Immune Reconstitution Inflammatory Syndrome - IRIS in Cryptococcal Meningitis

IRIS in Cryptococcal Meningitis

IRIS is particularly problematic in cryptococcal meningitis as IRIS is fairly common and can be fatal.

IRIS has been described in immunocompetent hosts who have meningitis caused by Cryptococcus gattii and Cryptococcus neoformans var. grubii, environmental fungi which often affect immunocompetent hosts. Several weeks or even months into appropriate treatment, there is a sudden onset deterioration with worsening meningitis symptoms and progression or development of new neurological symptoms.

Magnetic resonance imaging shows increase in the size of brain lesions, and CSF abnormalities (white cell count, protein, glucose) increase. CSF culture is typically sterile, and there is no increase in CSF cryptococcal antigen titre.

The increasing inflammation can cause brain injury or be fatal.

The general mechanism behind IRIS is increased inflammation as the recovering immune system recognizes the antigens of the fungus as immunosuppression is reversed. Cryptococcal IRIS has three phases: (1) before HAART, with a paucity of cerebrospinal fluid (CSF) inflammation and defects in antigen clearance; (2) during initial HAART 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 (Th(1)) interferon-gamma (IFN-γ) response. Three clinical predictors of cryptococcal-related paradoxical IRIS risk include: 1) lack of initial CSF pleocytosis (i.e. low CSF WBC count); 2) elevated C-reactive protein; 3) failure to sterilize the CSF before immune recovery.

IRIS may be the cause of paradoxically worse outcomes for cryptococcal meningitis in immunocompetent compared with immunocompromised hosts, in whom Cryptococcus neoformans is the usual pathogen. Treatment with systemic corticosteroids during IRIS may be beneficial in preventing death or progressive neurological deterioration. Steroids given to persons with anti-fungal treatment failure / cryptococcal relapse (in whom CSF cultures are not sterile) can be a fatal iatrogenic error.