Effects of Drinking Water, Sanitation, Handwashing, and Nutritional Interventions on Immune Status in Young Children: A Cluster-Randomised Controlled Trial in Rural Bangladesh

2021 
Background" We hypothesized that a combined drinking water, sanitation, handwashing, and nutritional intervention (N+WSH) would reduce systemic inflammation. Methods: Within a trial in rural Bangladesh, we cluster-randomised pregnant women into control and N+WSH arms (ClinicalTrials.gov NCT01590095). Among the birth cohort, we quantified plasma IL-1β, IL-6, TNF-α, IL-2, IL-12p70, IFN-γ, IL-4, IL-5, IL-13, IL-17A, IL-21, IL-10, and GM-CSF at ages 14 and 28 months. Cytokine ratios were included as prespecified outcomes to examine the net inflammatory environment. Analysis was intention-to-treat. Findings: We assessed 704 children. After one year, TNF-α/IL-10, IL-12/IL-10, and IL-17A/IL-10 ratios were lower in the intervention group compared to the control group (mean difference: -0.12 to -0.19, p<0.05), indicating the intervention promoted IL-10 driven immunoregulation. Similar reductions in ratios of pro-inflammatory cytokines to IL-10 were sustained in the intervention group after two years. After one year, IL-12/IL-4, IL-12/IL-5, IFN-γ/IL-5, and IL-12/IL-13 ratios were lower in the intervention group (-0.18 to -0.27, p<0.05), suggesting a shift towards a Th2 cytokine response. We observed sex-differential effects of the combined intervention on immune response. Interpretation: During the first year of life, the N+WSH intervention enhanced IL-10 driven immunoregulation which continued through year two. Th2 cytokine driven immune responses, which are important for elimination of extracellular pathogens were also enhanced in year one, but not in year two, perhaps because successful reduction of extracellular pathogens could facilitate a rebalancing of the Th1 and Th2 cytokine systems. Our results suggest that the N+WSH intervention enhanced the immunoprotective and immunoregulatory responses, and suppressed/counteracted the inflammatory/immunopathological response, of the immune triad. Trial Registration: The trial was registered at ClinicalTrials.gov (NCT01590095). icddr,b convened a data and safety monitoring board to oversee the trial. Funding: Bill & Melinda Gates Foundation Declaration of Interest: A.L. received funding for salary through a grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. All other authors have nothing to declare. Ethical Approval: Human subjects committees at icddr,b (PR- 11063 and PR-14108), the University of California, Berkeley (2011-09-3652 and 2014-07-6561) and Stanford University (25863 and 35583) approved study protocols.
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