Undernutrition Raises Risk and Changes Immune Response in Severe Infection

Researchers have long studied how nutritional status affects people who become critically ill, but most work has focused on obesity. Far less is known about how undernutrition shapes the body’s response when adults are hospitalized with serious infections. In a multicenter prospective study led by Matthew Cummings, investigators set out to fill that gap by following adults admitted with severe, undifferentiated infection at two public referral hospitals in Uganda. The study enrolled non-pregnant adults aged 18 years and older and collected clinical information alongside blood samples for detailed protein analysis. There were no experimental treatments or interventions; the research was observational, designed to compare people with different degrees of nutritional status as they presented to hospital. By looking closely at who was undernourished and how their bodies were responding, the team aimed to identify whether undernutrition is linked to a different, higher-risk clinical picture and whether measurable biological signatures accompany that risk. The study’s design allowed the team to connect bedside clinical findings with laboratory measures of immune, metabolic, and vascular function in a real-world hospital setting in Uganda.

The study analyzed clinical data and serum Olink proteomic data from 432 participants; the median age was 45 years (IQR, 31–57 years) and 44% were male. Nearly half of the patients—213 participants, or 49%—met prespecified criteria for undernutrition, and 52 people (12%) had severe undernutrition. Severe undernutrition was clinically associated with HIV coinfection, microbiologically diagnosed tuberculosis, greater physiologic instability, and higher mortality. The investigators adjusted analyses for potential confounders including age, sex, illness duration, study site, and coinfections with HIV, malaria, and tuberculosis. After those adjustments, severe undernutrition was linked to a distinct proteomic pattern: higher expression of proteins involved in pro-inflammatory immune signaling, endothelial and vascular remodeling, hypoxia and oxidative stress responses, and extracellular matrix remodeling; and lower expression of proteins tied to growth signaling, anticoagulant regulation, and lipid homeostasis. The cohort was a prospective observational sample at two public referral hospitals in Uganda, and there were no interventional drugs or therapies tested in this study.

The findings describe a clear, high-risk clinical and biological phenotype that accompanies severe undernutrition during acute infection. In practical terms, the results suggest that undernutrition does more than weaken the body generally: it is associated with measurable shifts in inflammation, blood vessel and tissue remodeling, oxygen and oxidative stress pathways, and metabolic controls that are central to how sepsis and severe infections unfold. Those shifts help explain why people with severe undernutrition had more physiologic instability and higher mortality in this study. For policymakers and clinicians working in low- and middle-income countries where undernutrition and infections like HIV and tuberculosis are common, the data point toward the value of strengthening nutritional support as part of acute care and recovery. They also suggest that nutritional status could inform risk stratification and the development of host-directed treatment strategies tailored to the biology of undernourished patients. Further work will be needed to translate these proteomic signatures into bedside tools or targeted therapies, but the study provides a biologic rationale for integrating nutrition into infection care pathways.