Chronic active Epstein-Barr virus disease

Background

• Life-threatening EBV-associated lymphoproliferative disorder caused by infection with Epstein-Barr virus involving primarily NK and T cells
• Classified as: polymorphic polyclonal/oligoclonal LPD, polymorphic monoclonal LPD, and monomorphic monoclonal LPD (which is similar to PTLD)
  • Related disorders of exclusion include aggressive NK-cell leukemia (ANKL) and extranodal NK/T-cell lymphoma (ENKTL), though there may be some overlap

Pathophysiology

• EBV infection involving B, T, and/or NK cells causing clonal proliferation

Epidemiology

• Most cases reported in Japan and East Asia
• In the Americas, more common in Indigenous populations
• However, can occur in people of all ethnicities

Clinical Manifestations

• The most common symptoms include fever, hepatitis, splenomegaly, lymphadenopathy, and thrombocytopenia12
  • Hypogammaglobulinemia and pancytopenia often seen
• Also commonly have hepatomegaly, anemia, mosquito bite hypersensitivity (see below), rashes (such as hydroa vacciniforme), oral ulcers, coronary artery aneurysm, liver failure, lymphoma, hemophagocytosis, and interstitial pneumonitis
• Occasionally has uveitis, CNS disease, intestinal perforation, and myocarditis
• Can progress to frank lymphoma or hemophagocytic lymphohistiocytosis

Related Disorders

Severe Mosquito Bite Allergy

• A severe hypersensitivity reaction to saliva in the bite of Aedes albopictus mosquitoes
• Characterized by local skin inflammation followed by high fever, lymphadenopathy, and liver dysfunction
• The bite can ulcerate and scar
• Resoves within a month

Hydroa Vacciniforme

• Characterized by light-induced vesicles
• Can also involve systemic inflammation

Differential Diagnosis

• Kawasaki disease
• Behçet disease

Diagnostic Criteria

• Criteria were proposed in 2005 based on Japanese cases3
• Requires all of the criteria
• Persistent or recurrent IM‐like symptoms
  • Symptoms generally include fever, lymphadenopathy, and hepatosplenomegaly
  • May also include hematological, gastrointestinal, neurological, pulmonary, ocular, dermal, or cardiovascular disorders
• Unusual pattern of anti-EBV antibodies with raised anti-VCA and anti-EA, and/or detection of increased EBV genomes in affected tissues, including the peripheral blood
  • Detection of EBV DNA or related antigens in affected tissue, including:
    • PCR, which typically shows >10^2.5 copies/µg DNA in the peripheral blood
    • In situ hybridization (e.g. EBER)
    • Immunofluorescence (e.g. EBNA, LMP)
    • Southern blotting, including clonality of EBV
    • Clarifying target cells of EBV infection, such as double-staining of EBNA or detection of EBER or EBV DNA in B, T, NK cells or monocytes/macrophages/histiocytes
  • Histopathological and molecular evaluation
    • General histopathology
    • Immunohistological staining
    • Chromosomal analysis
    • Rearrangement studies (e.g. immunoglobulin, T-cell receptor)
  • Immunological studies
    • In general
    • Marker analysis of peripheral blood
    • Cytokine analysis
• Chronic illness which cannot be explained by other known disease processes at diagnosis, including:
  • Primary EBV infection (infectious mononucleosis)
  • Primary immunodeficiencies
  • HIV
  • Iatrogenic immunosuppression
  • Autoimmune or collagen vascular diseases
  • Other malignant lymphoma (classic Hodgkin lymphoma, extranodal NK/T cell lymphoma, including nasal type, peripheral T cell lymphomas, and aggressive NK‐cell leukemia)
  • Note, however, that an EBV-associated disease such as HLH or lymphoma/LPD often develops in the course of illness

Diagnosis

• Can follow a series of stepwise diagnostic tests:
  • Anti-EBV antibodies demonstrating anti-VCA-IgG (necessary for diagnosis), anti-EA-IgG, and anti-VCA-IgA or anti-EA-IgA antibodies
    • Anti-EBNA antibodies may be negative
  • EBV DNA viral load ≥10^2.5 copies/μg DNA (i.e. 2.5 log) in peripheral blood mononuclear cells
  • Detection of EBV infection of T or NK cells in affected tissues or peripheral blood
• The diagnosis requires a combination of identifying EBV-infected T/NK cells in PB or affected tissues/organs and having compatible symptomatology

Management

• Hematopoietic stem cell transplantation is the only curative treatment
• Symptoms may be temporarily improved with corticosteroids

Further Reading

• Advances in the Study of Chronic Active Epstein-Barr Virus Infection: Clinical Features Under the 2016 WHO Classification and Mechanisms of Development. Front Pediatr. 2019;7:14. doi: 10.3389/fped.2019.00014