A Fatal Convergence: HLH, Disseminated MAC, and Opportunistic Fungal Infections in an Immunocompromised Host

Background: – Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of immune dysregulation that may be triggered or exacerbated by infections, malignancy, autoimmune disease, or iatrogenic immunosuppression. In rheumatologic conditions such as adult-onset Still's disease (AOSD), HLH can manifest as macrophage activation syndrome (MAS), a related hyperinflammatory state. Opportunistic infections, particularly with intracellular pathogens such as Mycobacterium avium complex (MAC), can mimic or precipitate HLH, creating diagnostic and therapeutic dilemmas. Methods: – We report the case of a 40-year-old woman with AOSD complicated by recurrent MAS who developed disseminated opportunistic infections while on prolonged immunosuppressive therapy, including anti–interferon-gamma (IFN-γ) monoclonal antibody. Clinical, radiologic, microbiologic, and pathologic findings were reviewed in detail along with focused literature review on disseminated nontuberculous mycobacterial (NTM) infections in non-HIV immunocompromised patients with HLH or MAS, emphasizing risk factors, diagnostic approaches, and management considerations. Results: – The patient was admitted with fever, cytopenias, and ulcerated skin lesions. Imaging demonstrated disseminated infection involving the lungs, liver, brain, lymph nodes, and soft tissues. Karius microbial cell-free DNA testing identified MAC, Mycobacteroides abscessus, Aspergillus fumigatus, and Verruconis gallopava. Histopathology revealed acid-fast bacilli (AFB)–positive infiltrates in skin and bone marrow. She subsequently developed fungal endophthalmitis and tricuspid valve endocarditis. Despite broad-spectrum antimicrobials and intensive care, she experienced progressive multiorgan failure and died. Postmortem examination confirmed disseminated MAC and V. gallopava, with extensive hemophagocytosis. Immunologic testing did not identify a primary immunodeficiency, though hypogammaglobulinemia and prolonged immunosuppression suggested profound acquired immune dysfunction. Discussion: – This case illustrates the complex interplay between HLH, immunosuppressive therapy, and opportunistic infection. IFN-γ blockade may impair host defenses against intracellular organisms such as MAC, whereas HLH-directed treatments further increase infectious risk. Functional immune testing may help identify patients at risk for opportunistic infections. Recognizing iatrogenic and secondary immunodeficiencies in HLH is crucial for optimizing management and improving outcomes in this high-risk population.