Performance of Diagnostic Tests for Histoplasmosis Across Clinical Syndromes and Immune Statuses

Background Histoplasmosis, caused by Histoplasma capsulatum, presents with a broad clinical spectrum from asymptomatic infection to disseminated disease (DH). Diagnostic modalities, culture, histopathology, antigen detection, and serologic testing, vary in performance. We evaluated their sensitivity and specificity across clinical presentations and immune statuses. Methods We conducted a retrospective diagnostic study of adults evaluated at Indiana University Health Medical Center who had serum and/or urine submitted for Histoplasma antigen testing to Miravista Diagnostics. Clinical classification (proven, probable) was based on laboratory, imaging, and clinical data according to EORTC/MSG criteria. Controls were patients tested for histoplasmosis but found to have an alternative diagnosis. Diagnostic methods included antigen enzyme immunoassay (EIA), antibody EIA (IgG/IgM), immunodiffusion (ID), complement fixation (CF), and fungal cultures. Results Among 205 patients, 125 were classified as histoplasmosis (54 proven, 71 probable) and 80 as controls. Antigen EIA in serum and/or urine had sensitivity 121/124 (97.6%) and specificity 75/80 (93.7%). IgG/IgM antibody EIA detected 89/111 (80.2%) cases with specificity 73/79 (92.4%) at a 20 EU/mL cutoff. Combining antigen and antibody testing increased sensitivity to 109/110 (99.1%). Among 75 patients with both serum and urine antigen tested, combined testing added 3/75 (4%) cases beyond urine alone. Antibody sensitivity declined in immunocompromised patients (75.0% vs 93.3% in immunocompetent, P = .0134), while antigen sensitivity remained high across groups. Conclusions Histoplasma antigen testing is the most sensitive diagnostic method. Antibody testing complements antigen in selected populations, particularly immunocompetent patients with pulmonary disease. Culture remains a complementary but less sensitive tool.