Epstein-Barr virus

Background

Microbiology

• 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

Epidemiology

• 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

Pathophysiology

• 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

Childhood

• 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

Complications

• 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

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

Diagnosis

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

Serology

• 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
–	–	–	Susceptible
		+	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

Disease	VCA-IgM	VCA-IgG	VCA-IgA	EA(D)-IgG	EA(R)-IgG	EA-IgA	EBNA-IgG
Chronic active infection	±	++	±	+	++	–	±
Burkitt lymphoma	–	++	–	±	++	–	+
ENT carcinoma	–	++	+	++	±	+	+
Hodgkin lymphoma	–	++	–	+	–	–	+
Reactivation	±	++	±	+	±	±	±

PCR

• Useful for diagnosis of:
  • Rare, chronic active Epstein-Barr virus disease
  • Early post-transplant lymphoproliferative disease
  • Nasopharyngeal carcinoma
• As well as monitoring response to treatment