++
The Epstein-Barr virus (EBV) is recognized as the major cause
of heterophil-positive and heterophil-negative infectious mononucleosis.
Manifestations of EBV infection are varied and range from asymptomatic
infection to fulminant lymphoproliferative disease. The virus is
associated with a number of malignancies, including African Burkitt
lymphoma, nasopharyngeal carcinoma, Hodgkin disease, and a spectrum
of posttransplant lymphoproliferative diseases. The specific role
of EBV in each tumor is now defined, in a number of circumstances,
to the level of specific cell type and receptors, intracellular
pathways, gene expression, and cytokine production.
++
It is important to recognize that acute primary Epstein-Barr
virus (EBV) infection is not synonymous with infectious mononucleosis.
Most EBV infections acquired at any age, but particularly during
childhood, are asymptomatic. Seroepidemiologic studies demonstrate
that from 20% to 100% of children worldwide have
antibodies to EBV by 6 years of age.9 In contrast,
in the United States, only 40% to 50% of adolescents
are seropositive,9-11 with higher socioeconomic
groups being less likely to have evidence of prior infection. Seropositivity
increases with age in all populations, so that almost all adults have
serologic evidence of past EBV infection. Seroconversion is particularly
high in college, where 10% to 15% of susceptible
persons become infected each year. This group of EBV-naive adolescents
in industrialized countries is susceptible to develop EBV-associated
IM, much more common in the United States and Western Europe than
in unindustrialized countries.
++
EBV is excreted in oropharyngeal secretions (low titer of virus
even during acute illness) and is transmitted by contact with saliva
via kissing or other mucosal contact with contaminated objects.12 Healthy
seropositive individuals intermittently shed EBV into their oropharynx.
Blood products or transplanted tissues can transmit EBV and are
particularly problematic for seronegative immunocompromised transplant
recipients. There is no evidence of urinary or fecal excretion.
Transplacental transmission appears to be rare. Shedding of virus
appears to be more frequent in immunosuppressed individuals, 60% of
whom may excrete EBV at any one time. Because virus shedding is
of a low titer in even immunocompromised patients, standard precautions
are adequate for isolation of patients with acute or past EBV infections.12
++
The epidemiology of infectious mononucleosis is closely related
to the age of primary EBV infection. In the United States, the incidence
of infectious mononucleosis is approximately 50 per 100,000 persons
per year, but in individuals 15 to 25 years old, the incidence doubles.13 Those
areas where children are infected at an early age have the lowest
incidence of the disease. Among susceptible adolescents and young adults,
studies measuring both apparent and inapparent EBV infections indicate
a clinical-to-subclinical ratio of 1:2 to 1:3. Although the ratio of
clinical-to-subclinical infections in young children is not well
defined, the incidence of the typical infectious mononucleosis syndrome
is low.
++
Epstein-Barr virus (EBV) is a member of the family Herpesviridae (gamma
herpesvirus), which contains linear double-stranded DNA surrounded
by a protein capsid with 162 capsomers in an icosahedral arrangement.1 The
nucleocapsid is covered by a lipid-containing envelope derived from
the nuclear membrane of the host cell. EBV causes lytic infection
of human oropharyngeal and salivary cells, and latent infection
of human and primate B lymphocytes and epithelium of the nasopharynx.2 This
virus has been long recognized to be lymphotropic for B lymphocytes
and to infect both oropharyngeal epithelial cells and myocytes,
but it has also been recognized that it infects T lymphocytes, natural killer
(NK) cells,3,4 and monocytes, which may serve as
an early site for viral replication.5
++
Infection of lymphocytes with EBV can transform them into continuously
growing lymphoblastoid cell lines containing circular genome as
a plasmid. Once infected, transformed lymphoblastoid cells rarely
continue to produce infectious virus in vitro, although EBV-induced antigens
can be detected in the cells. The appearance of new antigens on
the cell surface of EBV-infected cells is believed to be responsible
for the cellular immune response to the virus and for the pathogenesis
of the disease produced.6-8 The EBV receptor on
epithelial cells and B lymphocytes is the CD21 molecule (formerly
CR2), which is also the receptor for the C3d fragment of the third
component of complement. The virus elicits both humoral and cellular
immune responses.
