Age and sex normalization of intestinal permeability measures for the improved assessment of enteropathy in infancy and early childhood: Results from the MAL-ED study

Objectives: The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings.Methods: In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age- and sex-specific z scores for mannitol and lactulose recoveries and the L:M ratio.Results: A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex-specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age.Conclusions: Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M-z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations

Burden, clinical characteristics, risk factors, and seasonality of adenovirus 40/41 diarrhea in children in eight low-resource settings

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

Determinants of campylobacter infection and association with growth and enteric inflammation in children under 2 years of age in low-resource settings

Campylobacter species infections have been associated with malnutrition and intestinal inflammation among children in low-resource settings. However, it remains unclear whether that association is specific to Campylobacter jejuni/coli. The aim of this study was to assess the association between both all Campylobacter species infections and Campylobacter jejuni/coli infections on growth and enteric inflammation in children aged 1-24 months. We analyzed data from 1715 children followed from birth until 24 months of age in the MAL-ED birth cohort study, including detection of Campylobacter species by enzyme immunoassay and Campylobacter jejuni/coli by quantitative PCR in stool samples. Myeloperoxidase (MPO) concentration in stool, used as a quantitative index of enteric inflammation, was measured. The incidence rate per 100 child-months of infections with Campylobacter jejuni/coli and Campylobacter species during 1-24 month follow up were 17.7 and 29.6 respectively. Female sex of child, shorter duration of exclusive breastfeeding, lower maternal age, mother having less than 3 living children, maternal educational level of \u3c6 \u3eyears, lack of routine treatment of drinking water, and unimproved sanitation were associated with Campylobacter jejuni/coli infection. The cumulative burden of both Campylobacter jejuni/coli infections and Campylobacter species were associated with poor growth and increased intestinal inflammation

Relationships among common illness symptoms and the protective effect of breastfeeding in early childhood in MAL-ED: An eight-country cohort study

Children in low-income countries experience multiple illness symptoms in early childhood. Breastfeeding is protective against diarrhea and respiratory infections, and these illnesses are thought to be risk factors of one another, but these relationships have not been explored simultaneously. In the eight-site MAL-ED study, 1,731 infants were enrolled near birth and followed for 2 years. We collected symptoms and diet information through twice-weekly household visits. Poisson regression was used to determine if recent illness history was associated with incidence of diarrhea or acute lower respiratory infections (ALRI), accounting for exclusive breastfeeding. Recent diarrhea was associated with higher risk of incident diarrhea after the first 6 months of life (relative risk [RR] 1.10, 95% confidence interval [CI] 1.04, 1.16) and with higher risk of incident ALRI in the 3- to 5-month period (RR 1.23, 95% CI 1.03, 1.47). Fever was a consistent risk factor for both diarrhea and ALRI. Exclusive breastfeeding 0-6 months was protective against diarrhea (0-2 months: RR 0.39, 95% CI 0.32, 0.49; 3-5 months: RR 0.83, 95% CI 0.75, 0.93) and ALRI (3-5 months: RR 0.81, 95% CI 0.68, 0.98). Children with recent illness who were exclusively breastfed were half as likely as those not exclusively breastfed to experience diarrhea in the first 3 months of life. Recent illness was associated with greater risk of new illness, causing illnesses to cluster within children, indicating that specific illness-prevention programs may have benefits for preventing other childhood illnesses. The results also underscore the importance of exclusive breastfeeding in the first 6 months of life for disease prevention

A longitudinal study of household water, sanitation, and hygiene characteristics and environmental enteropathy markers in children less than 24 months in Iquitos, Peru

Funding Information: Financial support: The MAL-ED is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center. While conducting this work, Natalie Exum was supported by The NSF IGERT Grant 1069213, The Osprey Foundation of Maryland Grant 1602030014, the Johns Hopkins Water Institute, Johns Hopkins Fisher Center Discovery Program Grant 010 KOS2015, The Kazuyoshi Kawata fund in Sanitary Engineering and Science, and the Dr. C. W. Kruse Memorial Fund Scholarship. Publisher Copyright: © 2018 by The American Society of Tropical Medicine and Hygiene.Peer reviewedPublisher PD

Gut microbiota features associated with Campylobacter burden and postnatal linear growth deficits in a Peruvian birth cohort

BACKGROUND: Campylobacter infection is associated with impaired growth of children, even in the absence of symptoms. To examine the underlying mechanisms, we evaluated associations between Campylobacter infection, linear growth, and fecal microbial community features in a prospective birth cohort of 271 children with a high burden of diarrhea and stunting in the Amazonian lowlands of Peru. METHODS: Campylobacter was identified using a broadly reactive, genus-specific enzyme-linked immunosorbent assay. 16S rRNA-based analyses were used to identify bacterial taxa in fecal samples at ages 6, 12, 18, and 24 months (N = 928). Associations between infection, growth, and gut microbial community composition were investigated using multiple linear regression adjusting for within-child correlations, age, and breastfeeding. Indicator species analyses identified taxa specifically associated with Campylobacter burden. RESULTS: Ninety-three percent (251) of children had Campylobacter present in asymptomatic fecal samples during the follow-up period. A 10% increase in the proportion of stools infected was associated with mean reductions of 0.02 length-for-age z scores (LAZ) at 3, 6, and 9 months thereafter (P \u3c .01). We identified 13 bacterial taxa indicative of cumulative Campylobacter burden and 14 taxa significantly associated with high or low burden of enteroaggregative Escherichia coli, norovirus, or Giardia. CONCLUSIONS: Campylobacter infection is common in this cohort and associated with changes in microbial community composition. These results support the notion that disruptions to the fecal microbiota may help explain the observed effects of asymptomatic infections on growth in early life

