Background:Shigella is a leading cause of diarrheal illness in children in low- and middle-income countries, with evidence of contribution to prolonged diarrhoea, hospitalization, and impaired growth. Methods:In this prospective cohort study, we analysed data from 8756 children aged 6-35 months with acute (onset within the last seven days after at least two diarrhoea-free days) medically attended diarrhoea (defined as three or more abnormally loose or watery stools with or without blood in the previous 24 h) enrolled between June 2022-August 2024 from health facilities in Bangladesh (1341 children from 3 health facilities), Kenya (1390 children from 6 health facilities), Malawi (1325, 1), Mali (1341, 4), Pakistan (1365, 6), Peru (1058, 5), and The Gambia (937, 2). Eligible children resided in the pre-defined catchment area and were accompanied by a consenting caregiver. We evaluated associations between Shigella-attributed diarrhoea (compared to controls with no detected diarrheagenic pathogen) and three primary outcomes: prolonged/persistent diarrhoea, hospitalization, and linear growth faltering assessed at 4 weeks and 3 month follow-up visits. Pathogen attribution was based on culture or pathogen-specific quantitative PCR thresholds. Poisson regression and linear regression with generalised estimating equations were used to assess associations, stratified by antibiotic treatment and adjusted for sociodemographic and clinical variables. Findings:Shigella was the most prevalent attributed pathogen (20.6%). It was the only pathogen associated with both prolonged (≥seven days, adjusted Prevalence Ratio (aPR): 1.56, 95% CI: 1.34-1.82) and persistent (≥14 days, aPR: 1.66, 95% CI:1.03-2.68) diarrhoea. No associations were identified between Shigella and hospitalization or linear growth faltering. However, children with Shigella who did not receive effective antibiotics experienced greater decrements in linear growth (length-for-age z-score (LAZ)/height-for-Age Z-score (HAZ): -0.05, 95% CI: -0.09, -0.01) in the three months following infection compared to those without any pathogen detected. Rotavirus (adjusted Risk Ratio (aRR): 2.40, 95% CI: 1.53-3.76) and Cryptosporidium (aRR: 2.33, 95% CI: 1.35-4.04) were associated with hospitalization, and Cryptosporidium was linked to subsequent stunting (aRR: 1.36, 95% CI: 1.01-1.84). Interpretation:Shigella contributes to prolonged and persistent diarrhoea and, when untreated, can contribute to linear growth faltering. Pathogen-specific diagnosis, antibiotic access, and Shigella vaccination could reduce prolonged illness and growth impairment, with meaningful population-level benefits in low- and middle-income settings. Funding:Gates Foundation.

Abstract Although the co-occurrence of diarrhea and malnutrition is well documented, research has largely focused on the acute management of diarrheal illness. Despite its importance, longitudinal evidence characterizing post-diarrheal recovery trajectories is sparse. We sought to characterize post-diarrheal nutritional recovery trajectories among children aged 6–35 months who were malnourished at enrollment using data from the Enterics for Global Health (EFGH) Shigella Surveillance study (2022–2024). EFGH enrolled children aged 6–35 months presenting with medically-attended diarrhea and followed them at 4 weeks and 3 months post-enrollment. This analysis included children with baseline wasting, stunting, or underweight (z-score < −2) and complete anthropometric follow-up. Latent class mixed-effects models were used to identify distinct post-diarrheal growth trajectories based on changes in anthropometric z-scores over time. Multinomial modified Poisson regression models examined associations between baseline factors and trajectory membership. Among 9,480 enrolled children, 16.5% (n=1,561) were wasted, 22.7% (n=2,155) stunted, and 21.0% (n=1,994) underweight at baseline. Wasting showed greater recovery potential (80.8%) compared with stunting (38.5%) and underweight (40.3%). Recovery was shaped by factors across multiple levels. Clinical severity markers ( prolonged diarrhea, dehydration, and hypoxemia) increased the risk of nutritional failure. Age also influenced outcomes: infants were more likely to worsen, whereas older toddlers more often experienced stagnation. Interventions including exclusive breastfeeding, oral rehydration therapy, appropriate antibiotics, and zinc supplementation, improved outcomes, while unimproved sanitation undermined recovery. These findings highlight the need for integrated strategies combining infection control, nutritional rehabilitation, and water, sanitation, and hygiene interventions tailored to the children’s developmental stage. Key Messages Post-diarrheal nutritional recovery is highly heterogeneous, with wasting showing the greatest potential for improvement, while stunting and underweight often result in persistent growth stagnation. Baseline anthropometric deficits alone are insufficient to predict recovery, highlighting the need for dynamic monitoring and individualized management. Infants are particularly vulnerable to acute nutritional deterioration, while older toddlers frequently experience growth stagnation. Modifiable protective factors including exclusive breastfeeding, ORS, zinc, and appropriate antibiotics, improved outcomes, whereas poor sanitation undermined recovery. Integrated strategies, tailored to a child’s developmental stage, combining clinical care, nutrition, and environmental interventions are critical to support sustained child growth and development.

