Monday, April 9, 2012

Infectious Mononucleosis

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.

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.
 

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.
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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.

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.
 
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].
 
Is a vaccine available?

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.html

CDC: 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.