++
Epstein-Barr virus (EBV) acquired by ingestion appears to first
infect oropharyngeal epithelial cells. Subsequently, the virus infects susceptible
B lymphocytes within the lymphoid tissue of the pharynx. During
a 30- to 50-day incubation period, virus actively replicates and
disseminates throughout the entire lymphoreticular system.14
++
Cell-mediated immune function is essential in the control of
and recovery from EBV infection. In EBV infectious mononucleosis,
the initial infection of B lymphocytes is followed by an extensive
proliferation of suppressor cytoxic T lymphocytes (CD8+ positive). These
T cells are cytotoxic against EBV-infected lymphoid cells and prevent
their proliferation. Associated with the increase in these cytotoxic
and suppressor cytotoxic T cells is a concomitant decrease in the
number of T-helper/inducer cells (CD4+-positive
lymphocytes), resulting in an inversion of the CD4:CD8 ratio. Fatal
infectious mononucleosis and lymphoproliferative disorders, in which
B-cell lymphomas develop, have been identified in adults and children
with such cell-mediated immune defects, and, in particular, in their
natural killer (NK) cell activity. Groups identified as developing
this progressive B-immunoblastic disorder include kidney, heart,
and bone marrow transplant recipients and individuals with X-linked
lymphoproliferative syndrome, severe combined immunodeficiency syndrome,
AIDS, ataxia-telangiectasia, and certain autoimmune diseases.
++
More recently, EBV has been demonstrated to infect T cells or
NK cells to cause unique systemic lymphoproliferative diseases such
as EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH),
as well as chronic active EBV (CAEBV) infection, clinical features
of which are distinct from the tumor-forming diseases outlined previously.3,4 Systemic
EBV-related lymphoproliferative disease (LPD) is now classified
into B-cell LPD and T/NK-cell LPD. The former causes fulminant
infectious mononucleosis, whereas the latter causes EBV-HLH and
CAEBV.
+++
Clinical Manifestations
+++
Infectious Mononucleosis
++
The incubation period of infectious mononucleosis syndrome is
30 to 50 days. The clinical syndrome of infectious mononucleosis
is usually preceded by a 3- to 5-day prodrome of malaise, fatigue,
headache, nausea, or abdominal pain.15 Over the
next 7 to 20 days, sore throat and fever gradually increase. The
triad of fever, sore throat, and posterior cervical adenopathy occurs
in more than 80% of patients. Sore throat is often accompanied
by evidence of moderate-to-severe pharyngitis, with marked tonsillar
enlargement that may be covered with shaggy gray or white exudates. On
rare occasions, the tonsillar and peritonsillar swelling can result
in airway obstruction. Fine petechiae may cover the uvula and soft
palate during the initial week of illness. Throat cultures are positive
for group A β-hemolytic streptococci in about 30% of
patients, which may confuse the correct diagnosis of Epstein-Barr
virus (EBV) mononucleosis.2,15,16 Fever is present in
85% to 95% of patients, from 39°C (102°F) up to
40.5°C (105°F), and on average lasts 10 days, but may persist for
weeks.2
++
However, fever may persist for weeks in some patients with infectious
mononucleosis. Adenopathy most often involves only the bilateral
posterior cervical nodes but can involve any nodes, but the anterior
cervical and epitrochlear nodes may also be enlarged, or there may
be generalized adenopathy. The nodes are affected singly or in
groups (not necessarily symmetrically) and may be very large or
small (the size of grapes); they are most often firm, discrete,
and moderately tender to palpation. Splenomegaly, with the spleen
palpable 2 to 3 cm below the costal margin beyond the neonatal period,
occurs in about 50% of infections.17 Massive
splenomegaly may occur. Rupture is rare but can be a potentially
fatal complication. Hepatomegaly occurs in 10% to 30% of
patients, but less than 5% of patients develop jaundice.
Serum aspartate aminotransferase (AST) and serum lactate dehydrogenase
(LDH) are mildly elevated in the majority of patients and may persist
for weeks to months. Chronic liver disease, however, does not typically
result.
++
Other clinical findings include bilateral supraorbital edema
and rashes. A blanching, erythematous, maculopapular exanthema occurs
in about 5% to 15% of patients, but as many as
80% develop this rash if treated with ampicillin or other
beta-lactam antibiotics (Fig. 311-1). The
same rash may occur with cytomegalovirus (CMV)-associated mononucleosis and
so does not differentiate CMV- from EBV-associated mononucleosis.
