Inflammatory profiles in febrile children with moderate and severe malnutrition presenting at-hospital in Uganda are associated with increased mortality

Background Children in Africa carry a disproportionate burden of malnutrition and infectious disease. Together, malnutrition and infection are major contributors to global child mortality; however, their collective impact on im-mune activation are not well described. Methods This was a secondary analysis of a prospective cohort study of children hospitalized with acute febrile illness at a single centre in Uganda. We investigated the association between malnutrition (determined using the mid-upper arm circumference, MUAC), immune activation (as measured by inflammatory markers IL-6, IL-8, CXCL10, CHI3L1, sTNFR1, Cystatin C, granzyme B, and sTREM-1), and mortality. Findings Of the 1850 children eligible for this secondary analysis, 71 (3.8%) and 145 (11.7%) presented with severe acute malnutrition (SAM, MUAC <115 mm) and moderate malnutrition (MUAC 115 to < 125 mm), respectively. SAM was associated with increased concentrations of CHI3L1, sTNFR1, Cystatin C, and sTREM-1, and decreased concentrations of CXCL10 and granzyme B, even after controlling for age, sex, and disease severity at presentation. There were 77 deaths (4.2%). SAM was associated with a 9.2-fold (95% CI 4.8-46), 17-fold (95% CI 3.9-74), and 13-fold (95% CI 3.5-52) increased odds of death in children with pneumonia, malaria, and diarrheal illness, respectively. Mediation analysis implicated sTREM-1 and CHI3L1 in the effect of SAM on mortality, suggesting that enhanced activation of these inflammatory pathways is associated with the increased mortality in undernourished children with pneumonia and malaria. Interpretation Collectively, these data highlight systemic inflammation as a common pathway associated with malnutrition and infection that could be targeted to mitigate the burden of acute febrile illness in LMICs.