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| Epstein Barr Virus. Source: CDC |
Author: Dr Paul Auwaerter Johns Hopkins University Baltimore 2008-07-19
Introduction
Infectious mononucleosis [IM] is a viral illness that most commonly
afflicts adolescents and young adults. IM causes fever, severe sore
throat, swollen lymph glands, and fatigue; it is caused by the
Epstein-Barr virus [EBV], a member of the human herpesvirus family that
occurs throughout the globe. At some point in their lives, most people
eventually become infected with EBV, but the age that EBV is acquired is
a significant determinant of whether IM may develop. When EBV infects
during childhood, most often it causes no symptoms or only minimal
problems that may appear like a routine viral infection. However, in
teenagers and adults, significant symptoms may arise in 35-70% of newly
infected. Why IM develops appears to be due to the variability of an
individual's immune response that can be more vigorous against EBV as
one ages. The precise explanations are unknown, but likely depend on
individual genetic factors directing the immune system as well as prior
encounters with infections that have molded the immune responses. Introduction
Sometimes referred to colloquially as "mono" or "kissing disease," the virus is believed to be usually acquired when it is shed in an infected person's saliva and then transmitted to an uninfected individual by actions including kissing or sharing objects such as cups or utensils. Once infected with EBV, the virus eventually becomes latent in certain cells within the body, which means that nobody is ever cured of the infection. For the vast majority, this latency dynamic produces no ill effect, but EBV may periodically reactivate without causing symptoms yet yield virus that can be shed in the saliva. Some recent study has suggested that the virus can also be spread by sexual contact; however, whether this occurs commonly is not yet well understood as it is difficult to separate oral from potentially genitally spread EBV[1]. Interestingly, infectious mononucleosis is uncommon in lower socioeconomic settings and less developed countries. This is believed to be due to poorer hygiene that exposes children to EBV at younger ages, so that by adolescence the virus is nearly universally acquired. Delayed acquisition of the virus is more common in richer, industrialized societies—hence why IM is sometimes referred to as a disease of the 20th century.
While EBV may cause infectious mononucleosis, the virus has also been associated with a number of benign and malignant tumors including Burkitt's lymphoma, and nasopharyngeal and gastric carcinomas. In people who have profoundly suppressed immune systems due to medications required for organ transplantation or human immunodeficiency virus (HIV) infection, EBV also appears responsible for lymphoproliferative disorders that resemble lymphoma. Within the last few years, investigators have uncovered an apparent association with infectious mononucleosis and Hodgkin's lymphoma. Studied in Denmark, it appears that individuals who had IM have for the following four years a forty-fold increased risk of developing Hodgkin's lymphoma, although some have questioned this finding[2, 3]. EBV has also been linked in several studies to increased risk of autoimmune disorders such as multiple sclerosis and systemic lupus erythematosus[4].
Clinical Illness
Infectious mononucleosis has a triad of three classical complaints:
sore throat, fever, and enlarged lymph glands in the neck. About 70% to
80% of all teenagers with IM have all three symptoms. Other symptoms
that may be often experienced include headache, profound fatigue,
increased sleepiness, loss of appetite, and muscle aches. However, IM
may also present without all three components, but instead with a
predominant symptom set. The most common presentation is the so-called
"pharyngeal" form. Typically, the sore throat may be the worst ever
experienced but does not also cause the typical fever or swollen lymph
nodes in the neck. Not uncommonly, the symptoms may be dismissed as a
routine viral illness, or prompt concern for a sore throat due to Group A
streptococcal infection ("strep throat"). People who experience this
form of IM usually seek medical attention because of the severity of
throat pain.
A second form of IM is the "glandular" type. In these situations, swollen lymph glands predominate and the sore throat or the fever is absent or less prominent. Individuals often do not feel overly ill. The nodes of concern may be in the neck or elsewhere in the body including under the arms or in the groin region. Often, the enlarged lymph nodes persist for more than a week or two which leads to worry that a malignancy such as lymphoma is afoot.
The third type is the "febrile" presentation. This is seen more commonly in older adults, such as those over 35 years of age, who experience significant fevers and fatigue often with evidence of abnormal liver function tests that may lead to an intial concern for hepatitis A, hepatitis B or hepatitis C viral infections. Sore throat and swollen lymph glands are typically absent, and patients may even be labeled as having an FUO (fever of unknown origin) by their physician[5].
