Epstein-Barr virus

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  • A member of the Gammaherpesvirinae subfamily within the Herpesviridae family
  • Double-stranded DNA inside an icosahedral protein nucleocapsid surrounded by a lipid envelope with glycoproteins
  • Two strains (type 1 and 2) are serologically identical, but have unique epitopes
  • Infection can remain quiescent in B cells for life


  • Acquired via oral secretions, e.g. by kissing or sharing of food
  • Seroprevalence about 90-95% in adults, with about half of 5 year-olds already being seropositive
    • Acquired earlier in low-income countries
  • Highest morbidity is with young adults who develop infectious mononucleosis during primary disease
    • Includes barracks and universities


  • Acquired through mucous membrane contact of oral secretions
  • Immune response primarily with cytotoxic T cells and NK cells
    • Atypical lymphocytosis develops from CD8 cells
  • Early response is against lytic antigens (including VCA and EA), and later response against latent proteins (EBNA1, EBNA2, EBNA3, and EBNALP)
  • Response also creates IgM antibodies to sheep, horse, and cow RBCs, called heterophile antibodies

Clinical Manifestations


  • In childhood, mostly asymptomatic or mild febrile illness
  • May develop rashes, neutropenia, or pneumonia
  • Can cause lymphadenopathy
  • Heterophile antibody may be negative if young; about 80% are positive by 4 years, though

Infectious Mononucleosis

  • Caused by primary infection, typically in an adolescent or young adult
  • EBV causes about 80% of mononucleosis, with the rest being CMV
  • Incubation period 30 to 50 days, and can have asymptomatic viral shedding for up to a month before symptoms
  • Symptoms include a triad of sore throat, fever, and lymphadenopathy (classically posterior cervical chain)
    • Often preceded by prodromal symptoms of chils, sweats, anorexia, and malaise
    • Can also have retro-orbital headaches, myalgias, and abdominal discomfort
    • May have a rash which can take any form, and may have palatal petechiae
    • Tonsils are sometimes exudative
    • Often has splenomegaly, may have hepatomegaly, and rarely has jaundice
  • With exposure to amoxicillin, almost all patients develop a diffuse maculopapular rash
  • May have transient heterophile antibodies (see Diagnosis, below), as well as atypical lymphocytosis
  • Resolves over 2 to 3 weeks, with fevers lasting up to 14 days, and fatigue lasting months


  • Linked to a number of malignancies, including Burkitt lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disorders
  • Neurologic complications include meningitis, encephalitis, Guillain-Barré syndromes, optic neuritis, retrobulber neuritis, cranial nerve palsies, mononeuritis multiplex, brachial plexus neuropathy, seizures, subacute sclerosing panencephalitis, transverse, myelitis, psychosis, demyelination, and hemiplegia

Chronic Active EBV Disease

  • See also Chronic active Epstein-Barr virus disease
  • Classically in Japan and east Asia, possibly South America
  • Progressive disease related to infection of NK or T cells rather than B cells
  • Poor prognosis, with patients dying of progressive pancytopenia, hypogammaglobulinemia, or NK/T cell nasal lymphoma within a few years

Oral Hairy Leukoplakia

EBV-Associated Malignancies

Disease EBV Risk factors
Lymphoproliferative disease 90% Transplantation patients and immunosuppression
Primary CNS lymphoma 100% HIV with low CD4 and immunosuppression
Hodgkin lymphoma 50% Children and young adults
Nasopharyngeal carcinoma 100% Southern Chinese, Inuit
Gastric cancer 4 to 100% Unknown
Endemic Burkitt lymphoma 95% African children
Sporadic Burkitt lymphoma 20% HIV independent of CD4


Point-of-Care Testing

  • Monospot latex agglutination looking for heterophile antibodies
    • 50% sensitive in the first week of illness, but up to 80-95% sensitive by the third week, and 98-100% specific, overall
    • Less sensitive (10-50%) in young children (<4 years; lowest in those less than 2 years), with much lower negative predictive power
    • Peak 2 to 5 weeks after symptom onset then usually decline quickly, but can persist for up to 6 to 12 months
    • False positives are rare but can happen with rheumatoid disease, SLE, leukemia, lymphoma, and other infections including malaria, HIV, CMV, rubella, viral hepatitis and tularemia, and after administration of anti-thymocyte globulin


  • Reviewed in 1
  • Anti-VCA (viral capsid antigens): most useful
    • Anti-VCA IgM: appears by presentation and disappears within 4 to 6 weeks; most useful with acute and convalescent
    • Anti-VCA IgG: appears in acute phase, peaks at 2 to 4 weeks, then declines but remains positive for life
  • Anti-EA (early antigen) IgG: appears in acute phase and falls to undetectable within 3 to 6 months (but may persist for years)
    • Least useful test
  • Anti-EBNA (EBV nuclear antigen): negative during acute phase converts after 2 to 4 months and stays positive for life

Immunocompetent Hosts

VCA-IgM VCA-IgG EBNA-IgG Interpretation
+ Past infection or non-specific
+ Acute or past infection
+ Past infection
+ Acute infection or non-specific
+ Uninterpretable
+ Acute infection
+ Late primary infection or reactivation

EBV-Associated Diseases

Chronic active infection ± ++ ± + ++ ±
Burkitt lymphoma ++ ± ++ +
ENT carcinoma ++ + ++ ± + +
Hodgkin lymphoma ++ + +
Reactivation ± ++ ± + ± ± ±



  1. ^  Massimo De Paschale. Serological diagnosis of Epstein-Barr virus infection: Problems and solutions. World Journal of Virology. 2012;1(1):31. doi:10.5501/wjv.v1.i1.31.