Format

Send to

Choose Destination
Clin Infect Dis. 2014 Dec 1;59(11):1638-47. doi: 10.1093/cid/ciu641. Epub 2014 Aug 8.

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

Author information

1
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa.
2
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa Division of Mycobacterial Research, MRC National Institute for Medical Research.
3
Department of Medicine, University of Cape Town, South Africa.
4
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine.
5
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa Division of Mycobacterial Research, MRC National Institute for Medical Research Department of Medicine, Imperial College London, United Kingdom.

Abstract

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.

KEYWORDS:

HIV; antiretroviral therapy; therapy-complications; tuberculosis

PMID:
25107295
PMCID:
PMC4227574
DOI:
10.1093/cid/ciu641
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center