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 <i>Blastomyces dermatitidis</i> antibody. In addition, acid-fast bacilli culture eventually grew <i>Mycobacterium porcinum</i> (<i>M. porcinum</i>). 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 <i>Blastomyces dermatitidis</i> or <i>M. porcinum</i> 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.