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Background: Diarrheal disease is heterogeneous, including watery diarrhea (WD) and dysentery, some cases of which become persistent diarrhea (PD). Changes in risk over time necessitate updated knowledge of these syndromes in sub-Saharan Africa., Methods: The Vaccine Impact on Diarrhea in Africa (VIDA) study was an age-stratified, case-control study of moderate-to-severe diarrhea among children <5 years old in The Gambia, Mali, and Kenya (2015-2018). We analyzed cases with follow-up of about 60 days after enrollment to detect PD (lasting ≥14 days), examined the features of WD and dysentery, and examined determinants for progression to and sequelae from PD. Data were compared with those from the Global Enteric Multicenter Study (GEMS) to detect temporal changes. Etiology was assessed from stool samples using pathogen attributable fractions (AFs), and predictors were assessed using χ2 tests or multivariate regression, where appropriate., Results: Among 4606 children with moderate-to-severe diarrhea, 3895 (84.6%) had WD and 711 (15.4%) had dysentery. PD was more frequent among infants (11.3%) than in children 12-23 months (9.9%) or 24-59 months (7.3%), P = .001 and higher in Kenya (15.5%) than in The Gambia (9.3%) or Mali (4.3%), P < .001; the frequencies were similar among children with WD (9.7%) and those with dysentery (9.4%). Compared to children not treated with antibiotics, those who received antibiotics had a lower frequency of PD overall (7.4% vs 10.1%, P = .01), and particularly among those with WD (6.3% vs 10.0%; P = .01) but not among children with dysentery (8.5% vs 11.0%; P = .27). For those with watery PD, Cryptosporidium and norovirus had the highest AFs among infants (0.16 and 0.12, respectively), while Shigella had the highest AF (0.25) in older children. The odds of PD decreased significantly over time in Mali and Kenya while increasing significantly in The Gambia., Conclusions: The burden of PD endures in sub-Saharan Africa, with nearly 10% of episodes of WD and dysentery becoming persistent., Competing Interests: Potential conflicts of interest. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health, the Bill & Melinda Gates Foundation, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and the Medical Research Council. S. M. T. also reports payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines; consulting fees and travel support from the University of Washington for a grant proposal; multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines; and multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institute of Allergy and Infections Diseases, Institut Pasteur, and the Bill & Melinda Gates Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: To address knowledge gaps regarding diarrheagenic Escherichia coli (DEC) in Africa, we assessed the clinical and epidemiological features of enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), and Shiga toxin-producing E. coli (STEC) positive children with moderate-to-severe diarrhea (MSD) in Mali, The Gambia, and Kenya., Methods: Between May 2015 and July 2018, children aged 0-59 months with medically attended MSD and matched controls without diarrhea were enrolled. Stools were tested conventionally using culture and multiplex polymerase chain reaction (PCR), and by quantitative PCR (qPCR). We assessed DEC detection by site, age, clinical characteristics, and enteric coinfection., Results: Among 4840 children with MSD and 6213 matched controls enrolled, 4836 cases and 1 control per case were tested using qPCR. Of the DEC detected with TAC, 61.1% were EAEC, 25.3% atypical EPEC (aEPEC), 22.4% typical EPEC (tEPEC), and 7.2% STEC. Detection was higher in controls than in MSD cases for EAEC (63.9% vs 58.3%, P < .01), aEPEC (27.3% vs 23.3%, P < .01), and STEC (9.3% vs 5.1%, P < .01). EAEC and tEPEC were more frequent in children aged <23 months, aEPEC was similar across age strata, and STEC increased with age. No association between nutritional status at follow-up and DEC pathotypes was found. DEC coinfection with Shigella/enteroinvasive E. coli was more common among cases (P < .01)., Conclusions: No significant association was detected between EAEC, tEPEC, aEPEC, or STEC and MSD using either conventional assay or TAC. Genomic analysis may provide a better definition of the virulence factors associated with diarrheal disease., Competing Interests: Potential conflicts of interest. E. R. H. reports funding from the Bill & Melinda Gates Foundation. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. M.-A. W. reports salary support from the CDC and the Institute of Tropical Medicine. N. S. reports scientific consultation by Kenya Medical Research Institute scientists and assistance with writing. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health, Bill & Melinda Gates Foundation, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and the Medical Research Council; payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines; consulting fees and travel support from the University of Washington for a grant proposal; holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines; and holding multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. Y. L. reports funding from the Bill & Melinda Gates Foundation and the following funding contracts: National Institute of Health, Centers for Disease Control and Prevention, Agency for Healthcare Research and Quality, Institut Pasteur and National Institute of Allargy and Infectious Diseases prime; serving as the data and safety monitoring board statistician for a clinical trial titled “Matching Perfusion and Metabolic Activity in HFpEF (MPMA)” with the University of Pennsylvania; and reviewing of data from National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism studies involving human subjects. