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James A Plattsmills - One of the best experts on this subject based on the ideXlab platform.
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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
The Lancet Global Health, 2018Co-Authors: Elizabeth T Rogawski, James A Plattsmills, Ira Praharaj, Furqan Kabir, Paphavee Lertsethtakarn, Mery Siguas, Shaila S Khan, Arinao Murei, Rosemary Nshama, Buliga MujagaAbstract:Summary 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.
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optimization of quantitative pcr methods for Enteropathogen detection
PLOS ONE, 2016Co-Authors: Jie Liu, James A Plattsmills, Rosemary Nshama, Jean Gratz, Caroline Amour, Thomas Walongo, Athanasia Maro, Esto Mduma, Nadia Boisen, James P NataroAbstract:Detection and quantification of Enteropathogens in stool specimens is useful for diagnosing the cause of diarrhea but is technically challenging. Here we evaluate several important determinants of quantification: specimen collection, nucleic acid extraction, and extraction and amplification efficiency. First, we evaluate the molecular detection and quantification of pathogens in rectal swabs versus stool, using paired flocked rectal swabs and whole stool collected from 129 children hospitalized with diarrhea in Tanzania. Swabs generally yielded a higher quantification cycle (Cq) (average 29.7, standard deviation 3.5 vs. 25.3 ± 2.9 from stool, P<0.001) but were still able to detect 80% of pathogens with a Cq < 30 in stool. Second, a simplified total nucleic acid (TNA) extraction procedure was compared to separate DNA and RNA extractions and showed 92% (318/344) sensitivity and 98% (951/968) specificity, with no difference in Cq value for the positive results (ΔCq(DNA+RNA-TNA) = -0.01 ± 1.17, P = 0.972, N = 318). Third, we devised a quantification scheme that adjusts pathogen quantity to the specimen’s extraction and amplification efficiency, and show that this better estimates the quantity of spiked specimens than the raw target Cq. In sum, these methods for Enteropathogen quantification, stool sample collection, and nucleic acid extraction will be useful for laboratories studying enteric disease.
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impact of enterovirus and other enteric pathogens on oral polio and rotavirus vaccine performance in bangladeshi infants
Vaccine, 2016Co-Authors: Mami Taniuchi, Shihab U Sobuz, Sharmin Begum, James A Plattsmills, Marya P. Carmolli, Jashim Uddin, Beth D Kirkpatrick, Ross E Colgate, Dorothy M Dickson, Uma NayakAbstract:Abstract Background Oral polio vaccine (OPV) and rotavirus vaccine (RV) exhibit poorer performance in low-income settings compared to high-income settings. Prior studies have suggested an inhibitory effect of concurrent non-polio enterovirus (NPEV) infection, but the impact of other enteric infections has not been comprehensively evaluated. Methods In urban Bangladesh, we tested stools for a broad range of enteric viruses, bacteria, parasites, and fungi by quantitative PCR from infants at weeks 6 and 10 of life, coincident with the first OPV and RV administration respectively, and examined the association between Enteropathogen quantity and subsequent OPV serum neutralizing titers, serum rotavirus IgA, and rotavirus diarrhea. Results Campylobacter and enterovirus (EV) quantity at the time of administration of the first dose of OPV was associated with lower OPV1-2 serum neutralizing titers, while enterovirus quantity was also associated with diminished rotavirus IgA (−0.08 change in log titer per tenfold increase in quantity; P = 0.037), failure to seroconvert (OR 0.78, 95% CI: 0.64–0.96; P = 0.022), and breakthrough rotavirus diarrhea (OR 1.34, 95% CI: 1.05–1.71; P = 0.020) after adjusting for potential confounders. These associations were not observed for Sabin strain poliovirus quantity. Conclusion In this broad survey of Enteropathogens and oral vaccine performance we find a particular association between EV carriage, particularly NPEV, and OPV immunogenicity and RV protection. Strategies to reduce EV infections may improve oral vaccine responses. ClinicalTrials.gov Identifier: NCT01375647 .
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association between stool Enteropathogen quantity and disease in tanzanian children using taqman array cards a nested case control study
American Journal of Tropical Medicine and Hygiene, 2014Co-Authors: James A Plattsmills, Jie Liu, Jean Gratz, Caroline Amour, Athanasia Maro, Esto Mduma, Erling Svensen, Queen Saidi, Ndealilia Swai, Happiness KumburuAbstract:Etiologic studies of diarrhea are limited by uneven diagnostic methods and frequent asymptomatic detection of Enteropathogens. Polymerase chain reaction-based stool pathogen quantification may help distinguish clinically significant infections. We performed a nested case-control study of diarrhea in infants from a community-based birth cohort in Tanzania. We tested 71 diarrheal samples and pre-diarrheal matched controls with a laboratory-developed TaqMan Array Card for 19 Enteropathogens. With qualitative detection, no pathogens were significantly associated with diarrhea. When pathogen quantity was considered, rotavirus (odds ratio [OR] = 2.70 per log10 increase, P < 0.001), astrovirus (OR = 1.49, P = 0.01), and Shigella/enteroinvasive Escherichia coli (OR = 1.47, P = 0.04) were associated with diarrhea. Enterotoxigenic E. coli (0.15 SD decline in length-for-age z score after 3 months per log10 increase, P < 0.001) and Campylobacter jejuni/C. coli (0.11 SD decline, P = 0.003) in pre-diarrheal stools were associated with poor linear growth. Quantitative analysis can help refine the association between Enteropathogens and disease in endemic settings.
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etiology of diarrhea in bangladeshi infants in the first year of life analyzed using molecular methods
The Journal of Infectious Diseases, 2013Co-Authors: Mami Taniuchi, Shihab U Sobuz, Sharmin Begum, Xinqun Wang, James A Plattsmills, Zhengyu Yang, Rashidul Haque, William A Petri, Eric R HouptAbstract:(See the editorial commentary by Ryan on pages 1732–3.) Diarrhea accounts for 26.1% of childhood deaths in South Asia [1], with a peak incidence in the first year of life [2–4]. Beyond this immediate mortality burden, diarrheal episodes contribute to intestinal barrier dysfunction and malnutrition, which underlie additional mortality [5] and disability-adjusted life-years lost [6]. This large burden of disease continues despite improvements from measures such as oral rehydration solution, antibiotics, cleaner water, sanitation, breast-feeding, and rotavirus vaccination [7–10]. The etiology of diarrhea must be understood to accelerate additional preventive measures. Unfortunately, diarrhea is a nonspecific syndrome defined as ≥3 loose stools in a day and can be caused by a diversity of viruses, bacteria, protozoa, helminths, fungi, as well as non infectious triggers [11]. Rotavirus is widely accepted as the major diarrheal pathogen in the first year of life [12–14], but the relative importance of Enteropathogens thereafter is less clear. Several methods are needed to detect these Enteropathogens including culture, immunoassay, microscopy, and polymerase chain reaction (PCR), yet these are generally applied selectively and vary in their sensitivity [9, 10, 15, 16]. Certain bacteria, such as Campylobacter and Shigella, are difficult to grow, particularly in the global context of widespread antibiotic use. Mixed infections are common but difficult to interpret. For these reasons we developed a series of quantitative multiplex PCR assays for 32 of the main Enteropathogen targets, encompassing the major viruses, bacteria, protozoa, helminths, and fungi [17–21]. In this work we applied these assays to infants in Dhaka, Bangladesh, starting from birth, testing all assays with both monthly surveillance and diarrheal specimens . This detection strategy and knowledge of pathogen history preceding diarrhea allowed for a temporal examination of the etiology of diarrhea not possible with most study designs.
Margaret Kosek - One of the best experts on this subject based on the ideXlab platform.
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Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study.
EBioMedicine, 2017Co-Authors: Eric R Houpt, Richard L Guerrant, Laura E. Caulfield, Gagandeep Kang, Margaret Kosek, Tahmeed Ahmed, Zulfiquar Bhutta, Gwenyth Lee, Aldo A. M. LimaAbstract:Abstract 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 0–2years 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.
Herbert L. Dupont - One of the best experts on this subject based on the ideXlab platform.
