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Review
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Epstein-Barr Virus and Infectious Mononucleosis
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Mohammed
Rahman, MD
OBJECTIVES
Review
the Epstein-Barr virus and infectious mononucleosis including
general information, clinical presentation, diagnostic considerations,
as well as treatment and prognosis.
INTRODUCTION
Epstein-Barr
Virus (EBV) is a widely disseminated herpes virus almost
exclusively spread by contact with oral secretions. The
virus is frequently transmitted from asymptomatic adults
to infants and among young adults by transfer of saliva.
Transmission by less intimate contact is rare. EBV has also
been spread by blood transfusion and bone marrow transplantation.
Studies indicate that more than 90% of asymptomatic seropositive
individuals shed the virus in oropharyngeal secretions.
Infectious mononucleosis was first described in 1989 and
was called “Drusenfieber” or glandular fever1.
The term 'Infectious Mononucleosis' was coined in 1920 to
describe the febrile illness of six college students with
absolute lymphocytosis and atypical mononuclear cells in
the blood2.
VIROLOGY
AND PATHOGENESIS
EBV
belongs to the gamma-group herpes virus family. The EBV
genome consists of a linear 172 Kb double-stranded DNA that
was completely sequenced in 19843.
Much of the virology of EBV has come from genetic studies.
The EBV receptor on human cells is the B cell surface molecule
CD21, which is also the receptor for the C3d component of
complement. Infection is initiated by the interaction of
the major EBV outer envelope glycoprotein gp350/220 with
CD214.
Another small glycoprotein, gp 85, is a relatively small
virus protein that is involved in the fusion between the
virus and the cell membrane.
The
majority of EBV infections in humans are thought to originate
in the oropharynx. The oropharyngeal epithelial cells allow
permissive viral replication5,
however, EBV binds much less efficiently to epithelial cells
than to B cells. Once the virus penetrates the nasopharyngeal,
oropharyngeal and salivary epithelial cells, it spreads
into underlying lymphoid tissue, and more specifically to
the B-lymphocytes. Infection of B cells may take one of
two forms. In a minority of B cells there is a productive
infection that involves lysis of the infected cells and
the release of virions that re-infect oropharyngeal epithelium
and persist as a subclinical productive infection. Thus,
the agent is shed in the saliva. In most B cells, however,
the virus associates with the host cell genome giving rise
to a latent infection. B cells that harbor the EBV genome
undergo polyclonal activation and proliferation. The two
EBV proteins EBNA-2 (Epstein –Barr Virus Nuclear Antigen-2)
and LMP-1 (Latent Membrane Protein -1) are associated with
B cells6.
LMP-1 appears to act by binding to a host cell protein called
Tumor Necrosis Factor Receptor-Associated Factor, which
is involved in signal transduction and activation of B-lymphocytes.
The B cells then disseminate in the circulation and secrete
antibodies with several specificities, including well-known
heterophile anti-sheep red blood cell antibodies used for
the diagnosis of infectious mononucleosis.
Early
in the course of infection, IgM antibodies are formed against
viral capsid antigens and later, IgG antibodies, are formed
that persist for life. IgA antibodies prevent infection
of B cells but increase the infectivity of EBV for epithelial
cells7.
Cytotoxic CD8+ T cells and Natural Killer Cells are important
in controlling proliferation of polyclonal B cells. Interestingly,
a large number of activated T Cells with phenotypic attributes
of suppressor T Cells are also generated. Together with
virus specific cytotoxic T cells, these suppressor T cells
appear in the circulation as atypical lymphocytes (a characteristic
of this disease).
Latent
EBV remains in a few B cells as well as in the oropharyngeal
epithelial cells and is associated with the development
of Burkitt’s lymphoma and nasopharyngeal carcinoma.
CLINICAL
MANIFESTATIONS
Infectious
Mononucleosis (IM) classically presents with fever, sore
throat and lymphadenopathy. However, it may also present
with little or no fever, and only malaise, fatigue, and
lymphadenopathy. The incubation period for IM in young adults
is about 4 to 6 weeks. A prodrome of fatigue, malaise and
myalgias may last for 1 to 2 weeks before the onset of fever,
sore throat and lymphadenopathy. Fever is usually low grade
and most common in the first 2 weeks of illness, however,
it may persist for over a month. Lymphadenopathy and pharyngitis
are more prominent during the first 2 weeks, while splenomegaly
is more prominent during the 2nd and 3rd weeks. There is
a characteristic distribution of lymph nodes in IM, typically
symmetrical and involving the posterior cervical more than
the anterior chains. Lymhadenopathy may also include axillary
and inguinal areas. Pharyngitis may be accompanied by enlarged
tonsils with exudates resembling that of streptococcal pharyngitis.
A generalized maculopapular, urticarial, or petechial rash
is occasionally seen. A rash is more commonly seen following
administration of either ampicillin, amoxicillin, azithromycin,
levofloxacin, or cephalexin. The mechanism that causes the
rash is not clearly understood, but is believed to be due
to circulating antibodies to antibiotics. Patients may also
present with neurological symptoms and hematological abnormalities.