Sub-Saharan Africa bears the highest burden of diarrhea, often complicated by comorbidities that delay diagnosis, hinder treatment, and worsen outcomes. As the epidemiology of diarrheal disease evolves, understanding comorbidity patterns is critical for effective public health responses. We examined the temporal patterns and risk factors of diarrheal comorbidity in Kenyan children aged < 5. We conducted secondary pooled analysis with a retrospective cohort design leveraging data from the Global Enteric Multicenter Study (GEMS, 2008-2012), the Vaccine Impact on Diarrhea in Africa (VIDA, 2015-2018), the Enteric for Global Health (EFGH) Shigella surveillance study (2022-2024). The outcome was comorbidity count, defined by Integrated Management of Childhood Illnesses case definitions and clinician diagnoses of ten conditions: malaria, bacterial infection, pneumonia, severe acute malnutrition (SAM), meningitis, acute febrile illness (AFI), respiratory Illness (non-pneumonia), anemia, stunting and wasting. Temporal trends were assessed using descriptive statistics and the Cochran-Armitage trend test. Risk factors were identified using generalized estimating equations with a Poisson distribution, adjusting for clustering. We analyzed data from 4,148 children with moderate-to-severe diarrhea; 90.3% had ≥ one comorbidity, with a declining trend across studies: GEMS (92.9%), VIDA (89.3%), and EFGH (86.6%). Pneumonia (49.5%), malaria (48.3%), and stunting (24.7%) were most common comorbidities. The proportion of children with only one comorbidity increased (28.9% [2008] to 49.7% [2024]), while multiple comorbidities declined. Traditional comorbidities (malaria, pneumonia, wasting, SAM) significantly decreased, while AFI, anemia, and non-pneumonia respiratory illness increased. Multivariable analysis identified older age, lower caregiver education, dehydration, vomiting, 3-month lagged rainfall and temperature, and high respiratory rate as drivers of higher comorbidity counts, while female sex was associated with fewer comorbidities. Despite the high prevalence, we observed a 20-23% decline in comorbidity burden and a fundamental shift in disease profiles. Our findings support the need for a shift from single-disease control to integrated disease management.

BACKGROUND:Understanding the extent of protection against typhoid fever conferred by naturally occurring typhoid is essential for transmission modeling and vaccine policy development. However, data on the level of protection from natural typhoid against recurrent typhoid episodes are sparse. METHODS:We analyzed data from a cluster-randomized trial of a typhoid conjugate vaccine conducted in Dhaka, Bangladesh. A cohort of blood culture-confirmed typhoid patients (index cases) and matched controls (1:4 ratio) from the community who had not received the typhoid vaccine were followed for up to six years to identify recurrent typhoid episodes. A recurrent typhoid episode was defined as one occurring more than 30 days after the onset of the initial episode and/or involving a strain with a different antimicrobial resistance profile. Febrile patients who tested negative for Salmonella Typhi through passive surveillance were also evaluated as facility-based controls. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) for recurrent typhoid episodes. RESULTS:We identified 13 recurrent episodes among 940 index cases and 12 episodes among 3,760 community-based controls, yielding incidence rates of 741 and 158 per 100,000 person-years, respectively, with an adjusted hazard ratio (aHR) of 3.7; 95%CI: 1.8, 7.9; p<0.001. However, when using facility-based controls to prevent healthcare utilization bias, there was no statistically significant difference between groups (aHR: 1.5, 95%CI: 0.8, 2.8; p=0.160). CONCLUSION:In this typhoid-endemic population comprising both children and adults, we found no evidence that natural typhoid fever confers protection against recurrent typhoid episodes.

