An Unusual Case of Histoplasma Empyema in an Immunocompromised Host and Literature Review

Abstract Introduction Histoplasma capsulatum is a dimorphic fungus endemic to the Ohio and Mississippi River valleys that typically causes self-limited pulmonary disease in immunocompetent individuals. Immunocompromised patients, particularly those receiving TNF-α inhibitors, face substantially elevated risk for severe and disseminated infection. Empyema due to histoplasmosis is exceedingly rare, with fewer than five cases documented in the published literature. Case Description We report a 51-year-old woman with rheumatoid arthritis on adalimumab, methotrexate, and hydroxychloroquine who presented with progressive dyspnoea, fever, and hypoxia after multiple prior healthcare encounters. Imaging demonstrated diffuse bilateral micronodules, lingular consolidation, and a worsening left pleural effusion requiring chest tube drainage. Initial urine Blastomyces antigen testing returned positive due to cross-reactivity, but pleural fluid culture and PCR ultimately confirmed Histoplasma capsulatum thus establishing the diagnosis of Histoplasma empyema. Treatment with liposomal amphotericin B followed by itraconazole, combined with pleural drainage, resulted in clinical and radiographic resolution. Discussion This case highlights the diagnostic challenges of Histoplasma empyema, including nonspecific presentation, low pleural fluid culture sensitivity, and antigen cross-reactivity with Blastomyces. A multimodal diagnostic approach and early combined antifungal and drainage-based management are essential for favourable outcomes in immunocompromised patients with atypical or refractory pleural disease.