Pulmonary cryptococcosis beyond human immunodeficiency virus: a five-year cohort study of diagnostic challenges, radiologic mimics, and clinical predictors.

Background: Cryptococcosis is an opportunistic fungal infection that increasingly affects non-human immunodeficiency virus (HIV), immunocompetent or mildly immunocompromised individuals. Pulmonary cryptococcosis, in particular, poses diagnostic challenges due to its radiological resemblance to malignant lung lesions and often subtle or absent clinical symptoms. The aim of this study is to characterize the demographic features, clinical presentation, diagnostic pathways, radiological and pathological findings, and treatment patterns among hospitalized patients with histopathologically or molecularly confirmed pulmonary cryptococcosis. Methods: This retrospective descriptive study included 61 non-HIV patients hospitalized with confirmed pulmonary cryptococcal infection over a 5-year period. Data were extracted from medical records, including demographics, comorbidities, presenting symptoms, imaging features, diagnostic procedures, histopathological and molecular confirmation, laboratory parameters, and treatment details. Pearson correlation and linear regression analyses were used to explore predictors of hospital length of stay. Results: The cohort comprised predominantly male patients (72.1%) with a mean age of 51.6 years. Most cases (63.3%) were incidentally detected on imaging, while the remainder presented with non-specific respiratory symptoms. Radiological findings frequently included multiple pulmonary nodules (56.4%) and ground-glass opacities (16.4%). Surgical resection was performed in over half of the cases, primarily due to initial suspicion of malignancy. Diagnosis was confirmed through periodic acid-Schiff (PAS) (72.1%) or silver staining (57.4%), and supported by molecular testing in selected cases. Three patients (4.9%) had central nervous system (CNS) involvement confirmed by lumbar puncture and imaging. All patients received fluconazole as first-line antifungal therapy, while those with CNS involvement received a combination of amphotericin B and fluconazole followed by fluconazole maintenance therapy. In multivariate analysis, bilateral pulmonary nodules were associated with shorter hospital stays (β =-5.36, P=0.041), while the presence of cavitary lesions predicted longer hospitalization (β =5.04, P=0.03). Conclusions: Pulmonary cryptococcosis may mimic malignancy and frequently presents without overt symptoms, contributing to diagnostic delays and surgical interventions. Recognition of its radiological patterns and clinical spectrum in non-HIV patients is essential for timely diagnosis and appropriate antifungal treatment. This study highlights the importance of considering cryptococcosis in the differential diagnosis of pulmonary nodules, even in asymptomatic, immunocompetent individuals.