td. Blood was tested for serum immunoglobulin G (IgG) against PT and other vaccine antigens using a qualified Meso Scale Discovery multiplex immunoassay. The co-primary objectives evaluated safety and birth anti-PT levels. Infant immune responses to whole-cell pertussis vaccine (DTwP) were assessed. Statistical analysis was descriptive. This trial is registered with clinicaltrials.gov, NCT03589768. Findings: 133 women received Tdap and 67 received Td, with 126 and 66 livebirths, respectively. In the Tdap group, 22 serious adverse events (SAEs) including one maternal death occurred in 20 participants (15·0%), with 10 SAEs in 10 participants (14·9%) in the Td group. Among infants, 18 events occurred among 13 participants (10.3%) and 8 SAEs in 6 participants (9.1%), including three and two infant deaths, occurred in Tdap and Td groups, respectively. None were related to study vaccines. Anti-PT geometric mean concentration (GMC) at birth in the Tdap group was higher than in the Td group (55.4 [46.2-66.6] IU/ml vs 7.9 [5.4-11.5] IU/ml). One month after the third dose of DTwP, the GMC in infants born to mothers in the Tdap group were lower compared to the Td group (20.2 [13.7-29.9] IU/ml vs 77.2 [32.2-184.8] IU/ml). By 6 months of age, the anti- PT GMCs were 17.3 [12.8-23.4] IU/ml and 67.1 [35.5-126.7] IU/ml in Tdap and Td groups, respectively. At birth, anti-tetanus toxin (TT) GMCs were higher in infants in the Td vs Tdap group (5.9 [5.0-7.0] IU/ml vs 4.1 [3.5-4.8] IU/ml). Anti-diphtheria toxin GMCs were similar in both groups. Interpretation: Tdap administered to pregnant women in Mali is safe and well-tolerated. Infants of mothers who received Tdap were born with high PT and protective anti-TT antibody levels. By six months of age, after primary vaccination, the PT levels were lower in the Tdap group compared to the Td group. The blunted immune responses to primary DTwP vaccination in the Tdap infant group warrant further study. Funding: This project was funded by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under contract numbers 75N93021C00012 (The Emmes Company), and HHSN27220130000221 (University of Maryland, Baltimore). Dr. Susana Portillo was supported by NIH award no. T32AI007524. NIAID, NIH provided Tdap vaccine (BOOSTRIX).

Clinical severity of enteric viruses detected using a quantitative molecular assay compared to conventional assays in the Global Enteric Multicenter Study.

BACKGROUND: Quantitative molecular assays are increasingly used for detection of enteric viruses. METHODS: We compared the clinical severity using modified Vesikari score (mVS) of enteric viruses detected by conventional assays (enzyme immunoassays [EIA] for rotavirus and adenovirus 40/41 and conventional polymerase chain reaction for astrovirus, sapovirus, and norovirus) and a quantitative molecular assay (TaqMan Array Card [TAC]) among children aged 0-59 months in the Global Enteric Multicenter Study. For rotavirus and adenovirus 40/41, we compared severity between EIA-positive and TAC-positive cases assigned etiologies using different cycle threshold (CT) cutoffs. RESULTS: Using conventional assays, the median (interquartile range) mVS was 10 (8, 11) for rotavirus, 9 (7, 11) for adenovirus 40/41, 8 (6, 10) for astrovirus, sapovirus, and norovirus GII, and 7 (6, 9) for norovirus GI. Compared to rotavirus EIA-positive cases, the median mVS was 2 and 3 points lower for EIA-negative/TAC-positive cases with CT<32.6 and 32.6≤CT<35, respectively (p-value<.0001). Adenovirus 40/41 EIA-positive and EIA-negative/TAC-positive cases were similar, regardless of CT cutoff. CONCLUSIONS: Quantitative molecular assays compared to conventional assays, such as EIA, may influence severity of identified cases, especially for rotavirus. Cutoffs to assign etiology for quantitative assays should be considered in the design and interpretation of enteric virus studies.

Data Management in Multicountry Consortium Studies: The Enterics For Global Health (EFGH) Shigella Surveillance Study Example.

