Progressive Disseminated Histoplasmosis with Dermatomyositis and Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis

Histoplasmosis is the most common endemic mycosis in North and Central America, particularly in the Ohio and Mississippi River Valleys. Progressive disseminated histoplasmosis (PDH) occurs in ∼1 in 2,000 acute infections and may present atypically with multiorgan involvement, especially in immunocompromised hosts. We describe a case of PDH complicated by macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) in a patient with dermatomyositis who was receiving long-term immunosuppressive therapy. She developed two uncommon manifestations of PDH: biopsy-proven cellulitis and intracellular yeasts within neutrophils on a peripheral blood smear. Diagnosis was delayed because of fungal antigen cross-reactivity and overlapping clinical and laboratory features of PDH and MAS/HLH. This case highlights the importance of early recognition, timely treatment, and coordinated multidisciplinary management. Our patient died 17 days after admission, underscoring the high mortality rate of MAS/HLH-associated histoplasmosis.