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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: 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: 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: 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: 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]

Typhoid fever epidemiology was investigated rigorously in Santiago, Chile during the 1980s, when Salmonella enterica serovar Typhi (S. Typhi) caused seasonal, hyperendemic disease. Targeted interventions reduced the annual typhoid incidence rates from 128–220 cases/105 population occurring between 1977–1984 to <8 cases/105 from 1992 onwards. As such, Santiago represents a contemporary example of the epidemiologic transition of an industrialized city from amplified hyperendemic typhoid fever to a period when typhoid is no longer endemic. We used whole genome sequencing (WGS) and phylogenetic analysis to compare the genotypes of S. Typhi cultured from acute cases of typhoid fever occurring in Santiago during the hyperendemic period of the 1980s (n = 74) versus the nonendemic 2010s (n = 80) when typhoid fever was rare. The genotype distribution between "historical" (1980s) isolates and "modern" (2011–2016) isolates was similar, with genotypes 3.5 and 2 comprising the majority of isolations, and 73/80 (91.3%) of modern isolates matching a genotype detected in the 1980s. Additionally, phylogenomically 'ancient' genotypes 1.1 and 1.2.1, uncommon in the global collections, were also detected in both eras, with a notable rise amongst the modern isolates. Thus, genotypes of S. Typhi causing acute illness in the modern nonendemic era match the genotypes circulating during the hyperendemic 1980s. The persistence of historical genotypes may be explained by chronic typhoid carriers originally infected during or before the 1980s. Author summary: Studies of Salmonella Typhi (the cause of typhoid fever) rarely include isolates collected both before and after the interruption of hyperendemic transmission because this typically occurred decades before modern bacteria preservation methods. After interruption, it was assumed that sporadic cases and infrequent outbreaks were due to either chronic biliary carriers or importations, but this was difficult to characterize with low resolution bacterial typing methods. In Santiago, Chile, typhoid fever persisted at hyperendemic levels through the 1980s until organized control efforts in the 1980s and changes to wastewater policy in 1991 caused annual typhoid incidence to plummet. In this study, we used whole genome sequencing (WGS) to investigate whether recent sporadic cases occurring in Santiago in the 2010s were genomically similar to S. Typhi circulating in the 1980s, or dissimilar, possibly representing importations of S. Typhi from outside of Chile. We found concordance amongst S. Typhi genotypes between the 1980s and 2010s, and differences from genotypes circulating in Southeast Asia and Africa where typhoid remains hyperendemic. Our findings suggest that a proportion of modern, rare typhoid cases in Santiago are autochthonous, and that chronic carriers or another unknown reservoir likely contribute. Broadly, our findings corroborate the epidemiologic importance of long-term reservoirs of typhoid fever decades after typhoid elimination. [ABSTRACT FROM AUTHOR]

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250. Author summary: Cholera, a disease caused by infection with the bacterium Vibrio cholerae, remains a major cause of diarrheal illness and death, particularly in settings with poor sanitation and hygiene. We developed a synthetic chemical, named "iOWH032," as a potential treatment for cholera, which is administered as oral tablets. The chemical acts by blocking secretions from cells in the intestine, and thereby was expected to prevent fluid loss and dehydration caused by cholera illness. We tested iOWH032 in a clinical study using a cholera human challenge model. Study volunteers were intentionally infected with V. cholerae in an inpatient clinic setting to better study the effects of iOWH032 on infected individuals. This challenge model had been used previously to test cholera vaccine candidates, but this study represents the first test of a potential cholera treatment using the model. We found that treatment of individuals with iOWH032 was safe, but did not result in a significant reduction of cholera illness, based on several different measurements of diarrheal symptoms and severity. This study demonstrates how human challenge models incorporating a relatively small number of subjects can help support decision-making about potential new therapeutics and other interventions for infectious diseases. [ABSTRACT FROM AUTHOR]