Background: Rigorous data management systems and planning are essential to successful research projects, especially for large, multicountry consortium studies involving partnerships across multiple institutions. Here we describe the development and implementation of data management systems and procedures for the Enterics For Global Health (EFGH) Shigella surveillance study-a 7-country diarrhea surveillance study that will conduct facility-based surveillance concurrent with population-based enumeration and a health care utilization survey to estimate the incidence of Shigella--associated diarrhea in children 6 to 35 months old. Methods: The goals of EFGH data management are to utilize the knowledge and experience of consortium members to collect high-quality data and ensure equity in access and decision-making. During the planning phase before study initiation, a working group of representatives from each EFGH country site, the coordination team, and other partners met regularly to develop the data management systems for the study. Results: This resulted in the Data Management Plan, which included selecting REDCap and SurveyCTO as the primary database systems. Consequently, we laid out procedures for data processing and storage, study monitoring and reporting, data quality control and assurance activities, and data access. The data management system and associated real-time visualizations allow for rapid data cleaning activities and progress monitoring and will enable quicker time to analysis. Conclusions: Experiences from this study will contribute toward enriching the sparse landscape of data management methods publications and serve as a case study for future studies seeking to collect and manage data consistently and rigorously while maintaining equitable access to and control of data.

Exploring Natural Immune Responses to Shigella Exposure Using Multiplex Bead Assays on Dried Blood Spots in High-Burden Countries: Protocol From a Multisite Diarrhea Surveillance Study.

Background: Molecular diagnostics on human fecal samples have identified a larger burden of shigellosis than previously appreciated by culture. Evidence of fold changes in immunoglobulin G (IgG) to conserved and type-specific Shigella antigens could be used to validate the molecular assignment of type-specific Shigella as the etiology of acute diarrhea and support polymerase chain reaction (PCR)-based microbiologic end points for vaccine trials. Methods: We will test dried blood spots collected at enrollment and 4 weeks later using bead-based immunoassays for IgG to invasion plasmid antigen B and type-specific lipopolysaccharide O-antigen for Shigella flexneri 1b, 2a, 3a, and 6 and Shigella sonnei in Shigella-positive cases and age-, site-, and season-matched test-negative controls from all sites in the Enterics for Global Health (EFGH) Shigella surveillance study. Fold antibody responses will be compared between culture-positive, culture-negative but PCR-attributable, and PCR-positive but not attributable cases and test-negative controls. Age- and site-specific seroprevalence distributions will be identified, and the association between baseline antibodies and Shigella attribution will be estimated. Conclusions: The integration of these assays into the EFGH study will help support PCR-based attribution of acute diarrhea to type-specific Shigella, describe the baseline seroprevalence of conserved and type-specific Shigella antibodies, and support correlates of protection for immunity to Shigella diarrhea. These insights can help support the development and evaluation of Shigella vaccine candidates.

The Enterics for Global Health (EFGH) Shigella Surveillance Study in Mali.

Background: In 2002, the Centre pour le Développement des Vaccins du Mali (CVD-Mali) was established as a partnership between the Mali Ministry of Health and the University of Maryland, Baltimore. Since its creation, CVD-Mali has been dedicated to describing the epidemiology of infectious diseases, supporting the development of vaccines, and training a team of local researchers. CVD-Mali participated in the Global Enteric Multicenter Study from 2007 to 2010 and the Vaccine Impact on Diarrhea in Africa study from 2015 to 2018, where the importance of Shigella as an enteric pathogen was established. Methods: In the Enterics for Global Health (EFGH) Shigella surveillance study, CVD-Mali will conduct Shigella surveillance at 4 health centers serving the population currently participating in a demographic surveillance system and will measure the local incidence of Shigella diarrhea and related outcomes in 6- to 35-month-old children. Antibiotic sensitivity patterns and the costs related to these cases will also be measured. Results: We anticipate reporting the number of diarrhea episodes that are positive by stool culture, the antibiotic susceptibility of these isolates, and the management and outcomes of these cases. Conclusions: In Mali, the EFGH study will contribute valuable information to understanding the burden of Shigella in this population. These data will inform the evaluation of vaccine candidates.

Factors predicting mortality in hospitalised HIV-negative children with lower-chest-wall indrawing pneumonia and implications for management.

