• Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study

      Kosek, MN; Ahmed, T; Bhutta, ZA; Caulfield, L; Guerrant, RL; Houpt, E; Kang, G; Lee, G; Lima, AAM; McCormick, BJJ; Platts-Mills, J; Seidman, JC; Blank, RR; Gottlieb, M; Knobler, SL; Lang, DR; Miller, MA; Tountas, KH; Checkley, W; Mason, CJ; Murray-Kolb, LE; Petri, WA; Bessong, P; Haque, R; John, S; Mduma, ER; Oriá, RB; Shrestha, PS; Shrestha, SK; Svensen, E; Zaidi, AKM; Abreu, CB; Acosta, AM; Ahmed, I; Shamsir Ahmed, AM; Ali, A; Ambikapathi, R; Barrett, L; Bauck, A; Bayyo, E; Bodhidatta, L; Bose, A; Daniel Carreon, J; Chandyo, RK; Charu, V; Costa, H; Dillingham, R; Di Moura, A; Doan, V; Filho, JQ; Graham, J; Hoest, C; Hossain, I; Islam, M; Steffi Jennifer, M; Kaki, S; Koshy, B; Leite, ÁM; Lima, NL; Maciel, BLL; Mahfuz, M; Mahopo, C; Maphula, A; McGrath, M; Mohale, A; Moraes, M; Mota, FS; Muliyil, J; Mvungi, R; Nayyar, G; Nyathi, E; Olortegui, MP; Oria, R; Vasquez, AO; Pan, WK; Pascal, J; Patil, CL; Pendergast, L; Pinedo, SR; Psaki, S; Raghava, MV; Ramanujam, K; Rasheed, M; Rasmussen, ZA; Richard, SA; Rose, A; Roshan, R; Schaefer, B; Scharf, R; Sharma, SL; Shrestha, B; Shrestha, R; Simons, S; Soares, AM; Mota, RMS; Soofi, S; Strand, T; Tofail, F; Thomas, RJ; Turab, A (2017-04-01)
      © 2017 The Authors Background Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation. Funding Bill & Melinda Gates Foundation.
    • Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: Findings from the MAL-ED birth cohort study

      Murray-Kolb, LE; Acosta, AM; De Burga, RR; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Salas, MS; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Bhutta, ZA; Qureshi, S; Rasheed, M; Soofi, S; Turab, A; Zaidi, AKM; Bodhidatta, L; Mason, CJ; Babji, S; Bose, A; George, AT; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Kang, G; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Bose, A; Roshan, R; Sharma, SL; Sundaram, SE; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Charu, V; Doan, V; Graham, J; Hoest, C; Knobler, S; Lang, DR; McCormick, BJJ; McGrath, M; Miller, MA; Mohale, A; Nayyar, G; Psaki, S; Rasmussen, Z; Richard, SA; Seidman, JC; Wang, V; Blank, R; Gottlieb, M; Tountas, KH; Amour, C; Bayyo, E; Mduma, ER; Mvungi, R; Nshama, R; Pascal, J; Swema, BM; Yarrot, L; Ahmed, T; Ahmed, AMS; Haque, R; Hossain, I; Islam, M; Mahfuz, M; Mondal, D; Tofail, F; Chandyo, RK; Shrestha, PS; Shrestha, R; Ulak, M; Bauck, A; Black, RE; Caulfield, LE; Checkley, W; Kosek, MN; Lee, G; Schulze, K; Yori, PP; Murray-Kolb, LE; Catharine Ross, A; Schaefer, B; Simons, S; Pendergast, L; Abreu, CB; Costa, H (2018-07-01)
      © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. background Millions of children in low-income and middle-income countries (LMICs) are at risk of not reaching their full cognitive potential. Malnutrition and enteric infections in early life are implicated as risk factors; however, most studies on these risks and their associations with cognitive development have failed to adequately account for confounding factors or the accumulation of putative insults. Here, we examine the interaction between infections and illness on cognitive development in LMIC community settings. Methods As part of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study, children from eight LMICs were followed from birth to 24 months to understand the influence of repeated enteric infections on child growth and development. Here, data from six sites were employed to evaluate associations between infection, illness, the home environment, micronutrient intake and status, maternal reasoning, and cognitive development at 24 months. results Higher rates of enteropathogen detection and days with illness were associated with lower haemoglobin concentrations, which in turn were associated with lower cognitive scores at 24 months. Children with lower environmental health/safety scores and lower intakes of vitamin B 6 and folate had more enteropathogen detections and illness. Strength of associations varied by weight-for-age in the first 17 days of life; lower weight infants were more susceptible to the negative effects of enteropathogens and illness. Conclusions Enteropathogens were negatively related to child cognitive development. However, other factors were more strongly associated with child cognition. Targeting of interventions to improve cognitive development should include a focus on reducing frequency of illness, improving the safety and healthfulness of the child's environment, and improving dietary intake.
    • Early Life Child Micronutrient Status, Maternal Reasoning, and a Nurturing Household Environment have Persistent Influences on Child Cognitive Development at Age 5 years: Results from MAL-ED

