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Disease Categories > Infectious Disease > Viruses

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Epstein-Barr Virus - EBV

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

Diagnosis

Lab criteria include:
- Elevated atypical lymphocytes in CBC
- Positive heterophile antibody (IgM antibodies not specific for EBV)
  - Heterophile test is often negative in children less than 5 years of age
Diagnosis of acute disease due to virus depends mostly on testing for the immune response to EBV
- Immune response during acute infection, however, may be significantly delayed, especially in children and immunocompromised hosts
- Extensive work-up appropriate in markedly febrile patient with enlarged nodes and for whom prior testing was negative

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)

Differential Diagnosis

Cytomegalovirus (CMV)
Toxoplasmosis
Atypical mycobacterium
Lymphoma
Other viral agents

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

Indications for Ordering

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Infectious Mononucleosis Slide Test by LA 0050385 Method: Latex Agglutination	Initial testing to confirm infectious mononucleosis or recent EBV infection (Monospot test)	A negative Monospot test is common in children and immunocompromised adults	If test results are negative but a strong clinical suspicion exists, repeat testing in 7-14 days
Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgM 0050240 Method: Enzyme-Linked Immunosorbent Assay	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)		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
Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgG 0050235 Method: Enzyme-Linked Immunosorbent Assay	Clarify or confirm equivocal or negative Monospot test, especially in patients at risk for splenic rupture (contact sports)		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
Epstein-Barr Virus Antibody to Nuclear Antigen, IgG 0050245 Method: Enzyme-Linked Immunosorbent Assay	Confirm previous infection with EBV		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
Epstein-Barr Virus by PCR 0050246 Method: Polymerase Chain Reaction	Detect EBV in cerebrospinal fluid and serum specimens Diagnose EBV-related diseases in immunocompromised patients or patients with lymphoproliferative tumors	A negative result does not rule out the presence of PCR inhibitors in patient specimen or EBV DNA in concentrations below assay detection
Epstein-Barr Virus by Quantitative PCR 0051352 Method: Polymerase Chain Reaction	Monitor disease (plasma, serum or CSF specimens)	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
Epstein-Barr Virus by Quantitative PCR, Whole Blood 0051353 Method: Polymerase Chain Reaction	Monitor disease (whole blood specimens)	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
Epstein-Barr Virus (EBV) Probe, Paraffin 8030630 Method: In situ Hybridization	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)	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
Epstein-Barr Virus Antibody to Early D Antigen (EA-D), IgG 0050225 Method: Enzyme-Linked Immunosorbent Assay	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		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
Immunohistochemistry, EBVLMP 8033552	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)
Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgA 0051626 Method: Enzyme-Linked Immunosorbent Assay	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	IgA is variably seen; levels are not consistently elevated Results vary in acute infectious mononucleosis, chronic active mononucleosis and post-transplant lymphoproliferative disease	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
Immunohistochemistry Stain Offering arup005 Method: Immunohistochemistry	For fixed tissue samples, consultative services as well as immunohistochemical staining for the presence of EBV are available

Additional Tests Available

Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Comments
Epstein-Barr Virus Antibody to Viral Capsid Antigen, IgG & IgA 0051627 Method: Enzyme-Linked Immunosorbent Assay
Epstein-Barr Virus Antibody Panel I 0050600 Method: Enzyme-Linked Immunosorbent Assay
Epstein-Barr Virus Antibody Panel II 0050602 Method: Enzyme-Linked Immunosorbent Assay

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 (Link to NGC)

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. (Link to PubMed)

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. (Link to PubMed)

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

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

References from the ARUP Institute for Clinical and Experimental Pathology®

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. (Link to PubMed)

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. (Link to PubMed)

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. (Link to PubMed)

Reviewed by

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