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Background Sapovirus is one of the principal agents of acute viral enteritis in children. Because it has not been routinely included in diagnostic evaluations, the epidemiology and natural history remain poorly described. Methods A birth cohort of 1715 children from 8 countries contributed surveillance samples (n = 35 620) and diarrheal specimens (n = 6868) from 0 to 24 months of age. Sapovirus was detected by quantitative polymerase chain reaction concurrently to other enteropathogens using multiarray cards. Logistic regression was used to identify risk factors, and longitudinal models were employed to estimate incidence rates and evaluate evidence of protective immunity. Results Sapovirus was detected in 24.7% (n = 1665) of diarrheal stools and 12.8% (n = 4429) of monthly surveillance samples. More than 90% of children were infected and 60% experienced sapovirus diarrhea in the first 2 years of life. Breastfeeding and higher socioeconomic status were associated with reduced incidence of infection and illness. Specimens with sapovirus detected had an increased odds of coinfection with rotavirus (odds ratio [OR], 1.6 [95% confidence interval {CI}, 1.3–2.0]), astrovirus (OR, 1.5 [95% CI, 1.3–1.7]), adenovirus (OR, 1.3 [95% CI, 1.1–1.5]), and Shigella (OR, 1.4 [95% CI, 1.3–1.6]). Prior infection with sapovirus conferred a risk reduction of 22% for subsequent infection (hazard ratio [HR], 0.78 [95% CI, .74–.85]) and 24% for subsequent diarrhea (95% CI, 11.0%–35.0%; HR, 0.76). Conclusions Sapovirus is a common cause of early childhood diarrhea. Further research on coinfections is warranted. Evidence of acquired immunity was observed even in the absence of genotype-specific analysis for this pathogen of known genetic diversity.

Enteropathy is a pathophysiological condition characterized by decreased intestinal barrier function and absorption. Past studies have hypothesized that mycotoxins might impair children's growth by causing intestinal enteropathy, including interactions between mycotoxins and pathogens. We investigated the association of two mycotoxins, aflatoxin B

Background The application of molecular diagnostics has identified enteric group adenovirus serotypes 40 and 41 as important causes of diarrhea in children. However, many aspects of the epidemiology of adenovirus 40/41 diarrhea have not been described. Methods We used data from the 8-site Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project birth cohort study to describe site- and age-specific incidence, risk factors, clinical characteristics, and seasonality. Results The incidence of adenovirus 40/41 diarrhea was substantially higher by quantitative polymerase chain reaction than enzyme immunoassay and peaked at ∼30 episodes per 100 child-years in children aged 7–15 months, with substantial variation in incidence between sites. A significant burden was also seen in children 0–6 months of age, higher than other viral etiologies with the exception of rotavirus. Children with adenovirus 40/41 diarrhea were more likely to have a fever than children with norovirus, sapovirus, and astrovirus (adjusted odds ratio [aOR], 1.62; 95% CI, 1.16–2.26) but less likely than children with rotavirus (aOR, 0.66; 95% CI, 0.49–0.91). Exclusive breastfeeding was strongly protective against adenovirus 40/41 diarrhea (hazard ratio, 0.64; 95% CI, 0.48–0.85), but no other risk factors were identified. The seasonality of adenovirus 40/41 diarrhea varied substantially between sites and did not have clear associations with seasonal variations in temperature or rainfall. Conclusions This study supports the situation of adenovirus 40/41 as a pathogen of substantial importance, especially in infants. Fever was a distinguishing characteristic in comparison to other nonrotavirus viral etiologies, and promotion of exclusive breastfeeding may reduce the high observed burden in the first 6 months of life.

Background Environmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation. Objective We tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status. Methods Using data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods were quantified monthly from 9 to 15 mo and densities were averaged for analyses. α-1-Acid glycoprotein at 15 mo characterized systemic inflammation. Relations between variables were modeled using a Bayesian network. Results A greater risk of anemia was associated with LMZ [1.15 (95% CI: 1.01, 1.31)] and MPO [1.16 (1.01, 1.34)]. A greater risk of low ferritin was associated with AAT [1.19 (1.03, 1.37)] and NEO [1.22 (1.04, 1.44)]. A greater risk of low retinol was associated with LMZ [1.24 (1.08, 1.45)]. However, MPO was associated with a lower risk of high transferrin receptor [0.86 (0.74, 0.98)], NEO with a lower risk of low retinol [0.75 (0.62, 0.89)], and AAT with a lower risk of low plasma zinc [0.83 (0.70, 0.99)]. Greater nutrient intake densities (vitamins A and B6, calcium, protein, and zinc) were negatively associated with EED. Inverse associations between nutrient densities and micronutrient deficiency largely disappeared after adjustment for EED, suggesting that EED mediates these associations. Conclusions EED is independently associated with an increased risk of low ferritin, low retinol, and anemia. Greater nutrient density from complementary foods may reduce EED, and the control of micronutrient deficiencies may require control of EED.

