The Bottom Line: HIV-associated cryptococcal immune reconstitution inflammatory syndrome (CM-IRIS) occurs in two forms: classical or ‘paradoxical’ IRIS in patients diagnosed with cryptococcal disease before starting antiretroviral therapy (ART), who initially improve on antifungal therapy, but then deteriorate or develop new clinical manifestations as a result of ART-mediated immune restoration; and ‘unmasking IRIS’ in patients who present with a first episode of cryptococcal disease after starting ART. Immune restoration in these cases exacerbates the clinical symptoms and signs, triggering presentation of patients with previously subclinical but active cryptococcal infection.
References: Longley N, Harrison TS, Jarvis JN. Cryptococcal immune reconstitution inflammatory syndrome. Current Opinion in Infectious Diseases 2013; 26(1): 26-34.
Maziarz EK, Perfect JR. Cryptococcosis. Infectious Disease Clinics of North America 2016; 30(1): 179-206.
Summary: Risk factors for paradoxical CM-IRIS are a high organism or antigen load at baseline and at ART initiation, a low inflammatory response and CD4 cell count at baseline, and rapid immune restoration. Rapidly fungicidal induction therapy, optimal ART timing (at 2–4 weeks in the context of amphotericin B induction), and early recognition and management of paradoxical CM-IRIS should reduce overall mortality. Unmasking CM-IRIS is preventable through screening for cryptococcal antigen prior to ART and preemptive antifungal treatment for those testing positive, although prospective studies are needed.