Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development

Study Overview
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Brief Summary
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Malnutrition is considered one of the most prevalent risk factors for morbidity and mortality in children under five. An estimated 20% of children in the developing world are malnourished [1] and poor nutrition is linked to more than half of all child deaths worldwide [2]. Malnutrition in early childhood may lead to cognitive and physical deficits and may cause similar deficits in future generations as malnourished mothers give birth to low birth weight children [3]. In addition, malnutrition increases susceptibility and incidence of infections and is associated with diminished response to vaccines. The MAL-ED Project is designed to determine the impact of enteric infections/diarrhea that alter gut function and impair children's nutrition, growth and development to help develop new intervention strategies that can break the vicious enteric infection-malnutrition cycle and reduce its global burden. The overall objective of the MAL-ED Project is to quantify the associations of specific enteric pathogens, measures of physical and mental development, micronutrient malnutrition, gut function biomarkers, the gut microbiome, and immune responses in very young children in resource-limited settings across eight sites that vary by culture, economics, geography, and climate. The central hypothesis of the MAL-ED Project is that infection (and co-infection) with specific enteropathogens leads to impaired growth and development and to diminished immune response to orally administered vaccines by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. Data analyses will test for associations between enteropathogen infections and growth/development to help illuminate: which micro-organisms or mixed infections are most frequently associated with growth faltering and poor development; and at what age specific infections cause the most disruption to growth and development and impair immune response.

Official Title
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Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development

Conditions
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Diarrhea, Malnutrition, Stunting, Wasting, Immune Response, Cognitive Development

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Less than 17 days old. Exclusion Criteria: Mother is less than 16 years of age. Mother has another child inthe MAL-ED study. Pregnancy resulted in multiple birth (e.g., twins). Child has a severe disease requiring hospitalization for something other than for a typical healthy birth. Child has a severe or chronic condition diagnosed by a medical doctor (e.g., neonatal disease, renal disease, chronic heart failure, liver disease, cystic fibrosis, congenital conditions). Child has enteropathies diagnosed by medical doctor. Mother is living and unable to provide informed consent.

Ages Eligible for Study
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Minimum Age: 1 Minute
Maximum Age: 17 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Bangladesh<br>Birth cohort study community in Bangladesh is urban, and located in the Mirpur neighborhood of Dhaka. Case control study is being conducted in the same catchment area. Cases defined as children 6-24 months of age with <-2WAZ (weight for age) score, controls are age and community matched with >-1WAZ. | |
| Brazil<br>Birth cohort study community in Brazil is urban, and located within the Papoco area of Fortaleza. Case control study is being conducted in the same area as the cohort study. Cases are children 6 - 24 months of age, with <-2 WAZ (weight for age) score, controls are age and community matched children with >-1 WAZ. | |
| India<br>Birth cohort study community in India is urban, and located in the southern state of Tamil Nadu, specifically in Vellore. | |
| Nepal<br>Birth cohort study community in Nepal is semi-urban, and located in Bhaktapur, approximately 25km from Kathmandu. | |
| Pakistan<br>Birth cohort study community in Pakistan is rural, and located in Naushero Feroze, Sindh. | |
| Peru<br>Birth cohort study community in Peru is rural, and located approximately 15km from Iquitos in Loreto. | |
| South Africa<br>Birth cohort study community in South Africa is rural/peri-urban, and comprised of nine settlements within Limpopo Province. | |
| Tanzania<br>Birth cohort study community in Tanzania is rural, and located within Haydom. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diarrhea | All diarrheal samples are analyzed for the presence of bacterial, viral, and parasitic pathogens. Normal stool is collected monthly and analyzed for the same list of 57 different pathogens. | Each diarrheal episode willbe recorded for up to 24 months of age. | 
| Anthropometry | Head Circumference, length, and weight are measured monthly on the anniversary of the child's birth. | Anthropomentry will be recorded each month for up to 24 months of age. | 
| Cognitive development | A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices. | Cognitive development will be recorded at 6 months of age. | 
| Vaccine response | Antibody titers will be determined following immunization against rotavirus, polio virus, tetanus toxoid, pertussis toxin and measles vaccines. | Vaccine response will be recorded at 7 months of age. | 
| Cognitive development | A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices. | Cognitive development will be recorded at 8 months of age. | 
| Cognitive development | A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices. | Cognitive development will be recorded at 15 months of age. | 
| Vaccine response | Antibody titers will be determined following immunization against rotavirus, polio virus, tetanus toxoid, pertussis toxin and measles vaccines. | Vaccine response will be recorded at 15 months of age. | 
| Cognitive development | A battery of tests include the Bayley Scales of Infant Development, MacArthur Words and Gestures, Infant Temperament Scale, HOME inventory, SRQ-20 and Raven's Combined Progressive Matrices. | Cognitive development will be recorded 24 months of age. | 
| Vaccine response | Antibody titers will be determined following immunization against rotavirus, polio virus, tetanus toxoid, pertussis toxin and measles vaccines. | Vaccine response will be recorded at 24 months of age. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut inflammation | Stool biomarkers will be evaluated to detect gut and systemic inflammation. | Gut inflammation will be recorded each month for up to 24 months of age. | 
| Gut integrity | Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test. | Gut integritywill be recorded at at 3 months of age. | 
| Gut integrity | Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test. | Gut integritywill be recorded at at 6 months of age. | 
| Gut integrity | Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test. | Gut integritywill be recorded at at 9 months of age. | 
| Gut integrity | Intestinal absorptive capacity and barrier function will be assessed by dual sugar permeability test. | Gut integritywill be recorded at at 15 months of age. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diarrheal disease, Cognitive development, Enteric infections, Malnutrition, Vaccine Response, Enteropathy, Antibiotic use, Micronutrients, Breast feeding, Gut inflammation