medRxiv : the preprint server for health sciences · 2025
Immune subphenotypes of tuberculosis and mortality in adults with sepsis and a high prevalence of HIV in East Africa.
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Edwards Louisa, Jacob Shevin T, Majwala Albert, Banura Patrick, Heysell Scott K, Mpagama Stellah, Null Megan, Thomas Tania A, Rimoy Arestaricky, Said Bibie, Nuwagira Edwin, Muzoora Conrad, Sturek Jeffrey M, Moore Christopher C, Otoupalova Eva
Аннотация
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.
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.