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Inflammation and immunity in severe acute malnutrition

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Title: Inflammation and immunity in severe acute malnutrition
Authors: Jones, Kelsey David
Item Type: Thesis or dissertation
Abstract: Background: Malnutrition is responsible for 45% of child deaths because it is associated with an increased vulnerability to major infectious disease. The mechanisms behind this association are undefined. It occurs despite the fact that malnourished children have increased levels of enteric and systemic inflammatory activation. Methods: Case-control study of inflammatory activation and response to ex vivo pathogen challenge determined relationships between existing and potential inflammatory function and nutrition. Randomised controlled trial of a gut-specific immunomodulatory agent assessed for functional redundancy in enteric inflammation. Randomised controlled trial of nutritional rehabilitation strategies with enhanced n-3 polyunsaturated fatty acid provision assessed for potentially beneficial effects on inflammation. Results: SAM was not associated with abnormalities in systemic cytokine response to innate immune challenge in an ex vivo model compared to control children, but more severe intestinal inflammation, and kwashiorkor may be. Children with SAM and stunting have clear evidence of enteric inflammation, and have evidence of cytokine-mediated inhibition of the GH-IGF-1 axis, which may play a role in linear growth failure. Treatment of children with SAM and stunting with mesalazine appeared to be safe, and there was limited evidence of an impact on enteric inflammation. Stunting is associated with LC-PUFA deficiency, but acute malnutrition is not. Production and administration of a ready-to-use therapeutic food with elevated n-3 PUFA was technically feasible, but was not associated with positive outcomes in growth, recovery or immune function compared to standard treatment. Provision of pre-formed DHA in RUTF may be essential to preserve optimal tissue levels during nutritional rehabilitation. Conclusions: Further strategies targeting inflammatory activation as part of the management of SAM should be trialled. The relationship between systemic and enteric inflammation and nutrition deserves further study.
Content Version: Open Access
Issue Date: Mar-2016
Date Awarded: Oct-2016
URI: http://hdl.handle.net/10044/1/67687
DOI: https://doi.org/10.25560/67687
Supervisor: Warner, John
Mitchell, Jane
Sponsor/Funder: Wellcome Trust (London, England)
Bill and Melinda Gates Foundation
National Institute for Health Research (Great Britain)
Funder's Grant Number: Wellcome Trust 092088, 083579 and 093500
BMGF OPP1046183
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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