Chronic active Epstein-Barr virus disease
From IDWiki
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
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 >102.5 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
- Detection of EBV DNA or related antigens in affected tissue, including:
- 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 ≥102.5 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
- Anti-EBV antibodies demonstrating anti-VCA-IgG (necessary for diagnosis), anti-EA-IgG, and anti-VCA-IgA or anti-EA-IgA antibodies
- 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
References
- ^ Hiroshi Kimura, Yo Hoshino, Hirokazu Kanegane, Ikuya Tsuge, Takayuki Okamura, Keisei Kawa, Tsuneo Morishima. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood. 2001;98(2):280-286. doi:10.1182/blood.v98.2.280.
- ^ Jeffrey I. Cohen, Elaine S. Jaffe, Janet K. Dale, Stefania Pittaluga, Helen E. Heslop, Cliona M. Rooney, Stephen Gottschalk, Catherine M. Bollard, V. Koneti Rao, Adriana Marques, Peter D. Burbelo, Siu-Ping Turk, Rachael Fulton, Alan S. Wayne, Richard F. Little, Mitchell S. Cairo, Nader K. El-Mallawany, Daniel Fowler, Claude Sportes, Michael R. Bishop, Wyndham Wilson, Stephen E. Straus. Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States. Blood. 2011;117(22):5835-5849. doi:10.1182/blood-2010-11-316745.
- ^ Motohiko Okano, Keisei Kawa, Hiroshi Kimura, Akihiro Yachie, Hiroshi Wakiguchi, Akihiko Maeda, Shosuke Imai, Shouichi Ohga, Hirokazu Kanegane, Shigeru Tsuchiya, Tomohiro Morio, Masaaki Mori, Shumpei Yokota, Shinsaku Imashuku. Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. American Journal of Hematology. 2005;80(1):64-69. doi:10.1002/ajh.20398.
