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

Abstract

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 (<26) were predictive of CNS disease; low scores (<22) were associated with poor long-term cognition. Longitudinal event depiction demonstrated frequent complications in people with CNS disease; 25 subjects (35.2%) required >1 lumbar puncture and 8 (11.3%) required ventriculostomies. In multivariable models, older age (>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.

Keywords: cryptococcosis; cryptococcus; outcomes; transplant.

Figure 1.

Location of CINCH sites. Geographical location of sites active in the CINCH study. Each dot represents a site that activated the CINCH protocol during the study period, with the exception of 2 opened in Portland, Oregon. No sites were opened in Hawaii, Alaska, or Puerto Rico. Abbreviation: CINCH, Cryptococcus Infection Network in non-HIV Cohort. Modified from https://www.census.gov/geo/reference/webatlas/regions.html.

Figure 2.

Baseline distributions and diagnostic utility of MoCA scores in the cohort. A, Histogram depiction of MoCA scores among people with CNS infection and other (non-CNS). Scores >26 are considered “normal.” Shading represents areas of severe (<22) and mild impairment (22–26). B. Receiver operating characteristic curve of baseline MoCA performance as a measure to predict CNS disease. Cutoffs at scores of 22 and 26 are shown (AUC, 0.71). The results of the smoothed curve (shown) did not differ from the empirical curve (not shown). Abbreviations: AUC, area under the curve; CNS, central nervous system; MoCA, Montreal Cognitive Assessment.

Figure 3.

Timing of last positive serum antigen. Frequency distribution is depicted from 68 subjects who had more than 1 positive antigen result recorded, according to day of diagnosis (day 0), in months.

Figure 4.

Longitudinal assessments of neurological complications in people with CNS disease. A, Event depiction for management of CNS pressure complications. Each subject is represented by a line, with day 0 as day of diagnosis. Black dots represent “alive” but censored for follow-up. B. Dynamics of MoCA assessments are shown for people with documented CNS disease who had tests obtained for at least 1 year, according to severity of baseline dysfunction. Trendlines are shown in bold. Abbreviations: CHS, central nervous system; CSF, cerebrospinal fluid; LP, lumbar puncture; MoCA, Montreal Cognitive Assessment.

Figure 5.

Kaplan–Meier 1-year survival curves. Survival is shown after diagnosis of CNS and non-CNS disease (log-rank P value = .0086). Abbreviation: CNS, central nervous system.