PMID- 25107295 OWN - NLM STAT- MEDLINE DCOM- 20150702 LR - 20230704 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 59 IP - 11 DP - 2014 Dec 1 TI - Neutrophil-associated central nervous system inflammation in tuberculous meningitis immune reconstitution inflammatory syndrome. PG - 1638-47 LID - 10.1093/cid/ciu641 [doi] AB - 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. CI - (c) The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. FAU - Marais, Suzaan AU - Marais S AD - Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa. FAU - Wilkinson, Katalin A AU - Wilkinson KA AD - 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. FAU - Lesosky, Maia AU - Lesosky M AD - Department of Medicine, University of Cape Town, South Africa. FAU - Coussens, Anna K AU - Coussens AK AD - Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine. FAU - Deffur, Armin AU - Deffur A AD - Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa. FAU - Pepper, Dominique J AU - Pepper DJ AD - Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine. FAU - Schutz, Charlotte AU - Schutz C AD - Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine Department of Medicine, University of Cape Town, South Africa. FAU - Ismail, Zahiera AU - Ismail Z AD - Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine. FAU - Meintjes, Graeme AU - Meintjes G AD - 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. FAU - Wilkinson, Robert J AU - Wilkinson RJ AD - 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. LA - eng GR - WT 097254/WT_/Wellcome Trust/United Kingdom GR - U2R TW007370/TW/FIC NIH HHS/United States GR - 104803/WT_/Wellcome Trust/United Kingdom GR - U.1175.02.002.00014.01/MRC_/Medical Research Council/United Kingdom GR - 088316/WT_/Wellcome Trust/United Kingdom GR - U2R TW007373/TW/FIC NIH HHS/United States GR - 084323/WT_/Wellcome Trust/United Kingdom GR - PEPFAR/PEPFAR/United States GR - MC_U117588499/MRC_/Medical Research Council/United Kingdom GR - 098316/WT_/Wellcome Trust/United Kingdom GR - WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20140808 PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - 0 (Anti-Retroviral Agents) RN - 0 (Cytokines) SB - IM MH - Adult MH - Anti-Retroviral Agents/therapeutic use MH - Cytokines/blood MH - Female MH - HIV Infections/*blood/cerebrospinal fluid/drug therapy MH - Humans MH - Immune Reconstitution Inflammatory Syndrome/*blood/cerebrospinal fluid/*immunology MH - Inflammation/blood/cerebrospinal fluid/immunology MH - Leukocyte Count MH - Male MH - Mycobacterium tuberculosis/immunology MH - Neutrophils/*immunology/pathology MH - Prospective Studies MH - Tuberculosis, Meningeal/*blood/cerebrospinal fluid/*immunology PMC - PMC4227574 OTO - NOTNLM OT - HIV OT - antiretroviral therapy OT - therapy-complications OT - tuberculosis EDAT- 2014/08/12 06:00 MHDA- 2015/07/03 06:00 PMCR- 2014/08/08 CRDT- 2014/08/10 06:00 PHST- 2014/08/10 06:00 [entrez] PHST- 2014/08/12 06:00 [pubmed] PHST- 2015/07/03 06:00 [medline] PHST- 2014/08/08 00:00 [pmc-release] AID - ciu641 [pii] AID - 10.1093/cid/ciu641 [doi] PST - ppublish SO - Clin Infect Dis. 2014 Dec 1;59(11):1638-47. doi: 10.1093/cid/ciu641. Epub 2014 Aug 8.