Ngomu Akeem Akilimali1,2, Christina C Chang2,3, Daniel M Muema1,2,4, Tarylee Reddy5, Mahomed-Yunus S Moosa2,6, Sharon R Lewin3,7, Martyn A French8,9, Thumbi Ndung'u1,2,10,11. 1. Africa Health Research Institute. 2. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal (UKZN), Durban, South Africa. 3. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia. 4. Kenya Medical Research Institute-Wellcome Trust Research Programme, Centre for Geographic Medicine Research-Coast, Kilifi. 5. South African Medical Research Council, Overport. 6. Department of Infectious Diseases, UKZN, King Edward VIII Hospital, Durban, South Africa. 7. Peter Doherty Institute for Infection and Immunity, University of Melbourne, and Royal Melbourne Hospital. 8. Medical School and School of Biomedical Sciences, University of Western Australia, Perth. 9. Department of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Australia. 10. Max Planck Institute for Infection Biology, Berlin, Germany. 11. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge.
Abstract
BACKGROUND: Patients with human immunodeficiency virus/AIDS-associated cryptococcal meningitis (CM) frequently experience clinical deterioration, known as cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), upon initiation of antiretroviral therapy (ART). The immunological mechanisms underlying C-IRIS are incompletely defined and no reliable predictive biomarkers exist. We investigated whether plasma or cerebrospinal fluid (CSF) levels of cytokines and chemokines predicted C-IRIS and are potential predictive biomarkers. METHODS: Patients with CM who experienced C-IRIS (N = 27) upon ART initiation were compared to CD4+ T-cell count-matched patients without C-IRIS (N = 27). Plasma and CSF collected pre-ART were assayed for cytokines and chemokines using a 17-plex Luminex kit or enzyme-linked immunosorbent assay. Cox proportional hazards regression and principal component analyses were also performed. RESULTS: Plasma interleukin (IL) 2, IL-4, IL-5, IL-7, IL-17, interferon-γ, and tumor necrosis factor-α levels were higher in C-IRIS patients compared to controls (all P < .05), with IL-5 and IL-7 significant after Bonferroni-Holm correction. In multivariate Cox proportional hazards regression, high IL-5 (hazard ratio [HR], 5.76 [95% confidence interval {CI}, .77-43.0]; P = .088) and IL-7 (HR, 9.30 [95% CI, 1.96-44.0]; P = .005) were predictive of C-IRIS. Plasma IL-5 (P = .0008) and IL-10 (P = .0089) were lower in those who achieved CSF cryptococcal culture negativity compared to those with positive cultures pre-ART. There were no significant differences in CSF cytokine or chemokine levels between cases and controls. CONCLUSIONS: High plasma IL-5 and IL-7 levels pre-ART were associated with increased risk of developing C-IRIS. High IL-5 levels may reflect a Th2 environment associated with impaired clearance of cryptococci while high IL-7 levels may reflect IL-7/IL-7R pathway dysfunction in T cells, both of which could be associated with C-IRIS immunopathogenesis.
BACKGROUND: Patients with human immunodeficiency virus/AIDS-associated cryptococcal meningitis (CM) frequently experience clinical deterioration, known as cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), upon initiation of antiretroviral therapy (ART). The immunological mechanisms underlying C-IRIS are incompletely defined and no reliable predictive biomarkers exist. We investigated whether plasma or cerebrospinal fluid (CSF) levels of cytokines and chemokines predicted C-IRIS and are potential predictive biomarkers. METHODS: Patients with CM who experienced C-IRIS (N = 27) upon ART initiation were compared to CD4+ T-cell count-matched patients without C-IRIS (N = 27). Plasma and CSF collected pre-ART were assayed for cytokines and chemokines using a 17-plex Luminex kit or enzyme-linked immunosorbent assay. Cox proportional hazards regression and principal component analyses were also performed. RESULTS: Plasma interleukin (IL) 2, IL-4, IL-5, IL-7, IL-17, interferon-γ, and tumor necrosis factor-α levels were higher in C-IRIS patients compared to controls (all P < .05), with IL-5 and IL-7 significant after Bonferroni-Holm correction. In multivariate Cox proportional hazards regression, high IL-5 (hazard ratio [HR], 5.76 [95% confidence interval {CI}, .77-43.0]; P = .088) and IL-7 (HR, 9.30 [95% CI, 1.96-44.0]; P = .005) were predictive of C-IRIS. Plasma IL-5 (P = .0008) and IL-10 (P = .0089) were lower in those who achieved CSF cryptococcal culture negativity compared to those with positive cultures pre-ART. There were no significant differences in CSF cytokine or chemokine levels between cases and controls. CONCLUSIONS: High plasma IL-5 and IL-7 levels pre-ART were associated with increased risk of developing C-IRIS. High IL-5 levels may reflect a Th2 environment associated with impaired clearance of cryptococci while high IL-7 levels may reflect IL-7/IL-7R pathway dysfunction in T cells, both of which could be associated with C-IRIS immunopathogenesis.
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