Full breastfeeding protection against common enteric bacteria and viruses: Results from the MAL-ED cohort study

Background: Breastfeeding is known to reduce risk of enteropathogen infections, but protection from specific enteropathogens is not well characterized.Objective: To estimate the association between full breastfeeding (days fed breast milk exclusively or with non-nutritive liquids) and enteropathogen detection.Design: 2,145 newborns were enrolled in eight sites, of whom 1,712 had breastfeeding and key enteropathogen data through 6 months. We focused on eleven enteropathogens: adenovirus 40/41, norovirus, sapovirus, astrovirus, and rotavirus, enterotoxigenic Escherichia coli (ETEC), Campylobacter spp, and typical enteropathogenic E. coli as well as entero-aggregative E. coli, Shigella and Cryptosporidium. Logistic regression was used to estimate the risk of enteropathogen detection in stools and survival analysis to estimate the timing of first detection of an enteropathogen.Results: Infants with 10% more days of full breastfeeding within the preceding 30 days of a stool sample were less likely to have the three E. Coli and Campylobacter spp detected in their stool (mean odds 0.92-0.99) but equally likely (0.99-1.02) to have the viral pathogens detected in their stool. A 10% longer period of full breastfeeding from birth was associated with later first detection of the three E. Coli, Campylobacter, adenovirus, astrovirus, and rotavirus (mean hazard ratios of 0.52-0.75). The hazards declined and point estimates were not statistically significant at 3 months.Conclusions: In this large multi-center cohort study, full breastfeeding was associated with lower likelihood of detecting four important enteric pathogens in the first six months of life. These results also show that full breastfeeding is related to delays in the first detection of some bacterial and viral pathogens in the stool. As several of these pathogens are risk factors for poor growth during childhood, this work underscores the importance of exclusive or full breastfeeding during the first six months of life to optimize early health

Diarrhea as a potential cause and consequence of reduced gut microbial diversity among undernourished children in Peru

BACKGROUND: Detrimental effects of diarrhea on child growth and survival are well documented, but details of the underlying mechanisms remain poorly understood. Recent evidence demonstrates that perturbations to normal development of the gut microbiota in early life may contribute to growth faltering and susceptibility to related childhood diseases. We assessed associations between diarrhea, gut microbiota configuration, and childhood growth in the Peruvian Amazon. METHODS: Growth, diarrhea incidence, illness, pathogen infection, and antibiotic exposure were assessed monthly in a birth cohort of 271 children aged 0-24 months. Gut bacterial diversity and abundances of specific bacterial taxa were quantified by sequencing 16S rRNA genes in fecal samples collected at 6, 12, 18, and 24 months. Linear and generalized linear models were used to determine whether diarrhea was associated with altered microbiota and, in turn, if features of the microbiota were associated with the subsequent risk of diarrhea. RESULTS: Diarrheal frequency, duration, and severity were negatively associated with bacterial diversity and richness (P \u3c .05). Children born stunted (length-for-age z-score [LAZ] ≤ -2) who were also severely stunted (LAZ ≤ -3) at the time of sampling exhibited the greatest degree of diarrhea-associated reductions in bacterial diversity and the slowest recovery of bacterial diversity after episodes of diarrhea. Increased bacterial diversity was predictive of reduced subsequent diarrhea from age 6 to 18 months. CONCLUSIONS: Persistent, severe growth faltering may reduce the gut microbiota\u27s resistance and resilience to diarrhea, leading to greater losses of diversity and longer recovery times. This phenotype, in turn, denotes an increased risk of future diarrheal disease and growth faltering

Influences on catch-up growth using relative versus absolute metrics : evidence from the MAL-ED cohort study

Acknowledgements The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) was a collaborative project led by the Foundation for the National Institutes of Health and the National Institutes of Health, Fogarty International Center. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. National Institutes of Health or Department of Health and Human Services. Funding The MAL-ED study was supported by the Bill & Melinda Gates Foundation, through grants to the Foundation for the National Institutes of Health, and with additional support from the National Institutes of Health, Fogarty Inter- national Center. The funder had no direct role in the writing of the manu- script or in the study design, data collection, analysis or interpretation of study results. We are grateful to the children and caregivers who participated in the study for their invaluable contributions.Peer reviewedPublisher PD

Full breastfeeding protection against common enteric bacteria and viruses : results from the MAL-ED cohort study

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