Symptomatic
IM is uncommon in infants and young children. Very non-specific
symptoms of IM are often noticed in elderly patients, including
prolonged fever, fatigue, myalgias, and malaise. However,
pharyngitis, lymphadenopathy, spleenomegaly, and atypical
lymphocytes are relatively rare in elderly patients.
DIAGNOSIS
Diagnosis
of Infectious Mononucleosis depends on the following findings
in the increasing order of specificity:
1)
Peripheral blood smear: Lymphocytosis with characteristic
atypical lymphocytes in the peripheral blood
2)
Heterophile antibodies: A positive heterophile reaction
(monospot test)
3)
EBV specific antibodies: Specific antibodies for EBV antigens
(Viral Capsid Antigens, Early Antigens, and Epstein-Barr
Nuclear Antigen)
COMPLICATIONS
In
general, most cases involving IM are self-limited. Deaths
are very rare and most of them are due to CNS complications
(e.g. meningitis, encephalitis), splenic rupture, upper
airway obstruction, or bacterial super infection.
DISEASES
OTHER THAN IM ASSOCIATED WITH EBV
1)
EBV-Associated Lymphoproliferative Disease
2) Oral Hairy Leukoplakia
3) Lymphomatoid Granulomatosis
4) EBV is associated with several malignancies (i) Burkitt’s
Lymphoma (ii) Hodgkin’s Disease, especially Mixed
-Cellularity type (iii) CNS Lymphomas and Non-Hodgkin’s
Lymphoma in AIDS patients.
TREATMENT
Therapy for IM rarely requires more than supportive measures,
rest, and analgesia. Excessive physical activity should
be avoided in the first month to reduce the possibility
of splenic rupture. If splenic rupture occurs, splenectomy
is required.
Glucocorticoid therapy is not indicated for uncomplicated
IM may, in fact, predispose to bacterial superinfection.
However, a trial of corticosteroids has been recommended
and used in individuals with airway obstruction due to severe
tonsillar hypertrophy, severe life threatening infection,
and for autoimmune hemolytic anemia and severe thrombocytopenia.
Antiviral
therapy:
Acyclovir works via inhibiting EBV-DNA Polymerase. Short-term
suppression of viral shedding has been demonstrated, but
significant clinical benefit is lacking compared to placebo8.
Acyclovir at a dose of 400 to 800 mg five times daily has
been effective for Oral Hairy Leukoplakia but relapses were
very common9.
Other
therapies:
Agents such as Interleukin-2, Interferon Alfa, and intravenous
immunoglogulin have been used in patients with EBV-associated
diseases but no clear benefits have been demonstrated at
this time. The only exception is for lymphomatoid granulomatosis
and for post-transplant lymphoproliferative disease10.
Active Immunization:
Isolation of patients with IM is unnecessary and the vaccines
directed against EBV glycoprotein gp350/220 have shown promise
in animal studies and are currently undergoing clinical
trials in China.
REFERENCES
- Evans,
AS. The history of infectious mononucleosis.
Am J Med Sci 1974; 267:189
- Sprunt,
TP, Evans, FA. Mononucleosis leukocytosis in
reaction to acute infections (Infectious Mononucleosis).
John Hopkins Hosp Bull 1920; 31: 409
- Baer,
R, Bankier, A, Biggin, M. et al. DNA sequence
and expression of the B95-8 Epstein-Barr virus genome.
Nature 1984; 310: 207
- Tanner,
J, Weis, J, Fearon, D. et al. Epstein-Barr virus
gp350/220 binding to the B lymphocyte C3d receptor mediates
adsorption, capping, and endocytosis. Cell 1987;
50: 203
- Li,
QX, Young, LS, Niedobitek, G. et al. Epstein-Barr
virus infection and replication in human epithelial cell
system. Nature 1992; 356: 347
- Izumi,
KM, Kaye, KM, Kieff, ED. The Epstein-Barr virus
LMP1 amino acid sequence that engages tumor nacrosis factor
receptor associated is critical for primary B lymphocyte
growth transformation. Proc Natl Acad Sci USA
1997; 94: 1447
- Sixbey,
JW, Yao, Q-Y. Immunoglobulin A-Induced shift
of Epstein-Barr virus tissue tropism. Science
1992; 255: 1578
- Torre,
D, Tambini, R. Acyclovir for treatment infectious
mononucleosis: a meta-analysis. Scand J Infect Dis
1999; 31: 543
- Tynell,
E, Aurelius, E, Brandell, A. et al. Acyclovir
and prednisone treatment of acute infectious mononucleosis:
A multicenter, double-blind, placebo-vontrolled study.
J Infect Dis 1996; 174: 324
- Wilson,
WH, Kingma, DW, Raffeld, M. et al. Association
of lymphomatoid granulomatosis with Epstein-Barr viral
infection of B lymphocytes and response to interferon-alpha
2b. Blood 1996; 87: 4531
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