Immune subphenotypes of tuberculosis and mortality in adults with sepsis and a high prevalence of HIV in East Africa

IntroductionSepsis 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. MethodsWe 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. ResultsOf 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-{gamma}, IL-1{beta}, IL-6, IL-8, and MCP1MCAF, whereas mortality was associated with higher concentrations of G-CSF, IL-6, IL-8, IL-10, and MIP-1{beta}, and lower concentrations of IgM antibodies against oxidation-specific epidopes (IgMOSE). 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. ConclusionsIn 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 IgMOSE antibody responses.