Undernourished children are metabolically immature relative to those growing normally across 3 diverse epidemiologic contexts., Malnutrition continues to affect the growth and development of millions of children worldwide, and chronic undernutrition has proven to be largely refractory to interventions. Improved understanding of metabolic development in infancy and how it differs in growth-constrained children may provide insights to inform more timely, targeted, and effective interventions. Here, the metabolome of healthy infants was compared to that of growth-constrained infants from three continents over the first 2 years of life to identify metabolic signatures of aging. Predictive models demonstrated that growth-constrained children lag in their metabolic maturity relative to their healthier peers and that metabolic maturity can predict growth 6 months into the future. Our results provide a metabolic framework from which future nutritional programs may be more precisely constructed and evaluated.

In rural agricultural communities in Africa, particularly those with a single annual harvest, the preharvest period has been associated with increased food insecurity. We estimated the association between seasonal food insecurity and childhood malnutrition in Haydom, Tanzania. Children enrolled in a birth cohort study were followed twice weekly to document food intake and monthly for anthropometry until the age of 2 years. Household food insecurity was reported by caregivers every 6 months. We modeled the seasonality of food insecurity and food consumption, and estimated the impact of birth season on enrollment weight and subsequent malnutrition. Finally, we described the seasonality of admissions for acute malnutrition at a local referral hospital (Haydom Lutheran Hospital) from 2010 to 2015. Food insecurity was highly seasonal, with a peak from December to February. Children born during these 3 months had an average 0.35 z-score (95% CI: 0.12, 0.58) lower enrollment weight than children born in other months. In addition, weight-for-length z-scores measured in these months were on average 0.15 z-scores lower (95% CI: 0.10, 0.20) than that in other months, adjusting for enrollment weight and seasonal infectious diseases, and this disparity was sustained up to the age of 2 years. Correspondingly, the number of admissions with acute malnutrition at the local hospital was highest at this time, with twice as many cases in December–February compared with June–August. We identified acute and chronic malnutrition associated with seasonal food insecurity and intake. Targeting of prenatal care and child-feeding interventions during high food insecurity months may help reduce child malnutrition.

Summary: Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.

Summary: Background: Enteropathogen infections in early childhood not only cause diarrhoea but contribute to poor growth. We used molecular diagnostics to assess whether particular enteropathogens were associated with linear growth across seven low-resource settings. Methods: We used quantitative PCR to detect 29 enteropathogens in diarrhoeal and non-diarrhoeal stools collected from children in the first 2 years of life obtained during the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite cohort study. Length was measured monthly. We estimated associations between aetiology-specific diarrhoea and subclinical enteropathogen infection and quantity and attained length in 3 month intervals, at age 2 and 5 years, and used a longitudinal model to account for temporality and time-dependent confounding. Findings: Among 1469 children who completed 2 year follow-up, 35 622 stool samples were tested and yielded valid results. Diarrhoeal episodes attributed to bacteria and parasites, but not viruses, were associated with small decreases in length after 3 months and at age 2 years. Substantial decrements in length at 2 years were associated with subclinical, non-diarrhoeal, infection with Shigella (length-for-age Z score [LAZ] reduction −0·14, 95% CI −0·27 to −0·01), enteroaggregative Escherichia coli (−0·21, −0·37 to −0·05), Campylobacter (−0·17, −0·32 to −0·01), and Giardia (−0·17, −0·30 to −0·05). Norovirus, Cryptosporidium, typical enteropathogenic E coli, and Enterocytozoon bieneusi were also associated with small decrements in LAZ. Shigella and E bieneusi were associated with the largest decreases in LAZ per log increase in quantity per g of stool (−0·13 LAZ, 95% CI −0·22 to −0·03 for Shigella; −0·14, −0·26 to −0·02 for E bieneusi). Based on these models, interventions that successfully decrease exposure to Shigella, enteroaggregative E coli, Campylobacter, and Giardia could increase mean length of children by 0·12–0·37 LAZ (0·4–1·2 cm) at the MAL-ED sites. Interpretation: Subclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting. Funding: Bill & Melinda Gates Foundation.

Supplemental Digital Content is available in the text, Objectives: There is a lack of consensus on how to measure diarrheal severity. Within the context of a multisite, prospective cohort study, we evaluated the performance of a modified Vesikari score (MAL-ED), 2 previously published scores (Clark and CODA [a diarrheal severity score (Community DiarrheA) published by Lee et al]), and a modified definition of moderate-to-severe diarrhea (MSD) based on dysentery and health care worker diagnosed dehydration. Methods: Scores were built using maternally reported symptoms or fieldworker-reported clinical signs obtained during the first 7 days of a diarrheal episode. The association between these and the risk of hospitalization were tested using receiver operating characteristic analysis. Severity scores were also related to illness etiology, and the likelihood of the episode subsequently becoming prolonged or persistent. Results: Of 10,159 episodes from 1681 children, 143 (4.0%) resulted in hospitalization. The area under the curve of each score as a predictor of hospitalization was 0.84 (95% confidence interval: 0.81, 0.87) (Clark), 0.85 (0.82, 0.88) (MAL-ED), and 0.87 (0.84, 0.89) (CODA). Severity was also associated with etiology and episode duration. Although families were more likely to seek care for severe diarrhea, approximately half of severe cases never reached the health system. Conclusions: Community-based diarrheal severity scores are predictive of relevant child health outcomes. Because they require no assumptions about health care access or utilization, they are useful in refining estimates of the burden of diarrheal disease, in estimating the effect of disease control interventions, and in triaging children for referral in low- and middle-income countries in which the rates of morbidity and mortality after diarrhea remain high.