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A. Characteristics navigator

  1. Large, double stranded DNA virus
  2. Genome codes for approximately 100 Genes
  3. EBV Disease Associations
    1. Benign Lymphoproliferative Diseases - such as infectious mononucleosis ("mono")
    2. EBV also has definitive role in X-linked lymphoproliferative disease
    3. Malignant Disease - Burkitt Lymphoma, Nasopharyngeal Carcinoma, Hodgkin Lymphoma (HL)
    4. Strong role in B-cell lymphoma and leiomyosarcomas in immunosuppressed patients
    5. Specific EBV genes have been linked to cell cycle abnormalities, neoplasia
    6. Persistence of EBV infection can lead to chronic B cell activation and downstream effects
  4. EBV Transformation Associated Genes [2]
    1. Mediate latent infection (that is, non-replicative infection)
    2. EBNA-1: maintains EBV genome as episome in cell
    3. EBNA-2: upregulates cell gene expression, EBV LMP-1 and LMP-2
    4. EBNA-3a: upregulates cellular genes, required for cell transformation
    5. EBNA-3b: unknown function, not essential for transformation
    6. EBNA-3c: modulates EBNA-2 expression
    7. EBNA-LP (leader protein): augments EBNA-2 upregulation of LMP-1
    8. Latent Membrane Protein (LMP)-1: direct oncogene, prevents apoptosis
    9. LMP-2: prevents reactivation of EBV-infected B cells; not reqiured for transformation
  5. EBV Effects on Lymphocytes [11]
    1. EBV induces both humoral and cellular immunity
    2. EBV gp350 binds to CD21 (C3d complement receptor) - mainly found on B cells
    3. Causes marked B cell hyperproliferation
    4. This leads to severe lymphadenopathy and often splenomegaly
    5. Main peripheral blood abnormalities occur in T lymphocytes
    6. Bizarre appearing CD8+ T lymphocytes (large, mononuclear cells) found on smear
    7. Some of these cells are actually natural killer (NK) cells (CD3-, some CD8-)
    8. EBV codes for protein called BCRF-1 with >80% amino acid identity to Interleukin 10
    9. IL-10 inhibits gamma interferon, IL-1, IL-12 and TNF alpha synthesis
    10. This appears to block normal CTL and NK mechanisms for eliminating virus
    11. EBV+ HL is associated with polymorphisms in HLA Class I (but not class III) which may be associated with presentation of EBV antigens to cytotoxic T lymphocytes [4]
  6. LMP-1 [7]
    1. Potent transforming effects in vitro
    2. Viral analog of TNF receptors
    3. Cytoplasmic tail of LMP-1 which bines to intracellular TRAF proteins
    4. TRAFs are TNF receptor associated factors
    5. LMP-1 / TRAF complexes activate nuclear factor kappa B (NF-kB) transcription factor
    6. Burkitt Lymphomas do not have LMP-1 expression [7]
    7. EBV lymphomas from immunosuppressed patients showed LMP-1/TRAF complexes
    8. TRAF-1 and TRAF-3 have been found in the LMP-1/TRAF complexes in human tumors

