Early-Life Enteric Pathogen Exposure, Socioeconomic Status, and School-Age Cognitive Outcomes.

Early-life experiences of enteric infections and diarrheal illness are common in low-resource settings and are hypothesized to affect child development. However, longer-term associations of enteric infections with school-age cognitive outcomes are difficult to estimate due to lack of long-term studies. The objective of this study was to examine the relationship between enteropathogen exposure in the first 2 years of life with school-age cognitive skills in a cohort of children followed from birth until 6 to 8 years in low-resource settings in Brazil, Tanzania, and South Africa. The study included participants from three sites from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health Study who were enrolled just after birth and followed for enteric infections, diarrheal illness, and cognitive development until 2 years of age. When the children were school-age, further data were collected on reasoning skills and semantic/phonemic fluency. We estimated associations between the burden of specific enteric pathogens and etiology-specific diarrhea from 0 to 2 years with cognitive test scores at 6 to 8 years using linear regression and adjusting for confounding variables. In this study, children who carried more enteric pathogens in the first 2 years of life showed overall decreases in school-age cognitive abilities, particularly children who carried protozoa, although this was not statistically significant in this sample. Socioeconomic factors such as maternal education and income were more closely associated with school-age cognitive abilities. Early-life enteric pathogens may have a small, lasting influence on school-age cognitive outcomes, although other socioeconomic factors likely contribute more significantly.

Infant Nutritional Status, Feeding Practices, Enteropathogen Exposure, Socioeconomic Status, and Illness Are Associated with Gut Barrier Function As Assessed by the Lactulose Mannitol Test in the MAL-ED Birth Cohort.

The lactulose mannitol (LM) dual sugar permeability test is the most commonly used test of environmental enteropathy in developing countries. However, there is a large but conflicting literature on its association with enteric infection and host nutritional status. We conducted a longitudinal cohort using a single field protocol and comparable laboratory procedures to examine intestinal permeability in multiple, geographically diverse pediatric populations. Using a previously published systematic review to guide the selection of factors potentially associated with LM test results, we examined the relationships between these factors and mucosal breach, represented by percent lactulose excretion; absorptive area, represented by percent mannitol excretion; and gut barrier function, represented by the L/M ratio. A total of 6,602 LM tests were conducted in 1,980 children at 3, 6, 9, and 15 months old; percent lactulose excretion, percent mannitol excretion, and the L/M ratio were expressed as age- and sex-specific normalized values using the Brazil cohort as the reference population. Among the factors considered, recent severe diarrhea, lower socioeconomic status, and recent asymptomatic enteropathogen infections were associated with decreased percent mannitol excretion and higher L/M ratios. Poorer concurrent weight-for-age, infection, and recent breastfeeding were associated with increased percent lactulose excretion and increased L/M ratios. Our results support previously reported associations between the L/M ratio and factors related to child nutritional status and enteropathogen exposure. These results were remarkably consistent across sites and support the hypothesis that the frequency of these exposures in communities living in poverty leads to alterations in gut barrier function.

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.

Epidemiology and Impact of Campylobacter Infection in Children in 8 Low-Resource Settings: Results From the MAL-ED Study.

BACKGROUND: Enteropathogen infections have been associated with enteric dysfunction and impaired growth in children in low-resource settings. In a multisite birth cohort study (MAL-ED), we describe the epidemiology and impact of Campylobacter infection in the first 2 years of life. METHODS: Children were actively followed up until 24 months of age. Diarrheal and nondiarrheal stool samples were collected and tested by enzyme immunoassay for Campylobacter Stool and blood samples were assayed for markers of intestinal permeability and inflammation. RESULTS: A total of 1892 children had 7601 diarrheal and 26 267 nondiarrheal stool samples tested for Campylobacter We describe a high prevalence of infection, with most children (n = 1606; 84.9%) having a Campylobacter-positive stool sample by 1 year of age. Factors associated with a reduced risk of Campylobacter detection included exclusive breastfeeding (risk ratio, 0.57; 95% confidence interval, .47-.67), treatment of drinking water (0.76; 0.70-0.83), access to an improved latrine (0.89; 0.82-0.97), and recent macrolide antibiotic use (0.68; 0.63-0.74). A high Campylobacter burden was associated with a lower length-for-age Z score at 24 months (-1.82; 95% confidence interval, -1.94 to -1.70) compared with a low burden (-1.49; -1.60 to -1.38). This association was robust to confounders and consistent across sites. Campylobacter infection was also associated with increased intestinal permeability and intestinal and systemic inflammation. CONCLUSIONS: Campylobacter was prevalent across diverse settings and associated with growth shortfalls. Promotion of exclusive breastfeeding, drinking water treatment, improved latrines, and targeted antibiotic treatment may reduce the burden of Campylobacter infection and improve growth in children in these settings.

Limitations in verbal fluency following heavy burdens of early childhood diarrhea in Brazilian shantytown children.

The effects of heavy burdens of diarrhea in the first 2 years of life on specific executive control function like verbal fluency are not well understood. In previous studies, we have shown associations of early childhood diarrhea (ECD) with nonverbal intelligence and school functioning. Therefore, we postulated that ECD might affect early neuropsychological development leading to long-term deficits in normal cognitive development. Based on our extensive 14-year prospective cohort studies of early childhood diarrheal illnesses in a Brazilian shantytown community, we examined ECD correlations between specific impairments of higher mental function and executive skills in shantytown children 5-10 years later (now at 6-12) years of age. Specifically we examined whether heavy diarrheal illnesses correlate with reduced performance on selected tests of executive function. Our study, for the first time, suggests a disproportional impairment in semantic but not phonetic fluency in a subset of children with heavy burdens of diarrhea in their first 2 years of life even when controlling for maternal education, breastfeeding, and child schooling. Similar semantic decrements have been associated with impaired recovery from brain injury. These exploratory studies suggest the importance of verbal fluency tests to assess executive functioning in children challenged by poor nutrition and diarrhea in early life. In addition, our unique findings show the potential influences of early childhood diarrhea on language development that is so critical to productive adulthood and potentially set a foundation for new neuropsychological approaches, which assess early burdens of enteric illnesses on childhood development.

Magnitude and impact of diarrheal diseases.

Among the increasingly unacceptable costs of the diseases of poverty are the largely unmeasured but potentially huge human and economic long-term costs of common tropical infectious diseases, especially those such as repeated dehydrating and malnourishing diarrheal diseases (and enteric infections, even without overt liquid stools) that are so prevalent in the developmentally critical first year or two of early childhood. We review here the high costs of diseases of poverty, increasing diarrhea morbidity (despite decreasing mortality), and new emerging evidence for long-term consequences of early childhood diarrhea on growth and on physical and cognitive development, effects that may translate into costly impairment of human potential and productivity.

Updating the DALYs for diarrhoeal disease.

Estimates of global disease burden remain high on the international research and policy agenda as a forum for ranking health priorities. Within this, the quality of life or years lived with varying degrees of disability has been recognized as an important outcome that should be considered alongside estimates of mortality. Recent studies into the long-term consequences of diarrhoeal diseases on physical and mental development suggest that the disability adjusted life year calculations for these conditions could require updating.