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

Br J Haematol. 2022 Jan;196(1):31-44. doi: 10.1111/bjh.17638. Epub 2021 Jun 24.


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.

Keywords: Epstein-Barr virus (EBV); T/NK-cell lymphoma; chronic active EBV (CAEBV); haemophagocytic lymphohistiocytosis (HLH); paediatric oncology.

Publication types

  • Review

MeSH terms

  • Algorithms
  • Biomarkers
  • Biopsy
  • Bone Marrow / pathology
  • Clinical Decision-Making
  • Cytokines / metabolism
  • Disease Management
  • Disease Susceptibility*
  • Epstein-Barr Virus Infections / complications*
  • Epstein-Barr Virus Infections / virology*
  • Genetic Predisposition to Disease
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • Lymphohistiocytosis, Hemophagocytic / diagnosis
  • Lymphohistiocytosis, Hemophagocytic / etiology*
  • Lymphohistiocytosis, Hemophagocytic / metabolism*
  • Lymphohistiocytosis, Hemophagocytic / therapy
  • Lymphoma, T-Cell / diagnosis
  • Lymphoma, T-Cell / etiology
  • Lymphoma, T-Cell / metabolism
  • Mutation
  • Perforin / genetics
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology


  • Biomarkers
  • Cytokines
  • PRF1 protein, human
  • Perforin