View source for 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 [[thrombocytopenia]][[CiteRef::kimura2001cl]][[CiteRef::cohen2011ch]]
**[[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 cases[[CiteRef::okano2005pr]]
*Requires all of the criteria
*Persistent or recurrent [[Infectious mononucleosis|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<sup>2.5</sup> 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<sup>2.5</sup> 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: [https://doi.org/10.3389/fped.2019.00014 10.3389/fped.2019.00014]

[[Category:Hematology]]
[[Category:Infectious diseases]]