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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. [ABSTRACT FROM AUTHOR]

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. Stunting disproportionately impacts young children living in low-income countries. In the VIDA study among children <5 years old living in sub-Saharan Africa, an episode of moderate-to-severe diarrhea conferred a 30% higher odds of becoming stunted during 60 days of follow-up. [ABSTRACT FROM AUTHOR]

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. Despite reductions in the attributable burden of rotavirus following vaccine introduction, the association between moderate to severe diarrhea and stunting at a 2–3 month follow-up did not change between studies conducted before and after rotavirus vaccine introduction at 3 sub-Saharan African sites. [ABSTRACT FROM AUTHOR]

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. Among children <5 years, rotavirus, adenovirus 40/41, and astrovirus cause moderate to severe diarrhea (MSD) in Kenya, Mali, and The Gambia, and sapovirus causes MSD in Kenya. Rotavirus and adenovirus 40/41 MSD have the highest severity. [ABSTRACT FROM AUTHOR]

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. 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 necessitates appropriate management of clinical and nutritional consequences. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. This report updates our knowledge of the risk factors and etiology associated with persistent diarrhea and dysentery. We demonstrate that both persistent and bloody diarrhea remain serious problems with distinct etiology, presentation, and outcomes among sub-Saharan African infants. [ABSTRACT FROM AUTHOR]

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. We demonstrated exceptional reduction in diarrhea mortality over a decade. Among the risk factors considered, the largest declines in diarrhea mortality were attributed to reduction in childhood wasting and an increased rotavirus vaccine coverage, zinc, and oral rehydration salts for diarrhea treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Inappropriate antibiotic prescribing for diarrheal diseases can promote antimicrobial resistance. In VIDA, unnecessary or incorrect antibiotics were prescribed for 77% of diarrhea and 41% of dysentery cases. Interventions are needed to promote judicious adherence to international guidelines in low-/middle-income countries. [ABSTRACT FROM AUTHOR]

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. We evaluated the burden of Shigella spp from children 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 study from 2015 to 2018. [ABSTRACT FROM AUTHOR]

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. Norovirus genogroup II was the attributed etiology for 3% of all moderate-to-severe diarrhea (MSD) cases among children <5 years old in The Gambia, Mali, and Kenya post-rotavirus vaccine introduction; the highest disease burden concentrated in children 6–11 months old. [ABSTRACT FROM AUTHOR]

Background: Diarrheal diseases remain a health threat to children in low- and middle-income countries. The Vaccine Impact on Diarrhea in Africa (VIDA) study was a 36-month, prospective, matched case-control study designed to estimate the etiology, incidence, and adverse clinical consequences of moderate-to-severe diarrhea (MSD) in children aged 0–59 months. VIDA was conducted following rotavirus vaccine introduction at 3 censused sites in sub-Saharan Africa that participated in the Global Enteric Multicenter Study (GEMS) ∼10 years earlier. We describe the study design and statistical methods of VIDA and where they differ from GEMS. Methods: We aimed to enroll 8–9 MSD cases every 2 weeks from sentinel health centers in 3 age strata (0–11, 12–23, 24–59 months) and 1 to 3 controls matched by age, sex, date of case enrollment, and village. Clinical, epidemiological, and anthropometric data were collected at enrollment and ∼60 days later. A stool specimen collected at enrollment was analyzed by both conventional methods and quantitative PCR for enteric pathogens. For the matched case-control study, we estimated the population-based, pathogen-specific attributable fraction (AF) and attributable incidence adjusted for age, site, and other pathogens, and identified episodes attributable to a specific pathogen for additional analyses. A prospective cohort study nested within the original matched case-control study allowed assessment of (1) the association between potential risk factors and outcomes other than MSD status and (2) the impact of MSD on linear growth. Conclusions: GEMS and VIDA together comprise the largest and most comprehensive assessment of MSD conducted to date in sub-Saharan Africa populations at highest risk for morbidity and mortality from diarrhea. The statistical methods used in VIDA have endeavored to maximize the use of available data to produce more robust estimates of the pathogen-specific disease burden that might be prevented by effective interventions. We provide a description of the Vaccine Impact on Diarrhea in Africa (VIDA) study design, data collected, and a detailed explanation of the statistical methods, including where they differ from those of the study predecessor, the Global Enteric Multicenter Study. [ABSTRACT FROM AUTHOR]

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. We assessed water, sanitation, and animal-associated risk factors for moderate-to-severe diarrhea in children in a matched case-control study. Less availability (hours/day) and access to quality drinking water were consistent risk factors; poor sanitation and animal ownership were context-specific risk factors. [ABSTRACT FROM AUTHOR]