Other findings often play a role in diagnostic considerations. Enlargement of the spleen, an organ located in the upper left quadrant of the abdomen, is found in more than half of people who have IM. This can occasionally cause some discomfort in the abdomen, but is usually only noted when a healthcare provider exams the abdomen. The liver may also be increased in size, although this is less common – as is jaundice where accumulation of bilirubin not properly metabolized by an ill liver causes a yellow complexion to the skin and eyes. A rash may be seen in up to 10% of patients with IM; however, for unknown reasons, a rash is seen in nearly 100% of people who are given amoxicillin for a suspected Group A Streptococcal pharyngitis, but who instead have IM. In fact, a rash arising after taking amoxicillin should always prompt consideration of IM.
Occasionally, primary EBV infection can cause unusual problems outside of the typical presentations of IM. There are too many to list for the purposes of this article, but some of the more important ones include hematological problems such as hemolytic anemia, wherein red blood cells break apart from an immune reaction stimulated by the EBV infection. Neurological problems from IM often do not begin until a month or more after the initial onset of symptoms. Conditions such as brain inflammation (encephalitis), spinal cord abnormalities (transverse myelitis), Guillain-Barré syndrome and visual disturbances due to optic neuritis are among the more commonly noted of these rare problems arising from IM. Other organs that are affected from time to time may also include the heart, the kidneys and, sometimes rarely fulminant liver disease.
A second form of IM is the "glandular" type. In these situations, swollen lymph glands predominate and the sore throat or the fever is absent or less prominent. Individuals often do not feel overly ill. The nodes of concern may be in the neck or elsewhere in the body including under the arms or in the groin region. Often, the enlarged lymph nodes persist for more than a week or two which leads to worry that a malignancy such as lymphoma is afoot.
The third type is the "febrile" presentation. This is seen more commonly in older adults, such as those over 35 years of age, who experience significant fevers and fatigue often with evidence of abnormal liver function tests that may lead to an intial concern for hepatitis A, hepatitis B or hepatitis C viral infections. Sore throat and swollen lymph glands are typically absent, and patients may even be labeled as having an FUO (fever of unknown origin) by their physician[5].
Other findings often play a role in diagnostic considerations. Enlargement of the spleen, an organ located in the upper left quadrant of the abdomen, is found in more than half of people who have IM. This can occasionally cause some discomfort in the abdomen, but is usually only noted when a healthcare provider exams the abdomen. The liver may also be increased in size, although this is less common – as is jaundice where accumulation of bilirubin not properly metabolized by an ill liver causes a yellow complexion to the skin and eyes. A rash may be seen in up to 10% of patients with IM; however, for unknown reasons, a rash is seen in nearly 100% of people who are given amoxicillin for a suspected Group A Streptococcal pharyngitis, but who instead have IM. In fact, a rash arising after taking amoxicillin should always prompt consideration of IM.
Occasionally, primary EBV infection can cause unusual problems outside of the typical presentations of IM. There are too many to list for the purposes of this article, but some of the more important ones include hematological problems such as hemolytic anemia, wherein red blood cells break apart from an immune reaction stimulated by the EBV infection. Neurological problems from IM often do not begin until a month or more after the initial onset of symptoms. Conditions such as brain inflammation (encephalitis), spinal cord abnormalities (transverse myelitis), Guillain-Barré syndrome and visual disturbances due to optic neuritis are among the more commonly noted of these rare problems arising from IM. Other organs that are affected from time to time may also include the heart, the kidneys and, sometimes rarely fulminant liver disease.
Other Diagnostic Considerations
Other problems that may be confused with IM, especially with a
predominant sore throat, include Group A streptococcal pharyngitis, or
pharyngitis due to other respiratory tract viruses or bacteria.
Although IM can only be caused by EBV, a mononucleosis-like syndrome can
arise from other infections. Among the most common causes includes
another virus in the human herpesvirus family, cytomegalovirus (CMV).
