title: Neutrophil-associated central nervous system inflammation in tuberculous meningitis immune reconstitution inflammatory syndrome.
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.
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa.
authors.forename: Suzaan
authors.initials: S
authors.lastname: Marais
authors.affiliation: 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.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: Department of Medicine, University of Cape Town, South Africa.
authors.forename: Maia
authors.initials: M
authors.lastname: Lesosky
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Coussens
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa.
authors.forename: Armin
authors.initials: A
authors.lastname: Deffur
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine.
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Pepper
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schutz
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine.
authors.forename: Zahiera
authors.initials: Z
authors.lastname: Ismail
authors.affiliation: 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.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: 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.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000134:cerebrospinal fluid / Q000188:drug therapy; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000097:blood* / Q000134:cerebrospinal fluid / Q000276:immunology*; D007249:Inflammation / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D011446:Prospective Studies; D014390:Tuberculosis, Meningeal / Q000097:blood* / Q000134:cerebrospinal fluid / Q000276:immunology*
chemical_list: D044966:Anti-Retroviral Agents; D016207:Cytokines
keywords: HIV; antiretroviral therapy; therapy-complications; tuberculosis
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