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Mortality in severe HIV-TB associates with innate immune activation and dysfunction of monocytes

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Title: Mortality in severe HIV-TB associates with innate immune activation and dysfunction of monocytes
Authors: 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
Item Type: Journal Article
Abstract: BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
Issue Date: 24-Mar-2017
Date of Acceptance: 16-Mar-2017
URI: http://hdl.handle.net/10044/1/45413
DOI: https://dx.doi.org/10.1093/cid/cix254
ISSN: 1537-6591
Publisher: Oxford University Press (OUP)
Start Page: 73
End Page: 82
Journal / Book Title: Clinical Infectious Diseases
Volume: 65
Issue: 1
Copyright Statement: © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 104803/Z/14/ZR
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
Infectious Diseases
Microbiology
HIV
tuberculosis
mortality
innate immunity
mycobacteremia
PULMONARY TUBERCULOSIS
ANTIRETROVIRAL THERAPY
INTERFERON-GAMMA
SEPTIC SHOCK
SEPSIS
IMMUNOTHERAPY
DEATH
MYCOBACTEREMIA
PREDICTORS
mycobacteraemia
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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