B. Disease Associationsnavigator

  1. Benign Disease Associations
    1. Infectious Mononucleosis
    2. Benign lymphadenopathy syndromes
    3. X-Linked Lymphoproliferative Disease patients cannot control EBV infection
    4. Monoclonal gammopathy may be present
  2. Neoplastic Transformation
    1. Anaplastic nasopharyngeal carcinoma - nearly 100% are EBV genome positive
    2. Hodgkin's Lymphoma (HL) - ~50% are EBV+, mainly mixed and lymphocyte depleted types
    3. Non-Hodgkin's Lymphoma (NHL) of various types
    4. Burkitt Lymphoma - aggressive B cell type NHL (~20% of Americans with BL are EBV+)
    5. Granulomatous Lymphoma (T Cell) - associated / Lymphomatoid Granulomatosis
    6. AIDS Associated Lymphoproliferative Disease
    7. Post-Transplantation Lymphoproliferative Disease (PTLD) [16] - see below
    8. EBV may also be associated with gastric carcinoma
  3. EBV in Immunosuppressed Hosts
    1. EBV infection greatly increases risk for morbidity and malignancy in immunosuppression
    2. Congenital or acquired lymphoproliferative immunodeficiency
    3. Includes severe combined immunodeficiency, ataxia-telangiectasia
    4. Stem cell transplantation (PTLD)
    5. Immunosuppressive drugs (as in solid organ transplantation)
    6. HIV Infection and AIDS
  4. EBV and Human Immunodeficiency Virus (HIV)
    1. AIDS Associated Lymphoproliferative Disease
    2. Oral Hairy Leukoplakia - white, corrogated lesions on oral mucosa
    3. Lymphoid interstitial pneumonitis
    4. Non-Hodgkin's Lymphoma (NHL) - >50% of NHL tumors in HIV+ persons are EBV+
    5. These NHL tumors are classified as Burkitts or Immunoblastic
    6. Nearly all CNS lymphomas in HIV+ patients are EBV+ (immunoblastic)
    7. Greatly increases risk of HIV-associated malignancy in HIV+ children [18]
  5. Multiple Sclerosis (MS) [14]
    1. Antibodies (Abs0 to components of Epstein-Barr Virus (EBV) associated with MS
    2. EBNA-2 Abs highest association (~4.0X increased risk for MS)
    3. EBNA-1 Abs 2.5X increased risk for MS
    4. VCA Abs 1.6X increased risk for MS
    5. High titers of VCA or EBNA Abs associated with >15X increased MS risk [17]
    6. Children with MS ~2X more likely to have EBV Abs than unaffected children [20]
  6. Lymphomatoid Granulomatosis [5,23]
    1. Continuum of abnormal lymphocyte diseases from benign to malignant
    2. Strongly associated with Epstein Barr Virus (EBV) transformation of B lymphocytes
    3. Reactive T lymphocytes ± eosinophils may be present in large numbers
    4. Necrotic granulomas of lungs, skin, CNS, and kidneys
    5. May act as benign diseases or as highly malignant lymphomas
    6. Strong male predisposition
    7. Multiple lung nodules and cavitary lesions frequently occur
    8. Lymphadopathy not usually seen; may be mistaken for sarcoidosis
    9. Minority will spontaneously resolve; most progress to aggressive lymphomas
    10. Combination chemotherapy for severe and aggressive disease, usually with rituximab
    11. Rituximab (Rituxan®), anti-CD20 mAb, has shown good efficacy
    12. Interferon alpha (IFNa) has shown efficacy ~67% in moderate to severe disease
  7. Immune Dysregulation
  8. Chronic Fatigue Syndrome (CFS)
    1. High prevalence of EBV positive serology in patients with CFS
    2. However, majority of normal population has EBV antibodies
    3. There is currently no good evidence that EBV plays a role in CFS

C. Infectious Mononucleosis [8,9]navigator

  1. Major cause of fatigue, fevere, sore throat, lymphadenopathy in young persons
  2. Splenomegaly, malaise, headache occur in ~50% of patients
  3. Later Stages
    1. Pharyngeal exudates seen later in disease
    2. Presence of atypical lymphocytes usually later in disease
  4. Symptoms are usually less pronounced in patients >35 years of age
  5. Liver Effects
    1. Liver function test abnormalities - usually AST / ALT increases (hepatitis)
    2. Consider in differential of acute or subacute or viral hepatitis
    3. Hepatic enlargement can occur
    4. Acute worsening with alcohol use
  6. Severe symptoms [3]
    1. Painful splenomegaly - may progress to splenic rupture
    2. Hemolytic anemia
    3. Thrombocytopenia
    4. Increasing pharyngeal edema may progress to airway compromise
  7. Atypical Lymphocytes
    1. Abnormal (CTL, NK-like) T cells in blood
    2. Polyclonal proliferation with peripheral lymphocyte counts usually >4000/µL
    3. These are the mononuclear cells for which the disease is named
    4. Most are enlarged, increased basophilia and cytoplasm
  8. Differential Diagnosis of Mononucleosis
    1. EBV is the most common by far
    2. Toxoplasmosis
    3. Cytomegalovirus (CMV)
    4. Human herpesvirus 6
    5. HIV
  9. Serological tests are required for confirmation of diagnosis [12]
    1. Heterophile antibodies (Monospot Test) is used for initial diagnosis
    2. 90% of patients with mononucleosis have heterophile antibodies
    3. 10% of patients are heterophile negative
    4. Of heterophile negative mononucleosis, EBV causes 40% of cases
    5. CMV causes 40%, HHV-6 25%, Toxoplasma 6% of heterophile negative mononucleosis
  10. Any patient with fever of unknown origin should be evaluated for EBV
  11. Glucocorticoids should be given for ANY of the severe symptoms
  12. Association of Mononucleosis with HL [2,19]
    1. Infectious mononucleosis associated with 4X increased risk of EBV+ HL
    2. No increase in EBV negative HL following infectious mononucleosis