This virus accounts for a significant percentage of cases suspected to
be IM when tests do not prove acute EBV infection. CMV mononucleosis
typically causes less of a sore throat, but may yield prominent fatigue
and abnormal liver function tests. Another virus that is a leading cause
of a mono-like illness includes acute infection with the human
immunodeficiency virus (HIV). Risk factors for acquiring HIV infection
include using intravenous drugs and sharing needles or sexual contact
with an infected individual. Other less common reasons for causing an
illness that resembles features of mononucleosis include: the parasite
toxoplasmosis; viral infections including influenza, hepatitis virus A
or hepatitis virus B; rubella (German measles) or, finally; an adverse
drug reaction against a prescription medication.
Diagnosis
In order to secure a diagnosis of IM, lab tests must be ordered
usually in the context of anticipated symptoms [Box 1]. A standard
complete blood count test often shows an elevation in the total while
blood cell (WBC) count with 10-18,000 cells/ml. Lymphocytes comprise an
increased percentage than normal of the WBC population. A further
tip-off to IM may be indicated by the presence of atypical lymphocytes
that may account for 10-30% of the WBC count. In patients with a sore
throat, any liver function test abnormalities should bring to mind
whether IM may be the cause. These serum liver tests can include mild
elevations in the alanine transaminase (ALT), aspartate transaminase
(AST), and total bilirubin.
When
a typical set of symptoms occur in a teenager or young adult – fever,
sore throat and swollen glands – then a healthcare provider may be
confident of the diagnosis if a “Monospot™” is
found to be positive. A Monospot is a commercial test that takes
advantage of detecting so-called heterophile antibodies generated by the
acute EBV infection. Heterophile antibodies are unusual in that they
are generated by the body's immune system against foreign cells (such as
sheep or goat red blood cells) that are not actually present.
Approximately 85-90% of patients with IM have a positive Monospot test.
The percentage is lower in children. An initial negative test may be
repeated in a few days and then be positive. Despite rechecking, about
10% of people with IM never generate a positive Monospot assay. In these
individuals, specific antibody tests against components of the
Epstein-Barr virus offer a diagnosis [Box 2]. Although these specific
EBV antibody tests are more accurate, these results take a longer time
to return, hence why the Monospot remains preferred in the United States
as results are usually ready the same or the next day.
A typical profile of these EBV-specific antibodies that would indicate IM is as follows: positive IgM capsid antibody, positive IgG capsid antibody, and a negative EBNA antibody. The negative EBNA test is helpful as this particular antibody is only made when the virus establishes latency after acute infection (usually after six weeks of IM onset), hence the presence of EBNA antibodies suggests that actual EBV infection took place before the current symptom complex. These specific EBV antibody tests can sometime yield confusing results, and interpretation by a specialist well versed in their utility can be helpful in cases that are not straightforward.
A typical profile of these EBV-specific antibodies that would indicate IM is as follows: positive IgM capsid antibody, positive IgG capsid antibody, and a negative EBNA antibody. The negative EBNA test is helpful as this particular antibody is only made when the virus establishes latency after acute infection (usually after six weeks of IM onset), hence the presence of EBNA antibodies suggests that actual EBV infection took place before the current symptom complex. These specific EBV antibody tests can sometime yield confusing results, and interpretation by a specialist well versed in their utility can be helpful in cases that are not straightforward.
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Box 1 Typical symptoms and findings in adolescents and younger adults with infectious mononucleosis (adapted from [6, 7]) Common
Sore throat
Fever (over 99.5°F or 37.5°C)
Lymph gland enlargement (neck)
Fatigue
Less Common
Muscle aches
Abdominal pain
Jaundice
Painful joints
Lymph gland enlargement (other than neck)
Rash
Common physical findings
Enlarged lymph nodes
Enlarged spleen
Coating on tonsils
Common laboratory findings
Elevated white blood cell count
Elevated lymphocyte count
Circulating atypical lymphocytes (>10%)
Elevated liver function tests
Positive heterophile test (Monospot)
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Box 2 Interpretations of common patterns of EBV-specific antibody tests
|
EBV IgM Capsid
|
EBV IgG Capsid
|
EBNA
|
Comment
|
|
(-)
|
(-)
|
(-)
|
Susceptible to EBV infection
|
|
(+)
|
(+)
|
(-)
|
Acute EBV infection
|
|
(-)
|
(+)
|
(+)
|
Remote EBV infection, latency
|
Treatment
For the majority of previously healthy people, IM is an illness that
causes significant problems for a week, but within three to four weeks
most symptoms have completely resolved. Although fatigue may be
prominent, bed rest is not required although sleep requirements are
often increased. Perhaps the only study addressing this issue found that
patients with enforced bed rest had a slower recovery than those who
were allowed out of bed as soon as they felt able[8]. Non-strenuous
activities can be performed as tolerated. (Transmission concerns are
addressed below.)
