Cryptococcus-related Immune Reconstitution Inflammatory Syndrome (IRIS): Pathogenesis and its clinical implications

Darin L. Wiesner, David R. Boulware

Research output: Contribution to journalReview articlepeer-review

57 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)252-261
Number of pages10
JournalCurrent Fungal Infection Reports
Issue number4
StatePublished - Dec 2011

Bibliographical note

Funding Information:
Disclosure 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.


  • AIDS
  • Anti-inflammatory therapy
  • Antifungal therapy
  • Antiretroviral therapy
  • Biomarkers
  • Cryptococcal meningitis
  • HIV
  • Immune reconstitution inflammatory syndrome
  • Immunology
  • Pathogenesis
  • Review
  • Risk stratification


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