Cryptococcus-Related Immune Reconstitution Inflammatory Syndrome (IRIS): Pathogenesis and its Clinical Implications
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This review provides an overview of Cryptococcus neoformans immunology and focuses on the pathogenesis of Cryptococcus-related paradoxical immune reconstitution inflammatory syndrome (IRIS). Cryptococcal IRIS has three phases: (1) before antiretroviral therapy (ART), with a paucity of cerebrospinal fluid (CSF) inflammation and defects in antigen clearance; (2) during initial ART immune recovery, with pro-inflammatory signaling by antigen-presenting cells without an effector response; and (3) at IRIS, a cytokine storm with a predominant type-1 helper T-cell (Th1) interferon-gamma (IFN-γ) response. Understanding IRIS pathogenesis allows for risk stratification and customization of HIV/AIDS care. In brief, persons at high IRIS risk may benefit from enhancing microbiologic clearance by use of adjunctive agents in combination with amphotericin, prolonging initial induction therapy, and/or increasing the initial consolidation antifungal therapy dose to at least 800 mg of fluconazole daily until the 2-week CSF culture is known to be sterile. Prophylactic anti-inflammatory therapies or undue delay of ART initiation in an attempt to prevent IRIS is unwarranted and may be dangerous.
KeywordsHIV AIDS Cryptococcal meningitis CM-IRIS Immune reconstitution inflammatory syndrome Pathogenesis Review Antiretroviral therapy Immunology Risk stratification Biomarkers Antifungal therapy Anti-inflammatory therapy
Financial support is received from National Institutes of Health (K23AI073192-02: DRB; U01AI089244-01; DLW). Dr. Boulware thanks collaboration with Drs. Paul Bohjanen, David Meya, Andrew Kambugu, Edward Janoff, Tihana Bicanic, and the Infectious Disease Institute of Makerere University, Kampala, Uganda. We thank Dr. Bicanic for critical review of the manuscript.
Conflicts of Interest: D. Wiesner: none; D. Boulware: research support from GlaxoSmithKline’s HIV Collaborative Investigator Research Award and Merck’s Investigator-Initiated Studies Program; both of these firms manufacture HIV antiretroviral medications.
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