Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition

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.

The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia

“…Mortality has been associated with a sepsis-like host-response profile characterized by systemic inflammation and altered metabolism linked to bioenergetic deficits 2,[19][20][21][22] . In sepsis, mortality has been linked to immunoparalysis, organ damage including the cardiac, respiratory, hepatic and renal systems, uncontrolled inflammation, proteolysis, and defects of organ healing capability [23][24][25][26][27][28][29][30][31][32][33][34] .…”

“…There is much overlap in mechanisms described in sepsis and in severely malnourished children suggesting that deaths in malnutrition are largely due to sepsis and that malnutrition may predispose to these phenomena when sepsis occurs 22 . Finally, the role of hormones in metabolic regulation and reprogramming in sepsis and undernutrition has not been well investigated but recent studies show that leptin is associated with mortality 19,20,38 .…”

The synergistic interaction of systemic inflammation, dysbiosis and antimicrobial resistance promotes growth restriction in children with acute severe malnutrition: An emphasis on Escherichia coli

“…In an inverse way, the plasmatic growth factors insulin-like growth factor (IGF)-1 and its main ligand, IGF-binding protein 3 (IGFBP3), are downregulated in SAM children (Timothy, 2011;Bartels et al, 2019), and since IGF-1 is an anti-apoptotic peptide associated with mitosis and bone growth (Wen et al, 2022), it is expected that their low circulation levels reflect the slow growth rate seen in SAM. Certainly, a further secondary effect of systemic inflammation in SAM children is a negative linear growth (Njunge et al, 2020).…”

The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia

“…However, the pathways to mortality during such infections, other than via overwhelming sepsis, are unclear. Systemic inflammation and altered metabolism Mortality has been associated with a sepsis-like host-response profile characterized by systemic inflammation and altered metabolism linked to bioenergetic deficits 2 , 19 – 22 . In sepsis, mortality has been linked to immunoparalysis, organ damage including the cardiac, respiratory, hepatic and renal systems, uncontrolled inflammation, proteolysis, and defects of organ healing capability 23 – 34 .…”

“…There is also a well-recognised association between the degree of mitochondrial dysfunction and sepsis outcomes suggesting a role of immunometabolism and suggesting new routes for therapeutic intervention 35 – 37 . There is much overlap in mechanisms described in sepsis and in severely malnourished children suggesting that deaths in malnutrition are largely due to sepsis and that malnutrition may predispose to these phenomena when sepsis occurs 22 . Finally, the role of hormones in metabolic regulation and reprogramming in sepsis and undernutrition has not been well investigated but recent studies show that leptin is associated with mortality 19 , 20 , 38 .…”