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Despite antibiotic prescription being recommended for dysentery and suspected cholera only, diarrhea still triggers unwarranted antibiotic prescription. We evaluated antibiotic-prescribing practices and their predictors among children aged 2-59 months in the Vaccine Impact on Diarrhea in Africa (VIDA) Study performed in The Gambia, Mali, and Kenya., Methods: VIDA was a prospective case-control study (May 2015-July 2018) among children presenting for care with moderate-to-severe diarrhea (MSD). We defined inappropriate antibiotic use as prescription or use of antibiotics when not indicated by World Health Organization (WHO) guidelines. We used logistic regression to assess factors associated with antibiotic prescription for MSD cases who had no indication for an antibiotic, at each site., Results: VIDA enrolled 4840 cases. Among 1757 (36.3%) who had no apparent indication for antibiotic treatment, 1358 (77.3%) were prescribed antibiotics. In The Gambia, children who presented with a cough (adjusted odds ratio [aOR]: 2.05; 95% confidence interval [95% CI]: 1.21-3.48) were more likely to be prescribed an antibiotic. In Mali, those who presented with dry mouth (aOR: 3.16; 95% CI: 1.02-9.73) were more likely to be prescribed antibiotics. In Kenya, those who presented with a cough (aOR: 2.18; 95% CI: 1.01-4.70), decreased skin turgor (aOR: 2.06; 95% CI: 1.02-4.16), and were very thirsty (aOR: 4.15; 95% CI: 1.78-9.68) were more likely to be prescribed antibiotics., Conclusions: Antibiotic prescription was associated with signs and symptoms inconsistent with WHO guidelines, suggesting the need for antibiotic stewardship and clinician awareness of diarrhea case-management recommendations in these settings., Competing Interests: Potential conflicts of interest. E. L. D. reports grant funding to her institution from the National Institutes of Health (NIH; grant number T32AI007524). K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institute of Allergy and Infections Diseases, Institut Pasteur, and the Bill & Melinda Gates Foundation. M.-A. W. reports receiving funding from the Centers for Disease Control and Prevention (CDC) and the Institute of Tropical Medicine. S. M. T. reports multiple grants paid to her institution from NIH, BMGF, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and the Medical Research Council. She also reports payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines and consulting fees and travel support from the University of Washington for a grant proposal. She also reports holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines and hold multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Studies conducted before rotavirus vaccine introduction found that moderate-to-severe diarrhea (MSD) in children aged <5 years was associated with stunting at follow-up. It is unknown whether the reduction in rotavirus-associated MSD following vaccine introduction decreased the risk of stunting., Methods: The Global Enteric Multicenter Study (GEMS) and the Vaccine Impact on Diarrhea in Africa (VIDA) study, two comparable matched case-control studies, were conducted during 2007-2011 and 2015-2018, respectively. We analyzed data from 3 African sites where rotavirus vaccine was introduced after GEMS and before starting VIDA. Children with acute MSD (<7 days onset) were enrolled from a health center and children without MSD (diarrhea-free for ≥7 days) were enrolled at home within 14 days of the index MSD case. The odds of being stunted at a follow-up visit 2-3 months after enrollment for an episode of MSD was compared between GEMS and VIDA using mixed-effects logistic regression models controlling for age, sex, study site, and socioeconomic status., Results: We analyzed data from 8808 children from GEMS and 10 579 from VIDA. Among those who were not stunted at enrollment in GEMS, 8.6% with MSD and 6.4% without MSD became stunted during the follow-up period. In VIDA, 8.0% with MSD and 5.5% children without MSD developed stunting. An episode of MSD was associated with higher odds of being stunted at follow-up compared with children without MSD in both studies (adjusted odds ratio [aOR], 1.31; 95% confidence interval [CI]: 1.04-1.64 in GEMS and aOR, 1.30; 95% CI: 1.04-1.61 in VIDA). However, the magnitude of association was not significantly different between GEMS and VIDA (P = .965)., Conclusions: The association of MSD with subsequent stunting among children aged <5 years in sub-Saharan Africa did not change after rotavirus vaccine introduction. Focused strategies are needed for prevention of specific diarrheal pathogens that cause childhood stunting., Competing Interests: Potential conflicts of interest. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institute of Allergy and Infections Diseases, Institut Pasteur, and the Bill & Melinda Gates Foundation. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health (NIH), Bill & Melinda Gates Foundation, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council; payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines; consulting fees and travel support from the University of Washington, Seattle for a grant proposal; holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines; and holding multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. Y. L. reports receiving the following grants or contracts paid to their institution from Geneva Foundation (National Institute of Allergy and Infectious Diseases prime); serving as the data safety monitoring board statistician for a clinical trial related to the metabolic activity in HFpEF; and reviewing data from National Institute on Drug Abuse/ National Institute on alcohol Abuse and Alcoholism (NIDA/NIAAA) studies involving human subjects. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Non-typhoidal Salmonella (NTS) is a common cause of gastroenteritis in young children, with limited data on NTS serovars and antimicrobial resistance in Africa., Methods: We determined the prevalence of Salmonella spp. and frequency of antimicrobial resistance among serovars identified in stools of 0-59 month-old children with moderate-to-severe diarrhea (MSD) and controls enrolled in the Vaccine Impact on Diarrhea in Africa (VIDA) Study in The Gambia, Mali, and Kenya in 2015-2018, and compared with data from the Global Enteric Multicenter Study (GEMS; 2007-2010) and the GEMS-1A study (2011). Salmonella spp. was detected by quantitative real-time PCR (qPCR) and culture-based methods. Identification of serovars was determined by microbiological methods., Results: By qPCR, the prevalence of Salmonella spp. among MSD cases was 4.0%, 1.6%, and 1.9% and among controls was 4.6%, 2.4%, and 1.6% in The Gambia, Mali, and Kenya, respectively, during VIDA. We observed year-to-year variation in serovar distribution and variation between sites. In Kenya, Salmonella enterica serovar Typhimurium decreased (78.1% to 23.1%; P < .001) among cases and controls from 2007 to 2018, whereas serogroup O:8 increased (8.7% to 38.5%; P = .04). In The Gambia, serogroup O:7 decreased from 2007 to 2018 (36.3% to 0%; P = .001) but S. enterica serovar Enteritidis increased during VIDA (2015 to 2018; 5.9% to 50%; P = .002). Only 4 Salmonella spp. were isolated in Mali during all 3 studies. Multidrug resistance was 33.9% in Kenya and 0.8% in The Gambia across all 3 studies. Ceftriaxone resistance was only observed in Kenya (2.3%); NTS isolates were susceptible to ciprofloxacin at all sites., Conclusions: Understanding variability in serovar distribution will be important for the future deployment of vaccines against salmonellosis in Africa., Competing Interests: Potential conflicts of interest. M. A. W. reports receiving funding from the Centers for Disease Control and Prevention (CDC) and Institute of Tropical Medicine. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health (NIH), the Bill & Melindat Gates Foudation (BMGF), Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council. She also reports payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines and consulting fees and travel support from the University of Washington for a grant proposal. She also reports holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines and hold multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. E. R. Houpt reports funding from the Bill and Melinda Gates Foundation (OPP1129479). K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The magnitude of pediatric enteric pathogen exposures in low-income settings necessitates substantive water and sanitation interventions, including animal feces management. We assessed associations between pediatric enteric pathogen detection and survey-based water, sanitation, and animal characteristics within the Vaccine Impact on Diarrhea in Africa case-control study., Methods: In The Gambia, Kenya, and Mali, we assessed enteric pathogens in stool of children aged <5 years with moderate-to-severe diarrhea and their matched controls (diarrhea-free in prior 7 days) via the TaqMan Array Card and surveyed caregivers about household drinking water and sanitation conditions and animals living in the compound. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using modified Poisson regression models, stratified for cases and controls and adjusted for age, sex, site, and demographics., Results: Bacterial (cases, 93%; controls, 72%), viral (63%, 56%), and protozoal (50%, 38%) pathogens were commonly detected (cycle threshold <35) in the 4840 cases and 6213 controls. In cases, unimproved sanitation (RR, 1.56; 95% CI, 1.12-2.17), as well as cows (RR, 1.61; 95% CI, 1.16-2.24) and sheep (RR, 1.48; 95% CI, 1.11-1.96) living in the compound, were associated with Shiga toxin-producing Escherichia coli. In controls, fowl (RR, 1.30; 95% CI, 1.15-1.47) were associated with Campylobacter spp. In controls, surface water sources were associated with Cryptosporidium spp., Shigella spp., heat-stable toxin-producing enterotoxigenic E. coli, and Giardia spp., Conclusions: Findings underscore the importance of enteric pathogen exposure risks from animals alongside more broadly recognized water and sanitation risk factors in children., Competing Interests: Potential conflicts of interest. E. R. H., H. P., K. L. K., M. J. H., R. O., and S. O. S. report funding for their institution from the Bill & Melinda Gates Foundation. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. M.-A. W. reports funding from the CDC and the Institute of Tropical Medicine. S. M. T. reports receipt of grant funding for her institution from the Bill & Melinda Gates Foundation, National Institutes of Health, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and the Medical Research Council; royalty payments related to intellectual property for the development of salmonella vaccines and Klebsiella/Pseudomonas vaccines; consulting fees and travel support from the University of Washington, Seattle, Washington; has multiple planned, issued, and pending patents; and holds an unpaid position on multiple committees of the American Society of Tropical Medicine and Hygiene. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: As part of the Vaccine Impact on Diarrhea in Africa (VIDA) Study, we examined the prevalence, clinical presentation, and seasonality of Cryptosporidium in children to understand its relative burden after the introduction of rotavirus vaccine., Methods: VIDA was a 3-year, age-stratified, matched case-control study of medically attended acute moderate-to-severe diarrhea (MSD) in children aged 0-59 months residing in censused populations at sites in Kenya, Mali, and The Gambia. Clinical and epidemiologic data were collected at enrollment, and a stool sample was tested for enteropathogens by quantitative PCR. An algorithm was created based on the organism's cycle threshold (Ct) and association with MSD to identify the subset of Cryptosporidium PCR-positive (Ct <35) cases most likely to be attributed to MSD. Clinical outcomes were assessed at 2-3 months after enrollment., Results: One thousand one hundred six (22.9%) cases of MSD and 873 controls (18.1%) were PCR positive for Cryptosporidium; 465 cases (42.0%) were considered attributable to Cryptosporidium, mostly among children 6-23 months. Cryptosporidium infections peaked in The Gambia and Mali during the rainy season, while in Kenya they did not have clear seasonality. Compared with cases with watery MSD who had a negative PCR for Cryptosporidium, cases with watery MSD attributed to Cryptosporidium were less frequently dehydrated but appeared more severely ill using a modified Vesikari scale (38.1% vs 27.0%; P < 0.001), likely due to higher rates of hospitalization and intravenous fluid administration, higher prevalence of being wasted or very thin very thin (23.4% vs 14.7%; P < 0.001), and having severe acute malnutrition (midupper arm circumference <115 mm, 7.7% vs 2.5%; P < 0.001). On follow-up, Cryptosporidium-attributed cases had more prolonged and persistent episodes (43.2% vs 32.7%; P <0 .001) and linear growth faltering (change in height-for-age z score between enrollment and follow-up: -0.29 vs -0.17; P < 0.001)., Conclusions: The burden of Cryptosporidium remains high among young children in sub-Saharan Africa. Its propensity to cause illness and further impact children longer term by compromising nutritional status early in life calls for special attention to enable appropriate management of clinical and nutritional consequences., Competing Interests: Potential conflicts of interest . E. R. H. reports financial support from the Bill and Melinda Gates Foundation (OPP1129479). K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health (NIH), Bill & Melinda Gates Foundation (BMGF), Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council. She also reports payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines and consulting fees and travel support from the University of Washington for a grant proposal. She also reports holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines and hold multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. S. R. C. H. reports salary funding from the UK Medical Research Council and the University of Auckland. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Giardia has been associated with reduced risk of diarrhea in children in low-resource settings, but the mechanism underlying this association is unknown. To assess whether Giardia may shape colonization or infection with other enteric pathogens and impact associations with diarrhea, we examined Giardia and enteric pathogen codetection among children <5 years old in Kenya, The Gambia, and Mali as part of the Vaccine Impact on Diarrhea in Africa study., Methods: We tested for Giardia and other enteric pathogens using enzyme-linked immunosorbent assays and real-time polymerase chain reaction (PCR) on stool, respectively. We evaluated associations between Giardia and enteric pathogen detection using multivariable logistic regression models separately for children with moderate-to-severe diarrhea (MSD, cases) and free of diarrhea (controls)., Results: Among 11 039 enrolled children, Giardia detection was more common among controls (35%) than cases (28%, P < .001). Campylobacter coli/jejuni detection was associated with Giardia in controls in The Gambia (adjusted odds ratio [aOR] [95% confidence interval {CI}]: 1.51 [1.22‒1.86]) and cases across all sites (1.16 [1.00‒1.33]). Among controls, the odds of astrovirus (1.43 [1.05‒1.93]) and Cryptosporidium spp. (1.24 [1.06‒1.46]) detection were higher among children with Giardia. Among cases, the odds of rotavirus detection were lower in children with Giardia in Mali (.45 [.30‒.66]) and Kenya (.31 [.17‒.56])., Conclusions: Giardia was prevalent in children <5 years old and was associated with detection of other enteric pathogens, with differing associations in cases versus controls and by site. Giardia may affect colonization or infection by certain enteric pathogens associated with MSD, suggesting an indirect mechanism of clinical impact., Competing Interests: Potential conflicts of interest. All authors report no potential conflicts related to this manuscript. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Reducing diarrhea-related morbidity and mortality is a global priority, particularly in low-resource settings. We assessed adherence to diarrhea case management indicators in the Global Enteric Multisite Study (GEMS) and Vaccine Impact of Diarrhea in Africa (VIDA) study., Methods: GEMS (2007-2010) and VIDA (2015-2018) were age-stratified case-control studies of moderate-to-severe diarrhea (MSD) in children aged <5 years. In this case-only analysis, we included children enrolled in The Gambia, Kenya, and Mali. A case with no dehydration received adherent care at home if they were offered more than usual fluids and at least the same as usual to eat. Children with diarrhea and some dehydration are to receive oral rehydration salts (ORS) in the facility. The recommendation for severe dehydration is to receive ORS and intravenous fluids in the facility. Adherent care in the facility included a zinc prescription independent of dehydration severity., Results: For home-based management of children with MSD and no signs of dehydration, 16.6% in GEMS and 15.6% in VIDA were adherent to guidelines. Adherence to guidelines in the facility was likewise low during GEMS (some dehydration, 18.5%; severe dehydration, 5.5%). The adherence to facility-based rehydration and zinc guidelines improved during VIDA to 37.9% of those with some dehydration and 8.0% of children with severe dehydration., Conclusions: At research sites in The Gambia, Kenya, and Mali, suboptimal adherence to diarrhea case management guidelines for children aged <5 years was observed. Opportunities exist for improvement in case management for children with diarrhea in low-resource settings., Competing Interests: Potential conflicts of interest. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institute of Allergy and Infections Diseases, Institut Pasteur, and the Bill & Melinda Gates Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: To address a paucity of data from sub-Saharan Africa, we examined the prevalence, severity, and seasonality of norovirus genogroup II (NVII) among children <5 years old in The Gambia, Kenya, and Mali following rotavirus vaccine introduction., Methods: Population-based surveillance was conducted to capture medically-attended moderate-to-severe diarrhea (MSD) cases, defined as a child 0-59 months old passing ≥3 loose stools in a 24-hour period with ≥1 of the following: sunken eyes, poor skin turgor, dysentery, intravenous rehydration, or hospitalization within 7 days of diarrhea onset. Diarrhea-free matched controls randomly selected from a censused population were enrolled at home. Stools from cases and controls were tested for enteropathogens, including norovirus and rotavirus, by TaqMan quantitative polymerase chain reaction (PCR) and conventional reverse transcription PCR. We used multiple logistic regression to derive adjusted attributable fractions (AFe) for each pathogen causing MSD, which takes into consideration the prevalence in both cases and controls, for each site and age. A pathogen was considered etiologic if AFe was ≥0.5. In further analyses focusing on the predominant NVII strains, we compared rotavirus and NVII severity using a 20-point modified Vesikari score and examined seasonal fluctuations., Results: From May 2015 to July 2018, we enrolled 4840 MSD cases and 6213 controls. NVI was attributed to only 1 MSD episode. NVII was attributed to 185 (3.8%) of all MSD episodes and was the sole attributable pathogen in 139 (2.9%); peaking (36.0%) at age 6-8 months with majority (61.2%) aged 6-11 months. MSD cases whose episodes were attributed to NVII alone compared with rotavirus alone were younger (median age, 8 vs 12 months, P < .0001) and had less severe illness (median Vesikari severity score, 9 vs 11, P = .0003) but equally likely to be dehydrated. NVII occurred year-round at all study sites., Conclusions: Infants aged 6-11 months bear the greatest burden of norovirus disease, with NVII predominating. An early infant vaccine schedule and rigorous adherence to guidelines recommended for management of dehydrating diarrhea may offer substantial benefit in these African settings., Competing Interests: Potential conflicts of interest. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. M. A. W. reports receiving funding from the CDC and Institute of Tropical Medicine. S. M. T. reports multiple grants paid to their institution from the National Institutes of Health (NIH), BMGF, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council. They also report payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines; consulting fees and travel support from the University of Washington for a grant proposal. They also report holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines; and holds multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: While rotavirus causes severe diarrheal disease in children aged <5 years, data on other viral causes in sub-Saharan Africa are limited., Methods: In the Vaccine Impact on Diarrhea in Africa study (2015-2018), we analyzed stool from children aged 0-59 months with moderate-to-severe diarrhea (MSD) and without diarrhea (controls) in Kenya, Mali, and The Gambia using quantitative polymerase chain reaction. We derived the attributable fraction (AFe) based on the association between MSD and the pathogen, accounting for other pathogens, site, and age. A pathogen was attributable if the AFe was ≥0.5.The severity of attributable MSD was defined by a modified Vesikari score (mVS). Monthly cases were plotted against temperature and rainfall to assess seasonality., Results: Among 4840 MSD cases, proportions attributed to rotavirus, adenovirus 40/41, astrovirus, and sapovirus were 12.6%, 2.7%, 2.9%, and 1.9%, respectively. Attributable rotavirus, adenovirus 40/41, and astrovirus MSD cases occurred at all sites, with mVS of 11, 10, and 7, respectively. MSD cases attributable to sapovirus occurred in Kenya, with mVS of 9. Astrovirus and adenovirus 40/41 peaked during the rainy season in The Gambia, while rotavirus peaked during the dry season in Mali and The Gambia., Conclusions: In sub-Saharan Africa, rotavirus was the most common cause of MSD; adenovirus 40/41, astrovirus, and sapovirus contributed to a lesser extent among children aged <5 years. Rotavirus- and adenovirus 40/41-attributable MSD were most severe. Seasonality varied by pathogen and location. Efforts to increase the coverage of rotavirus vaccines and to improve prevention and treatment for childhood diarrhea should continue., Competing Interests: Potential conflicts of interest. E. R. H. reports funding from the Bill & Melinda Gates Foundation. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health, Bill & Melinda Gates Foundation, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council; payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines; consulting fees and travel support from the University of Washington for a grant proposal; holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines; and holding multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: We evaluated the burden of Shigella spp from children aged 0-59 months with medically attended moderate-to-severe diarrhea and matched controls at sites in Mali, The Gambia, and Kenya participating in the Vaccine Impact on Diarrhea in Africa (VIDA) study from 2015 to 2018., Methods: Shigella spp were identified using coprocultures and serotyping in addition to quantitative polymerase chain reaction (qPCR). Episode-specific attributable fractions (AFe) for Shigella were calculated using Shigella DNA quantity; cases with AFe ≥0.5 were considered to have shigellosis., Results: The prevalence of Shigella was determined to be 359 of 4840 (7.4%) cases and 83 of 6213 (1.3%) controls by culture, and 1641 of 4836 (33.9%) cases and 1084 of 4846 (22.4%) controls by qPCR (cycle threshold <35); shigellosis was higher in The Gambia (30.8%) than in Mali (9.3%) and Kenya (18.7%). Bloody diarrhea attributed to Shigella was more common in 24- to 59-month-old children (50.1%) than 0- to 11-month-old infants (39.5%). The Shigella flexneri serogroup predominated among cases (67.6% of isolates), followed by Shigella sonnei (18.2%), Shigella boydii (11.8%), and Shigella dysenteriae (2.3%). The most frequent S. flexneri serotypes were 2a (40.6%), 1b (18.8%), 6 (17.5%), 3a (9.0%), and 4a (5.1%). Drug-specific resistance among 353 (98.3%) Shigella cases with AMR data was as follows: trimethoprim-sulfamethoxazole (94.9%), ampicillin (48.4%), nalidixic acid (1.7%), ceftriaxone (0.3%), azithromycin (0.3%), and ciprofloxacin (0.0%)., Conclusions: A high prevalence of shigellosis continues in sub-Saharan Africa. Strains are highly resistant to commonly used antibiotics while remaining susceptible to ciprofloxacin, ceftriaxone, and azithromycin., Competing Interests: Potential conflicts of interest. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. M.-A. W. reports receiving funding from the CDC and the Institute of Tropical Medicine. S. M. T. reports multiple grants (paid to institution) from the National Institutes of Health, Bill & Melinda Gates Foundation, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council; payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines; consulting fees and travel support from the University of Washington for a grant proposal; multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines; and multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Pediatric exposures to unsafe sources of water, unsafely managed sanitation, and animals are prevalent in low- and middle-income countries. In the Vaccine Impact on Diarrhea in Africa case-control study, we examined associations between these risk factors and moderate-to-severe diarrhea (MSD) in children <5 years old in The Gambia, Kenya, and Mali., Methods: We enrolled children <5 years old seeking care for MSD at health centers; age-, sex-, and community-matched controls were enrolled at home. Conditional logistic regression models, adjusted for a priori confounders, were used to evaluate associations between MSD and survey-based assessments of water, sanitation, and animals living in the compound., Results: From 2015 to 2018, 4840 cases and 6213 controls were enrolled. In pan-site analyses, children with drinking water sources below "safely managed" (onsite, continuously accessible sources of good water quality) had 1.5-2.0-fold higher odds of MSD (95% confidence intervals [CIs] ranging from 1.0 to 2.5), driven by rural site results (The Gambia and Kenya). In the urban site (Mali), children whose drinking water source was less available (several hours/day vs all the time) had higher odds of MSD (matched odds ratio [mOR]: 1.4, 95% CI: 1.1, 1.7). Associations between MSD and sanitation were site-specific. Goats were associated with slightly increased odds of MSD in pan-site analyses, whereas associations with cows and fowl varied by site., Conclusions: Poorer types and availability of drinking water sources were consistently associated with MSD, whereas the impacts of sanitation and household animals were context-specific. The association between MSD and access to safely managed drinking water sources post-rotavirus introduction calls for transformational changes in drinking water services to prevent acute child morbidity from MSD., Competing Interests: Potential conflicts of interest. H. P., R, O., S. O. S., and M. J. H. report receiving grant funding for their institution from the Bill and Melinda Gates Foundation. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. M. A. W. reports receiving salary pay from the Centers for Disease Control and Prevention and the Institute for Tropical Medicine. S. M. T. reports receiving grant funding for their institution from the Bill and Melinda Gates Foundation, National Institutes of Health, Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and the Medical Research Council. They report receiving royalty payments related to intellectual property for the development of salmonella vaccines and klebsiella/Pseudomonas vaccines and consulting fees and travel support from the University of Washington, in addition to multiple planned, issued and pending patents. They hold an unpaid position on multiple committees with the American Society of Tropical Medicine and Hygiene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Previously studied risk factors for rotavirus vaccine failure have not fully explained reduced rotavirus vaccine effectiveness in low-income settings. We assessed the relationship between histo-blood group antigen (HBGA) phenotypes and clinical rotavirus vaccine failure among children <2 years of age participating in the Vaccine Impact on Diarrhea in Africa Study in 3 sub-Saharan African countries., Methods: Saliva was collected and tested for HBGA phenotype in children who received rotavirus vaccine. The association between secretor and Lewis phenotypes and rotavirus vaccine failure was examined overall and by infecting rotavirus genotype using conditional logistic regression in 218 rotavirus-positive cases with moderate-to-severe diarrhea and 297 matched healthy controls., Results: Both nonsecretor and Lewis-negative phenotypes (null phenotypes) were associated with decreased rotavirus vaccine failure across all sites (matched odds ratio, 0.30 [95% confidence interval: 0.16-0.56] or 0.39 [0.25-0.62], respectively]. A similar decrease in risk against rotavirus vaccine failure among null HBGA phenotypes was observed for cases with P[8] and P[4] infection and their matched controls. While we found no statistically significant association between null HBGA phenotypes and vaccine failure among P[6] infections, the matched odds ratio point estimate for Lewis-negative individuals was >4., Conclusions: Our study demonstrated a significant relationship between null HBGA phenotypes and decreased rotavirus vaccine failure in a population with P[8] as the most common infecting genotype. Further studies are needed in populations with a large burden of P[6] rotavirus diarrhea to understand the role of host genetics in reduced rotavirus vaccine effectiveness., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Statistical modeling suggests that decreasing diarrhea-associated mortality rates in recent decades are largely attributed to improved case management, rotavirus vaccine, and economic development., Methods: We examined data collected in 2 multisite population-based diarrhea case-control studies, both conducted in The Gambia, Kenya, and Mali: the Global Enteric Multicenter Study (GEMS; 2008-2011) and Vaccine Impact on Diarrhea in Africa (VIDA; 2015-2018). Population-level diarrhea mortality and risk factor prevalence, estimated using these study data, were used to calculate the attribution of risk factors and interventions for diarrhea mortality using a counterfactual framework. We performed a decomposition of the effects of the changes in exposure to each risk factor between GEMS and VIDA on diarrhea mortality for each site., Results: Diarrhea mortality among children under 5 in our African sites decreased by 65.3% (95% confidence interval [CI]: -80.0%, -45.0%) from GEMS to VIDA. Kenya and Mali had large relative declines in diarrhea mortality between the 2 periods with 85.9% (95% CI: -95.1%, -71.5%) and 78.0% (95% CI: -96.0%, 36.3%) reductions, respectively. Among the risk factors considered, the largest declines in diarrhea mortality between the 2 study periods were attributed to reduction in childhood wasting (27.2%; 95% CI: -39.3%, -16.8%) and an increased rotavirus vaccine coverage (23.1%; 95% CI: -28.4%, -19.4%), zinc for diarrhea treatment (12.1%; 95% CI: -16.0%, -8.9%), and oral rehydration salts (ORS) for diarrhea treatment (10.2%)., Conclusions: The VIDA study sites demonstrated exceptional reduction in diarrhea mortality over the last decade. Site-specific differences highlight an opportunity for implementation science in collaboration with policymakers to improve the equitable coverage of these interventions globally., Competing Interests: Potential conflicts of interest. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institutes of Health, Institut Pasteur, and the Bill & Melinda Gates Foundation. E. L. D. reports a T32 grant from the National Institutes of Health for training through the University of Maryland School of Medicine Center for Vaccine Development and Global Health (T32AI007524). M. D. T. reports support for attending an investigator meeting from the Bill & Melinda Gates Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Stunting affects >20% of children <5 years old worldwide and disproportionately impacts underserved communities. The Vaccine Impact on Diarrhea in Africa (VIDA) Study examined the association between an episode of moderate-to-severe diarrhea (MSD) and the risk of subsequent stunting in children <5 years living in 3 sub-Saharan African countries., Methods: In this prospective, matched, case-control study among children <5 years, data were collected over 36 months from 2 groups. "Children with MSD" visited a health center within 7 days of illness onset experiencing ≥3 loose stools/day plus sunken eyes, poor skin turgor, dysentery, intravenous rehydration, or hospitalization. "Children without MSD" were enrolled from the community within 14 days of the index MSD child; they were diarrhea-free during the previous 7 days and were matched to the index case by age, sex, and residence. Using generalized linear mixed-effects models, we estimated the effect of an MSD episode on odds of being stunted, defined as height-for-age z-scores <-2, at a follow-up visit 2-3 months post-enrollment., Results: The proportion of stunting at enrollment was similar when 4603 children with MSD and 5976 children without MSD were compared (21.8% vs 21.3%; P = .504). Among children not stunted at enrollment, those with MSD had 30% higher odds of being stunted at follow-up than children without MSD after controlling for age, sex, study site, and socioeconomic status (adjusted OR: 1.30; 95% CI: 1.05-1.62: P = .018)., Conclusions: Children <5 years in sub-Saharan Africa without stunting experienced an increased likelihood of stunting during 2-3 months following an episode of MSD. Strategies for control of early childhood diarrhea should be integrated into programs intended to reduce childhood stunting., Competing Interests: Potential conflicts of interest. I. G. C. reports receiving grant funding from the National Heart, Lung, and Blood Institute (NHLBI) and consulting fees from the University of California, San Francisco. They also report receiving travel support from Research in Implementation Science for Equity program from the University of San Francisco institute to travel to San Francisco. K. L. K. reports consultation fees and travel support from PATH and the University of Washington related to diarrheal diseases and grant support to her institution from the National Institute of Allergy and Infections Diseases, Institut Pasteur, and the Bill & Melinda Gates Foundation. M.-A. W. reports receiving funding from the Centers for Disease Control and Prevention (CDC) and Institute of Tropical Medicine. S. M. T. reports multiple grants paid to her institution from the National Institutes of Health (NIH), Bill & Melinda Gates Foundation (BMGF), Wellcome Trust, Affinivax, Lumen Biosciences, PATH, and Medical Research Council. She also reports payments as royalties related to intellectual property for Salmonella vaccines and Klebsiella/Pseudomonas vaccines and consulting fees and travel support from the University of Washington for a grant proposal. She also reports holding multiple planned, issued, and pending patents on Salmonella, Klebsiella, and Pseudomonas vaccines and hold multiple unpaid committee roles with the American Society of Tropical Medicine and Hygiene. Y. L. reports receiving the following grants or contracts paid to their institution: R01NS122855, U54CK000615-01, 1R18 HS027750-01, R03 AG067927, U01 AI143493, U01 AI148054, U01 AI148081, NCT04078022, HHS-NIH-NIAID-BAA2018, R01 HD093946-01, 2R01-DA026868-06A1, 2R01-AA014988-12A1, R01 AA014988-S1, R01 DK109323, R01-NR016269, Geneva Foundation (National Institute for Allergy and Infectious Diseases [NIAID] prime), R01-HD075936, and BAA FY2018-OADS-01. They also report serving as the Data Safety Monitoring Board statistician for the clinical trial entitled “Matching Perfusion and Metabolic Activity in HFpEF (MPMA),” and reviewed data from National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism (NIDA/NIAAA) studies involving human subjects. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)