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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: Cryptosporidium is a leading cause of moderate-to-severe diarrhea (MSD) in young children in Africa. We examined factors associated with Cryptosporidium infection in MSD cases enrolled at the rural western Kenya Global Enteric Multicenter Study (GEMS) site from 2008-2012. Methodology/Principal findings: At health facility enrollment, stool samples were tested for enteric pathogens and data on clinical, environmental, and behavioral characteristics collected. Each child’s health status was recorded at 60-day follow-up. Data were analyzed using logistic regression. Of the 1,778 children with MSD enrolled as cases in the GEMS-Kenya case-control study, 11% had Cryptosporidium detected in stool by enzyme immunoassay; in a genotyped subset, 81% were C. hominis. Among MSD cases, being an infant, having mucus in stool, and having prolonged/persistent duration diarrhea were associated with being Cryptosporidium-positive. Both boiling drinking water and using rainwater as the main drinking water source were protective factors for being Cryptosporidium-positive. At follow-up, Cryptosporidium-positive cases had increased odds of being stunted (adjusted odds ratio [aOR] = 1.65, 95% CI: 1.06–2.57), underweight (aOR = 2.08, 95% CI: 1.34–3.22), or wasted (aOR = 2.04, 95% CI: 1.21–3.43), and had significantly larger negative changes in height- and weight-for-age z-scores from enrollment. Conclusions/Significance: Cryptosporidium contributes significantly to diarrheal illness in young children in western Kenya. Advances in point of care detection, prevention/control approaches, effective water treatment technologies, and clinical management options for children with cryptosporidiosis are needed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate factors associated with rotavirus diarrhea and to describe severity of illness among children <5 years old with non-dysenteric, moderate-to-severe diarrhea (MSD) in rural western Kenya. Methods: We analyzed data from children <5 years old with non-dysenteric MSD enrolled as cases in the Global Enteric Multicenter Study (GEMS) in Kenya. A non-dysenteric MSD case was defined as a child with ≥3 loose stools in 24 hrs. and one or more of the following: sunken eyes, skin tenting, intravenous rehydration, or hospitalization, who sought care at a sentinel health center within 7 days of illness onset. Rotavirus antigens in stool samples were detected by ELISA. Demographic and clinical information was collected at enrollment and during a single follow-up home visit at approximately 60 days. We analyzed diarrhea severity using a GEMS 17 point numerical scoring system adapted from the Vesikari score. We used logistic regression to evaluate factors associated with rotavirus infection. Results: From January 31, 2008 to September 30, 2012, among 1,637 (92%) non-dysenteric MSD cases, rotavirus was detected in stools of 245 (15.0%). Rotavirus-positive compared with negative cases were: younger (median age, 8 vs. 13 months; p<0.0001), had more severe illness (median severity score, 9 vs 8; p<0.0001) and had to be hospitalized more frequently (37/245 [15.1%] vs. 134/1,392 [9.6%]), p <0.013). Independent factors associated with rotavirus infection included age 0–11 months old (aOR = 5.29, 95% CI 3.14–8.89) and presenting with vomiting ≥3 times/24hrs (aOR = 2.58, 95% CI [1.91–3.48]). Rotavirus was detected more commonly in warm and dry months than in the cool and rainy months (142/691 [20%] vs 70/673 [10%]) p<0.0001). Conclusions: Diarrhea caused by rotavirus is associated with severe symptoms leading to hospitalization. Consistent with other settings, infants had the greatest burden of disease. [ABSTRACT FROM AUTHOR]

Background: The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. Methods: Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged <24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. Findings: Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9% (95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27–4.67) and 3.18 (95% CI, 1.85–4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73–2.08) and 1.36 (95% CI, 0.66–2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33–5.01) and 4.88 (95% CI, 0.82–8.92) in infants and 4.04 (95% CI, 0.56–7.51) and 4.71 (95% CI, 0.24–9.18) in toddlers. We estimate 2.9 and 4.7 million Cryptosporidium-attributable cases annually in children aged <24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and ~202,000 Cryptosporidium-attributable deaths (regions combined). ~59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. Conclusions: The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies. [ABSTRACT FROM AUTHOR]

