Neutrophil-associated central nervous system inflammation in tuberculous meningitis immune reconstitution inflammatory syndrome

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Abstract

Background.The immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains incompletely understood and only one disease site-specific study of the underlying immunology exists; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of tuberculous meningitis (TBM) patients are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the site-of-disease in TBM-IRIS patients.Methods.We performed lumbar puncture at three to five timepoints in HIV-infected TBM patients (n=34), including: TBM diagnosis; antiretroviral therapy (ART) initiation (day 14); 14 days after starting ART; TBM-IRIS presentation; and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) by Luminex or ELISA. 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 two weeks after ART initiation, TBM-IRIS associated with severe, compartmentalized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators and matrix metalloproteinases, compared to TBM-non-IRIS. TBM-non-IRIS cases who were culture-positive for Mycobacterium tuberculosis from CSF at TBM diagnosis (n=6) showed inflammatory responses similar to those of TBM-IRIS cases at both timepoints. However, S100A8/A9 was significantly increased in TBM-IRIS patients, compared to baseline culture-positive TBM-non-IRIS patients, two weeks after ART initiation.Conclusions.A high baseline Mycobacterium tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, TBM patients. Neutrophils and their mediators, especially S100A8/A9, associate closely with the central nervous system inflammation that characterizes TBM-IRIS.

Journal details

Volume 59
Issue number 11
Pages 1638-1647
Publication date

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