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. We assessed survey-based water, sanitation, and animal factors associated with enteric pathogens in cases of moderate to severe diarrhea and controls. Animals, cows and sheep (cases) and fowl (controls), were associated with bacterial carriage; surface water was associated with bacteria and protozoa in controls. [ABSTRACT FROM AUTHOR]

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. Giardia was prevalent in children <5 years old and was associated with detection of other enteric pathogens, including rotavirus. Giardia may affect colonization or infection by certain enteric pathogens associated with MSD, suggesting an indirect mechanism of clinical impact. [ABSTRACT FROM AUTHOR]

Background: The association between childhood diarrheal disease and linear growth faltering in developing countries is well described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment.Methods: The Global Enteric Multicenter Study enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models.Results: Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below -1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0-11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02).Conclusions: Linear growth faltering among children aged 0-23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella. [ABSTRACT FROM AUTHOR]

Background The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. Methods Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313. Results Of 370 Salmonella- positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics. Conclusions Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

In an environment of constrained resources, policymakers must identify solutions for financing and delivering health services that are efficient and sustainable. However, such solutions require that policymakers understand the complex interaction between household utilization patterns, factors influencing household medical decisions, and provider performance. This study examined whether and under what conditions out-of-pocket, transportation, and time costs influenced Kenyan households' choice of medical provider for childhood diarrhoeal illnesses. It compared these decisions with the actual cost and quality of those providers to assess strategies for increasing the utilization of high quality, low-cost primary care. This study analyzed nationally-representative survey data through several multinomial nested logit models. On average, time costs accounted for the greatest share of total costs. Households spent the most time and transportation costs utilizing public care, yet were more likely to incur catastrophic time and out-of-pocket costs seeking private care for their child's diarrhoeal illness. Out-of-pocket, transportation, and time costs influenced households' choice of provider, though demand was cost inelastic and households were most responsive to transportation costs. Poorer households were the most responsive to changes in all cost types and most likely to self-treat or utilize informal care. Many households utilized informal care that, relative to formal care, cost the same but was of worse quality-suggesting that such households were making poor medical decisions for their children. To achieve public policy objectives, such as financial risk protection for childhood illnesses and equitable access to primary care, policymakers could focus on three areas: (1) refine financing strategies for further reducing household out-of-pocket costs; (2) reduce or subsidize time and transportation costs for households seeking public and private care; and (3) increase transparency of costs and quality to improve household decisions. [ABSTRACT FROM AUTHOR]

The overall aim of the Global Enteric Multicenter Study–1 (GEMS-1) is to identify the etiologic agents associated with moderate-to-severe diarrhea (MSD) among children <5 years of age, and thereby the attributable pathogen-specific population-based incidence of MSD, to guide investments in research and public health interventions against diarrheal disease. To accomplish this, 9 core assumptions were vetted through widespread consultation: (1) a limited number of etiologic agents may be responsible for most MSD; (2) a definition of MSD can be crafted that encompasses cases that might otherwise be fatal in the community without treatment; (3) MSD seen at sentinel centers is a proxy for fatal diarrheal disease in the community; (4) matched case/control is the appropriate epidemiologic design; (5) methods across the sites can be standardized and rigorous quality control maintained; (6) a single 60-day postenrollment visit to case and control households creates mini-cohorts, allowing comparisons; (7) broad support for GEMS-1 messages can be achieved by incorporating advice from public health spokespersons; (8) results will facilitate the setting of investment and intervention priorities; and (9) wide acceptance and dissemination of the GEMS-1 results can be achieved. [ABSTRACT FROM AUTHOR]

The Cooperative Studies Program Coordinating Center provided the data management, administrative, and statistical support to the Global Enteric Multicenter Study (GEMS). The GEMS study, the largest epidemiological study in the diarrheal disease area among children <5 years of age, was carried out in 4 African countries and 3 Asian countries. Given the geographical and geopolitical differences among the countries, the administration of a centralized data management operation was a major challenge. The sheer volume of the data that were collected, regular transfer of the data to a centralized database, and the cleaning of the same also posed some challenges. This paper outlines the details of the support that the data coordinating center provided and the challenges faced during the course of the study. [ABSTRACT FROM AUTHOR]