Background: Diarrheal disease is the second leading cause of disease in children less than 5 y of age. Poor water, sanitation, and hygiene conditions are the primary routes of exposure and infection. Sanitation and hygiene interventions are estimated to generate a 36% and 48% reduction in diarrheal risk in young children, respectively. Little is known about whether the number of households sharing a sanitation facility affects a child's risk of diarrhea. The objective of this study was to describe sanitation and hygiene access across the Global Enteric Multicenter Study (GEMS) sites in Africa and South Asia and to assess sanitation and hygiene exposures, including shared sanitation access, as risk factors for moderate-to-severe diarrhea (MSD) in children less than 5 y of age.Methods/findings: The GEMS matched case-control study was conducted between December 1, 2007, and March 3, 2011, at seven sites in Basse, The Gambia; Nyanza Province, Kenya; Bamako, Mali; Manhiça, Mozambique; Mirzapur, Bangladesh; Kolkata, India; and Karachi, Pakistan. Data was collected for 8,592 case children aged <5 y old experiencing MSD and for 12,390 asymptomatic age, gender, and neighborhood-matched controls. An MSD case was defined as a child with a diarrheal illness <7 d duration comprising ≥3 loose stools in 24 h and ≥1 of the following: sunken eyes, skin tenting, dysentery, intravenous (IV) rehydration, or hospitalization. Site-specific conditional logistic regression models were used to explore the association between sanitation and hygiene exposures and MSD. Most households at six sites (>93%) had access to a sanitation facility, while 70% of households in rural Kenya had access to a facility. Practicing open defecation was a risk factor for MSD in children <5 y old in Kenya. Sharing sanitation facilities with 1-2 or ≥3 other households was a statistically significant risk factor for MSD in Kenya, Mali, Mozambique, and Pakistan. Among those with a designated handwashing area near the home, soap or ash were more frequently observed at control households and were significantly protective against MSD in Mozambique and India.Conclusions: This study suggests that sharing a sanitation facility with just one to two other households can increase the risk of MSD in young children, compared to using a private facility. Interventions aimed at increasing access to private household sanitation facilities may reduce the burden of MSD in children. These findings support the current World Health Organization/ United Nations Children's Emergency Fund (UNICEF) system that categorizes shared sanitation as unimproved. [ABSTRACT FROM AUTHOR]

Information is limited on the effect of zinc on immune responses in children with diarrhea due to enterotoxigenic Escherichia coli (ETEC), the most common bacterial pathogen in children. We studied the immunological effect of zinc treatment 120 mg/d) and supplementation (10 mg/d) in children with diarrhea due to ETEC. A total of 148 children aged 6-24 mo were followed up for 9 mo after a 10-d zinc treatment (ZT; n = 74) or a 10-d zinc treatment plus 3-mo supplementation (ZT+S; n = 74), as well as 50 children with ETEC-induced diarrhea that were not treated with zinc (UT). Fifty control children (HC) of the same age group from the same location were also studied. Serum zinc concentrations were higher in both the ZT (P < 0.001) and ZT+S groups (P < 0.0011 than in the UT group but did not differ from the HC group. We found higher serum complement C3 immediately after zinc administration in both ZT (P < 0.0011 and ZT+S (P < 0.0011 groups than in the UT group. Phagocytic activity in children in both ZT (P < 0.01) and ZT+S (P < 0.01) groups was greater than in the UT group. However, oxidative burst capacity was lower in zinc-receiving groups (ZT, P < 0.001 and ZT+S, P < 0.0011 than in the UT group. The naïve:memory T cell ratio in both ZT (P < 0.05) and ZT+S (P < 0.011 groups was higher than in the UT group from d 2 to 15. Increased responses, including complement C3, phagocytic activity, and changes in T cell phenotypes, suggest that zinc administration enhances innate immunity against ETEC infection in children. [ABSTRACT FROM AUTHOR]

The Global Enteric Multicenter Study (GEMS) demonstrated that Shigella and enterotoxigenic Escherichia coli (ETEC) producing heat stable toxin (ST) (either alone or in combination with heat labile toxin) are among the most important pathogens associated with moderate-to-severe diarrhea (MSD) in children younger than 5 years of age living in developing countries. To inform the design of vaccines and other interventions, we reviewed published data and new results from GEMS characterizing the burden of Shigella and ST-ETEC infections. Clinical parameters were assessed to examine the value of various case definitions as indicators of MSD associated with Shigella and ST-ETEC for use in clinical trials. We discussed advantages and disadvantages of culture-based and culture-independent molecular diagnostics for detecting clinically and epidemiologically relevant disease. Shigella serotyping data from GEMS were examined to identify desirable components of Shigella and ETEC vaccines likely to confer broad protection. These findings can inform the development and implementation of vaccines to prevent these important infections among infants and children in developing countries. [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]

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]