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

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

Modelling stunting in LiST: the effect of applying smoothing to linear growth data

Background: The Lives Saved Tool (LiST) is a widely used resource for evidence-based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older.Methods: We identified datasets with serial measurements of children\u27s lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children\u27s stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next ( stunting-to-stunting ORs ) using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs.Results: A total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights.Conclusions: Smoothing of children\u27s measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions

Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil

OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ) received 200,000 IU of retinol (every four months), zinc (40 mg twice weekly), or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z-scores, weight-forheight z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4-6.6) later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+), with an allele frequency of 13.9%. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+) children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z-scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+) children and improved delta lactulose/mannitol. Apolipoprotein E4(-) children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may function concomitantly with gut-tropic nutrients to benefit immediate nutritional status, which can translate into better long-term cognitive outcomes

Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil

OBJECTIVE: Apolipoprotein E4 may benefit children during early periods of life when the body is challenged by infection and nutritional decline. We examined whether apolipoprotein E4 affects intestinal barrier function, improving short-term growth and long-term cognitive outcomes in Brazilian shantytown children. METHODS: A total of 213 Brazilian shantytown children with below-median height-for-age z-scores (HAZ) received 200,000 IU of retinol (every four months), zinc (40 mg twice weekly), or both for one year, with half of each group receiving glutamine supplementation for 10 days. Height-for-age z-scores, weight-for-age z-scores, weight-forheight z-scores, and lactulose:mannitol ratios were assessed during the initial four months of treatment. An average of four years (range 1.4-6.6) later, the children underwent cognitive testing to evaluate non-verbal intelligence, coding, verbal fluency, verbal learning, and delayed verbal learning. Apolipoprotein E4 carriage was determined by PCR analysis for 144 children. RESULTS: Thirty-seven children were apolipoprotein E4(+), with an allele frequency of 13.9%. Significant associations were found for vitamin A and glutamine with intestinal barrier function. Apolipoprotein E4(+) children receiving glutamine presented significant positive Pearson correlations between the change in height-for-age z-scores over four months and delayed verbal learning, along with correlated changes over the same period in weight-for-age z-scores and weight-for-height z-scores associated with non-verbal intelligence quotients. There was a significant correlation between vitamin A supplementation of apolipoprotein E4(+) children and improved delta lactulose/mannitol. Apolipoprotein E4(-) children, regardless of intervention, exhibited negative Pearson correlations between the change in lactulose-to-mannitol ratio over four months and verbal learning and non-verbal intelligence. CONCLUSIONS: During development, apolipoprotein E4 may function concomitantly with gut-tropic nutrients to benefit immediate nutritional status, which can translate into better long-term cognitive outcomes

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

Measuring socioeconomic status in multicountry studies: Results from the eight-country MAL-ED study

Background: There is no standardized approach to comparing socioeconomic status (SES) across multiple sites in epidemiological studies. This is particularly problematic when cross-country comparisons are of interest. We sought to develop a simple measure of SES that would perform well across diverse, resource-limited settings. Methods: A cross-sectional study was conducted with 800 children aged 24 to 60 months across eight resource-limited settings. Parents were asked to respond to a household SES questionnaire, and the height of each child was measured. A statistical analysis was done in two phases. First, the best approach for selecting and weighting household assets as a proxy for wealth was identified. We compared four approaches to measuring wealth: maternal education, principal components analysis, Multidimensional Poverty Index, and a novel variable selection approach based on the use of random forests. Second, the selected wealth measure was combined with other relevant variables to form a more complete measure of household SES. We used child height-for-age Z-score (HAZ) as the outcome of interest. Results: Mean age of study children was 41 months, 52% were boys, and 42% were stunted. Using cross-validation, we found that random forests yielded the lowest prediction error when selecting assets as a measure of household wealth. The final SES index included access to improved water and sanitation, eight selected assets, maternal education, and household income (the WAMI index). A 25% difference in the WAMI index was positively associated with a difference of 0.38 standard deviations in HAZ (95% CI 0.22 to 0.55). Conclusions: Statistical learning methods such as random forests provide an alternative to principal components analysis in the development of SES scores. Results from this multicountry study demonstrate the validity of a simplified SES index. With further validation, this simplified index may provide a standard approach for SES adjustment across resource-limited settings.publishedVersio

Intestinal permeability and inflammation mediate the association between nutrient density of complementary foods and biochemical measures of micronutrient status in young children: results from the MAL-ED study

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

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

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