Unraveling the enigma of Epstein-Barr virus: pathogenesis, diagnosis, and cutting-edge treatments for EBV-HLH

Epstein-Barr virus (EBV) is closely related to various lymphomas and hemophagocytic lymphohistiocytosis (HLH). Immunocompetent patients can control EBV through antibodies after infection, but immunodeficient patients may continuously activate the immune system and over-release cytokines, leading to fatal HLH. Mechanistically, EBV’s latency gene products activate key signaling pathways, triggering the release of numerous proinflammatory factors, which lead to T helper cell type 1 (Th1)/T helper cell type 2 (Th2) imbalance and cytokine storms. Host genetic factors, such as Slam-associated protein (SAP) gene defects and Killer-cell immunoglobulin-like receptor (KIR) gene polymorphisms, impact susceptibility to EBV-HLH and can overactivate T cells. Diagnosis relies on the HLH-2004 criteria along with EBV activation markers, while the HScore model and soluble CD25 (sCD25) detection boost specificity. Treatments involve etoposide-dexamethasone combinations, interferon-γ (IFN-γ) monoclonal antibodies, Programmed Death-1 (PD-1) inhibitors, and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing. However, diagnosis and treatment face challenges like a lack of specific biomarkers and genetic heterogeneity. This review synthesizes EBV-HLH’s pathogenesis, diagnosis, and treatment to inform future research.