A Complex Case of Hemophagocytic Lymphohistiocytosis Secondary to Untreated Hepatitis C: Diagnostic Challenges

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by uncontrolled activation of cytotoxic T cells and macrophages, leading to cytokine storm and organ failure. Secondary HLH is the acquired form that is commonly triggered by underlying malignancies, autoimmune diseases, or infections. While Epstein-Barr virus (EBV) is a common infectious trigger for HLH, hepatitis C virus (HCV) is rarely reported in the literature. Herein, we present the case of a patient with HLH with multiple possible infectious triggers that was ultimately attributed to HCV. A 61-year-old male with a history of untreated HCV was admitted with concerns for septic shock. Infectious workup was largely negative throughout his hospitalization. Lumbar puncture was concerning for a fungal meningitis, but fungal workup was negative except for a positive Blastomyces dermatitidis antibody. In addition, acid-fast bacilli culture eventually grew Mycobacterium porcinum (M. porcinum). He was treated with broad-spectrum antibiotics and anti-fungals but continued to fever. He met five of eight criteria per HLH-2004 protocol and was initiated on HLH-directed therapy with immediate resolution of his fevers. A Karius test did not identify pathogenic levels of Blastomyces dermatitidis or M. porcinum in the serum, and the causative trigger was determined to be his untreated HCV. This case highlights the importance of early recognition and treatment of HLH in a patient with fever of unknown origin. It brings attention to HCV as a highly unusual trigger of HLH. It also illustrates the difficulty in addressing the underlying source of secondary HLH when a broad infectious workup yields several rare but possible pathogens.