Unfortunately, there are no specific drug treatments for IM. Several studies have examined the use of the antiviral medication acyclovir, but could find no clinical benefit[9]. Corticosteroids such as prednisone are sometimes used by practitioners to alleviate the sometime incapacitating fatigue or severe throat pain. Although studies are by no means comprehensive, there is little support for the use of corticosteroids in the routine treatment of IM, and concerns have been voiced that such routine use may predispose to abnormal immune responses to the virus or late complications such as neurological disease[10].
Between 10-20% of individuals with IM may also suffer from Group A streptococcal pharyngitis. This should be treated, but one should refrain from using amoxicillin because of the predictable precipitation of a rash. Importantly, this rash doesn't predict a true penicillin allergy, but rather is a consequence of deranged immunological reactions in the setting of IM.
Unfortunately, there are no specific drug treatments for IM. Several studies have examined the use of the antiviral medication acyclovir, but could find no clinical benefit[9]. Corticosteroids such as prednisone are sometimes used by practitioners to alleviate the sometime incapacitating fatigue or severe throat pain. Although studies are by no means comprehensive, there is little support for the use of corticosteroids in the routine treatment of IM, and concerns have been voiced that such routine use may predispose to abnormal immune responses to the virus or late complications such as neurological disease[10].
Between 10-20% of individuals with IM may also suffer from Group A streptococcal pharyngitis. This should be treated, but one should refrain from using amoxicillin because of the predictable precipitation of a rash. Importantly, this rash doesn't predict a true penicillin allergy, but rather is a consequence of deranged immunological reactions in the setting of IM.
Complications
Though
the symptoms are a bothersome and sometimes slow to resolve nuisance,
IM is usually an illness without immediately concerning features.
However, rarely the vigorous immune response can produce
life-threatening problems that demand immediate attention. There are too
many uncommon complications to fully enumerate, but below are the among
the most concerning problems.
· Splenic rupture:
The most feared complication arises most often during the first three
weeks of IM when a massively enlarged spleen either spontaneously
ruptures or rupture is provoked by trauma that would otherwise be
insignificant. Affecting at most 0.1-0.5% of patients, onset of severe
abdominal pain or severe left shoulder pain (referred pain from blood
irritating the diaphragmatic nerves) should demand urgent medical
attention. Death may occur from bleeding. Although emergency surgery to
remove the spleen has been routinely advocated, some ruptures have been
managed without surgery[11].
· Airway obstruction: Tonsillar
enlargement from EBV may be so significant as to close off the airway
resulting in death from asphyxiation. Any sore throat associated with
shortness of breath should lead to urgent medical attention.
Corticosteroids are used in this severe form of IM in an effort to
quickly shrink tonsillar tissue. Physicians may elect to place an airway
tube or even perform a tracheotomy to mechanically ventilate such
patients until it is again safe for them to breathe on their own.
· Hemolytic anemia:
Breakdown of red blood cells can be severe and result in dizziness, low
blood pressure and shortness of breath. Along with airway obstruction,
these are the two solid reasons why corticosteroids are used in IM.
· Severe fatigue: Although
fatigue commonly accompanies the acute symptoms of EBV, for most people
normal activities are resumed within three or four weeks. Significant
fatigue can persist in a minority of patients. Perhaps the best study on
this subject found prospectively that about 11% of individuals suffered
severe fatigue six months after illness onset[12]. Risk factors for
whom is more prone to developing this severe fatigue are not clear,
though female gender and pre-existing depression have been identified as
risk factors[13]. Why fatigue can be a significant problem for some is
not well understood, although some recent work has suggested that
following IM, abnormalities in control of the hypothalamic-pituitary
hormone axis or changes in mitochondrial function may play some role[14,
15]. There is little information on the best treatment for this
fatigue. Taking a leaf from chronic fatigue syndrome, some advocate
low-impact, aerobic conditioning along with cognitive behavioral therapy
as a strategies to help minimize bothersome symptoms[16]. Use of
antidepressant medication may yield benefit in some.
