期刊
CLINICAL INFECTIOUS DISEASES
卷 59, 期 11, 页码 1638-1647出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cid/ciu641
关键词
tuberculosis; HIV; therapy-complications; antiretroviral therapy
资金
- Carnegie Corporation Training Award
- Discovery Foundation Academic Fellowship Award
- Perinatal HIV Research Unit
- US Agency for International Development
- President's Emergency Plan for AIDS Relief
- Wellcome Trust [WT 097254, 084323, 098316, 088316]
- National Institutes of Health
- Fogarty International Center South Africa TB/AIDS training awards [NIH/FIC U2RTW007373-01A, U2RTW007370-01A1, U2RTW007373 ICORTA]
- National Research Foundation of South Africa [UID 85858]
- Medical Research Council (UK) [U.1175.02.002.00014.01]
- Medical Research Council [MC_U117588499] Funding Source: researchfish
- Wellcome Trust [104803/Z/14/Z] Funding Source: researchfish
- MRC [MC_U117588499] Funding Source: UKRI
Background. The immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the disease site in patients with TBM-IRIS. Methods. We performed lumbar puncture at 3-5 time points in human immunodeficiency virus (HIV)-infected patients with TBM (n = 34), including at TBM diagnosis, at initiation of antiretroviral therapy (ART) (day 14), 14 days after ART initiation, at presentation of TBM-IRIS, and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) with Luminex or enzyme-linked immunosorbent assays. Findings were compared between patients who developed TBM-IRIS (n = 16) and those who did not (TBM-non-IRIS; n = 18). Results. At TBM diagnosis and 2 weeks after ART initiation, TBM-IRIS was associated with severe, compartmentalized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators, and matrix metalloproteinases, compared with TBM-non-IRIS. Patients with TBM-non-IRIS whose CSF cultures were positive for M. tuberculosis at TBM diagnosis (n = 6) showed inflammatory responses similar to those seen in patients with TBM-IRIS at both time points. However, at 2 weeks after ART initiation, S100A8/A9 was significantly increased in patients with TBM-IRIS, compared with patients with TBM-non-IRIS whose cultures were positive at baseline. Conclusions. A high baseline M. tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, patients with TBM. Neutrophils and their mediators, especially S100A8/A9, are closely associated with the central nervous system inflammation that characterizes TBM-IRIS.
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