If individuals in a case/control study are subsequently observed as a cohort of cases and a cohort of controls, weighted regression analyses can be used to estimate the association between the exposures initially recorded and events occurring during the follow-up of the 2 cohorts. Such analyses can be conceptualized as being undertaken on a reconstructed source population from which cases and controls stem. To simulate this population, the cohort of cases is added to the cohort of controls expanded with the reciprocal of the case disease incidence odds (the sampling weight) to include all individuals in the source population who did not develop the case disease. We use a simulated dataset to illustrate how weighted generalized linear model regression can be used to estimate the association between an exposure captured during the case/control study component and an outcome that occurs during follow-up. [ABSTRACT FROM AUTHOR]

Background. Diarrhea is a leading cause of illness and death among children aged <5 years in developing countries. This paper describes the clinical and epidemiological methods used to conduct the Global Enteric Multicenter Study (GEMS), a 3-year, prospective, age-stratified, case/control study to estimate the population-based burden, microbiologic etiology, and adverse clinical consequences of acute moderate-to-severe diarrhea (MSD) among a censused population of children aged 0–59 months seeking care at health centers in sub-Saharan Africa and South Asia.Methods. GEMS was conducted at 7 field sites, each serving a population whose demography and healthcare utilization practices for childhood diarrhea were documented. We aimed to enroll 220 MSD cases per year from selected health centers serving each site in each of 3 age strata (0–11, 12–23, and 24–59 months), along with 1–3 matched community controls. Cases and controls supplied clinical, epidemiologic, and anthropometric data at enrollment and again approximately 60 days later, and provided enrollment stool specimens for identification and characterization of potential diarrheal pathogens. Verbal autopsy was performed if a child died. Analytic strategies will calculate the fraction of MSD attributable to each pathogen and the incidence, financial costs, nutritional consequences, and case fatality overall and by pathogen.Conclusions. When completed, GEMS will provide estimates of the incidence, etiology, and outcomes of MSD among infants and young children in sub-Saharan Africa and South Asia. This information can guide development and implementation of public health interventions to diminish morbidity and mortality from diarrheal diseases. [ABSTRACT FROM AUTHOR]

In addition to being a major cause of mortality in South Asia, childhood diarrhea creates economic burden for affected households. We used survey data from sites in Bangladesh, India, and Pakistan to estimate the costs borne by households due to childhood diarrhea, including direct medical costs, direct nonmedical costs, and productivity losses. Mean cost per episode was $1.82 in Bangladesh, $3.33 in India, and $6.47 in Pakistan. The majority of costs for households were associated with direct medical costs from treatment. Mean costs understate the distribution of costs, with 10% of cases exceeding $6.61, $8.07, and $10.11 in Bangladesh, India, and Pakistan, respectively. In all countries there was a trend toward lower costs among poorer households and in India and Pakistan there were lower costs for episodes among girls. For both poor children and girls this may reflect rationing of care, which may result in increased risks of mortality. [ABSTRACT FROM AUTHOR]

Beyond the morbidity and mortality burden of childhood diarrhea in sub-Saharan African are significant economic costs to affected households. Using survey data from 3 of the 4 sites in sub-Saharan Africa (Gambia, Kenya, Mali) participating in the Global Enteric Multicenter Study (GEMS), we estimated the direct medical, direct nonmedical, and indirect (productivity losses) costs borne by households due to diarrhea in young children. Mean cost per episode was $2.63 in Gambia, $6.24 in Kenya, and $4.11 in Mali. Direct medical costs accounted for less than half of these costs. Mean costs understate the distribution of costs, with 10% of cases exceeding $6.50, $11.05, and $13.84 in Gambia, Kenya, and Mali. In all countries there was a trend toward lower costs among poorer households and in 2 of the countries for diarrheal illness affecting girls. For poor children and girls, this may reflect reduced household investment in care, which may result in increased risks of mortality. [ABSTRACT FROM AUTHOR]

The Global Enteric Multicenter Study (GEMS) is an investigation of the burden (number of cases and incidence) of moderate-to-severe diarrhea (MSD) in children <60 months of age at 7 sites in sub-Saharan Africa and South Asia. The population attributable fraction for a putative pathogen, either unadjusted or adjusted for other pathogens, is estimated using the proportion of MSD cases from whom the pathogen was isolated and the odds ratio for MSD and the pathogen from conditional logistic regression modeling. The adjusted attributable fraction, proportion of MSD cases taken to a sentinel health center (SHC), number of cases presenting to an SHC, and the site's population are used to estimate the annual number of MSD cases and MSD incidence rate attributable to a pathogen or group of pathogens. Associations with death and nutritional outcomes, ascertained at follow-up visits to case and control households, are evaluated both in MSD cases and in the population. [ABSTRACT FROM AUTHOR]