INTRODUCTION: In 2012, the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) but no 'danger signs', to recommend home-based treatment. We analysed data from children hospitalized with LCWI pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) study to identify sub-groups with high odds of mortality, who might continue to benefit from hospital management but may not be admitted by staff implementing the 2012 guidelines. We compare the proportion of deaths identified using the criteria in the 2012 guidelines, and the proportion of deaths identified using an alternative set of criteria from our model. METHODS: PERCH enrolled a cohort of 2189 HIV-negative children aged 2-59 months who were admitted to hospital with LCWI pneumonia (without obvious cyanosis, inability to feed, vomiting, convulsions, lethargy or head nodding) between 2011-2014 in Kenya, Zambia, South Africa, Mali, The Gambia, Bangladesh, and Thailand. We analysed risk factors for mortality among these cases using predictive logistic regression. Malnutrition was defined as mid-upper-arm circumference <125mm or weight-for-age z-score <-2. RESULTS: Among 2189 cases, 76 (3·6%) died. Mortality was associated with oxygen saturation <92% (aOR 3·33, 1·99-5·99), HIV negative but exposed status (4·59, 1·81-11·7), moderate or severe malnutrition (6·85, 3·22-14·6) and younger age (infants compared to children 12-59 months old, OR 2·03, 95%CI 1·05-3·93). At least one of three risk factors: hypoxaemia, HIV exposure, or malnutrition identified 807 children in this population, 40% of LCWI pneumonia cases and identified 86% of the children who died in hospital (65/76). Risk factors identified using the 2012 WHO treatment guidelines identified 66% of the children who died in hospital (n = 50/76). CONCLUSIONS: Although it focuses on treatment failure in hospital, this study supports the proposal for better risk stratification of children with LCWI pneumonia. Those who have hypoxaemia, any malnutrition or those who were born to HIV positive mothers, experience poorer outcomes than other children with LCWI pneumonia. Consistent identification of these risk factors should be prioritised and children with at least one of these risk factors should not be managed in the community.

Burden of child mortality from malaria in high endemic areas: Results from the CHAMPS network using minimally invasive tissue sampling.

BACKGROUND: Malaria is a leading cause of childhood mortality worldwide. However, accurate estimates of malaria prevalence and causality among patients who die at the country level are lacking due to the limited specificity of diagnostic tools used to attribute etiologies. Accurate estimates are crucial for prioritizing interventions and resources aimed at reducing malaria-related mortality. METHODS: Seven Child Health and Mortality Prevention Surveillance (CHAMPS) Network sites collected comprehensive data on stillbirths and children <5 years, using minimally invasive tissue sampling (MITS). A DeCoDe (Determination of Cause of Death) panel employed standardized protocols for assigning underlying, intermediate, and immediate causes of death, integrating sociodemographic, clinical, laboratory (including extensive microbiology, histopathology, and malaria testing), and verbal autopsy data. Analyses were conducted to ascertain the strength of evidence for cause of death (CoD), describe factors associated with malaria-related deaths, estimate malaria-specific mortality, and assess the proportion of preventable deaths. FINDINGS: Between December 3, 2016, and December 31, 2022, 2673 deaths underwent MITS and had a CoD attributed from four CHAMPS sites with at least 1 malaria-attributed death. No malaria-attributable deaths were documented among 891 stillbirths or 924 neonatal deaths, therefore this analysis concentrates on the remaining 858 deaths among children aged 1-59 months. Malaria was in the causal chain for 42.9% (126/294) of deaths from Sierra Leone, 31.4% (96/306) in Kenya, 18.2% (36/198) in Mozambique, 6.7% (4/60) in Mali, and 0.3% (1/292) in South Africa. Compared to non-malaria related deaths, malaria-related deaths skewed towards older infants and children (p < 0.001), with 71.0% among ages 12-59 months. Malaria was the sole infecting pathogen in 184 (70.2%) of malaria-attributed deaths, whereas bacterial and viral co-infections were identified in the causal pathway in 24·0% and 12.2% of cases, respectively. Malnutrition was found at a similar level in the causal pathway of both malaria (26.7%) and non-malaria (30.7%, p = 0.256) deaths. Less than two-thirds (164/262; 62.6%) of malaria deaths had received antimalarials prior to death. Nearly all (98·9%) malaria-related deaths were deemed preventable. INTERPRETATION: Malaria remains a significant cause of childhood mortality in the CHAMPS malaria-endemic sites. The high bacterial co-infection prevalence among malaria deaths underscores the potential benefits of antibiotics for severe malaria patients. Compared to non-malaria deaths, many of malaria-attributed deaths are preventable through accessible malaria control measures.

Post-mortem investigation of deaths due to pneumonia in children aged 1-59 months in sub-Saharan Africa and South Asia from 2016 to 2022: an observational study.

