Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis Presenting as Pyrexia of Unknown Origin With Splenic...

BACKGROUND Histoplasma capsulatum is a thermally dimorphic fungus capable of causing progressive disseminated histoplasmosis, particularly in immunocompromised hosts. Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome resulting from uncontrolled immune activation. The coexistence of HLH and disseminated histoplasmosis is uncommon and poses significant diagnostic and therapeutic challenges. CASE REPORT A 72-year-old immunosuppressed woman with rheumatoid arthritis treated with methotrexate, hydroxychloroquine, and adalimumab presented with a 2-month history of intermittent high-grade fevers, weight loss, fatigue, and left upper quadrant pain. Physical examination revealed pallor, lethargy, and splenomegaly. Laboratory evaluation showed pancytopenia, markedly elevated ferritin, hypertriglyceridemia, and hypofibrinogenemia. Imaging demonstrated splenomegaly with splenic masses, hepatic lesions, and pulmonary nodules. Disseminated histoplasmosis was confirmed by positive urine Histoplasma antigen testing, immunodiffusion assays (H and M bands), and tissue biopsy demonstrating intracellular yeast forms consistent with Histoplasma. Bone marrow biopsy revealed hypercellularity with histiocytosis and hemophagocytosis. Elevated soluble interleukin-2 receptor levels and decreased natural killer cell activity supported secondary HLH. The patient was treated with liposomal amphotericin B followed by oral itraconazole, resulting in rapid clinical improvement and normalization of inflammatory markers, with radiographic resolution at 12 months. This case is notable for HLH associated with disseminated histoplasmosis presenting with splenic masses, an uncommon finding that can mimic malignancy or other infectious etiologies. CONCLUSIONS This case underscores the importance of considering HLH in patients with disseminated histoplasmosis presenting with persistent fever, cytopenias, and organomegaly. Early recognition and prompt antifungal therapy are critical for favorable outcomes. Although histoplasmosis can occur in immunocompetent individuals, it more commonly affects immunocompromised hosts, as in this patient, highlighting the need for vigilance in high-risk populations.