Inflammatory profiles in febrile children with moderate and severe malnutrition presenting at-hospital in Uganda are associated with increased mortalityResearch in context
Andrea M. Weckman,
Chloe R. McDonald,
Michelle Ngai,
Melissa Richard-Greenblatt,
Aleksandra Leligdowicz,
Andrea L. Conroy,
Kevin C. Kain,
Sophie Namasopo,
Michael T. Hawkes
Affiliations
Andrea M. Weckman
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
Chloe R. McDonald
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
Michelle Ngai
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada
Melissa Richard-Greenblatt
Public Health Ontario, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom
Aleksandra Leligdowicz
Division of Critical Care Medicine, Department of Medicine, Schulich School of Medicine and Dentistry, Western University and Robarts Research Institute, Western University, Canada
Andrea L. Conroy
Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, IN, USA
Kevin C. Kain
SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, Canada; Toronto General Hospital Research Institute, University Health Network, Canada; Department of Medicine, University of Toronto, Canada; Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada; Toronto General Research Institute, Toronto General Hospital, Toronto, Canada
Sophie Namasopo
Department of Paediatrics, Kabale Regional Referral Hospital, Kabale, Uganda
Michael T. Hawkes
Division of Pediatric Infectious Diseases, University of Alberta, Edmonton, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada; School of Public Health, University of Alberta, Edmonton, AB, Canada; Distinguished Researcher, Stollery Science Lab, University of Alberta, Edmonton, AB, Canada; Department of Paediatrics, Kabale Regional Referral Hospital, Kabale, Uganda; Women and Children's Research Institute, University of Alberta, Edmonton, AB, Canada; Corresponding author. Department of Pediatrics, University of Alberta, 3-588D Edmonton Clinic Health Academy, 11405 87 Ave NW, Edmonton, T6G 1C9, Canada.
Summary: 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 immune 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. Funding: This work was supported in part by the Canadian Institutes of Health Research, and by kind donations from The Tesari Foundation and Kim Kertland. The funders had no role in design, analysis, or reporting of these studies.
