Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition
Bijun Wen, James M. Njunge, Céline Bourdon, Gerard Bryan Gonzales, Bonface M. Gichuki, Dorothy Lee, David S. Wishart, Moses M. Ngari, Emmanuel Chimwezi, Johnstone Thitiri, Laura Mwalekwa, Wieger Voskuijl, James A. Berkley, Robert Bandsma
Abstract
Children admitted to hospital with an acute illness and concurrent severe malnutrition [complicated severe malnutrition (CSM)] have a high risk of dying. The biological processes underlying their mortality are poorly understood. In this case-control study nested within a multicenter randomized controlled trial among children with CSM in Kenya and Malawi, we found that blood metabolomic and proteomic profiles robustly differentiated children who died ( n = 92) from those who survived ( n = 92). Fatalities were characterized by increased energetic substrates (tricarboxylic acid cycle metabolites), microbial metabolites (e.g., propionate and isobutyrate), acute phase proteins (e.g., calprotectin and C-reactive protein), and inflammatory markers (e.g., interleukin-8 and tumor necrosis factor–α). These perturbations indicated disruptions in mitochondria-related bioenergetic pathways and sepsis-like responses. This study identified specific biomolecular disturbances associated with CSM mortality, revealing that systemic inflammation and bioenergetic deficits are targetable pathophysiological processes for improving survival of this vulnerable population.