Children with severe acute malnutrition (SAM) are at high risk of infectious mortality and morbidity during and after hospital discharge. This risk persists despite nutritional and prophylactic antibiotic interventions among children with SAM, implicating persistent deficits in their immune defenses. Here we test the hypothesis that innate immune cells from children (0-59 months) hospitalized with SAM in Zambia and Zimbabwe (n=141) have distinct capacity to respond to bacteria relative to adequately-nourished healthy controls from the same communities (n=92). Neutrophils and monocytes from SAM inpatients had a higher capacity to bind E. coli but lower monocyte activation and pro-inflammatory mediator secretion in response to E. coli lipopolysaccharide (LPS) or heat-killed Salmonella typhimurium (HKST) than controls. Bacterial binding capacity differentiated children with SAM from controls after adjusting for clinical and demographic heterogeneity and normalized with duration of hospital treatment. Wasting severity, HIV status, and age group were associated with LPS and HKST-induced cytokine secretion, monocyte activation, and myeloperoxidase secretion, respectively. Bacterial binding capacity and monocyte activation during hospitalization were associated with higher odds of persistent SAM at discharge; a risk factor for subsequent mortality. Thus, SAM shifts anti-bacterial innate immune cell function, favoring bacterial containment over pro-inflammatory activation upon challenge, which contributes to persistent health deficits among hospitalized children.

TEASER Children with severe acute malnutrition have distinct anti-bacterial innate immune cell function compared to healthy children which persists during their hospitalization and contributes to persistent wasting.

The authors have declared no competing interest.

https://bmjopen.bmj.com/content/9/1/e023077.info

This study was funded by a joint Wellcome and the Royal Society Sir Henry Dale Research Fellowship, Wellcome, Medical Research Council, UK and UNICEF Zimbabwe.

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The University of Zambia Biomedical Research Ethics Committee and the Medical Research Council of Zimbabwe gave ethical approval for this work. The ethics committee of the Queen Mary University of London provided an advisory review of the study protocol. Caregivers of all participants provided written informed consent for their participation.

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Requests for further information, resources and reagents should be directed to the study Principle Investigator, Claire D. Bourke (c.bourkeqmul.ac.uk). Participant samples were collected in Zambia and Zimbabwe under local ethical approval and consenting procedures and are therefore restricted my Material Transfer Agreements.