Aging and Host Responses to Severe Infection: Proteomic Analysis of a Prospective Multicenter Cohort From Uganda.

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.