Abstract Introduction A cluster randomized trial (CRT) in Bangladesh found that Vi-tetanus toxoid (Vi-TT) vaccine conferred 85% protection to vaccinees at 18 months of follow-up; however, it failed to confer significant herd protection to non-vaccinees. Methods In the CRT, children aged 9 months to <16 years from 150 clusters received one dose of either Vi-TT or Japanese encephalitis vaccine. To evaluate whether herd protection was evident, we analyzed two years of follow-up data by quartiles of clusters with ascending levels of Vi-TT coverage. Results The average vaccine coverage across all clusters was 69% among targeted children and 20% in the entire population. Vi-TT provided 83% (95%CI: 74%,89%) total protection among vaccinees, 12% (95%CI: -17%,34%) indirect protection among non-vaccinees, and 53% (95%CI: 40%,63%) overall protection among entire population, irrespective of vaccine coverage. Significant herd protection (47%; 95%CI: 3%,71%) was observed only in the highest quartile of vaccine coverage in the entire population (range 21.5%-26%). No herd protection was evident among targeted children (<16 years), including the highest coverage quartile (72.1%-78.9%), where protection was - 8% (95%CI: -108%,44%). Conclusion Vaccine herd protection, essential for typhoid conjugate vaccines to achieve high overall protection, was evident only in clusters with higher, albeit still modest, coverage in the entire population. Since even high coverage among children <16 years did not generate significant herd protection, higher vaccine coverage across all age groups, including vaccination of adults, may be necessary for TCVs to confer the combined direct and herd protection required for effective typhoid control. Summary box What is already known on this topic? Vi-tetanus toxoid (Vi-TT) vaccine provides high-level protection against typhoid fever in vaccinated children. However, overall analysis of a cluster-randomized trial of Vi-TT given to children under 16 years of age found no evidence of indirect (herd) protection by Vi-TT to unvaccinated individuals. What this study adds In further analysis of the cluster randomized trial of Vi-TT, significant indirect protection (47%; 95%CI:3%,71%) was observed, but only in clusters with the highest levels of vaccine coverage of the entire population. In contrast, we found no evidence of vaccine herd protection in clusters with the highest levels of vaccine coverage of children, who were targeted by vaccination. How this study might affect research, practice, or policy Achieving herd protection from typhoid conjugate vaccines (TCVs) may require higher vaccine coverage across the entire population, not only among children. Vaccination strategies that include adults may be necessary to maximize the public health impact of TCVs. These findings have important implications for typhoid control policies in endemic settings.

BACKGROUND:Shigella vaccine development is a critical priority due to high burden and long-term outcomes among children. Choosing a clinical efficacy endpoint for Shigella vaccine trials requires comparing existing diarrhea severity definitions among children with Shigella. METHODS:Six- to 35-month-old children presenting with diarrhea were enrolled at 7 EFGH study sites. Among children with Shigella, 6 diarrhea severity definitions (Global Enteric Multicenter Study [GEMS] moderate-to-severe diarrhea [MSD], modified Vesikari score [MVS], MVS +/- dysentery, Clark score, MAL-ED score, and Shigella mortality score) were examined against 2 outcomes: change in length/height-for-age z-score (ΔLAZ/HAZ) over 3 months and death or hospitalization within 14 days. We compared the performance of each severity score to predict outcomes using linear regression and measures of diagnostic accuracy. RESULTS:Moderate or severe diarrhea was negatively associated with ΔLAZ/HAZ by MVS (-0.07 z-score, 95% CI -0.10 to -0.03), MVS +/- dysentery (-0.05, 95% CI -0.09 to -0.02), and MAL-ED score (-0.04, 95% CI -0.07 to 0.00). GEMS MSD (93.6%), MAL-ED (87.2%), MVS +/- dysentery (85.1%), and MVS (80.9%) had high sensitivity in predicting death or hospitalization. CONCLUSIONS:MVS, MVS +/- dysentery, and MAL-ED score identified adverse outcomes following Shigella diarrhea and are viable options for a vaccine trial case definition.

