Cryptococcal Immune Reconstitution Inflammatory Syndrome: a Paradoxical Response to a Complex Organism

Abstract

To describe the host-pathogen factors that impact the management of cryptococcal meningitis (CM) in immunosuppressed patients that lead to the development of cryptococcal immune reconstitution inflammatory syndrome (C-IRIS). The pre-screening of HIV-infected patients in resource-poor countries with the lateral flow cryptococcal antigen assay could prevent C-IRIS. Delaying ART by 4 weeks is associated with improved survival and recommended by guidelines; this approach remains controversial in wealthier areas as there is limited data. A 5-flucytosine-based combination regimen and avoidance of corticosteroids on initial treatment improve cryptococcus clearance from cerebrospinal fluid. New monoclonal antibodies and kinase inhibitors that alter the immune system, such as ibrutinib and ruxolitinib, have been associated with cryptococcosis. It is important to recognize that restoration of the immune system, regardless of the host, can lead to C-IRIS. Prevention of C-IRIS by pre-screening patients, delaying antiretroviral therapy, and using a 5-flucytosine backbone regimen are important in the management of meningitis. C-IRIS management requires the exclusion of therapeutic failure or antifungal resistance. Further research is needed on whether delaying antiretroviral therapy by 4 weeks is necessary in wealthier countries to improve C-IRIS outcomes, and whether C-IRIS can be seen with new immunologic agents.