Haemophagocytic lymphohistiocytosis and Epstein–Barr virus: a complex relationship with diverse origins, expression and outcomes

Summary Epstein–Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life‐threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non‐familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X‐linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non‐neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV‐associated T/natural killer (NK)‐cell lymphoproliferative disorders and lymphomas can cause neoplasia‐associated HLH. The present review will discern between EBV‐associated familial and non‐familial HLH and highlight diagnostic and therapeutic considerations. Non‐familial EBV‐associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non‐neoplastic EBV‐HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV‐positive T‐cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV‐related complications is desperately needed to improve survival for patients with neoplasia‐associated HLH.