We estimated rotavirus vaccine effectiveness among children <2 years of age in Mali from 2015-2018. Using a test-negative case-control design, rotavirus vaccine was 60% (95% confidence interval: 3%-84%) effective among children <2 years of age. Rotavirus vaccines are an effective tool for reducing rotavirus disease burden in Mali.

ABSTRACT Shigella is a major cause of childhood diarrhea in sub-Saharan Africa. Current World Health Organization (WHO) guidelines recommend empiric antibiotics only for dysentery, yet non-dysenteric presentations account for 40–89% of Shigella infections. We quantified the performance of existing guidelines to identify Shigella infection and evaluated enhanced syndromic criteria for improved management of Shigella cases. We leveraged data from the Enteric for Global Health (EFGH) Kenyan site, which enrolled children aged 6-35 months with medically attended diarrhea, collected rectal swabs at enrolment, and tested these for Shigella using both the culture and TaqMan-array cards (TAC). Shigella positivity was defined as either a culture-confirmed Shigella or a TAC-attributable result (CT <29.5). We compared categorical variables using the χ² test or Fisher’s exact as appropriate while continuous variables were compared between groups using the Wilcoxon rank-sum test. A logistic regression model was fitted to identify a parsimonious set of predictors. Out of the enrolled 1400 MAD cases, of whom 175 (12.5%) were Shigella positive, of which 134 (76.5%) being non-dysenteric. Among all enrolled children, 148 (10.6%) were dysenteric and 1,252 (89.4%) were non-dysenteric. Of the non-dysenteric cases, 57/1,252 (4.6%) and 129/1,251 (10.3%) of children were Shigella attributable by culture and TAC, respectively. Compared to Shigella negative cases, positive cases were older (Median age in months [Q1-Q3]: 20 [14–24] vs 13 [8–19], p<0.001), had higher stool frequency (5 [3–6] vs 4 [3–5], p<0.049) and were more likely to be dysenteric (42 [24%] vs 106 [8.7%], p<0.001). Contrarily, Shigella positive cases were less likely to present with vomiting (66 [37.7%] vs 587 [47.9%], p=0.014) and difficulty in breathing (0 (0%) vs 27 [2.2%], p<0.040). Dysentery alone had minimal predictive power to identify Shigella (area under the ROC curve (AUC) [95% CI]: 0.58 [0.54-0.61]), while Dysentery and Age binary (<17 months) (0.70 [0.66–0.74]), and Dysentery, Vomiting, Difficult breathing, and Age binary (0.72 [0.68-0.76]) had acceptable predictive performance. Our data shows that current guidelines miss up to 76.5% of Shigella -positive cases which are non-dysenteric. This suggests that dysentery alone has limited predictive power, but incorporating additional symptoms increases discriminatory ability by up to 14%, with age alone improving it by 12%. These findings support the need to re-evaluate the current syndromic based guidelines to better detect Shigellosis and strengthen antibiotic stewardship.

Abstract Background Despite the adverse health outcomes associated with longer duration diarrhea (LDD), there are currently no clinical decision tools for timely identification and better management of children with increased risk. This study utilizes machine learning (ML) to derive and validate a predictive model for LDD among children presenting with diarrhea to health facilities. Methods LDD was defined as a diarrhea episode lasting ≥ 7 days. We used 7 ML algorithms to build prognostic models for the prediction of LDD among children < 5 years using de-identified data from Vaccine Impact on Diarrhea in Africa study (N = 1,482) in model development and data from Enterics for Global Health Shigella study (N = 682) in temporal validation of the champion model. Features included demographic, medical history and clinical examination data collected at enrolment in both studies. We conducted split-sampling and employed K-fold cross-validation with over-sampling technique in the model development. Moreover, critical predictors of LDD and their impact on prediction were obtained using an explainable model agnostic approach. The champion model was determined based on the area under the curve (AUC) metric. Model calibrations were assessed using Brier, Spiegelhalter’s z-test and its accompanying p-value. Results There was a significant difference in prevalence of LDD between the development and temporal validation cohorts (478 [32.3%] vs 69 [10.1%]; p < 0.001). The following variables were associated with LDD in decreasing order: pre-enrolment diarrhea days (55.1%), modified Vesikari score(18.2%), age group (10.7%), vomit days (8.8%), respiratory rate (6.5%), vomiting (6.4%), vomit frequency (6.2%), rotavirus vaccination (6.1%), skin pinch (2.4%) and stool frequency (2.4%). While all models showed good prediction capability, the random forest model achieved the best performance (AUC [95% Confidence Interval]: 83.0 [78.6–87.5] and 71.0 [62.5–79.4]) on the development and temporal validation datasets, respectively. While the random forest model showed slight deviations from perfect calibration, these deviations were not statistically significant (Brier score = 0.17, Spiegelhalter p-value = 0.219). Conclusions Our study suggests ML derived algorithms could be used to rapidly identify children at increased risk of LDD. Integrating ML derived models into clinical decision-making may allow clinicians to target these children with closer observation and enhanced management.