BACKGROUND: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network programme undertakes post-mortem minimally invasive tissue sampling (MITS), together with collection of ante-mortem clinical information, to investigate causes of childhood deaths across multiple countries. We aimed to evaluate the overall contribution of pneumonia in the causal pathway to death and the causative pathogens of fatal pneumonia in children aged 1-59 months enrolled in the CHAMPS Network. METHODS: In this observational study we analysed deaths occurring between Dec 16, 2016, and Dec 31, 2022, in the CHAMPS Network across six countries in sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and one in South Asia (Bangladesh). A standardised approach of MITS was undertaken on decedents within 24-72 h of death. Diagnostic tests included blood culture, multi-organism targeted nucleic acid amplifications tests (NAATs) of blood and lung tissue, and histopathology examination of various organ tissue samples. An interdisciplinary expert panel at each site reviewed case data to attribute the cause of death and pathogenesis thereof on the basis of WHO-recommended reporting standards. FINDINGS: Pneumonia was attributed in the causal pathway of death in 455 (40·6%) of 1120 decedents, with a median age at death of 9 (IQR 4-19) months. Causative pathogens were identified in 377 (82·9%) of 455 pneumonia deaths, and multiple pathogens were implicated in 218 (57·8%) of 377 deaths. 306 (67·3%) of 455 deaths occurred in the community or within 72 h of hospital admission (presumed to be community-acquired pneumonia), with the leading bacterial pathogens being Streptococcus pneumoniae (108 [35·3%]), Klebsiella pneumoniae (78 [25·5%]), and non-typeable Haemophilus influenzae (37 [12·1%]). 149 (32·7%) deaths occurred 72 h or more after hospital admission (presumed to be hospital-acquired pneumonia), with the most common pathogens being K pneumoniae (64 [43·0%]), Acinetobacter baumannii (19 [12·8%]), S pneumoniae (15 [10·1%]), and Pseudomonas aeruginosa (15 [10·1%]). Overall, viruses were implicated in 145 (31·9%) of 455 pneumonia-related deaths, including 54 (11·9%) of 455 attributed to cytomegalovirus and 29 (6·4%) of 455 attributed to respiratory syncytial virus. INTERPRETATION: Pneumonia contributed to 40·6% of all childhood deaths in this analysis. The use of post-mortem MITS enabled biological ascertainment of the cause of death in the majority (82·9%) of childhood deaths attributed to pneumonia, with more than one pathogen being commonly implicated in the same case. The prominent role of K pneumoniae, non-typable H influenzae, and S pneumoniae highlight the need to review empirical management guidelines for management of very severe pneumonia in low-income and middle-income settings, and the need for research into new or improved vaccines against these pathogens. FUNDING: Bill & Melinda Gates Foundation.

Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics.

BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.

Immunogenicity and Vaccine Shedding After 1 or 2 Doses of rVSVΔG-ZEBOV-GP Ebola Vaccine (ERVEBO®): Results From a Phase 2, Randomized, Placebo-controlled Trial in Children and Adults.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older. METHODS: The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1-17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR. RESULTS: In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2. CONCLUSIONS: A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18).

Provider adherence to clinical care recommendations for infants and children who died in seven low- and middle-income countries in the Child Health and Mortality Prevention Surveillance (CHAMPS) network.

Background: Most childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe adherence to World Health Organization recommendations for the management of leading causes of death among children. Methods: We conducted a retrospective, descriptive study examining clinical data for children aged 1-59 months who were hospitalized and died in a Child Health and Mortality Prevention Surveillance (CHAMPS) catchment, December 2016-June 2021. Catchment areas included: Baliakandi and Faridpur, Bangladesh; Kersa, Haramaya, and Harar, Ethiopia; Kisumu and Siaya, Kenya; Bamako, Mali; Manhiça and Quelimane, Mozambique; Makeni, Sierra Leone; Soweto, South Africa. We reviewed medical records of those who died from lower respiratory tract infections, sepsis, malnutrition, malaria, and diarrheal diseases to determine the proportion who received recommended treatments and compared adherence by hospitalization duration. Findings: CHAMPS enrolled 460 hospitalized children who died from the leading causes (median age 12 months, 53.0% male). Median hospital admission was 31 h. There were 51.0% (n = 127/249) of children who died from lower respiratory tract infections received supplemental oxygen. Administration of intravenous fluids for sepsis (15.9%, n = 36/226) and supplemental feeds for malnutrition (14.0%, n = 18/129) were uncommon. There were 51.4% (n = 55/107) of those who died from malaria received antimalarials. Of the 80 children who died from diarrheal diseases, 76.2% received intravenous fluids. Those admitted for ≥24 h more commonly received antibiotics for lower respiratory tract infections and sepsis, supplemental feeds for malnutrition, and intravenous fluids for sepsis than those admitted <24 h. Interpretation: Provision of recommended clinical care for leading causes of death among young children was suboptimal. Further studies are needed to understand the reasons for deficits in clinical care recommendation adherence. Funding: Bill & Melinda Gates Foundation.

