Abstract
INTRODUCTION: Sepsis causes high mortality among people living with HIV in Africa, yet immune response data are limited. We identified immune subphenotypes of adults with sepsis and a high prevalence of HIV in East Africa. METHODS: We determined the association of serum cytokine and antibody concentrations with CD4+ T-cell and blood lactate concentration, tuberculosis, and 30-day mortality with K-means clustering, principal component analysis (PCA), and logistic regression. We validated results in a separate cohort of adults with sepsis in East Africa. RESULTS: Of 208 participants in the discovery cohort, 117 (56%) were female and 175 (84%) were living with HIV, with a mean (±SD) age of 35 (±10) years. Participants with tuberculosis had higher concentrations of G-CSF, IFN-γ, IL-1β, IL-6, IL-8, and MCP1MCAF, whereas mortality was associated with higher concentrations of G-CSF, IL-6, IL-8, IL-10, and MIP-1β, and lower concentrations of IgM antibodies against oxidation-specific epidopes (IgM (OSE) ). PCA identified G-CSF, IL-5, IL-6, IL-8, and IL-13 as the main contributors to tuberculosis, and IL-4, IL-6, IL-8, IL-12, and IL-13 as the main contributors to mortality. Comprehensive biomarker and clinical and multivariable models accurately predicted tuberculosis (AUC = 0.84) and mortality (AUC = 0.78), which was replicated in the validation cohort. Cross-testing showed that the tuberculosis model delineated pathogen-specific immune activation, while the mortality model represented non-pathogen-specific immune dysregulation. CONCLUSIONS: In adults with sepsis and high HIV prevalence in East Africa, tuberculosis was associated with pathogen-specific inflammation, and mortality was associated with broader immune dysregulation and diminished IgM (OSE) antibody responses.