Aging and Host Responses to Severe Infection: Proteomic Analysis of a Prospective Multicenter Cohort From Uganda
Gabriel Conte Cortez Martins1, Julius J Lutwama2, Nicholas Owor2
1Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY.
Objective:
Severe infectious diseases are a leading cause of morbidity and mortality worldwide, particularly in sub-Saharan Africa (SSA), where young and middle-aged adults are disproportionately affected. Although age-related immune changes such as inflammaging and immunosenescence have been well characterized in high-income countries, their relevance to host responses during infection in SSA remains poorly understood. We aimed to characterize age-associated differences in immune, metabolic, and endothelial responses to severe infection in a prospective, multicenter cohort of adults in Uganda.
Design:
Prospective cohort study.
Setting:
Two public referral hospitals in Uganda.
Patients:
Non-pregnant adults (18 yr old or older) hospitalized with severe, undifferentiated infection.
Interventions:
None.
Measurements And Main Results:
We analyzed clinical data and serum Olink proteomic profiles from 434 participants (median age: 45 yr old, interquartile range : 31-57). Clinically, illness severity and mortality were highest and comparable among adults 35-44, 45-59, and 60 years old or older, relative to younger adults. HIV prevalence peaked in the 35-44 and 45-59 age groups. Although most host responses were conserved across age groups after adjustment for sex and high-burden co-infections, patients 60 years old or older exhibited distinct immune dysregulation characterized by signs of Th1-predominant innate immune activation (increased CXCL9, CCL18, MCP1, and MCP4 expression, reduced interleukin-13 expression), dysregulated adaptive immunity (increased soluble CD27 and CD70 expression, reduced CD21 [CR2] expression), and increased cellular turnover and endothelial remodeling.
Conclusions:
Older age (60 yr old or older) is associated with distinct host responses to severe infection in SSA. These findings may inform development of age-stratified, host-directed treatment strategies for severe infectious diseases.
