Purpose of Review
Cryptococcal meningitis (CM) causes significant mortality among HIV-infected patients, despite antifungal therapy and use of antiretroviral therapy (ART). In patients with CM, ART is often complicated by immune reconstitution inflammatory syndrome (IRIS), manifesting as unmasking of previously unrecognized subclinical infection (unmasking CM-IRIS) or paradoxical worsening of symptoms in the central nervous system after prior improvement with antifungal therapy (paradoxical CM-IRIS). We review our current understanding of the pathogenesis of this phenomenon, focusing on unifying innate and adaptive immune mechanisms leading to the development of this often fatal syndrome.
Recent Findings
We propose that HIV-associated CD4+ T cell depletion, chemokine-driven trafficking of monocytes into cerebrospinal fluid (CSF) in response to CM, and poor localized innate cytokine responses lead to inadequate cryptococcal killing and clearance of the fungus. Subsequent ART-associated recovery of T cell signaling and restored cytokine responses, characterized by Interferon-γ production, triggers an inflammatory response. The inflammatory response triggered by ART is dysregulated due to impaired homeostatic and regulatory mechanisms, culminating in the development of CM-IRIS.
Summary
Despite our incomplete understanding of the immunopathogenesis of CM-IRIS, emerging data exploring innate and adaptive immune responses could be exploited to predict, prevent and manage CM-IRIS and associated morbid consequences.