      McCormick, BJJ; Richard, SA; Caulfield, LE; Pendergast, LL; Seidman, JC; Koshy, B; Roshan, R; Shrestha, R; Svensen, E; Blacy, L; Rasmussen, Z; Maphula, A; Scharf, R; Nahar, B; Haque, S; Rasheed, M; Oria, R; Rogawski, ET; Murray-Kolb, LE; Acosta, AM; De Burga, RR; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Salas, MS; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Bhutta, ZA; Qureshi, S; Soofi, S; Turab, A; Zaidi, AKM; Bodhidatta, L; Mason, CJ; Babji, S; Bose, A; George, AT; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Kang, G; Karunakaran, P; Lazarus, RP; Muliyil, J; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Sharma, SL; Sundaram, SE; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Charu, V; Doan, V; Graham, J; Hoest, C; Knobler, S; Lang, DR; McGrath, M; Miller, MA; Mohale, A; Nayyar, G; Psaki, S; Wang, V; Blank, R; Gottlieb, M; Tountas, KH; Amour, C; Bayyo, E; Mduma, ER; Mvungi, R; Nshama, R; Pascal, J; Swema, BM; Yarrot, L; Ahmed, T; Ahmed, AMS; Haque, R; Hossain, I; Islam, M; Mahfuz, M; Mondal, D; Tofail, F; Chandyo, RK; Shrestha, PS; Ulak, M; Bauck, A; Black, RE; Checkley, W; Kosek, MN; Lee, G; Schulze, K (2019-08-01)
      © Copyright American Society for Nutrition 2019. Background: Child cognitive development is influenced by early-life insults and protective factors. To what extent these factors have a long-term legacy on child development and hence fulfillment of cognitive potential is unknown. Objective: The aim of this study was to examine the relation between early-life factors (birth to 2 y) and cognitive development at 5 y. Methods: Observational follow-up visits were made of children at 5 y, previously enrolled in the community-based MAL-ED longitudinal cohort. The burden of enteropathogens, prevalence of illness, complementary diet intake, micronutrient status, and household and maternal factors from birth to 2 y were extensively measured and their relation with the Wechsler Preschool Primary Scales of Intelligence at 5 y was examined through use of linear regression. Results: Cognitive T-scores from 813 of 1198 (68%) children were examined and 5 variables had significant associations in multivariable models: mean child plasma transferrin receptor concentration (β: -1.81, 95% CI: -2.75, -0.86), number of years of maternal education (β: 0.27, 95% CI: 0.08, 0.45), maternal cognitive reasoning score (β: 0.09, 95% CI: 0.03, 0.15), household assets score (β: 0.64, 95% CI: 0.24, 1.04), and HOME child cleanliness factor (β: 0.60, 95% CI: 0.05, 1.15). In multivariable models, the mean rate of enteropathogen detections, burden of illness, and complementary food intakes between birth and 2 y were not significantly related to 5-y cognition. Conclusions: A nurturing home context in terms of a healthy/clean environment and household wealth, provision of adequate micronutrients, maternal education, and cognitive reasoning have a strong and persistent influence on child cognitive development. Efforts addressing aspects of poverty around micronutrient status, nurturing caregiving, and enabling home environments are likely to have lasting positive impacts on child cognitive development.
    • Norovirus infection and acquired immunity in 8 countries: Results from the MAL-ED study

