| Summary: | <p>Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear.</p> <p>Objective: We investigated the interrelationships between diarrhea, intestinal pathogens, systemic inflammation, and indicators of intestinal inflammation and function to assess their associations with mortality in children with SAM.</p> <p>Design: Children aged 6-59 months (n=79) hospitalized in Malawi for complicated SAM were studied. Stool and serum were collected at admission and clinical data recorded. Intestinal pathogens (n=15), cytokines (n=29), fecal calprotectin and the short chain fatty acids (SCFA) butyrate and propionate were determined. Relationships between variables, diarrhea and death were assessed with partial least squares (PLS) path modeling.</p> <p>Results: Fatal cases (n=14, 18%) were younger (17 vs. 25 months, p=0.01) and had higher prevalence of diarrhea (46% vs. 18%, p=0.03). Most children had pathogens (84%) and Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated. However, pathogens were not associated with death or diarrhea. Calprotectin, a marker of intestinal inflammation, was clinically elevated in most patients (median 740 mg/kg feces (interquartile range (IQR) 1560-269)) and significantly higher with death (median 1360 mg/kg feces (IQR 2443-535) vs. 698 (IQR 1438-244), p=0.03). Also, both butyrate (31 ng/ml (IQR 112-22), vs. 2036 (IQR 5800-149), p=0.02) and propionate (167 ng/ml (IQR 831-131) vs. 3174 (IQR 5819-357), p=0.04) were lower with death. PLS-path modelling indicated that mortality was directly related to high systemic inflammation (path coefficient = 0.49); whereas diarrhea, high calprotectin and low SCFA may be related to death through their association with systemic inflammation.</p> <p>Conclusions: Diarrhea, high intestinal inflammation, low levels of fecal SCFA and high systemic inflammation are significantly related to mortality in SAM. However, these relationships were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies.</p>
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