D. Oral Hairy Leukoplakia (OHL) navigator

  1. Non-neoplastic condition caused by lytic replication of EBV in oral epithelium
  2. Usually in HIV infected persons, some
  3. Sometimes mistaken for candida infection, but white lesions of OHL do not scrape off
  4. May be a precursor lesion for squamous cell carcinoma of head and neck
  5. May respond to acyclovir

E. Role in Neoplasia [2] navigator

  1. African Burkitt's Lymphoma (high grade)
  2. Nasopharyngeal Carcinoma
    1. Particularly anaplastic type
    2. Certain anti-EBV responses are associated with highly increased risk [13]
  3. Also strongly associated with nasal NK-T cell lymphoma
  4. Lymphoproliferative Disease in Immunosuppressed Persons [6,22]
    1. PTLD
    2. Non-Hodgkin lymphomas in immunosuppressed patients
    3. Common in HIV and organ transplantation
    4. Occurs in ~5% of pediatric heart transplant patients
    5. Multiagent chemotherapy, radiation ± antiviral agents have been used
    6. Usually requires reduction in immunosuppressive therapy
  5. Smooth Muscle Tumors
    1. EBV associated with these tumors (Leiomyosarcomas) in children with liver transplants
    2. Tumors containued clonal EBV genes
    3. Leimyosarcomas associated with EBV occur in children with AIDS
    4. No apparent role of EBV in HIV-negative patients with leiomyomas / leiomyosarcomas
  6. Gene Expression in Tumors [2]
    1. EBV Lymphoproliferative Disease - EBNA-1 and -2, LMP-1 and -2
    2. Burkitt Lymphoma (NHL form) - EBNA-1 only
    3. Nasopharyngeal Carcinoma - EBNA-1, LMP-1 and -2
    4. Hodgkin's Lymphoma - EBNA-1, LMP-1 and -2
    5. Peripheral T Cell Lymphoma - EBNA-1, LMP-1 and -2

F. Diagnosisnavigator

  1. Heterophile Antibody Test
    1. Most commonly used diagnostic test when suspicious of EBV
    2. Detects anti-animal RBC antibodies (called heterophile antibodies)
    3. The test is nonspecific but fairly sensitive
  2. Other serologies may be used to confirm test or study neoplastic EBV derived cells
  3. EBNA-1 (Epstein-Barr Nuclear Antigen 1)
    1. Usually requires many weaks after infection to become positive
    2. Appears important for cell alterations, possibly neoplastic induction
    3. Antibodies (Abs) generally remain detectable for many years
  4. VCA (Viral Capsid Antigens)
    1. Both IgM (early) and IgG (later, secondary) Abs can be detected
    2. IgM requires 2-3 weeks in primary infection to become positive
    3. IgG is strongly positive on reactivation of EBV (as in immunosuppressed)
    4. IgA is a risk factor for nasopharyngeal carcinoma development [13]
    5. Neutralizing anti-EBV DNAse Abs are also a risk for nasopharyngeal carcinoma [13]
    6. Presence of both IgA anti-VCA and neutralizing DNAse Abs carries 32X increased risk for nasopharyngeal ca [13]
  5. Early Antigens
    1. Diffuse (EA-D) and Restricted (EA-R) Abs can be detected
    2. Provide mainly confirmatory results for suspected infection
  6. Easiest method for detection is analysis of blood smear
    1. Main peripheral blood anomalies are seen in T cells
    2. Bizzarre appearing CD8+ T lymphocytes (large, mononuclear cells) are found on smear
    3. EBV causes B cell hyperproliferation generally restricted to lymph nodes
    4. This can appear as a pseudolymphoma on lymph node biopsy
  7. Evaluate any case of fever of unknown origin for EBV infection [9]

G. Serological Responses to EBV InfectionnavigatorTable: Serologic Responses to EBV Infection

Host StatusHeterophileIgM-VCAIgG-VCAEA-DEA-REBNA-1
Uninfectednegnegnegnegnegneg
Primary Infectionpos1:32-2561:160-640posnegweak
Recent Primary Infectionvariableneg-1:32high posposneg1:5-10
Remote Infectionnegneg1:40-160negweak1:10-40
Reactivation-immunosuppressednegneghigh posnegposvariable

