EPSTEIN-BARR INFECTION/MONONUCLEOSIS
Melissa Mattison, M.D.
October 10, 2002
HISTORY
First described in 1889 and called “glandular fever.” In 1921, the term infectious mononucleosis
(IM) was coined by Sprunt and Evans who described 6 cases of fever and adenopathy with
associated lymphocytosis and atypical appearing cells. In 1932, the serum of patients with similar
symptoms was found to aggluninate the red cells of sheep (“heterophile antibodies”). These
heterophile Ab are IgM antibodies directed at sheep or horse RBC’s and make up the basis for
the Monospot test.
EPIDEMIOLOGY
EBV is a ubiquitous herpes virus that has infected 90% of all humans, 25-50% of people by age 4
Primary EBV infection is usually sub-clinical, particularly in young children, however, if it occurs in
teenagers or young adults, often a more protracted syndrome results, with the peak incidence of
IM in ages 15-24.
Symptomatic reactivation of EBV infection can occur in immunocompromised or
immunosuppressed patients.
PATHOGENESIS
It is transmitted via intimate contact with saliva (“kissing disease”).
Incubation period is 30-50 days from the time of infection to the appearance of symptoms.
EBV is a dsDNA virus that encodes for 100 proteins. EBV receptors are found on the
nasopharyngeal epithelium, the cervix and B lymphocytes.
The major viral envelope glycoprotein gp350 binds to a viral receptor (CD21) on the
surface of the B cell. MHC Class affects the ability of the virus to bind. Patients with Xlinked agammaglobulinemia lack mature B cells and their B cells cannot be infected by the
virus.
The virus infects epithelial cells, replicates and lyses the cell. Viral shedding can occur
for up to 18 months following recovery of the clinical syndrome. The virus, when in B cells
results in production of “latent EBV proteins” that upregulate growth factors (oncogenes)
and prevent cell death.
The clinical syndrome is felt due to the body’s lymphocytic response to the virus, not viral
replication itself.
Infection leads to both humoral and cellular immunity to the virus. The antibodies produced are
useful for diagnosis of infection, but the cellular immune response is critical for the control of EBV
infection.
CLINICAL MANIFESTATIONS
Classic Triad: Fever, pharyngitis, adenopathy
Other symptoms include: sore throat, malaise, h/a, myalgias, nausea.
Signs of infection: LAD (particularly posterior cervical, though can see ant. Cervical, axillary and
inguinal), pharyngitis, fever, HSM, palatel enanthem, rash, jaundice, erythema nodosum (rare)
Complications: hemolytic anemia, thrombocytopenia, granulocytopenia, aplastic anemia,
hemophagocytic syndrome, encephalitis, Guillian-Barre, Bell’s palsy, optic neuritis, myocarditis,
pericarditis, hepatitis, larygotonsilar obstruction, pneumonia, pleuritis, ampicillin-associated rash,
leukocytoclastic vasculitis, acrocyanosis, interstitial nephrtitis, glomerulonephritis, Reye’s
syndrome, splenic rupture
Older patients (40-78 yo) commonly have fevers, myalgias and pharyngitis without
lymphadenopathy.
Beth Israel Deaconess Medical Center Interns’ Report
Hemolytic anemia: 0.5-3% of all patients with acute EBV. Most are cold-agglutinins. Hemolysis
develops during the second to third week of the illness and can last 1-2 months.
Splenic Rupture: occurs b/c lymphocytic infiltration of the spleen weakens its structural integrity
and the organ is growing rapidly. Fortunately, this complication is rare. Contact sports are to be
avoided. Note, spontaneous rupture is as common as traumatic rupture in the setting of acute
EBV infection.
DIAGOSIS
WBC – increased number of peripheral mononuclear cells and atypical lymphocytes. The atypical
lymphocytes are mainly T-cells responding to EBV-infected B cells.
Heterophile Antibodies, also called Paul-Bunnell antibodies, detected by the Monospot test:
present in 90% of patients at some point in their illness. Can be negative initially and turn
positive. Stays positive for 9 mo to 1 year. 95% sensitive, 93% specific. Delayed appearance
can be associated with longer convalescence.
EBV-specific Antibodies
EB-VCA-IgM (viral capsid antigen) – highly sensitive and specific for acute IM, persist for
4-8 weeks.
EB-VCA-IgG – persist for life and used as an epidemiolgic tool.
EB-NA –EBV nuclear antigen – appears 3 wks after infection, peaks at 8 weeks and stays
positive for life.
EB-NA-IgG seen 6-12 wks after the onset of symptoms, positive results early in course of
infectious illness rules out acute EBV as the cause. Stays positive for life.
DIFFERENTIAL DIAGNOSIS
In sero-negative syndrome, consider acute CMV, HIV, hepatitis and toxoplasmosis infection.
TREATMENT
Largely supportive and non-specific (fluids, analgesics, NSAIDs).
Various antivirals (acyclovir, gancyclovir, alpha-interferon) have all been tried but none has shown
clinical benefit
Corticosteroids are indicated when impending airway compromise is possible, there is severe
thrombocytopenia or hemolytic anemia.
CANCERS ASSOCIATED WITH EBV
Nasopharyngeal carcinoma – particularly in southern China, northern Africa and the Alaskan
Eskimo population. Approx 100% of poorly differentiated nasopharyngeal carcinoma contain the
EBV genomes and express EBV proteins.
Burkitt’s Lymphoma: high-grade malignant lymphoma of small, non-cleaved B cells. In equatorial
Africa, it’s associated with Plasmodium falciparum malaria. The malarial infection is thought to
inhibit the T-cells ability to control the proliferating EBV infected B cells. Contain a chromosomal
translocation resulting in up-regulation of the c-myc gene and increased tumorigenicity of the
cells.
Hodgkin’s Disease: EBV DNA is found in 40-60% of tumor in patient’s with HD in the USA.
Lymphoproliferative Disease: associated with EBV in patients with immunodeficiency.
EBV AND HIV
Patients with AIDS have 10-20x more circulating infected B cells than healthy persons.
They are prone to developing:
Oral Hairy Leukoplakia
Lymphoid Instersitial Pneumonia (particularly children with AIDS)
Non-Hodgkin’s Lymphoma
Virtually all primary CNS lymphoma in patients with HIV contain EBV DNA
Beth Israel Deaconess Medical Center Interns’ Report