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Background Cryptococcosis is increasingly recognized in people without human immunodeficiency virus (HIV). Methods A multicenter, prospective cohort study was performed in 25 US centers. Consenting patients were prospectively followed for ≤2 years. Neurological morbidities were assessed with longitudinal event depiction and functional scores (Montreal Cognitive Assessment [MoCA]). Risks of death were analyzed using Cox regression. Results One hundred forty-five subjects were enrolled. Most were male (95; 65.5%) and had immunosuppression (120; 82.8%), including solid organ transplant (SOT; 33.8%), autoimmunity (15.9%), and hematologic malignancies (11.7%). Disease involved the central nervous system (CNS) in 71 subjects (49%). Fever was uncommon, documented in 40 (27.8%) subjects, and absence was associated with diagnostic delay (mean: 48.2 vs 16.5 days; P = .007). Abnormal MoCA scores (&amp;lt;26) were predictive of CNS disease; low scores (&amp;lt;22) were associated with poor long-term cognition. Longitudinal event depiction demonstrated frequent complications in people with CNS disease; 25 subjects (35.2%) required &amp;gt;1 lumbar puncture and 8 (11.3%) required ventriculostomies. In multivariable models, older age (&amp;gt;60 years) was associated with higher risks of death (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.05–4.38; P = .036), and lower risks were noted with underlying hematologic malignancy (HR, 0.29; 95% CI, 0.09–0.98; P = .05) and prior SOT (HR, 0.153; 95% CI, 0.05–0.44; P = .001). Conclusions Despite aggressive antifungal therapies, outcomes of CNS cryptococcosis in people without HIV are characterized by substantial long-term neurological sequelae. Studies are needed to understand mechanism(s) of cognitive decline and to enable better treatment algorithms.

A Multicenter, Longitudinal Cohort Study of Cryptococcosis in Human Immunodeficiency Virus–negative People in the United States