Urticarial, bullous, hemorrhagic, and scarlatiniform rashes, as
well as the Gianotti-Crosti syndrome, are also associated with infectious
mononucleosis.
++
++
Neurologic complications include aseptic meningitis, encephalitis,
optic neuritis, Guillain-Barré syndrome, transverse myelitis,
Bell palsy, and, in numerous more recent epidemiologic studies,
multiple sclerosis following EBV-associated infectious mononucleosis.18 An
autoimmune hemolytic anemia occurs in 0.5% to 3% of infectious
mononucleosis patients and is usually mediated by antibodies against
the “i” antigen. A mild thrombocytopenia below
140,000 platelets/μL, but with absence
of profound thrombocytopenia or bleeding, occurs in approximately 50% of
patients. Granulocytopenia, or thrombocytopenia may occur
during the acute illness or in the immediate recovery period. Respiratory
and cardiac complications include interstitial pneumonia, laryngeal
obstruction, pharyngeal edema, myocarditis, and pericarditis.
++
In young children, infection with EBV does not usually present
with typical infectious mononucleosis as described for adolescents
in developed countries. Children younger than 4 years are more likely
to exhibit rashes and hepatosplenomegaly. Failure to thrive, otitis media,
abdominal pain, and recurrent pharyngitis are also more common in
young children. Involvement of the hematopoietic system or the central
nervous system, or the occurrence of prolonged fever, may be the
primary or only manifestation of acute EBV infection in this population.
In children and adults, EBV infection may be followed by persistent
pharyngitis, lymphadenopathy, fever, headaches, arthralgia, fatigue,
and psychoneurosis. Theories, yet unproven, about the role of EBV
in causing these persistent signs and symptoms include infection
followed by perturbation of the cytokine cascade, coinfection with
other pathogens, or an epigenetic phenomenon.
+++
EBV Infection
in Young Children
++
Infection with EBV usually does not present in children younger
than 4 years of age with the symptoms and signs of typical infectious mononucleosis
as described for adolescents in developed countries above. When
infected, younger children are more likely to exhibit rashes and
hepatosplenomegaly. Failure to thrive, otitis media, abdominal pain,
and recurrent pharyngitis are also more common in young children.
Involvement of the hematopoietic system or the central nervous system,
or the occurrence of prolonged fever, may be the primary or only
manifestation of acute EBV infection in this population. In children
and adults, EBV infection may be followed by persistent pharyngitis,
lymphadenopathy, fever, headaches, arthralgia, fatigue, and psychoneurosis.
+++
Other EBV-Related
Disorders
++
Oral hairy leukoplakia of the tongue is a benign EBV-associated
lesion commonly found in HIV-infected persons, and it is associated
with few or no symptoms. Oral hairy leukoplakia is the only lesion
presently known to arise as a direct consequence of the replication
of the linear genome of EBV. The X-linked lymphoproliferative syndrome
(Duncan disease or Purtilo syndrome) manifests as fatal EBV infection
in males in particular families or sporadically in girls and boys
with no family history.19 In these individuals,
EBV infection is usually fatal and is associated with either a lymphoproliferative
response, such as fatal mononucleosis, lymphoma, hemophagocytic syndrome,
and B-cell immunoblastic sarcoma (seen in 75% of cases),
or with an aproliferative response such as agammaglobulinemia, aplastic
anemia, agranulocytosis, recurrent bacterial infections, and late
malignancies (seen in 25% of cases). Alternatively, although
an immunocompromised status is suspected in the development of EBV-associated
hemophagocytic lymphohistiocytosis (EBV-HLH), the exact characteristics
of host vulnerability are largely unknown. The majority
of EBV-HLH cases occur in apparently immunocompetent children. Based
on the current diagnostic guidelines from the Histiocyte Society, patients
diagnosed with EBV-HLH should fulfill at least five of the following
eight criteria: fever, splenomegaly, cytopenia of at least two cell
lines, hypertriglyceridemia/hypofibrinogenemia, hemophagocytosis,
low/absent natural killer (NK)-cell activity, hyperferritinemia,
and high soluble IL-2 receptor.20 EBV is also associated
with a number of malignant disorders, including nasopharyngeal carcinoma,
Burkitt lymphoma, leiomyosarcoma in immunocompromised patients,
and, to a lesser extent, Hodgkin lymphoma (40% of Hodgkin disease
in the developed world and as much as 80% of cases in the
developing world).14
++
The diagnosis of Epstein-Barr virus (EBV)-associated infectious
mononucleosis (IM) in an immunocompetent child or adolescent
is based on clinical manifestations, characteristic blood abnormalities, and
positive heterophil or EBV antibodies. By the second week of infection,
the relative and absolute numbers of lymphocytes increase, with
at least 10% to 20% atypical cells. Early in the
disease, the atypical cells, or Downey cells, are both B and T lymphocytes
(Fig. 311-2). The atypical lymphocyte, or
Downey cell, has a higher cytoplasm-to-nucleus ratio than a normal
lymphocyte. The nucleus has coarse chromatin, and nucleoli are occasionally
seen; the cytoplasm is more basophilic and vacuolated than normal. By
early convalescence, the majority of the atypical lymphocytes are cytotoxic
suppressor cytotoxic T cells (CD8+). The
total leukocyte count is usually 10,000 to 20,000 cells/μL,
but may be as high as 50,000 cells/μL.