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enteroaggregative escherichia coli as a major etiologic agent in traveler s diarrhea in 3 regions of the world
Clinical Infectious Diseases, 2001Co-Authors: Javier A Adachi, John J Mathewson, Charles D Ericsson, Zhi Dong Jiang, Mangala P Verenkar, Sharon Thompson, Francisco Martinezsandoval, Robert Steffen, Herbert L. DupontAbstract:Enteroaggregative Escherichia coli (EAEC) has been reported to cause traveler's diarrhea and persistent diarrhea in children in developing countries and in immunocompromised patients. To clarify the prevalence of EAEC in traveler's diarrhea, we studied 636 US, Canadian, or European travelers with diarrhea: 218 in Guadalajara, Mexico (June-August 1997 and 1998), 125 in Ocho Rios, Jamaica (September 1997-May 1998), and 293 in Goa, India (January 1997-April 1997 and October 1997-February 1998). Stool samples were tested for conventional Enteropathogens. EAEC strains were identified by use of the HEp-2 assay. EAEC was isolated in 26% of cases of traveler's diarrhea (ranging from 19% in Goa to 33% in Guadalajara) and was second only to enterotoxigenic E. coli as the most common Enteropathogen in all areas. Identification of EAEC reduced the number of cases for which the pathogen was unknown from 327 (51%) to 237 (37%) and explained 28% of cases with unknown etiology. EAEC was a major cause of traveler's diarrhea in 3 geographically distinct study areas.
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in vitro antimicrobial susceptibility testing of bacterial Enteropathogens causing traveler s diarrhea in four geographic regions
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Harumi Gomi, Herbert L. Dupont, Javier A Adachi, Zhi Dong Jiang, Mangala P Verenkar, Robert Steffen, David Ashley, Brett LoweAbstract:The emergence of resistant Enteropathogens has been reported worldwide. Few data are available on the contemporary in vitro activities of commonly used antimicrobial agents against Enteropathogens causing traveler's diarrhea (TD). The susceptibility patterns of antimicrobial agents currently available or under evaluation against pathogens causing TD in four different areas of the world were evaluated. Pathogens were identified in stool samples from U.S., Canadian, or European adults (18 years of age or older) with TD during 1997, visiting India, Mexico, Jamaica, or Kenya. MICs of 11different antimicrobials were determined against 284 bacterial Enteropathogens by the agar dilution method. Ciprofloxacin, levofloxacin, ceftriaxone, and azithromycin were highly active in vitro against the Enteropathogens, while traditional antimicrobials such as ampicillin, trimethoprim, and trimethoprim/sulfamethoxazole showed high levels and high frequencies of resistance. Rifaximin, a promising and poorly absorbable drug, had an MIC at which 90% of the strains tested were inhibited of 32 μg/ml, 250 times lower than the concentration of this drug in the stools. Amdinocillin, nalidixic acid, and doxycycline showed moderate activity. Fluoroquinolones are still the drugs of choice for TD in most regions of the world, although our study has a limitation due to the lack of Escherichia coli samples from Kenya and possible bias in selection of the patients for evaluation. Azithromycin and rifaximin should be considered as promising new agents. The widespread in vitro resistance of the traditional antimicrobial agents reported since the 1980s and the new finding of resistance to fluoroquinolones in Southeast Asia are the main reasons for monitoring carefully the antimicrobial susceptibility patterns worldwide and for developing and evaluating new antimicrobial agents for the treatment of TD.
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Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers' diarrhea.
Digestion, 1998Co-Authors: Herbert L. Dupont, John J Mathewson, Charles D Ericsson, Zhi Dong Jiang, Ernesto Palazzini, Margaret W. Dupont, A. Mosavi, Francisco J De La CabadaAbstract:Background/Aims: Bacterial Enteropathogens, the major cause of travelers’ diarrhea, are customarily treated with antibacterial drugs. Rifaximin, a nonabsorbed antimicrobial was exam
Eric R Houpt - One of the best experts on this subject based on the ideXlab platform.
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Enteropathogens and Gut Inflammation in Asymptomatic Infants and Children in Different Environments in Southern India.
