Research: Mortality in severe HIV-TB associates with innate immune activation and dysfunction of Monocytes

21 Apr 2017
HIV and TB
21 Apr 2017

SATVI Dr Elisa Nemes has co-authored: "Mortality in severe HIV-TB associates with innate immune activation and dysfunction of Monocytes" appearing in the Clinical Infectious Diseases Journal. 

HIV AIDS Mortality

 

Background: Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population.

Methods: This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized 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 Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium 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. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia.

Results: Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22-132); 16 (27%) died after a median of 12 (IQR, 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 antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis.

 

HIV; tuberculosis; mortality; innate immunity; mycobacteremia.
Principal component analysis. A, Values for principal component 1 (PC1) for patients with human immunodeficiency virus–associated tuberculosis who died vs those who survived; patients who died had significantly higher values for PC1. B, Loadings of respective variables on PC1; variables significantly associated with clinical outcome are red. Variables significantly associated with clinical outcome (Mann-Whitney U test q < .10 and P < .05) tend to have high loadings, hence, contribute strongly to PC1. C, Heat map showing variables associated significantly with mortality in principal component analysis. Survivors are shown in blue, nonsurvivors in red. Increased production of proinflammatory cytokines in unstimulated samples appeared to be associated with mortality, as well as impaired production of proinflammatory cytokines in response to all antigen stimuli used. Abbreviations: CSF-3, CSF-2, colony-stimulating factor; IL, interleukin; LPS, lipopolysaccharide; Mtb, heat-killed Mycobacterium tuberculosis; S. pneumoniae, Streptococcus pneumoniae; TNF, tumour necrosis factor; US, unstimulated.

Conclusions: Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis.

 

Citation: Janssen S, Schutz C, Ward A, Nemes E, Wilkinson KA, Scriven J, Huson MA, Aben N, Maartens G, Burton R, Wilkinson RJ, Grobusch MP, Van der Poll T, Meintjes G. 2017. Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes. Clinical Infectious Diseases, 65(1):73-82. Click here.