The leukocyte abnormalities may persist for 4 to 8 weeks.
++
++
The heterophil test detects the presence of antibodies induced
by the virus that are directed against EBV-specific antigens, as
well as to nonspecific heterophil antigens (polyclonal B-cell stimulation),
which cross-react with sheep and horse red-cell agglutinins. Heterophil
antibodies are present in as many as 90% of EBV-associated
IM in children older than 4 years. The titer reported is the highest
serum dilution at which sheep or horse erythrocytes agglutinate after
serum absorption with guinea pig kidney cells. Such absorption decreases
interference (false positives) caused by Forssman antibodies and
by antibodies that are associated with serum sickness. The antibodies
detected by the Paul Bunnell or monospot tests agglutinate antibodies
to equine and ovine erythrocytes and are directed to no known EBV
antigens. These IgM antibodies usually appear during the first
or, more commonly, the second or third week of illness and become
undetectable by 1 year in about 25% of individuals, when
using the horse red-cell agglutination test, and in 70% when
using sheep red-cell agglutinins. A number of rapid spot kits for
detecting heterophil antibodies (using equine or ovine erythrocytes)
are now available commercially. The correlation between results
obtained by the spot and slide tests and the classic tube heterophil
test is usually excellent. False-positive monospot tests have occasionally been
reported in patients with lymphoma, pancreatitis, mumps, or hepatitis.
False-negative tests occur most frequently in children younger than
4 years or in older children tested in the first 2 weeks of illness.
Following infection with EBV, only 5% to 10% of
children younger than 2 years have positive heterophil antibodies,
in contrast to as many as 50% of children between 2 and
4 years of age.
++
In older children, the most common cause of heterophile-negative
infectious mononucleosis is still the EBV infection. CMV is the
second most common cause of heterophil-negative mononucleosis (Chapter 310). Streptococcus pyogenes pharyngitis,
hepatitis A and B, acute toxoplasmosis, rubella, and enteroviral
infection may each result in fever, lymphadenopathy, malaise, atypical
lymphocytosis, and rash. Throat cultures are positive for group
A β-hemolytic streptococci in about 30% of
patients, which may confuse the correct diagnosis of EBV. Hematologic
abnormalities seen in infectious mononucleosis such as lymphadenopathy,
and splenomegaly associated with infectious mononucleosis may suggest
the possibility of lymphoma or acute lymphocytic leukemia. The heterophil
test may be helpful in differentiation. Bone marrow should be examined
in any individual who has a lymphoproliferative disease without
evidence of infectious mononucleosis.
