Hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation. It usually occurs in children, mainly during the first year of life. Primary hemophagocytic lymphohistiocytosis is more common and usually occurs in immunocompromised patients. Secondary hemophagocytic lymphohistiocytosis, on the other hand, is less common, especially in immunocompetent patients. Here, we intend to present a case of a 55-year-old male patient who had no known immune deficiency, presented with epistaxis, and was found to have Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by a pathologic immune response in the setting of infection, malignancy, acute illness, or any immunological stimulus. Infection is the most common etiology of HLH. HLH involves aberrant activation of lymphocytes and macrophages with resultant hypercytokinemia due to an inappropriately stimulated and ineffective immune response. Here, we present the case of a previously healthy 19-year-old male presenting with hiccups and scleral icterus, who was found to have HLH due to a severe Epstein-Barr virus infection. Despite a morphologically normal bone marrow biopsy, the patient met the diagnostic criteria for HLH, including a low natural killer cell count and elevated soluble interleukin-2 receptor. Notably, ferritin was severely elevated at 85,810 ng/mL. The patient was treated with an induction course of dexamethasone intravenously for eight weeks. Since HLH can progress into multi-organ failure, timely diagnosis and prompt initiation of treatment are critical. Novel disease-modifying therapies and further clinical trials are warranted to treat this potentially fatal immunological disease with multisystem ramifications.

Primary infection with Epstein-Barr virus (EBV) is very common, often manifesting as mononucleosis syndrome with fatigue, sore throat, fever, and enlarged lymph nodes. Liver involvement occurs in many cases with mildly elevated liver enzymes. However, it is rare to see EBV infection present as cholestatic hepatitis. Another rare complication of primary EBV infection is hemophagocytic lymphohistiocytosis (HLH). We describe a patient with primary EBV infection who presented with fatigue and jaundice, subsequent rash, and reactive lymphocytosis. The patient was noted to have cholestatic hepatitis and was highly suspected to have HLH based on laboratory values, including elevated ferritin, triglyceride, and interleukin-2 levels. He showed clinical improvement with HLH treatment using dexamethasone, etoposide, and rituximab. We further review the clinical manifestations, pathogenesis, and management of EBV-associated cholestatic hepatitis and EBV-HLH. Early diagnosis of primary EBV infection is emphasized in order to properly recognize and treat potentially life-threatening complications.