Accurate and timely diagnosis is crucial given the overlapping presentations of endemic mycoses. Clinicians must integrate clinical history, imaging, and laboratory tests to distinguish among infections such as histoplasmosis, blastomycosis, and coccidioidomycosis. Fungal cultures and histopathologic examinations provide definitive identification despite longer incubation periods, while serologic assays and antigen detection tests offer rapid support—each with considerations for host immune status and potential cross-reactivity.

Key diagnostic approaches include:

• Combining clinical history and imaging (eg, PET-CT scan findings like the “fungal flip-flop sign”) to raise early suspicion
• Utilizing fungal cultures and tissue histopathology for definitive organism identification
• Employing serologic testing (enzyme immunoassays, complement fixation, and immunodiffusion) to detect host antibodies
• Incorporating antigen detection in serum and urine to improve diagnostic sensitivity in severe or disseminated cases

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