SummaryBackgroundEnteropathogen 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.MethodsWe 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.FindingsAmong 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.InterpretationSubclinical 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.FundingBill & Melinda Gates Foundation.

SummaryBackgroundOptimum 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.MethodsWe 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.FindingsWe 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]).InterpretationQuantitative 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.FundingBill & Melinda Gates Foundation.

HighlightsChildren living in these settings had a high prevalence of enteropathogens, high levels of intestinal inflammation, abnormal intestinal permeability, high markers of systemic inflammation, and postnatal acquired linear growth deficits when compared to children living in the US or EuropeThis study contributes empiric evidence to demonstrate that enteric infection alters both fecal markers of inflammation and permeabilityCurrent markers of enteropathy fail to account for a large portion of the observed shortfalls in linear growth in these populations, and markers of systemic inflammation appear as the most promising predictive biomarkers for identifying linear growth failure in childrenEnvironmental enteropathy (EE) is hypothesized as a mediator of growth faltering, but few prospective studies have evaluated pathways linking enteropathogen exposure, intestinal inflammation and permeability, and growth. The MAL-ED study represents a novel analytical framework and explicitly evaluates multiple putative EE pathways in combination and using an unprecedented quantity of data. Despite evidence that gut inflammation and altered gut permeability are frequently present and that associations between enteropathogen exposure and gut dysfunction exist, the observed attributable effects of EE on growth faltering in young children were small.

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The Indian Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) site is in Vellore, Tamil Nadu, in south India and is coordinated by the Christian Medical College, Vellore, which has many years of experience in establishing and following cohorts. India is a diverse country, and no single area can be representative with regard to many health and socioeconomic indicators. The site in Vellore is an urban semiorganized settlement or slum. In the study site, the average family size is 5.7, adults who are gainfully employed are mostly unskilled laborers, and 51% of the population uses the field as their toilet facility. Previous studies from Vellore slums have reported stunting in well over a third of children, comparable to national estimates. The infant mortality rate is 38 per 1000 live births, with deaths due mainly to perinatal and infectious causes. Rigorous staff training, monitoring, supervision and refinement of tools have been essential to maintaining the quality of the significantly large quantity of data collected. Establishing a field clinic within the site has minimized inconvenience to participants and researchers and enabled better rapport with the community and better follow-up. These factors contribute to the wealth of information that will be generated from the MAL-ED multisite cohort, which will improve our understanding of enteric infections and its interactions with malnutrition and development of young children.