Source: Patient Care
By: Jeff Bytomski, DO, Elizabeth Rothschild, MMSc, PA-C, Tom Colletti, MPAS, PA-C
Originally published: January 1, 2006

JEFF BYTOMSKI, DO, Assistant Clinical Professor, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC.

ELIZABETH ROTHSCHILD, MMSc, PA-C, Clinical Associate, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC.

TOM COLLETTI, MPAS, PA-C, Assistant Clinical Professor, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC.

Infectious mononucleosis (IM), an infection caused by the Epstein-Barr virus (EBV), is a self-limiting disorder that is common in persons 10 to 30 years of age. Estimates are that more than 90% of adults worldwide have been infected with EBV.1 The diagnosis of IM is often made on the basis of characteristic clinical findings of fever, pharyngitis, lymphadenopathy, and positive findings on a heterophile antibody test. Negative findings on a heterophile test, however, warrant further serologic testing for antibodies to specific antigen complexes that help confirm the presence of the causative EBV and differentiate acute from past EBV infections. Negative EBV serologic findings should prompt consideration of other pathogens that cause similar symptoms. Chronic EBV infection is a rare diagnosis that requires a detailed history, serologic evaluation, and physical examination (see "EBV and the span of lasting infection").

The clinical syndrome now known as IM was first described as glandular fever in 1889 by German physicians, and the cause—infection with the herpesvirus EBV—was not identified until the 1960s.2 Like all herpesviruses, EBV becomes latent in the host; insufficient cellular immune responses may result in EBV-induced malignancy, such as B lymphoproliferative disease and Hodgkin's disease.3 Other forms of cancer associated with EBV include nasopharyngeal carcinoma and Burkitt's lymphoma.2

Epidemiology

Because current data is lacking, most of the epidemiologic data regarding IM are derived from studies done in the 1970s. The disease is commonly seen in older children and adolescents and is less common in those younger than 10 and older than 30. There is no apparent seasonal peak. The annual incidence in persons between 10 and 19 years of age is 6 to 8 cases per 1000, and among college students, the incidence is 11 to 48 cases per 1000.4 The risk of developing symptomatic infection is significantly lower in those older than 35.5

Primary infection with EBV often occurs subclinically during childhood, resulting in a latent infection of B lymphocytes. The virus is transmitted by direct salivary contact, which earned IM the moniker of "the kissing disease." Although EBV has been detected in genital secretions, sexual transmission has not been confirmed.2 No special precautions or isolation procedures are recommended in the care of patients with IM.6

Clinical presentation of acute IM

The incubation period for IM is 4 to 8 weeks.4 Following a prodrome of 3 to 5 days' duration, more than 50% of patients will have the classic triad of fever, exudative or nonexudative pharyngitis, and lymphadenopathy; patients may also complain of malaise, fatigue, and headache, with symptoms lasting 2 to 4 weeks.7,8 Lymphadenopathy is commonly seen in the posterior and anterior cervical chain and can also affect the axillary and inguinal nodes.9 Physical examination often reveals hepatosplenomegaly, palatal petechiae, and a characteristic erythematous scarletiniform rash, and Hoagland sign (bilateral transient upper eyelid edema) may be seen during the first several days of illness.1,7 Note that 90% of patients with acute IM develop an erythematous, maculopapular rash following administration of ampicillin.7 The virus is shed from the oropharynx for as long as 18 months after the acute infection and may continue to be shed intermittently for many years by 15% to 25% of healthy EBV-positive persons.9

Other causes of pharyngitis that must be ruled out include infections caused by group A beta-hemolytic streptococcus (GABHS), cytomegalovirus, adenovirus, and Toxoplasmosis gondii. Note that positive findings for GABHS on throat culture does not exclude IM; the patient may either be a strep carrier or may be one of the as many as 30% of patients with simultaneous GABHS and acute EBV infection.10 When a patient has positive GABHS findings on culture and does not improve with penicillin within 3 days, testing for IM is warranted.7

Diagnosis: Signs, symptoms, and serology

A presumptive diagnosis of acute IM can be made on the evidence of recent exposure to an infected contact and a constellation of characteristic symptoms and physical findings, none of which are diagnostic.

