title: Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis.
abstract: Understanding the host immune response during cryptococcal meningitis (CM) is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF) immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA). PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL)-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS). In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS), more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and IRIS following peripheral immune reconstitution with ART. These results provide a rational basis for future studies of immune modulation in CM, and demonstrate the potential of baseline immune profiling to identify CM patients most at risk of mortality and subsequent IRIS.
authors: Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Botswana-UPenn Partnership, Gaborone, Botswana; Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
authors: Joseph N
authors: JN
authors: Jarvis
authors: Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, South Africa; Department of Medicine, Imperial College London, London, United Kingdom.
authors: Graeme
authors: G
authors: Meintjes
authors: Research Centre for Infection and Immunity, Division of Clinical Sciences, St. George's University of London, London, United Kingdom.
authors: Tihana
authors: T
authors: Bicanic
authors: Research Centre for Infection and Immunity, Division of Clinical Sciences, St. George's University of London, London, United Kingdom.
authors: Viviana
authors: V
authors: Buffa
authors: Research Centre for Infection and Immunity, Division of Clinical Sciences, St. George's University of London, London, United Kingdom.
authors: Louise
authors: L
authors: Hogan
authors: Department of Medicine, Imperial College London, London, United Kingdom.
authors: Stephanie
authors: S
authors: Mo
authors: Division of Infection and Immunity, University College London, London, United Kingdom.
authors: Gillian
authors: G
authors: Tomlinson
authors: Department of Medicine, Imperial College London, London, United Kingdom.
authors: Pascale
authors: P
authors: Kropf
authors: Division of Infection and Immunity, University College London, London, United Kingdom.
authors: Mahdad
authors: M
authors: Noursadeghi
authors: Research Centre for Infection and Immunity, Division of Clinical Sciences, St. George's University of London, London, United Kingdom.
authors: Thomas S
authors: TS
authors: Harrison
mesh_terms: D000328:Adult; D016207:Cytokines / Q000134:cerebrospinal fluid*; D005260:Female; D015658:HIV Infections / Q000134:cerebrospinal fluid / Q000150:complications* / Q000276:immunology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000134:cerebrospinal fluid* / Q000276:immunology; D008297:Male; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000401:mortality; D025341:Principal Component Analysis
chemical_list: D016207:Cytokines