Stunting, Malnutrition; Protein, Enteric Pathogens, Campylobacter Infections
Conditions
Keywords
linear growth, infant feeding, environmental enteric dysfunction
Brief summary
This cluster-randomized controlled trial is designed to address linear growth faltering in 6-12-mo-old Bangladesh infants through a proof-of-concept package of interventions to a) increase intake of high quality protein and b) control enteric pathogens.
Detailed description
Stunting a major public health problem in Bangladesh, where 36% of children under the age of five are too short for their age. While dietary data indicate that protein intakes of infants and young children are largely in line with requirements, the extent to which requirements derived for healthy infants and young children are relevant in the context of frequent infections remains an important research question. Recent investigations indicate widespread pathogen carriage among Bangladeshi infants, with virtually all having at least one detectable pathogen in nondiarrheal stools by six months of age. Campylobacter and pathogenic E. Coli predominate in this setting. Enteric pathogens can compete with the host for available nutrients or alter nutrient metabolism. Acting via environmental enteric dysfunction, they can alter both digestion-through loss of digestive enzymes-and absorption of nutrients. Microbial translocation may further alter specific amino acid requirements. Even in the absence of acute diarrheal disease, enteric pathogen carriage is strongly associated with linear growth faltering. Combining the effects of high pathogen burden and poor diet, as indicated by low energy and protein from complementary foods, observational evidence suggests that the potentially preventable length-for-age Z-score deficit may be as high as 0.98. The present trial will test the combination of a) protein supplementation in the form of a protein-rich blended food or an egg, both fed daily to infants 6-12 months of age, and b) azithromycin treatment for enteric pathogens. The primary outcome will be change in length-for-age Z-score from the 6 to 12 months. Biochemical, microbiological and clinical intermediates will be measured to inform our secondary aims.
Interventions
Azithromycin oral suspension (10 mg/kg; 3 days) administered by study personnel at 6 and 9 months of age
Contain inert excipients only
Blended food providing 125 kcal and 10 g protein as egg white powder prepared as porridge and fed daily to infants from 6-12 months of age
Blended food providing 125 kcal and 1 g protein as rice powder prepared as porridge and fed daily to infants from 6-12 months of age
Egg provided daily to infants from 6-12 months of age
Monthly messaging on infant and young child feeding
Sponsors
Study design
Masking description
Participants, care providers, investigators and outcomes assessors will be blinded to the azithromycin or placebo interventions. Neither participants nor outcomes assessors will be masked to the nutrition interventions. Investigators will be masked to the nutrition interventions.
Intervention model description
For this 2 x 4 factorial, cluster-randomized trial, 566 previously defined clusters will be assigned independently to 8 different combinations of interventions: 1) azithromycin and protein supplementation; 2) azithromycin and isocaloric supplementation; 3) azithromycin and egg; 4) azithromycin and control (nutrition education); 5) placebo and protein supplementation; 6) placebo and isocaloric supplementation; 7) placebo and egg; 8) placebo and control (nutrition education).
Eligibility
Inclusion criteria
* Born to women enrolled in ongoing community trial (NCT02909179) over a one-year period
Exclusion criteria
* Born to women not registered as part of the ongoing community trial (NCT02909179)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Length-for-age Z-score (LAZ) at 12 months of age | 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inflammatory biomarkers | 6 and 12 months | Plasma alpha-1 acid glycoprotein, C-reactive protein and interleukin-6, by ELISA; stool inflammatory cytokines, by ELISA |
| Bone biomarkers | 6 and 12 months | Plasma collagen type X and N-Terminal Pro-C-Type Natriuretic Peptide (NT-ProCNP), by ELISA |
| Morbidity incidence | 6-12 months | Incident diarrhea/dysentery or respiratory infection, based on weekly recalls |
| Nutrient biomarkers | 6 and 12 months | Serum essential, conditionally essential amino acids and choline (by metabolomic analysis); retinol and tocopherols (HPLC); vitamin B12 (microbiological assay); zinc (AAS); ferritin and thyroglobulin (ELISA) |
| Body composition | 6, 9, 12, 15, and 18 months | Fat mass by bioelectrical impedence |
| Enteropathogen burden | 6, 6.5, 9, 9.5, 12, 15, and 18 months | Campylobacter, enterotoxigenic Escherichia coli (ETEC), enteroaggregative Escherichia coli (EAEC), enteropathogenic Escherichia coli (EPEC), Shigella and Cryptosporidium, by quantitative polymerase chain reaction (qPCR) |
| Gut microbiota composition | 6, 6.5, 9, 9.5, 12, 15, and 18 months | Microbial diversity and abundance, by 16S ribosomal RNA sequencing |
| Environmental enteric dysfunction biomarkers | 6 and 12 months | Stool myeloperoxidase and intestinal fatty acid-binding protein concentrations and plasma Endogenous endotoxin-core antibody (EndoCAb), by ELISA |
| Antibiotic resistance | 6, 9, 12, 15, and 18 months | Resistance of commensal E. coli (stool) or S. pneumoniae (nasopharyngeal swab) to panel of antibiotics, by culture |
| Growth hormone and stress axes biomarkers | 6 and 12 months | Serum insulin-like growth factor 1 (IGF-1), IGF binding protein 3, cortisol, by ELISA |
Countries
Bangladesh