Poor water, sanitation, and hygiene (WASH) are the primary risks of exposure to enteric viral infection. Our study aimed to describe the role of WASH conditions and practices as risk factors for enteric viral infections in children under 5. Literature on the risk factors associated with all-cause diarrhea masks the taxa-specific drivers of diarrhea from specific pathogens, limiting the application of relevant control strategies. We analyzed data from children enrolled in the Global Enteric Multicenter Study (GEMS) across seven study sites between December 2007 and March 2011 as cases (moderate-to-severe diarrhea: MSD) and asymptomatic controls. MSD was defined as new and acute diarrhea, with at least one of the following criteria for MSD: dehydration based on the study clinician's assessment, dysentery, or hospitalization with diarrhea or dysentery. Multiple logistic regression was used to examine the role of water quality, sanitation access, and hygiene facilities on the enteric viral pathogens adjusted for potential covariates. Among MSD symptomatic children (cases), longer water retrieval time (≥15 vs <15 min) was associated with increased Norovirus (aOR 1.33, 95 % CI 1.08–1.64) and Astrovirus (aOR 1.43, 95 % CI 1.01–2.02); scooping as drinking water retrieval method was associated with lower Rotavirus (aOR 0.77, 95 % CI 0.62–0.96), but higher Adenovirus (aOR 2.3, 95 % CI 1.32–4.11) infection compared to non-users. Among asymptomatic children (controls), consumption of non-tube well drinking water was associated with higher Norovirus infection (aOR 1.38, 95 % CI 1.01–1.89). Longer drinking water retrieval time (≥15 vs <15 min) increased Norovirus (aOR 1.47, 95 % CI 1.21–1.78) and Rotavirus (aOR 1.51, 95 % CI 1.20–1.89) infections. Pouring (aOR 0.51, 95 % CI 0.32–0.83) or scooping drinking water with a cup (aOR: 0.52; 95 % CI: 0.32, 0.86) lower Astrovirus infection; restricted water access (aOR 1.57, 95 % CI 1.21–2.02) higher Rotavirus infection. Handwashing before cooking was associated with lower Astrovirus (aOR 0.64, 95 % CI 0.47–0.88) infection in asymptomatic children. Our analysis did not find a significant effect of poor sanitation on different enteric viral pathogens examined. Norovirus and Astrovirus were detected more commonly in sub-Saharan Africa while Rotavirus was less prevalent than South Asia. Though we found statistically significant associations, we did not observe any overall pattern between WASH and enteric viral pathogens. Our findings provide insights to guide further research on targeted interventions for enteric viral pathogens, responsible for a major burden of pediatric diarrhea globally.

Background:Shigella spp are among the notable causes of global diarrheal disease and death, accounting for 13.2% of deaths in 2016. Antimicrobial resistance complicates shigellosis management. Understanding local disease epidemiology is crucial for developing effective preventive strategies, including vaccine use. Methods:We investigated antimicrobial resistance, risk factors (socioeconomic, behavioral, and water, sanitation and hygiene (WaSH), and clinical characteristics of Shigella diarrhea in Mukuru informal settlement and surrounding villages in Nairobi, Kenya. Patients presenting with diarrhea, fever, or both in treatment centers had stool or rectal swab samples cultured, and bacteria was identified through biochemical and serologic tests. Results:The rate of Shigella isolation among the 4689 individuals presenting with diarrhea was 1.4% across all ages, with a similar isolation rate (1.5%) among children <5 years of age. The majority of the Shigella spp (40 [59.7%]) were Shigella flexneri, and the majority of S flexneri (34 of 40 [85%]) were resistant to trimethoprim-sulfamethoxazole; however, all were sensitive to amoxicillin-clavulanate, ceftazidime, ceftriaxone, and cefpodoxime. The rate of multidrug resistance was higher in Shigella sonnei (13 [48.1%]) than in S flexneri (3 [7.5%]). Shigella positivity was associated with bloody diarrhea, severe/moderate dehydration, coated tongue, and high fever. Consumption of street food was also associated with Shigella diarrhea. Conclusions:Despite low prevalence, shigellosis still poses a significant burden of diarrheal disease, warranting future incidence studies. First-line antibiotics against Shigella remain effective, but intermediate resistance to azithromycin and ciprofloxacin is a concerning trend. Improving household food preparation and handling could potentially reduce Shigella infections.

