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

Abstract

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.