Unmasking Epstein-Barr Virus (EBV)-Positive Large B-Cell Lymphoma as an Underlying Trigger in a Post-COVID Hemophagocytic Lymphohistiocytosis Case.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by dysregulated activation of cytotoxic T cells and macrophages, most commonly triggered by infection or malignancy. We describe a 79-year-old male with a remote history of multiple malignancies, all in remission, who presented with persistent fevers and was found to have pancytopenia and transaminitis following a COVID-19 infection two weeks earlier. An elevated H-score prompted early bone marrow biopsy, which confirmed hemophagocytosis and revealed a smoldering Epstein-Barr virus (EBV)-positive large B-cell lymphoma as the likely underlying trigger. Initiation of dexamethasone monotherapy led to rapid clinical and laboratory improvement before definitive chemotherapy for lymphoma was considered. This case highlights the "threshold model" of HLH, in which compounding insults such as COVID-19 infection and occult EBV-positive lymphoma can breach the immunologic tipping point. It also underscores the importance of maintaining a high index of suspicion for rare but life-threatening conditions such as HLH. Prompt H-score calculation and bone marrow sampling can secure the diagnosis, uncover the underlying trigger, and expedite appropriate therapy in patients with HLH.