· Chronic EBV infection: True
chronic EBV infection is a rare occurrence that appears as relapsing
IM-like symptoms with generalized lymph node enlargement, abnormal liver
function tests, and enlarged liver and spleen size persisting for more
than 16 weeks. This entity is described more commonly in Japan, and
arguably may be within the spectrum of a lymphoproliferative
disorder[17]. This condition is easily differentiated from the
post-infectious fatigue problems of IM since large amounts of
Epstein-Barr virus may be detected in the blood by the polymerase chain
reaction (PCR) method.
Common Questions Regarding Infectious Mononucleosis and EBV
Can I catch infectious mononucleosis from my roommate or household member?Those living in the same dormitory room with a student diagnosed with IM were not found to be at risk for infection[18]. It would be prudent to not share utensils and cups without washing since infected saliva can transmit the infection.
How quickly can I return to playing sports?
Unfortunately there are no good studies that provide a sound basis for recommendations. The prime consideration is to reduce the potential for splenic rupture. If participating in non-contact sports, a gradual resumption of physical activities may begin after the third week. For players of contact sports (such as football, hockey, diving, etc.) or activities associated with increased intra-abdominal pressure (such as weightlifting), the general recommendation is to wait until the spleen has returned to normal size, usually by the fourth week after the onset of symptoms[6]. Since physical examination of the spleen is unreliable, many clinicians use an ultrasound to determine if the spleen has returned to normal for those who participate in high-impact sports. Sometimes, spleen size does not appear to return to normal. Studies of normal college student show a wide variation in the size of the spleen, including a proportion who have "enlarged" splenic measurements that may indeed be their norm based on height and weight. One recent study suggested that 7% of normal student athletes met criteria for spleen enlargement on ultrasound study[19]. This situation poses a conundrum for both the student athlete and the physician, although the latest that splenic rupture from IM has been reported is seven weeks after onset.
Can I get mononucleosis twice?
Infectious mononucleosis is only caused by the Epstein-Barr virus. Once infected, the virus settles into a latency state that becomes life-long. There is no convincing evidence that once infected with EBV, a second EBV infection can be acquired that produces IM. If somebody has what appears to be IM on more than one occasion, several possibilities arise. First, the original diagnosis of IM may have been incorrect. Second, an infection other than EBV has caused a mononucleosis-like syndrome such as one of the infections listed in the "Other Diagnostic Considerations" section (e.g., cytomegalovirus, HIV or toxoplasmosis). A third and perhaps most common reason is that after experiencing a full recovery from IM, some experience a relapse of fatigue sometimes accompanied by sore throat or swollen lymph glands. Rather than truly experiencing IM twice, for the first six or more months after IM, immune dynamics sometimes seem to precipitate a bout of fatigue that has characteristics similar to the original presentation. Although this is not well studied, these flares tend to be briefer than the original illness, and tend to dissipate over time with lessening frequency and severity.
Infectious mononucleosis is only caused by the Epstein-Barr virus. Once infected, the virus settles into a latency state that becomes life-long. There is no convincing evidence that once infected with EBV, a second EBV infection can be acquired that produces IM. If somebody has what appears to be IM on more than one occasion, several possibilities arise. First, the original diagnosis of IM may have been incorrect. Second, an infection other than EBV has caused a mononucleosis-like syndrome such as one of the infections listed in the "Other Diagnostic Considerations" section (e.g., cytomegalovirus, HIV or toxoplasmosis). A third and perhaps most common reason is that after experiencing a full recovery from IM, some experience a relapse of fatigue sometimes accompanied by sore throat or swollen lymph glands. Rather than truly experiencing IM twice, for the first six or more months after IM, immune dynamics sometimes seem to precipitate a bout of fatigue that has characteristics similar to the original presentation. Although this is not well studied, these flares tend to be briefer than the original illness, and tend to dissipate over time with lessening frequency and severity.
I always feel tired, should my healthcare provider check me for EBV?
In the 1980's, EBV was considered as a potential explanation for chronic fatigue syndrome (CFS). Although post-infectious fatigue can clearly linger after IM, it is by no means clear that EBV is responsible for CFS. EBV serologic titers are often markedly elevated in patients with CFS, but this may merely reflect some general immune activation rather than a causal role. In patients with chronic fatigue, EBV testing is not advised[20].