H. Treatment navigator
  1. Mononucleosis
    1. Supportive therapy in most cases
    2. Glucocorticoids for severe disease
    3. Airway compromise - patients should be carefully monitored AND all treated
    4. Splenic Enlargement - usually with thrombocytopenia, concern for rupture
    5. Splenectomy may be indicated in resistant mononucleosis
    6. Very high dose acyclovir or valacyclovir may be of some benefit in severe disease
  2. Glucocorticoids
    1. Indicated for patients with severe mononucleosis
    2. Swallowing difficulty
    3. Airway compromise or concern for impending compromise
    4. Generally initiate prednisone 40-60mg po qd x 2-3 days with taper over 1-2 weeks
    5. For swallowing problems, IV methylprednisolone may be given initially
    6. Generous short-term use of glucocorticoids is strongly advocated in symptomatic patients
  3. Neoplastic and pre-neoplastic syndromes may respond to antiviral agents
  4. Reducing or eliminating immunosuppression can sometimes cause tumor regression
  5. EBV Lymphoproliferative Disease [1]
    1. Reduce immunosuppressive regimen
    2. Irradiation of localized lesions may be helpful
    3. Acyclovir or ganciclovir (usually given intravenously first)
    4. Interferon alpha
    5. Hydroxyurea - eradicates extrachromsoomal DNA elements, has been effective [10]
    6. Monoclonal antibodies to CD21 (EBV receptor) and CD24 (pan B cell Ab)
    7. Monoclonal antibody to CD20 (rituximab)
    8. Bone marrow / stem cell transplantation
    9. Donor derived, EBV specific cytotoxic T cells
    10. Partly HLA-matched allogeneic cytoxic T cell lines [15]
  6. EBV Levels in Nasopharyngeal Carcinoma [21]
    1. Plasma EBV levels detectable in >90% of patients with advanced nasopharyngeal cancers
    2. Patients with persistently detectable plasma EBV levels had worse overall prognosis than those with undetectable levels one week after completion of radiotherapy

References navigator

  1. Cohen JI. 2000. NEJM. 343(7):481 abstract
  2. Thorley-Lawson DA and Gross A. 2004. NEJM. 350(13):1328 abstract
  3. Greene WL and Craft J. 1997. Lancet. 349:696 (Case Report) abstract
  4. Diepstra A, Niens M, vellenga E, et al. 2005. Lancet. 365(9478):2216 abstract
  5. Hochberg EP, Gilman MD, Hasserjian RP. 2006. NEJM. 354(23):2485 (Case Record) abstract
  6. Stone RM, Mark EJ, Ferry JA. 1997. NEJM. 337(15):1065
  7. Liebowitz D. 1998. NEJM. 338(20):1413 abstract
  8. Auwaerter PG. 1999. JAMA. 281(5):454 (Case Discussion) abstract
  9. Borer A, Gilad J, Haikin H, et al. 1999. Am J Med. 107(2):144 abstract
  10. Slobod KS, Taylor GH, Sandlund JT, et al. 2000. Lancet. 356(9240):1493 abstract
  11. Caligaris-Cappio F. 2001. Lancet. 358(9275):49 abstract
  12. Tsaparas YF, Gribdeen ML, Mathias R, et al. 2000. Arch Pathol Lab Med. 124:1324 abstract
  13. Chien YC, Chen JY, Liu MY, et al. 2001. NEJM. 345(26):1877 abstract
  14. Ascherio A, Munger KL, Lennette ET, et al. 2001. JAMA. 286(24):3083 abstract
  15. Haque T, Wilkie GM, Taylor C, et al. 2002. Lancet. 360(9331):436 abstract
  16. Timms JM, Bell A, Flavell JR, et al. 2003. Lancet. 361(9353):217 abstract
  17. Levin LI, Munger KL, Rubertone MV, et al. 2003. JAMA. 289(12):1533 abstract
  18. Pollock BH, Jenson BH, Leach CT, et al. 2003. JAMA. 289(18):2393 abstract
  19. Hjalgrim H, Askling J, Rostgaard K, et al. 2003. NEJM. 349(14):1324 abstract
  20. Alotaibi S, Kennedy J, Tellier R, et al. 2004. JAMA. 291(15):1875 abstract
  21. Lin JC, Wang WY, Chen KY, et al. 2004. NEJM. 350(24):2461 abstract
  22. Webber SA, Naftel DC, Fricker FJ, et al. 2006. Lancet. 367(9506):232 abstract
  23. Calfee CS, Shah SJ, Wolters PJ, et al. 2007. NEJM. 356(5):504 (Case Discussion) abstract