Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study

Abstract

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.

Presence of Giardia lamblia in stools of six‐ to 18‐month old asymptomatic Malawians is associated with children's growth failure

“…If this was the case, the use of three‐month follow‐up could obscure the importance of viral infections in linear growth restriction. Few studies have addressed the association between asymptomatic viral infections and growth . To better assess the growth impact of non‐chronic viral infections, one should thus probably use with a short follow‐up period a more sensitive outcome variable, such as knemometry, plasma concentrations of insulin‐like growth factor or collagen X .…”

Virulence-Related Genes and Coenteropathogens Associated with Clinical Outcomes of Enteropathogenic Escherichia coli Infections in Children from the Brazilian Semiarid Region: a Case-Control Study of Diarrhea

“…Other studies have tried to associate enteropathogens, including diarrheagenic E. coli, such as enteroaggregative E. coli (EAEC), with undernutrition in child populations (42,43). Recent data emerging from MAL-ED studies have reinforced the importance of even asymptomatic enteric infections as a cause of growth impairment in children from developing countries (44,45), which was observed due to the use of molecular diagnostic techniques instead of conventional techniques (46,47). Indeed, the higher prevalence of aEPEC than tEPEC in asymptomatic children was recently supported by Rogawski and colleagues (47) and requires further investigation.…”

Giardiasis in children: molecular genotyping, growth and calprotectin levels

“…It is known that a direct correlation between the content of calprotectin and linear growth is present 21 . Clarifying the relationship between intestinal pathogens [22][23] , ecological enteropathy 24 and growth retardation 25 can help to develop behavioral and therapeutic interventions to reduce this disease manifestation in susceptible pediatric populations.…”