      Rouhani, S; Peñataro Yori, P; Paredes Olortegui, M; Siguas Salas, M; Rengifo Trigoso, D; Mondal, D; Bodhidatta, L; Platts-Mills, J; Samie, A; Kabir, F; Lima, AAM; Babji, S; Mason, CJ; Kalam, A; Bessong, P; Ahmed, T; Mduma, E; Bhutta, ZA; Lima, I; Ramdass, R; Lang, D; George, A; Zaidi, AKM; Kang, G; Houpt, E; Kosek, MN; Brett, N; Acosta, AM; De Burga, RR; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Salas, MS; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Qureshi, S; Rasheed, M; Soofi, S; Turab, A; Bose, A; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Roshan, R; Sharma, SL; Shanmuga Sundaram, E; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Charu, V; Doan, V; Graham, J; Hoest, C; Knobler, S; McCormick, BJJ; McGrath, M; Miller, MA; Mohale, A; Nayyar, G; Psaki, S; Rasmussen, Z; Richard, SA; Seidman, JC; Wang, V; Blank, R; Gottlieb, M; Tountas, KH; Amour, C; Bayyo, E; Mvungi, R; Nshama, R; Pascal, J; Swema, BM; Yarrot, L; Ahmed, AS; Haque, R; Hossain, I; Islam, M; Mahfuz, M; Tofail, F; Chandyo, RK; Shrestha, PS; Shrestha, R; Ulak, M; Bauck, A (2016-05-15)
      © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. Background. Norovirus is an important cause of childhood diarrhea. We present data from a longitudinal, multicountry study describing norovirus epidemiology during the first 2 years of life. Methods. A birth cohort of 1457 children across 8 countries contributed 7077 diarrheal stools for norovirus testing. A subset of 199 children contributed additional asymptomatic samples (2307) and diarrheal stools (770), which were used to derive incidence rates and evaluate evidence for acquired immunity. Results. Across sites, 89% of children experienced at least 1 norovirus infection before 24 months, and 22.7% of all diarrheal stools were norovirus positive. Severity of norovirus-positive diarrhea was comparable to other enteropathogens, with the exception of rotavirus. Incidence of genogroup II (GII) infection was higher than genogroup I and peaked at 6-11 months across sites. Undernutrition was a risk factor for symptomatic norovirus infection, with an increase in 1 standard deviation of length-for-age z score associated with a 17% reduction (odds ratio, 0.83 [95% confidence interval,. 72-.97]; P =. 011) in the odds of experiencing diarrhea when norovirus was present, after accounting for genogroup, rotavirus vaccine, and age. Evidence of acquired immunity was observed among GII infections only: Children with prior GII infection were found to have a 27% reduction in the hazard of subsequent infection (hazard ratio, 0.727; P =. 010). Conclusions. The high prevalence of norovirus across 8 sites in highly variable epidemiologic settings and demonstration of protective immunity for GII infections provide support for investment in vaccine development.
    • Relationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: Findings from the MAL-ED birth cohort study

      Acosta, AM; De Burga, RR; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Salas, MS; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Bhutta, ZA; Qureshi, S; Rasheed, M; Soofi, S; Turab, A; Zaidi, AKM; Bodhidatta, L; Mason, CJ; Babji, S; Bose, A; George, AT; Hariraju, D; Steffi Jennifer, M; John, S; Kaki, S; Kang, G; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Bose, A; Roshan, R; Sharma, SL; Shanmuga Sundaram, E; Thomas, RJ; Pan, WK; Ambikapathi, R; Daniel Carreon, J; Charu, V; Doan, V; Graham, J; Hoest, C; Knobler, S; Lang, DR; McCormick, BJJ; McGrath, M; Miller, MA; Mohale, A; Nayyar, G; Psaki, S; Rasmussen, Z; Richard, SA; Seidman, JC; Wang, V; Blank, R; Gottlieb, M; Tountas, KH; Amour, C; Bayyo, E; Mduma, ER; Mvungi, R; Nshama, R; Pascal, J; Swema, BM; Yarrot, L; Ahmed, T; Shamsir Ahmed, AM; Haque, R; Hossain, I; Islam, M; Mahfuz, M; Mondal, D; Tofail, F; Chandyo, RK; Shrestha, PS; Shrestha, R; Ulak, M; Bauck, A; Black, RE; Caulfield, LE; Checkley, W; Kosek, MN; Lee, G; Schulze, K; Yori, PP; Murray-Kolb, LE; Catharine Ross, A; Schaefer, B; Simons, S; Pendergast, L; Abreu, CB; Costa, H; Di Moura, A (2017-01-01)
      © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. Background Dietary and illness factors affect risk of growth faltering; the role of enteropathogens is less clear. As part of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, we quantify the effects of enteropathogen infection, diarrhoea and diet on child growth. Methods Newborns were enrolled and followed until 24 months. Length and weight were assessed monthly. Illnesses and breastfeeding practices were documented biweekly; from 9 to 24 months, non-breast milk intakes were quantified monthly. Routinely collected non-diarrhoeal stools were analysed for a broad array of enteropathogens. A linear piecewise spline model was used to quantify associations of each factor with growth velocity in seven of eight MAL-ED sites; cumulative effects on attained size at 24 months were estimated for mean, low (10th percentile) and high (90th percentile) exposure levels. Additionally, the six most prevalent enteropathogens were evaluated for their effects on growth. results Diarrhoea did not have a statistically significant effect on growth. Children with high enteropathogen exposure were estimated to be 1.21±0.33 cm (p<0.001; 0.39 length for age (LAZ)) shorter and 0.08±0.15 kg (p=0.60; 0.08 weight-for-age (WAZ)) lighter at 24 months, on average, than children with low exposure. Campylobacter and enteroaggregativeEscherichia coli detections were associated with deficits of 0.83±0.33 and 0.85±0.31 cm in length (p=0.011 and 0.001) and 0.22±0.15 and 0.09±0.14 kg in weight (p=0.14 and 0.52), respectively. Children with low energy intakes and protein density were estimated to be 1.39±0.33 cm (p<0.001; 0.42 LAZ) shorter and 0.81±0.15 kg (p<0.001; 0.65 WAZ) lighter at 24 months than those with high intakes. conclusions Reducing enteropathogen burden and improving energy and protein density of complementary foods could reduce stunting.
    • Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study

      Platts-Mills, JA; Liu, J; Rogawski, ET; Kabir, F; Lertsethtakarn, P; Siguas, M; Khan, SS; Praharaj, I; Murei, A; Nshama, R; Mujaga, B; Havt, A; Maciel, IA; McMurry, TL; Operario, DJ; Taniuchi, M; Gratz, J; Stroup, SE; Roberts, JH; Kalam, A; Aziz, F; Qureshi, S; Islam, MO; Sakpaisal, P; Silapong, S; Yori, PP; Rajendiran, R; Benny, B; McGrath, M; McCormick, BJJ; Seidman, JC; Lang, D; Gottlieb, M; Guerrant, RL; Lima, AAM; Leite, JP; Samie, A; Bessong, PO; Page, N; Bodhidatta, L; Mason, C; Shrestha, S; Kiwelu, I; Mduma, ER; Iqbal, NT; Bhutta, ZA; Ahmed, T; Haque, R; Kang, G; Kosek, MN; Houpt, ER; Acosta, AM; Rios de Burga, R; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Rasheed, M; Soofi, S; Turab, A; Yousafzai, A; Zaidi, AK; Shrestha, B; Rayamajhi, BB; Strand, T; Ammu, G; Babji, S; Bose, A; George, AT; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Ragasudha, P; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Rose, A; Roshan, R; Sharma, SL; Sundaram, S; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Doan, V; Hoest, C; Knobler, S; Miller, MA (2018-12-01)
      © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Optimum 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. Methods: We 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. Findings: We 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]). Interpretation: Quantitative 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. Funding: Bill & Melinda Gates Foundation.
    • 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

      Rogawski, ET; Liu, J; Platts-Mills, JA; Kabir, F; Lertsethtakarn, P; Siguas, M; Khan, SS; Praharaj, I; Murei, A; Nshama, R; Mujaga, B; Havt, A; Maciel, IA; Operario, DJ; Taniuchi, M; Gratz, J; Stroup, SE; Roberts, JH; Kalam, A; Aziz, F; Qureshi, S; Islam, MO; Sakpaisal, P; Silapong, S; Yori, PP; Rajendiran, R; Benny, B; McGrath, M; Seidman, JC; Lang, D; Gottlieb, M; Guerrant, RL; Lima, AAM; Leite, JP; Samie, A; Bessong, PO; Page, N; Bodhidatta, L; Mason, C; Shrestha, S; Kiwelu, I; Mduma, ER; Iqbal, NT; Bhutta, ZA; Ahmed, T; Haque, R; Kang, G; Kosek, MN; Houpt, ER; Acosta, AM; Rios de Burga, R; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Rasheed, M; Soofi, S; Turab, A; Yousafzai, A; Zaidi, AK; Shrestha, B; Rayamajhi, BB; Strand, T; Ammu, G; Babji, S; Bose, A; George, AT; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Ragasudha, P; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Rose, A; Roshan, R; Sharma, SL; Sundaram, S; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Doan, V; Hoest, C; Knobler, S; McCormick, BJ; Miller, MA; Psaki, S (2018-12-01)
      © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Enteropathogen 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. Methods: We 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. Findings: Among 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. Interpretation: Subclinical 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. Funding: Bill & Melinda Gates Foundation.