Epstein-Barr Virus

Clinical Background

Epstein-Barr virus (EBV) is the cause of a variety of disorders, including mononucleosis.

Epidemiology

Age - most common age of infection is <21 years
- 50% seropositive before 5 years
Transmission - salivary contact

Organism

EBV belongs to the Herpesviridae family
Like other herpes viruses, may remain dormant for years as a latent infection
- Infects B lymphocytes, which can then be reactivated

Clinical Presentation

Primary infection often manifests as infectious mononucleosis (IM)
- IM usually self-limiting, characterized by:
  - Fever
  - Sore throat
  - Myalgias
  - Lymphadenopathy
  - Hepatosplenomegaly
Rare complications - hemolytic anemia and splenic rupture
Other serious symptoms that occur in extremes of age and among immunocompromised include:
- Thrombocytopenia
- Bulky adenopathy
- Hemolytic anemia
- Hepatitis
- Meningitis
- Myocarditis
Disorders associated with EBV
- Infectious mononucleosis
- Endemic Burkitt lymphoma
  - Primarily in Africa, less common in developed countries
  - High grade B-cell lymphoma
  - >80% of nonendemic Burkitt lymphomas are EBV negative
- Nasopharyngeal carcinoma (endemic in China)
  - Malignant nasopharyngeal tumor of the squamous epithelium
- Other cancers
  - EBV-associated Hodgkin lymphoma (mixed cellularity subtypes)
  - Tonsillar carcinoma
  - T-cell lymphomas (especially sinonasal T-cell lymphomas)
  - Thymoma
- X-linked lymphoproliferative syndrome (Duncan disease)
  - Often results in fatal, polyclonal B-cell proliferation
- Progressive lymphoproliferative diseases
  - Children with primary immunodeficiencies
  - Post-transplant lymphoproliferative disorders
  - Immunosuppressed or AIDS patients
- No good evidence to implicate EBV in chronic fatigue syndrome

Treatment

Treatment is supportive
- Due to risk of splenomegaly and splenic rupture
  - No contact sports for 6-8 weeks
- Steroids often used for severe symptoms

See Also

Cold Agglutinin Disease

Cryoglobulinemia - Cryoglobulin

Cytomegalovirus - CMV

Hemolytic Anemias

Herpesvirus 6 - HHV6

Leukemia Lymphoma Phenotyping

Lymphocytic Choriomeningitis - LCM

Lymphomas, B-Cell - B-Cell Lymphomas

Lymphomas, T-Cell - T-Cell Lymphomas

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Infectious Mononucleosis Slide Test by LA

ARUP #: 0050385

Methodology: Latex Agglutination

Use:

Initial testing to confirm infectious mononucleosis or recent EBV infection (Monospot test)

Limitations:

A negative Monospot test is common in children and immunocompromised adults

Follow-up:

If test results are negative but a strong clinical suspicion exists, repeat testing in 7-14 days

Test name: Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgM

ARUP #: 0050240

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Clarify or confirm equivocal or negative Monospot test, especially in patients at risk for splenic rupture (contact sports)

Discriminate EBV from other IM-like diseases (e.g., CMV, toxoplasmosis)

Limitations:

Follow-up:

To rule out other causes of lymphadenopathy, order antibody tests for Toxoplasma and CMV

Repeat testing in 10-14 days may be helpful if results are equivocal

Test name: Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgG

ARUP #: 0050235

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Clarify or confirm equivocal or negative Monospot test, especially in patients at risk for splenic rupture (contact sports)

Limitations:

Follow-up:

To rule out other causes of lymphadenopathy, order antibody tests for Toxoplasma and CMV

Repeat testing in 10-14 days may be helpful if results are equivocal

Test name: Epstein-Barr Virus Antibody to Nuclear Antigen, IgG

ARUP #: 0050245

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Confirm previous infection with EBV

Limitations:

Follow-up:

To rule out other causes of lymphadenopathy, order antibody tests for Toxoplasma and CMV

Repeat testing in 10-14 days may be helpful if results are equivocal

Test name: Epstein-Barr Virus by PCR

ARUP #: 0050246

Methodology: Polymerase Chain Reaction

Use:

Detect EBV in cerebrospinal fluid and serum specimens

Diagnose EBV-related diseases in immunocompromised patients or patients with lymphoproliferative tumors

Limitations:

A negative result does not rule out the presence of PCR inhibitors in patient specimen or EBV DNA in concentrations below assay detection

Follow-up:

Test name: Epstein-Barr Virus by Quantitative PCR

ARUP #: 0051352

Methodology: Polymerase Chain Reaction

Use:

Monitor disease (plasma, serum or CSF specimens)

Limitations:

A negative result does not rule out the presence of PCR inhibitors in the patient specimen or EBV DNA nucleic acid in concentrations below the level of detection of the assay

Inhibition may also lead to underestimation of viral quantitation

Follow-up:

Test name: Epstein-Barr Virus by Quantitative PCR, Whole Blood

ARUP #: 0051353

Methodology: Polymerase Chain Reaction

Use:

Monitor disease (whole blood specimens)

Limitations:

A negative result does not rule out the presence of PCR inhibitors in the patient specimen or EBV DNA nucleic acid in concentrations below the level of detection of the assay

Inhibition may also lead to underestimation of viral quantitation

Follow-up:

Test name: Epstein-Barr Virus (EBV) Probe, Paraffin

ARUP #: 8030630

Methodology: In situ Hybridization

Use:

Diagnose EBV-related diseases in immunocompromised patients or patients with lymphoproliferative tumors

Determine involvement of EBV in nasopharyngeal carcinoma

Discriminate between EBV and other IM-like diseases (CMV, toxoplasmosis)

Limitations:

