Clinical spectrum, immune status, and prognostic factors of cryptococcosis: insights from a large, multi-center, ambispective cohort study in southeastern China

Abstract Background Cryptococcosis is a major opportunistic fungal infection with heterogeneous clinical outcomes; however, data on clinical features and prognostic factors in non-HIV populations remain limited. This study aimed to provide real-world evidence on the clinical characteristics, immune stratification, diagnostic performance, treatment patterns, and outcomes of cryptococcosis. Methods We performed a multi-center ambispective cohort study of patients with cryptococcosis diagnosed between 2013 and 2025 across 48 hospitals in southeastern China, including Jiangsu and Fujian provinces. Patients were stratified according to immune status, disease type, and prognosis. Categorical variables were compared using the chi-square test or Fisher's exact test, and continuous variables were analyzed using the Mann-Whitney U test or Kruskal-Wallis test, as appropriate. Results A total of 396 patients were included, with a median age of 52 years; 61.9% were male. Most patients were immunocompetent (57.1%), while 33.1% had mild and 9.9% severe immunodeficiency. Pulmonary disease predominated (89.7%), whereas 10.1% had meningitis/dissemination. Severe immunodeficiency (SID) was associated with fever, neurological symptoms, lymphopenia, and elevated C-reactive protein (CRP) (all P < 0.01). Patients with meningitis/dissemination had more neurological manifestations and a markedly worse prognosis than those with pulmonary disease (mortality 35.1% vs. 2.1%). Among 319 patients with available follow-up data, follow-up duration varied from several days to several years, with prospective patients followed for up to 12 months. Overall, 89.0% recovered or improved, while 6.0% deteriorated or died. Poor outcomes were associated with older age, SID, central nervous system (CNS) involvement, lymphopenia, and elevated CRP. Serum cryptococcal antigen (CrAg) assays showed 94.6% concordance (122/129) between qualitative and quantitative methods. Quantitative ELISA identified four additional positive cases but missed three qualitative positive cases. In pulmonary cryptococcosis, amphotericin B-containing regimens were rarely used, while azole monotherapy was administered to over 95% of patients across severity groups and achieved favorable outcomes. Conclusions Host immune status, CNS involvement, and systemic inflammation are key predictors of outcome in cryptococcosis. Quantitative and qualitative CrAg assays demonstrate high diagnostic performance and azole monotherapy remained effective for pulmonary disease. These findings support risk-stratified diagnostic and therapeutic strategies in routine clinical practice, particularly in resource-limited settings. Graphical abstract