The American journal of tropical medicine and hygiene, 2017Co-Authors: Ira Praharaj, Eric R Houpt, R. Revathy, Rini Bandyopadhyay, Blossom Benny, Jie Liu, Gagandeep KangAbstract:Environmental enteropathy (EE) or environmental enteric dysfunction (EED) is a poorly defined condition of the small intestine usually associated with gut inflammation and increased gut permeability. This condition is common in less developed settings and has been hypothesized to be linked to the high Enteropathogen load in infants in developing countries, which leads to chronic enteric T-cell–mediated inflammation.1 This, in turn, has been linked with linear growth failure, impaired cognition, and suboptimal response to oral vaccines.2 Although studies, such as the “Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and Consequences for Child Health and Development” (MAL-ED), have looked at biomarkers of EE among children in deprived settings, there are few studies evaluating differences, if any, in the levels of proposed biomarkers of EE or EED in children living in different environments in the same geographic location. The MAL-ED study looked at the role played by Enteropathogen infection in malnutrition, gut inflammation, and other long-term health outcomes by focusing on resource-deprived settings with high incidence of diarrheal disease.3 However, this and other such studies have not evaluated heterogeneity in Enteropathogen exposure and its consequences in communities with varying access to clean water and sanitation. In the following study, we compared the prevalence of asymptomatic Enteropathogens and biomarkers of gut inflammation as a component of EE/EED,4 among infants and children living in different environmental conditions in southern India.
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Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study.
EBioMedicine, 2017Co-Authors: Eric R Houpt, Richard L Guerrant, Laura E. Caulfield, Gagandeep Kang, Margaret Kosek, Tahmeed Ahmed, Zulfiquar Bhutta, Gwenyth Lee, Aldo A. M. LimaAbstract:Abstract 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 0–2years 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.
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etiology of diarrhea in bangladeshi infants in the first year of life analyzed using molecular methods
The Journal of Infectious Diseases, 2013Co-Authors: Mami Taniuchi, Shihab U Sobuz, Sharmin Begum, Xinqun Wang, James A Plattsmills, Zhengyu Yang, Rashidul Haque, William A Petri, Eric R HouptAbstract:(See the editorial commentary by Ryan on pages 1732–3.) Diarrhea accounts for 26.1% of childhood deaths in South Asia [1], with a peak incidence in the first year of life [2–4]. Beyond this immediate mortality burden, diarrheal episodes contribute to intestinal barrier dysfunction and malnutrition, which underlie additional mortality [5] and disability-adjusted life-years lost [6]. This large burden of disease continues despite improvements from measures such as oral rehydration solution, antibiotics, cleaner water, sanitation, breast-feeding, and rotavirus vaccination [7–10]. The etiology of diarrhea must be understood to accelerate additional preventive measures. Unfortunately, diarrhea is a nonspecific syndrome defined as ≥3 loose stools in a day and can be caused by a diversity of viruses, bacteria, protozoa, helminths, fungi, as well as non infectious triggers [11]. Rotavirus is widely accepted as the major diarrheal pathogen in the first year of life [12–14], but the relative importance of Enteropathogens thereafter is less clear. Several methods are needed to detect these Enteropathogens including culture, immunoassay, microscopy, and polymerase chain reaction (PCR), yet these are generally applied selectively and vary in their sensitivity [9, 10, 15, 16]. Certain bacteria, such as Campylobacter and Shigella, are difficult to grow, particularly in the global context of widespread antibiotic use. Mixed infections are common but difficult to interpret. For these reasons we developed a series of quantitative multiplex PCR assays for 32 of the main Enteropathogen targets, encompassing the major viruses, bacteria, protozoa, helminths, and fungi [17–21]. In this work we applied these assays to infants in Dhaka, Bangladesh, starting from birth, testing all assays with both monthly surveillance and diarrheal specimens . This detection strategy and knowledge of pathogen history preceding diarrhea allowed for a temporal examination of the etiology of diarrhea not possible with most study designs.
Aldo A. M. Lima - One of the best experts on this subject based on the ideXlab platform.
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Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study.
EBioMedicine, 2017Co-Authors: Eric R Houpt, Richard L Guerrant, Laura E. Caulfield, Gagandeep Kang, Margaret Kosek, Tahmeed Ahmed, Zulfiquar Bhutta, Gwenyth Lee, Aldo A. M. LimaAbstract:Abstract 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 0–2years 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.