Abstract
Cryptococcus is an important cause of central nervous system infections in both immunocompromised patients such as those with HIV/AIDS as well as previously healthy individuals. Deficiencies in T-cell activation are well-known to be highly associated with host susceptibility in HIV/AIDS as well in animal modeling studies, resulting in poor microbiological control and little host inflammation. However, recent studies conducted in human patients have demonstrated roles for macrophage signaling defects as an important association with disease susceptibility. For example, an autoantibody to granulocyte monocyte stimulating factor (GMCSF) resulted in defective STAT5 signaling and susceptibility to cryptococcosis. In addition, severe cases of cryptococcal meningo-encephalitis in previously healthy patients, with or without anti-GMCSF autoantibody, developed a highly activated intrathecal T-cell population but had defects in effective macrophage polarization. Intrathecal inflammation correlated with neurological damage, measured by the axonal damage protein, neurofilament light chain 1. Based on these studies, we propose a new syndrome of cryptococcal post-infectious inflammatory response syndrome (PIIRS) defined in previously healthy patients with cryptococcal meningo-encephalitis as the presence of a poor clinical response in the setting of at least 1 month of amphotericin-based fungicidal therapy and sterile cerebrospinal cultures. These findings are discussed in light of the potential for improving therapy.