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.

Cryptococcosis

“…87 Differences in baseline CSF cytokine and chemokine expression are thought to facilitate the development of cryptococcal IRIS, potentially via myeloid cell trafficking to the CNS and, consequently, production of excessive inflammation. 88,89 In fact, evidence of increased macrophage activation and linked CSF pleocytosis have been observed in patients receiving early ART and may mediate increased mortality, even before recognition of the clinical syndrome of IRIS. 87 …”

HIV infection and immune activation

“…Jarvis et al demonstrated that cytokine responses of IFNγ (Th1), IL4 and IL10 (Th2) and IL17 (Th17) in the CSF of patients with HIV-associated CM were linked to increased macrophage activation, more rapid clearance of cryptococci from CSF, and survival at 2 weeks with IL-6 to contribute the most to this protective effect [56]. Strikingly, chemokines consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) were identified as predictive markers of IRIS.…”

Cerebrospinal fluid cytokines in the diagnosis of bacterial meningitis in infants

“…Recent studies of sepsis, systemic inflammatory response syndrome and meningitis have employed a PCA approach to evaluate the diagnostic ability of multiple cytokines measured simultaneously24,25 . In our study TNF-α, IL-1 and IL-6 were the major elements of the first principal component score (PC1),…”