Antenatal, intrapartum and infant azithromycin to prevent stillbirths and infant deaths: study protocol for SANTE, a 2×2 factorial randomised controlled trial in Mali.

INTRODUCTION: In high mortality settings, prophylactic azithromycin has been shown to improve birth weight and gestational age at birth when administered antenatally, to reduce the incidence of neonatal infections when administered intrapartum, and to improve survival when administered in infancy. Questions remain regarding whether azithromycin can prevent stillbirths, and regarding the optimal strategy for the delivery of azithromycin to pregnant women and their infants. METHODS AND ANALYSIS: Sauver avec l'Azithromycine en Traitant les Femmes Enceintes et les Enfants (SANTE) is a 2×2 factorial, individually randomised, placebo-controlled, double-masked trial in rural Mali. The primary aims are: (1A) to assess the efficacy of antenatal and intrapartum azithromycin on a composite outcome of stillbirths and infant mortality through 6-12 months and (1B) to assess the efficacy of azithromycin administered concurrently with the first and third doses of pentavalent vaccines (Penta-1/3) on infant mortality through 6-12 months. Pregnant participants (n=49 600) and their infants are randomised 1:1:1:1 to one of four treatment arms: (1) mother and infant receive azithromycin, (2) mother and infant receive placebo, (3) mother receives azithromycin and infant receives placebo or (4) mother receives placebo and infant receives azithromycin. Pregnant participants receive three single 2 g doses: two antepartum and one intrapartum. Infants receive a single 20 mg/kg dose at the Penta-1 and 3 visits. An additional cohort of 12 000 infants is recruited at the Penta-1 visit and randomised 1:1 to receive azithromycin or placebo at the same time points. The SANTE trial will inform guidelines and policies regarding the administration of antenatal and infant azithromycin using routine healthcare delivery platforms. ETHICS AND DISSEMINATION: This trial was approved by the Institutional Review Board at the University of Maryland School of Medicine (Protocol #HP-00084242) and the Faculté de Médecine et d'Odonto-Stomatologie in Mali. The findings of this trial will be published in open access peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03909737.

Safety and immunogenicity of quadrivalent meningococcal polysaccharide vaccine (MPV ACYW135) compared with quadrivalent meningococcal conjugate vaccine (Menactra®) in Malian children.

Affordable, polyvalent meningococcal vaccines are needed for use in emergency reactive immunization campaigns. A phase IV randomized, observer-blind, controlled study compared the safety and immunogenicity of a quadrivalent meningococcal polysaccharide vaccine (MPV-4, MPV ACYW135) and quadrivalent meningococcal ACWY conjugate vaccine (MCV-4, Menactra®). Healthy, 2- to 10-year-old children in Bamako, Mali, were randomized 1:1 to receive one dose of MPV-4 or MCV-4. Safety outcomes were evaluated for 6 months post-immunization. Immunogenicity for all serogroups was assessed for non-inferiority between MPV-4 and MCV-4 30 days post immunization by serum bactericidal antibody assay using baby rabbit complement (rSBA). From December 2020 to July 2021, 260 healthy subjects were consented and randomized. At Day 30 post-immunization, the proportions of subjects with rSBA titers ≥ 128 for all serogroups in the MPV-4 group were non-inferior to those in MCV-4 group. The proportions of subjects with rSBA ≥ 4-fold increase and rSBA titers ≥ 8 for all serogroups were similar among vaccine groups (P > .05). Geometric Mean Titers and Geometric Mean Fold Increases for all serogroups in both vaccine groups were similar (P > .05). Few local and systemic post-immunization reactions of similar severity and duration were observed within 7 days and were similar in both groups (P > .05). All resolved without sequelae. Unsolicited adverse events were similar in both groups regarding relationship to study vaccine, severity and duration. No serious adverse events were reported during the study period. MPV ACYW135 showed a non-inferior immunogenicity profile and a comparable reactogenicity profile to MCV-4 in Malian children aged 2-10 years.Clinical Trial Registration: NCT04450498.