About Epstein-Barr Virus

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Epstein-Barr virus (EBV) is an omnipresent member of the Herpesviridae family. It is a linear, double-stranded DNA virus with an icosahedral capsid. EBV is also known as HHV-4. EBV is a member of the Gammaherpesvirinae subfamily, along with HHV-8. The virus was discovered in 1964 by Drs. Epstein and Barr, after whom it was named. The virions which make up EBV are hexagonal nucleocapsids, with a complex surrounding envelope. EBV is most commonly found in B lymphocytes and also in epithelial cells of the nasopharynx. The virus has also been seen in epithelial cells, T lymphocytes, smooth muscle cells, and follicular dendritic cells. EBV enters the B lymphocyte and the viral DNA forms a self-replicating circular episome within the cell nucleus. EBV establishes latency in the B lymphocytes following primary infection. As B lymphocytes proliferate, the number of cells available to carry the virus increases. In an immunocompetent individual, specific cytotoxic T lymphocytes control the amount of B cell proliferation. In an immunocompromised patient, a latent EBV infection can reactivate and potentially cause lymphoproliferative disease, which can progress to a malignancy. This is due to a lack of T cells to control the EBV-driven proliferation of B cells.

 

EPSTEIN-BARR VIRUS CLINICAL MANIFESTATIONS

EBV is the causative agent of heterophile-positive infectious mononucleosis, which is most commonly seen in young adults or older adolescents. In transplant patients, EBV is the most common cause of post-transplant lymphoproliferative disorder (PTLD)1.

EBV antibodies are found in nearly 90% of all populations by the time they reach adulthood2,3. In developed countries, approximately 50% of the population seroconverts before the age of 53. Childhood primary EBV infections are usually asymptomatic. Between the ages of 10 and 20, a second wave of seroconversion typically occurs2. When adolescents or adults experience a primary EBV infection, it takes the form of infectious mononucleosis (IM), which most often manifests itself clinically in individuals who are not exposed to EBV until their second decade of life. IM typically presents with sore throat, fever, lymphadenopathy, and enlarged spleen. This disease is generally self-limiting and lasts approximately 1 to 4 weeks4. Immunocompetent individuals usually do not experience additional complications, but some develop a chronic, persistent manifestation of the disease which can involve significant organ system dysfunction and last over 6 months4.

Immunocompromised patients, such as hematopoietic stem cell transplant (HSCT) patients and solid organ transplant patients, are at risk for EBV-associated lymphoproliferation5-7. EBV-induced proliferation may lead to PTLD. Transplant patients who are seronegative at the time of transplant are at highest risk for PTLD. If patients experience a primary EBV infection while being treated with immunosuppressive drugs, the risk of developing PTLD is dramatically increased5,7. This is particularly common in the pediatric transplant population6.

Additional risk factors for development of PTLD in the HSCT population include the intensity and duration of immunosuppressive therapy, unrelated donor, T-cell-depleted allografts, use of antithymocyte globulin, and immunosuppression to prevent graft-versus-host disease (GVHD)7. The disease can manifest itself in forms ranging from benign polyclonal hyperplasia to malignant lymphoma. HIV patients sometimes develop nonmalignant lymphoproliferative diseases, such as follicular hypoplasia, primary lymphoid hyperplasia, and oral hairy leukoplasia, as well as lymphoid, muscular, and epithelial cell malignancies7,8.

 

EPSTEIN-BARR VIRUS LABORATORY DIAGNOSIS

Testing for these antibodies has been important to the diagnosis of IM. In some cases of IM and other EBV-associated illnesses, testing for EBV-specific antibodies has been shown to be useful2,4. It is important, particularly in the pediatric population, to ascertain the EBV serostatus prior to transplantation, since seronegative patients are at significantly higher risk for PTLD when they acquire an EBV primary infection2,5,7,8. Molecular testing methods that facilitate early detection of EBV replication can facilitate early intervention, with the goal of restoring adequate function of the immune system to control EBV replication. For these reasons, real-time, quantitative polymerase chain reaction (PCR) is considered the most accurate option for detecting and monitoring the overall EBV burden (viral load)5,7,9,10. Although both PBMCs and plasma are useful material for detection of EBV in immunocompromised patients, a higher positive predictive value for PTLD is achieved if plasma is used5.

 

EPSTEIN-BARR VIRUS TREATMENT

Most cases of IM require only supportive care, as over 95% of patients recover without therapy or complications3. Rituximab, a chimeric anti-CD20 monoclonal antibody developed for the treatment of B cell lymphoma, has been utilized with some success to curb the proliferation of EBV driven proliferating B cells11. Currently, the best approach appears to be restoration of T cell function by reduction of immunosuppression, to as great of an extent as possible11.

 

REFERENCES

1. Knipe D HP. Fields Virology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.
2. Cohen JI. Epstein-Barr virus infection. The New England Journal of Medicine. Aug 17 2000;343(7):481-492.
3. Papadakis MA. Infectious mononucleosis. The Western Journal of Medicine. Aug 1982;137(2):141-144.
4. Epstein-Barr Virus and Infectious Mononucleosis. http://www.cdc.gov/ncidod/diseases/ebv.htm. Accessed 08/26/2011, 2011.
5. Tsai DE, Douglas L, Andreadis C, et al. EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. May 2008;8(5):1016-1024.
6. Rose C, Green M, Webber S, Ellis D, Reyes J, Rowe D. Pediatric solid-organ transplant recipients carry chronic loads of Epstein-Barr virus exclusively in the immunoglobulin D-negative B-cell compartment. Journal of Clinical Microbiology. Apr 2001;39(4):1407-1415.
7. van Esser JW, van der Holt B, Meijer E, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell--depleted SCT. Blood. Aug 15 2001;98(4):972-978.
8. Cohen JM, Cooper N, Chakrabarti S, et al. EBV-related disease following haematopoietic stem cell transplantation with reduced intensity conditioning. Leukemia & Lymphoma. Feb 2007;48(2):256-269.
9. Kinch A, Oberg G, Arvidson J, Falk KI, Linde A, Pauksens K. Post-transplant lymphoproliferative disease and other Epstein-Barr virus diseases in allogeneic haematopoietic stem cell transplantation after introduction of monitoring of viral load by polymerase chain reaction. Scandinavian Journal of Infectious Diseases. 2007;39(3):235-244.
10. Gulley ML, Tang W. Using Epstein-Barr viral load assays to diagnose, monitor, and prevent posttransplant lymphoproliferative disorder. Clinical Microbiology Reviews. Apr 2010;23(2):350-366.
11. Parker A, Bowles K, Bradley JA, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients - BCSH and BTS Guidelines. British Journal of Haematology. Jun 2010;149(5):693-705.