Mortality in Severe HIV-TB Associates with Innate Immune Activation and Dysfunction of Monocytes.

Case fatality rates among hospitalised patients diagnosed with HIV-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. We aimed to define the nature of innate immune responses associated with 12-week mortality in this population. This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalised HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with E. coli derived lipopolysaccharide, heat-killed S. pneumoniae and M. tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex) were assessed for associations with 12-week mortality using Cox-proportional hazard models. Secondly, we investigated associations of these immune markers with tuberculosis mycobacteremia. Sixty patients were included (median CD4 count 53 cells/µL (interquartile range 22-132)), sixteen (27%) died after a median of 12 (interquartile range 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony stimulating factor 3), and anti-inflammatory markers (increased interleukin-1RA and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis. Twelve-week mortality was associated with greater pro- and anti-inflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis.