The Impact of Malnutrition on Host Responses to Severe Infection in Adults: A Multicenter Analysis from Uganda

Abstract Objective Studies of nutritional status and host responses during severe and critical illness have focused predominantly on obesity; in contrast, the relationship between undernutrition, host responses, and clinical outcomes in adults hospitalized with severe infection remains poorly defined. We sought to determine whether severe undernutrition is associated with distinct host responses and clinical outcomes in adults hospitalized with severe infection. Design Prospective cohort study. Setting Two public referral hospitals in Uganda. Patients Non-pregnant adults (≥18 yr) hospitalized with severe, undifferentiated infection. Interventions None. Measurements and Main Results We analyzed clinical data and serum Olink proteomic data from 432 participants (median age, 45 yr [IQR, 31–57 yr]; 44% male). Overall, 213 participants (49%) met prespecified criteria for undernutrition, including 52 (12%) with severe undernutrition. Clinically, severe undernutrition was associated with HIV coinfection, microbiologically diagnosed tuberculosis, greater physiological instability, and higher mortality. After adjustment for age, sex, illness duration, study site, and HIV, malaria, and tuberculosis coinfection, severe undernutrition was associated with higher expression of proteins involved in pro-inflammatory immune signaling, endothelial and vascular remodeling, hypoxia and oxidative stress responses, and extracellular matrix remodeling, together with lower expression of proteins linked to growth signaling, anticoagulant regulation, and lipid homeostasis. Conclusions Severe undernutrition is associated with a distinct high-risk clinical phenotype and biologic signature in adults hospitalized with severe infection. These findings suggest that undernutrition may potentiate key domains of sepsis pathobiology, with implications for strengthening nutritional support and informing host-directed treatment strategies in low- and middle-income countries where malnutrition is common. Key Points Question How does undernutrition influence immune, metabolic, and endothelial responses to severe infection in adults? Findings In this multicenter cohort study of 432 adults hospitalized with severe infection in Uganda, severe undernutrition was associated with greater physiologic instability, higher mortality, and a distinct proteomic host-response profile. Adults with severe undernutrition exhibited a proteomic signature characterized by pro-inflammatory immune signaling, endothelial and extracellular matrix remodeling, and hypoxia and oxidative stress responses, together with lower expression of proteins involved in growth signaling, anticoagulant regulation, and lipid homeostasis. Meaning Severe undernutrition is associated with a distinct high-risk clinical and biologic phenotype during severe infection, with implications for nutritional support, risk stratification, and host-directed therapeutic strategies, particularly in low- and middle-income countries.