More than 90% of patients with IM have a total leukocyte count between 10,000 and 20,000 cells/µL.11 Hoagland's criteria for the diagnosis of IM include 50% lymphocytes, with at least 10% atypical lymphocytes in combination with fever, pharyngitis, lymphadenopathy, and a positive serologic test.12 Lymphocytosis peaks during the second or third week of illness, and a finding of a lymphocytosis of 10% to 20% supports the diagnosis.4

During the first week of infection, the false negative rate for the commonly used heterophile antibody test is 25%, compared with 10% during the second week, and 5% during the third week.4 Approximately 85% of adults develop heterophile antibodies, which are often absent in young children.2 Once the antibody response is established, subsequent tests may remain positive for 3 to 12 months.1

Owing to the long viral incubation period that allows for the detection of IgM and IgG to Epstein-Barr viral capsid antigen (VCA) early in the disease, IgM-VCA is the most specific and diagnostic serologic test for acute infection.3 IgM-VCA persists for approximately 2 to 3 months, whereas IgG-VCA, which appears at about 4 weeks after initial infection, persists for life.2,11 Early antigen titers are elevated in acute illness, peak during convalescence, remain detectable at low levels for several months, and persist for years thereafter. 11

EBV nuclear antigen (EBNA) antibodies appear 6 to 12 weeks after initial infection and are therefore not associated with acute infection, but their presence does indicate previous infection.13 Serology of a patient with acute EBV during the first month of infection would likely be positive for IgM-VCA and IgG-VCA and negative for EBNA.5 If the serologic results are IgG-VCA positive, EBNA either positive or negative, and IgM-VCA negative, then the patient was previously infected but does not have acute disease.

Assessing for splenomegaly and the risk of splenic rupture

Splenomegaly occurs in 50% to 60% of patients within the first 2 weeks of symptom onset, and usually begins to recede by the third week of infection.6,7 Recall that the normal spleen obeys the "rule of odds": 1 3 5 inches in size, weighing 7 oz [about 200 g], and lying between ribs 9 and 11.14 (A recent study showed that the mean splenic length of 10 cm increased by 0.1 cm for each 1-inch increase in height in women taller than 5 ft 6 inches [168 cm], while the mean splenic length of 11 cm increased by 0.2 cm for each inch taller than 6 ft [180 cm] in men.)15

For athletes with IM, strenuous activity or contact sports should not be resumed for an absolute minimum of 21 days after the onset of symptoms or the date of diagnosis. The 2 factors that govern the decision to return to play for athletes with IM are the risk of splenic rupture and resolution of the active illness. Return to action should not occur until there is no evidence of a palpable spleen, the acute illness has resolved, and laboratory values have normalized.16

Because splenomegaly is often difficult to detect by physical examination alone, imaging studies should be obtained following an equivocal exam at 21 days, or earlier for athletes eager to return to play.16-18 CT and ultrasound (US) are comparable in demonstrating splenomegaly, but US is less costly. 17 CT should be used, however, in patients with suspected splenic rupture, which most often occurs within 21 days of the onset of clinical symptoms—thus the 21-day absolute disqualification-from-play period. Athletes can resume training for sports after 21 days, taking precautions to avoid chest or abdominal trauma.5 Splenic rupture after the fourth week of symptom onset is rare.19,20

An equally important factor in returning the athlete to training and competition is the resolution of acute illness, as determined by clinical examination and serum laboratory tests. The patient should have no subjective complaints, and findings on physical examination should confirm that lymphadenopathy, pharyngitis, and hepatosplenomegaly have resolved. The results of laboratory studies—including the CBC, asparagine aminotransferase, ALT, and lactate dehydrogenase values—must be within the normal reference range before the patient resumes athletic training. Training should resume gradually, beginning at about half the pre-illness level of intensity and duration. It may take several months before the athlete achieves pre-illness performance.

Treatment—patience and support

Acute IM is a self-limited illness and most symptoms resolve within several weeks of onset. Treatment is supportive, including adequate hydration, nutrition, and rest. Acetaminophen (Tylenol) or NSAIDs may be used for fever, sore throat, and malaise, but aspirin should be avoided due to rare potential complications of splenic rupture or thrombocytopenia.4,5 Patient education regarding the natural history of IM, including its pathogenicity, incubation period, infectivity, and expected course of recovery, is an integral part of management.

In addition to the lack of evidence that corticosteroid use affects the duration of symptoms, concern about immunomodulation of the virus and the potential for malignancy argue against corticosteroid therapy for routine treatment of IM. Corticosteroids should, however, be considered in patients who have marked tonsillar hypertrophy, impending airway obstruction, or other severe complications.3,4,11

Antivirals have not been shown to be beneficial against IM, and their use is not recommended.3-5 Researchers have found that the combination of acyclovir and prednisolone decreased viral shedding, but no clinical improvement was noted.3

This article was contributed by Dr Bytomski, Ms Rothschild, and Mr Colletti and edited by Julia M. Russell.

The authors disclose that they have no financial relationships with any manufacturer in this area of medicine.

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