Cryptococcus in the absence of immunosuppression: Diagnostic and therapeutic challenges

Invasive cryptococcal infections, particularly those caused by Cryptococcus neoformans, are significant contributors to morbidity and mortality among immunocompromised patients, especially individuals living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Recognized as a critical fungal pathogen by the WHO in 2022, the increasing prevalence of such infections raises concerns, particularly as case reports emerge detailing instances in seemingly immunocompetent individuals. Here we report two cases, one in which the host had no known immunocompromising condition at time of diagnosis, and the other in which invasive infection was found without clear evidence of pulmonary or neurological involvement. We discuss the evolving epidemiology and diverse manifestations of invasive cryptococcal infections, and emerging associations with conditions that may predispose to infection in the seemingly immunocompetent host. These cases highlight disseminated cryptococcosis in patients without traditional severe immunosuppression, emphasizing the need for high clinical suspicion.