BackgroundGlobally, moderate wasting affects approximately 33 million children. Complex bidirectional interactions exist between wasting and infection in children. Children who experience both conditions have an increased risk of adverse outcomes including progression to severe wasting and mortality. Breaking the cycle between moderate wasting and infection could help improve growth and survival in these children. The NUTRIMAM trial will aim to investigate the efficacy of a 12-week regimen of three different nutritional interventions in at-risk young children (i.e., children who are moderately wasted and have one/more acute infections) on anthropometric recovery. Further, the study will explore whether recovery can be sustained with a post-intervention package that includes counseling and food vouchers. Sustaining anthropometric recovery beyond supplement administration will have important implications for programs.MethodsNUTRIMAM is a multi-country, multi-center individually randomized, open-label, trial in five countries including Bangladesh, India, Mali, Pakistan, and Tanzania. A total of 6360 moderately wasted children aged 6 to 24 months with acute illness will be enrolled at health centers. Children will be randomly allocated to receive one of three dietary supplements (locally available foods, ready-to-use supplementary foods, or microbiota-directed supplementary foods) for 12 weeks. Anthropometric recovery will be assessed over this period. Participants who recover will then be re-randomized to a post-recovery support intervention comprising either counseling and food vouchers or routine standard of care for recovered children for an additional 12 weeks to determine if this intervention facilitates sustained recovery at 24 weeks.DiscussionChildren who are moderately wasted and have an infection are at higher risk of adverse outcomes. There are very few clinical trials that have been performed among children with moderate wasting with infectious illnesses to investigate if it is possible to break the undernutrition-infection cycle and thereby reduce the risk of nutritional deterioration to severe wasting or mortality and decrease the risk of acute infections. The results of the trial are anticipated to fill important evidence gaps in feeding recommendations for moderately wasted children with acute illness as well as interventions to sustain anthropometric recovery in children beyond the period of the nutritional intervention.Trial registrationISRCTN registry, ISRCTN53213318. Registered on April 03, 2023.

Abstract Enteric viral pathogens are associated with a significant burden of childhood morbidity and mortality. We investigated the relationship between viral pathogens and child growth among under-5 children. We analyzed data from 5572/22,567 children enrolled in the Global Enteric Multicenter Study across seven study sites (2007–2011). Multiple linear regression was used to examine the association between the viral pathogens and changes of length/height-for-age (HAZ), weight-for-age (WAZ), and weight-for-length/height (WHZ) z-scores, stratified by diarrheal symptoms and adjusted for potential covariates. Rotavirus (18.51%) and norovirus (7.33%) were the most prevalent enteric viral pathogens among symptomatic and asymptomatic under-5 children, respectively. Infection with individual enteric viral pathogens hurts child growth in asymptomatic children. However, the relationship with HAZ was less clear and statistically non-significant. On the other hand, the combined viral pathogens demonstrated a strong negative influence on child growth [WAZ: β coef.: − 0.10 (95%, CI − 0.15, − 0.05); P < 0.001 and WHZ: β: − 0.12 (95% CI − 0.17, − 0.07); P < 0.001] among asymptomatic children. Infection with any viral pathogen was associated with growth shortfalls [HAZ: β: − 0.05 (95% CI − 0.09, 0.00); P = 0.03 and WAZ: β: − 0.11 (95% CI − 0.16, − 0.07); P < 0.001 and WHZ: β: − 0.13 (95% CI − 0.18, − 0.09); P < 0.001], though the relationship with HAZ was less evident and became statistically non-significant in older children. Notably, among symptomatic children with moderate-to-severe diarrhea, individual enteric viral pathogens, as well as the combined effects of these pathogens [WHZ: β: 0.07; (95% CI 0.01, 0.14); P = 0.03] and the presence of any virus [HAZ: β: 0.09 (95% CI 0.05, 0.13) & WAZ: β: 0.08 (95% CI 0.03, 0.12); P < 0.001], exhibited positive effects on child growth. While previous studies hypothesized that several viral pathogens had a conflicting controversial role in child growth, we find clear indications that enteric viral pathogens are associated with growth shortfalls, specifically among asymptomatic children. These findings highlight the need for preventive strategies targeting children with enteric viral pathogens, which could address the consequences of growth faltering.