++
The availability of sensitive and specific EBV antibody tests
has enabled more accurate diagnosis of EBV infection. Antibodies
detected by indirect immunofluorescence include IgG and IgM antibody
to viral capsid antigen (IgG-VCA and IgM-VCA); antibodies to early
antigens (EAs), which consist of either a diffuse pattern (antigen
present diffusely in cytoplasm and membrane), anti-D, or a restricted
pattern (antigen restricted to cytoplasm only), anti-R; and IgG
antibody to Epstein-Barr virus nuclear antigen (EBNA). IgG antibodies
to VCA are present in almost 100% of patients during the
acute phase of infectious mononucleosis. Similarly, more than 95% of
patients with infectious mononucleosis will have demonstrable IgM-VCA
on presentation, and all will have detectable antibody if tested
at the appropriate time.13,21,22 Because IgM antibody
usually lasts only 2 to 3 months, occasionally the antibody response
may not be detected. Following recovery, IgG-VCA antibody remains
detectable throughout life. Antibodies to early antigens are present
in 70% to 80% of patients with acute IM. Because
these antibodies have a relatively similar time course to that of
IgM-VCA, they may not often add to the clinical interpretation of
acute, subacute, or past EBV infection. That being said, EA may sometimes
be useful because these antibodies may persist for 3 to 6 months
after infectious mononucleosis (as opposed to 2-3 months of IgM-VCA)
and may be very elevated in patients with Burkitt lymphoma or chronic
active EBV (CAEBV). IgG antibodies to EBNA appear late in the course
of infectious mononucleosis and remain detectable for life. Therefore,
when antibody to EBNA is absent in the presence of other EBV-specific
antibodies, recent infection is likely. Table
311-1 and Figure 311-3 summarize these
patterns.
++
++
++
Qualitative and quantitative EBV polymerase chain reaction of
whole blood or plasma may be used to aid in the diagnosis of EBV
infection and disease in patients with primary or acquired immune
deficiency or in patients with systemic, severe EBV-associated diseases
such as overwhelming IM, hemophagocytic syndrome, or chronic active
EBV infection. DNA-DNA hybridization and testing for EBV RNA (electron beam
electro-reflectance [EBER]) can aid in detection
of EBV in histopathologic samples.
++
Currently, there is no specific antiviral therapy for Epstein-Barr
virus (EBV) infection. Symptomatic treatment with antipyretics may
be helpful. Although forced rest is neither helpful nor indicated,
contact sports or other activities that may result in abdominal
trauma should be avoided while the spleen is enlarged (usually 1-3
months). In some instances, vigorous examination of the abdomen
can result in splenic rupture. Caution should be used when examining the
abdomen of a child with suspected EBV-associated infectious mononucleosis.
Corticosteroids are not indicated for most patients but may be used
for potentially life-threatening complications, including airway
obstruction, neurologic complications, fulminant hepatitis, myocarditis,
pericarditis, thrombocytopenic purpura, or hemolytic anemia. A short
course of prednisone, 1 to 2 mg/kg/day given the
first day in divided doses and rapidly tapered over 7 to 10 days,
is usually sufficient, although longer courses may be necessary
to treat hemolytic anemia and certain neurologic complications.
++
Specific antiviral therapy has generally not been beneficial
in treating EBV infections. If group A β-hemolytic
streptococci are isolated from the throat, then appropriate antibiotic
therapy is indicated. Ampicillin and other beta-lactam antibiotics
should be avoided because of the high frequency of rashes associated
with their use during infectious mononucleosis. Acyclovir treatment
of patients with infectious mononucleosis results in interruption
of viral shedding in the throat, but has little clinical effect.
Similarly, prophylactic interferon-α decreases
the incidence of EBV shedding by kidney transplant recipients but
is not widely used for prophylaxis or treatment.
++
Lesions of oral hairy leukoplakia respond to oral or intravenous
acyclovir, but they frequently recur in patients with HIV infection after
treatment is discontinued. Aggressive, successful antiretroviral
therapy frequently causes remission of lesions of oral hairy leukoplakia without
specific therapy of EBV. Occasional remissions of polyclonal and monoclonal
tumors have been described in persons with lymphoproliferative disorders
treated with interferon-α and intravenous gamma
globulin.
++
Acyclovir is not helpful because it is active only on the lytic
phase of EBV and not on the latent phase of EBV occurring in the lymphoproliferative
conditions. Except for the rare occurrence of splenic rupture, severe
central nervous system complications, severe hematologic problems,
untreated respiratory compromise, or specific immunologic defects,
the prognosis for the patient infected with EBV is excellent. Complete recovery
is to be expected. During convalescence, some patients experience
marked fatigue, which occasionally persists for months after the acute
infection.