In the 1980's, EBV was considered as a potential explanation for chronic fatigue syndrome (CFS). Although post-infectious fatigue can clearly linger after IM, it is by no means clear that EBV is responsible for CFS. EBV serologic titers are often markedly elevated in patients with CFS, but this may merely reflect some general immune activation rather than a causal role. In patients with chronic fatigue, EBV testing is not advised[20].
A vaccine (recombinant gp350) has been used in a small trial that demonstrated protection for recipients against developing IM, but did not prevent acquisition of EBV infection on an asymptomatic basis[21]. Further study will be required to understand whether this approach is truly safe and efficacious.
Web Links
Medline Plus: http://www.nlm.nih.gov/medlineplus/infectiousmononucleosis.htmlCDC: http://www.cdc.gov/ncidod/diseases/ebv.htm
References
1. Higgins, C.D., et al., A study of risk factors for acquisition of Epstein-Barr virus and its subtypes. J Infect Dis, 2007. 195(4): p. 474-82.
2. Hjalgrim, H., et al., Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med, 2003. 349(14): p. 1324-32.
3. Meyer, R.M., R.F. Ambinder, and S. Stroobants, Hodgkin's lymphoma: evolving concepts with implications for practice. Hematology (Am Soc Hematol Educ Program), 2004: p. 184-202.
4. Auwaerter, P.G., Recent advances in the understanding of infectious mononucleosis: are prospects improved for treatment or control? Expert Rev Anti Infect Ther, 2006. 4(6): p. 1039-49.
5. Auwaerter, P.G., Infectious mononucleosis in middle age [clinical conference]. Jama, 1999. 281(5): p. 454-9.
6. Aronson, M.D., et al., Heterophil antibody in adults with sore throat: frequency and clinical presentation. Ann Intern Med, 1982. 96(4): p. 505-8.
7. Auwaerter, P.G., Infectious mononucleosis: return to play. Clin Sports Med, 2004. 23(3): p. 485-97, xi.
8. Dalrymple, W., Infectious Mononucleosis. 2. Relation of Bed Rest and Activity to Prognosis. Postgrad Med, 1964. 35: p. 345-9.
9. Torre, D. and R. Tambini, Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis, 1999. 31(6): p. 543-7.
10. Candy, B. and M. Hotopf, Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev, 2006. 3: p. CD004402.
11. Brichkov, I., et al., Nonoperative
management of spontaneous splenic rupture in infectious mononucleosis:
the role for emerging diagnostic and treatment modalities. Am Surg, 2006. 72(5): p. 401-4.
12. Hickie, I., et al., Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ, 2006. 333(7568): p. 575.
13. Petersen, I., et al., Risk and predictors of fatigue after infectious mononucleosis in a large primary-care cohort. Qjm, 2006. 99(1): p. 49-55.
14. Vernon, S.D., et al., Correlation of psycho-neuroendocrine-immune (PNI) gene expression with symptoms of acute infectious mononucleosis. Brain Res, 2006. 1068(1): p. 1-6.
15. Vernon, S.D., et al., Preliminary
evidence of mitochondrial dysfunction associated with post-infective
fatigue after acute infection with Epstein Barr virus. BMC Infect Dis, 2006. 6: p. 15.
16. Whiting, P., et al., Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA, 2001. 286(11): p. 1360-8.
17. Kimura, H., Pathogenesis
of chronic active Epstein-Barr virus infection: is this an infectious
disease, lymphoproliferative disorder, or immunodeficiency? Rev Med Virol, 2006. 16(4): p. 251-61.
18. Brodsky, A.L. and C.W. Heath, Jr., Infectious mononucleosis: epidemiologic patterns at United States colleges and universities. Am J Epidemiol, 1972. 96(2): p. 87-93.
19. Hosey, R.G., et al., Ultrasound assessment of spleen size in collegiate athletes. Br J Sports Med, 2006. 40(3): p. 251-4; discussion 251-4.
20. Straus, S.E., et al., NIH conference. Epstein-Barr virus infections: biology, pathogenesis, and management. Ann Intern Med, 1993. 118(1): p. 45-58.
21. Sokal, E.M., et al., Recombinant
gp350 vaccine for infectious mononucleosis: a phase 2, randomized,
double-blind, placebo-controlled trial to evaluate the safety,
immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy
young adults. J Infect Dis, 2007. 196(12): p. 1749-53.