Age-stratified path analyses modeled associations between enteric pathogen reservoirs, transmission pathways and height-for-age z-scores (HAZ) to identify determinants of childhood growth in the Kolkata, India site of the Global Enteric Multicenter Study (GEMS). Models tested direct associations of potential pathogen reservoirs with HAZ at 60-day follow-up in separate moderate and severe diarrhea (MSD) case and control cohorts or indirectly when mediated by enteric infections. In the MSD cohort, rotavirus and typical EPEC (tEPEC) infections among children 0-11 months of age and ST-ETEC infections among children 12-23 months of age were associated with lower HAZ. Handwashing after defecating and before cooking reduced impaired growth through reductions in rotavirus and tEPEC infections. Water storage increased rotavirus and ST-ETEC infection risks, resulting in increased impaired growth, but was reduced with reported child feces disposal. The GII norovirus variant was inversely associated with HAZ among children 12-59 months of age in the control cohort. Reported handwashing before the handling of children reduced GII infections and impaired growth. Boiling water and the disposal of children's feces mediated by stored water were positively associated with HAZ. The targeting of pathogen-specific reservoirs and transmission pathways may more effectively improve childhood linear growth in South Asian urban communities.

Background Although Shigella is an important cause of diarrhea in Kenyan children, robust research platforms capable of conducting incidence-based Shigella estimates and eventual Shigella-targeted clinical trials are needed to improve Shigella-related outcomes in children. Here, we describe characteristics of a disease surveillance platform whose goal is to support incidence and consequences of Shigella diarrhea as part of multicounty surveillance aimed at preparing sites and assembling expertise for future Shigella vaccine trials.Methods We mobilized our preexisting expertise in shigellosis, vaccinology, and diarrheal disease epidemiology, which we combined with our experience conducting population-based sampling, clinical trials with high (97%-98%) retention rates, and healthcare utilization surveys. We leveraged our established demographic surveillance system (DSS), our network of healthcare centers serving the DSS, and our laboratory facilities with staff experienced in performing microbiologic and molecular diagnostics to identify enteric infections. We joined these resources with an international network of sites with similar capabilities and infrastructure to form a cohesive scientific network, designated Enterics for Global Health (EFGH), with the aim of expanding and updating our knowledge of the epidemiology and adverse consequences of shigellosis and enriching local research and career development priorities.Conclusions Shigella surveillance data from this platform could help inform Shigella vaccine trials. A diarrhea-specific research platform able to perform population-based enumeration and hospital-based surveillance plus support mentorship of young scientists has been established in western Kenya to support Enterics for Global Health-Shigella surveillance and future vaccine trials.

Background Accurate estimation of diarrhea incidence from facility-based surveillance requires estimating the population at risk and accounting for case patients who do not seek care. The Enterics for Global Health (EFGH) Shigella surveillance study will characterize population denominators and healthcare-seeking behavior proportions to calculate incidence rates of Shigella diarrhea in children aged 6-35 months across 7 sites in Africa, Asia, and Latin America.Methods The Enterics for Global Health (EFGH) Shigella surveillance study will use a hybrid surveillance design, supplementing facility-based surveillance with population-based surveys to estimate population size and the proportion of children with diarrhea brought for care at EFGH health facilities. Continuous data collection over a 24 month period captures seasonality and ensures representative sampling of the population at risk during the period of facility-based enrollments. Study catchment areas are broken into randomized clusters, each sized to be feasibly enumerated by individual field teams.Conclusions The methods presented herein aim to minimize the challenges associated with hybrid surveillance, such as poor parity between survey area coverage and facility coverage, population fluctuations, seasonal variability, and adjustments to care-seeking behavior. The Enterics for Global Health (EFGH): Shigella Surveillance Study will utilize a hybrid surveillance design to characterize population denominators and healthcare-seeking behavior to calculate Shigella diarrhea incidence rates in children aged 6 to 35 months across sites in Africa, Asia, and Latin America.

