The Diagnostic Challenge in Pulmonary Cryptococcosis Among Immunocompetent Patients: The ‘False-Negative’ Serum Cryptococcal Antigen

Objective: To delineate the demographic, clinical, and radiological features of immunocompetent patients with pulmonary cryptococcosis (PC) who test negative for serum cryptococcal antigen (CrAg), a subgroup that poses a diagnostic challenge. Methods: Participants were stratified into CrAg-positive (n = 128) and CrAg-negative (n = 71) cohorts. Comparative analyses were performed on clinical presentation, chest computed tomography (CT) imaging features, and laboratory parameters. Results: Patients with false-negative CrAg results were more likely to be asymptomatic (46.5% vs. 20.3% in the CrAg-positive group; p < 0.05). Their chest CT scans typically revealed solitary pulmonary nodules, frequently unilateral and located in the right lung, with a notable absence of pleural effusion or lymphadenopathy. Laboratory findings in the CrAg-negative group were characterized by a lower neutrophil ratio and erythrocyte sedimentation rate. Furthermore, higher CrAg titers were significantly correlated with the presence of respiratory symptoms, specific CT signs (e.g., air bronchogram, lymphadenopathy), and elevated systemic inflammatory markers. Conclusions: False-negative serum CrAg in immunocompetent PC patients is characterized by an asymptomatic presentation and a solitary nodule on imaging, with normal laboratory parameters. CrAg titers may reflect disease severity and warrant prospective evaluation as a potential biomarker for guiding antifungal therapy.