Epstein-Barr virus (EBV) Probe, Paraffin, requires tissue

In situ hybridization may not be possible in poorly fixed or necrotic tissue with inadequate nucleic acid preservation

Follow-up:

Test name: Epstein-Barr Virus Antibody to Early D Antigen (EA-D), IgG

ARUP #: 0050225

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Confirm chronic active mononucleosis, post-transplant lymphoproliferative disease and nasopharyngeal carcinoma

This antibody test is more useful and appropriate than Early Antigen R for mononucleosis assessment

Limitations:

Follow-up:

To rule out other causes of lymphadenopathy, order antibody tests for Toxoplasma and CMV

Repeat testing in 10-14 days may be helpful if results are equivocal

Test name: Immunohistochemistry, EBVLMP 8033552

ARUP #:

Methodology:

Use:

Determine involvement of EBV in nasopharyngeal carcinoma

Diagnose EBV-related diseases in immunocompromised patients or patients with lymphoproliferative tumors

Discriminate between EBV and other IM-like diseases (CMV, toxoplasmosis)

Limitations:

Follow-up:

Test name: Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgA

ARUP #: 0051626

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

May be used in conjunction with Epstein-Barr Virus Antibody to Early D Antigen (EA-D), IgG to confirm chronic active mononucleosis, post-transplant lymphoproliferative disease, Burkitt lymphoma, nasopharyngeal carcinoma

Limitations:

IgA is variably seen; levels are not consistently elevated

Results vary in acute infectious mononucleosis, chronic active mononucleosis and post-transplant lymphoproliferative disease

Follow-up:

To rule out other causes of lymphadenopathy, order antibody tests for Toxoplasma and CMV

Repeat testing in 10-14 days may be helpful if results are equivocal

Test name: Immunohistochemistry Stain Offering

ARUP #: arup005

Methodology: Immunohistochemistry

Use:

For fixed tissue samples, consultative services as well as immunohistochemical staining for the presence of EBV are available

Additional Tests Available

Test name: Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgG & IgA

ARUP #: 0051627

Methodology: Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Epstein-Barr Virus Antibody Panel I

ARUP #: 0050600

Methodology: Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Epstein-Barr Virus Antibody Panel II

ARUP #: 0050602

Methodology: Enzyme-Linked Immunosorbent Assay

Comments:

Test name: Heterophile Antibody by Latex Agglutination with Reflex to Titer

ARUP #: 0050621

Methodology: Latex Agglutination

Comments:

References

Guidelines

Evidence based clinical practice guideline for management of post transplant lymphoproliferative disease (PTLD) following solid organ transplant. Cincinnati Children's Hospital Medical Center - Hospital/Medical Center. 2003 Feb 4. 14 pages. NGC:003167

Cited References

Cohen JI. Epstein-Barr Virus Infections, Including Infectious Mononucleosis. In Kasper D et al. eds. Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2005. pp. 1046-1049.

General References

Auwaerter PG. Infectious mononucleosis: return to play. Clin Sports Med. 2004;23(3):485-97, xi.

Bell AT, Fortune B, Sheeler R. Clinical inquiries. What test is the best for diagnosing infectious mononucleosis?. J Fam Pract. 2006;55(9):799-802.

Hutt-Fletcher LM. Epstein-Barr virus entry. J Virol. 2007;81(15):7825-7832.

Klein E, Kis LL, Klein G. Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions. Oncogene. 2007;26(9):1297-1305.

Razonable RR, Paya CV. Herpesvirus infections in transplant recipients: current challenges in the clinical management of cytomegalovirus and Epstein-Barr virus infections. Herpes. 2003;10(3):60-65.

Smith TF, Espy MJ, Mandrekar J, Jones MF, Cockerill FR, Patel R. Quantitative real-time polymerase chain reaction for evaluating DNAemia due to cytomegalovirus, Epstein-Barr virus, and BK virus in solid-organ transplant recipients. Clin Infect Dis. 2007;45(8):1056-1061.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Herrmann MG, Durtschi JD, Bromley LK, Wittwer CT, Voelkerding KV. Amplicon DNA melting analysis for mutation scanning and genotyping: cross-platform comparison of instruments and dyes. Clin Chem. 2006;52(3):494-503.

Salama ME, Perkins SL, Mariappan MR. Images in HIV/AIDS. Primary bone marrow presentation of Epstein-Barr virus-driven HIV-associated Hodgkin lymphoma. AIDS Read. 2007;17(12):604-605.

She RC, Stevenson J, Phansalkar AR, Hillyard DR, Litwin CM, Petti CA. Limitations of polymerase chain reaction testing for diagnosing acute Epstein-Barr virus infections. Diagn Microbiol Infect Dis. 2007;58(3):333-335.

Medical Reviewers

Hillyard, David R., M.D. Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Perkins, Sherrie L. , M.D., Ph.D. Medical Director, Hematopathology at ARUP Laboratories; Professor, Anatomic Pathology, University of Utah

Comprehensive Review: January 2008
Last Update: January 2008

Serologic Features of EBV-Associated Diseases
Condition	Anti-VCA Heterophile	Anti-VCA IgM	Anti-VCA IgG	Anti-EA EA-D	Anti-EA EA-R*	Anti-EBNA
Acute infectious mononucleosis	+	+	++	+	-	-
Convalescence	±	-	+	-	±	+
Past infection	-	-	+	-	-	+
Reactivation immunodeficiency	-	-	++	+	+	±
Burkitt lymphoma	-	-	+++	±	++	+
Nasopharyngeal carcinoma	-	-	+++	++	±	+
*EA-R antibody testing is not recommended for mononucleosis assessment since the antibodies are uncommonly present; however, EA-R antibody testing may be useful for diagnosing the African form of Burkitt lymphoma which is rare in the U.S.
(Adapted with permission from Cohen, 2005, 1148)