BACKGROUND:Diarrhoeal diseases cause a heavy burden in developing countries. Although studies have described the seasonality of diarrhoeal diseases, the association of weather variables with diarrhoeal diseases has not been well characterized in resource-limited settings where the burden remains high. We examined short-term associations between ambient temperature, precipitation and hospital visits due to diarrhoea among children in seven low- and middle-income countries. METHODOLOGY:Hospital visits due to diarrhoeal diseases under 5 years old were collected from seven sites in The Gambia, Mali, Mozambique, Kenya, India, Bangladesh, and Pakistan via the Global Enteric Multicenter Study from December 2007 to March 2011. Daily weather data during the same period were downloaded from the ERA5-Land. We fitted time-series regression models to examine the relationships of daily diarrhoea cases with daily ambient temperature and precipitation. Then, we used meta-analytic tools to examine the heterogeneity between the site-specific estimates. PRINCIPAL FINDINGS:The cumulative relative risk (RR) of diarrhoea for temperature exposure (95th percentile vs. 1st percentile) ranged from 0.24 to 8.07, with Mozambique and Bangladesh showing positive associations, while Mali and Pakistan showed negative associations. The RR for precipitation (95th percentile vs. 1st percentile) ranged from 0.77 to 1.55, with Mali and India showing positive associations, while the only negative association was observed in Pakistan. Meta-analysis showed substantial heterogeneity in the association between temperature-diarrhoea and precipitation-diarrhoea across sites, with I2 of 84.2% and 67.5%, respectively. CONCLUSIONS:Child diarrhoea and weather factors have diverse and complex associations across South Asia and Sub-Saharan Africa. Diarrhoeal surveillance system settings should be conceptualized based on the observed pattern of climate change in these locations.

Background:Shigella is a leading cause of acute watery diarrhea, dysentery, and diarrhea-attributed linear growth faltering, a precursor to stunting and lifelong morbidity. Several promising Shigella vaccines are in development and field efficacy trials will require a consortium of potential vaccine trial sites with up-to-date Shigella diarrhea incidence data. Methods:The Enterics for Global Health (EFGH) Shigella surveillance study will employ facility-based enrollment of diarrhea cases aged 6-35 months with 3 months of follow-up to establish incidence rates and document clinical, anthropometric, and financial consequences of Shigella diarrhea at 7 country sites (Mali, Kenya, The Gambia, Malawi, Bangladesh, Pakistan, and Peru). Over a 24-month period between 2022 and 2024, the EFGH study aims to enroll 9800 children (1400 per country site) between 6 and 35 months of age who present to local health facilities with diarrhea. Shigella species (spp.) will be identified and serotyped from rectal swabs by conventional microbiologic methods and quantitative polymerase chain reaction. Shigella spp. isolates will undergo serotyping and antimicrobial susceptibility testing. Incorporating population and healthcare utilization estimates from contemporaneous household sampling in the catchment areas of enrollment facilities, we will estimate Shigella diarrhea incidence rates. Conclusions:This multicountry surveillance network will provide key incidence data needed to design Shigella vaccine trials and strengthen readiness for potential trial implementation. Data collected in EFGH will inform policy makers about the relative importance of this vaccine-preventable disease, accelerating the time to vaccine availability and uptake among children in high-burden settings.

Background Quantitative molecular assays are increasingly used for detection of enteric viruses. Methods We compared the clinical severity using the modified Vesikari score (mVS) of enteric viruses detected by conventional assays (enzyme immunoassays [EIAs] 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 mVS (interquartile range) 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 with rotavirus EIA-positive cases, the median mVS was 2 and 3 points lower for EIA-negative/TAC-positive cases with Ct <32.6 or Ct >= 32.6 and <35, respectively (P < .001). Adenovirus 40/41 EIA-positive and EIA-negative/TAC-positive cases were similar, regardless of Ct cutoff. Conclusions Quantitative molecular assays compared with conventional assays, such as EIA, may influence the 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.