• The classic triad of acute infectious mononucleosis consists of fever, lymphadenopathy, and pharyngitis.
• The diagnosis of infectious mononucleosis is usually based on the clinical picture, the presence of at least 10% atypical lymphocytes in the peripheral blood, and positive heterophil serology.
• In most patients, infectious mononucleosis is self-limited and requires only symptomatic treatment.
• Steroids and antiviral therapy have no place in the therapy of uncomplicated acute infectious mononucleosis in healthy persons.
Epidemiology and Risk Factors
One must distinguish between the epidemiology of Epstein-Barr virus (EBV) infection and that of infectious mononucleosis (IM), the most common symptomatic manifestation of primary EBV infection.
Almost all adults have been infected with EBV. The symptomatology of primary EBV infection varies with the infected person’s age at the time, with younger children usually having inapparent or mild infections. In developing countries and in lower socioeconomic groups in industrialized nations, up to 90% of children acquire primary EBV infection by 6 years of age, and IM almost never develops. In contrast, in higher socioeconomic groups, only 40% to 50% of adolescents have previously experienced EBV infection. From 10% to 20% of susceptible adolescents and adults contract EBV every year thereafter, with IM developing in a significant fraction of these patients.
Saliva is the main vehicle for transmission of EBV, a double-stranded DNA herpesvirus. Transmission usually requires direct and prolonged contact with infected oropharyngeal secretions, with salivary exchange being the main mode of transmission. The infection begins with viral replication in oropharyngeal epithelial cells and then spreads to local B lymphocytes, which then disseminate throughout the reticuloendothelial system and induce vigorous T- and NK-cell responses and neutralizing antibodies. The atypical lymphocytes that are produced are mainly suppressor T cells directed against EBV- infected B cells.
It is thought that most of the clinical manifestations of IM are due to these T- and NK-cell responses, which might explain why young children, whose immune responses are incompletely developed, are usually asymptomatic with primary EBV infection. All EBV- seropositive persons shed virus intermittently throughout their lives. EBV may rarely be spread via blood transfusion or transplantation.
IM is usually an acute, self-limited, benign lymphoproliferative disease. EBV is responsible for nearly all heterophil-positive and most heterophil-negative cases. Other causes of heterophil-negative mononucleosis include cytomegalovirus, toxoplasmosis, hepatitis A and B, adenovirus, HIV, rubella, and human herpesvirus 6.
The classic triad of IM consists of fever, lymphadenopathy, and pharyngitis. Other typical findings include lymphocytosis with atypical lymphocytes and the presence of heterophil antibodies. After a 4- to 6-week incubation period, the illness begins with a 3- to 5-day prodrome of malaise, headache, and fatigue, typically followed in about half of all cases by onset of the triad. Additional symptoms can include anorexia, nausea, vomiting, periorbital or facial edema, and generalized lymphadenopathy, which is usually symmetrical.
Splenomegaly occurs by the second or third week of illness in about half of all cases; rarely, splenic rupture can occur and may be fatal. Hepatomegaly occurs in 10% to 15%, with hepatitis occurring in about 5% of cases. Up to 20% of patients have a rash that may be erythematous, maculopapular, morbilliform, scarlatiniform, or urticarial, especially if ampicillin or one of its derivatives has been given. Other symptoms can include arthritis and jaundice.
IM is a self-limited disease in nearly all patients. Median illness duration is 16 days.
The diagnosis is usually based on the clinical picture, atypical lymphocytosis, and positive heterophil serology. Most adolescents and young adults with IM have most or all of these features, as well as an abnormal white blood cell count with a relative lymphocytosis.
Atypical lymphocytes generally represent more than 9% to 10% of the white blood cell count. Many infected persons also have mild thrombocytopenia and elevated hepatocellular enzymes. Heterophil antibody positivity is usually measured as a positive monospot test. If IM is suspected and heterophil antibodies are negative, specific titers for EBV, including viral capsid antigen (VCA), early antigen (EA), and Epstein–Barr nuclear antigen (EBNA), should be obtained, as well as serologic testing for cytomegalovirus (CMV) and toxoplasmosis.
Acute EBV infection is characterized by the presence of IgM and IgG VCA antibodies and EA antibodies and the absence of EBNA antibodies.
If liver chemistries are markedly elevated and antibodies against EBV, CMV, and toxoplasmosis are unrevealing, serology for hepatitis A, B, and C should be measured. If risk factors are present, HIV antibodies should be checked. A throat culture is indicated in patients with pharyngitis or tonsillitis because the tonsillitis of acute IM can be indistinguishable from that of group A streptococcal pharyngitis.
In most patients, IM is self-limited and requires only symptomatic treatment, including bed rest, acetaminophen (Tylenol, 10–15 mg/kg every 4–6 hours), aspirin (10–15 mg/kg every 4–6 hours), or nonsteroidal antiinflammatory agents such as ibuprofen (Advil, 5– 10 mg/kg every 6–8 hours). Saline gargles can be useful in treating a sore throat. In severe cases, meperidine (Demerol, 1–1.5 mg/kg every 3–4 hours) may be required.
Although a short, tapering course of corticosteroid therapy (e.g., 2 mg/kg of prednisone1 for 5 days, 1 mg/kg for 5 days, and then 0.5 mg/kg for 5 days) is often prescribed, there is little evidence for its clinical efficacy, and caution is warranted. Infection is ultimately self- limited in nearly all cases, and rare reports of neurologic or septicemic complications after steroid use have appeared. Long-term immune responses following steroid use appear to be normal. Corticosteroid therapy should, however, be considered for the treatment of severe cases of IM associated with hemolysis, respiratory embarrassment, or thrombocytopenic purpura. The use of corticosteroids in atypical or antibody-negative cases is inappropriate because the diagnosis of lymphoma can then be confounded.
Parenteral administration of acyclovir1 (Zovirax, 10–20 mg/kg IV every 8 hours) to patients with acute IM secondary to EBV reduces the level of oropharyngeal viral replication; however, replication returns to the previously high levels after cessation of treatment, little or no reduction is seen in the number of EBV-infected B cells in the peripheral circulation, and the drug has little or no effect on the clinical course. Acyclovir administered in high doses orally1 (20 mg/kg, maximum dose of 800 mg qid for 5 days) is also ineffective. Antiviral therapy is therefore not recommended for acute IM in a normal host.
In immunosuppressed or severely ill patients, however, specific therapy has a role in many cases. For example, etoposide (VePesid),1 a drug that reduces macrophage activation, is often used in cases of infection-associated hemophagocytic syndrome. In posttransplant lymphoproliferative disorders, first-line therapy is often a reduction in immunosuppression; other options include rituximab1 (Rituxan, 375 mg/m2 IV weekly for 4 weeks). Oral leukoplakia in patients with AIDS responds to oral acyclovir1 (20 mg/kg, maximum dose of 800 mg qid for 20 days), whereas a tapering course of steroids (as recommended earlier) may be used for lymphocytic interstitial pneumonitis (see below).
Quarantine is not indicated. Ampicillin and related drugs should be avoided when treating secondary bacterial complications because of their association with rash in persons with IM. Contact sports should be avoided as long as splenomegaly is still evident because of the rare possibility of splenic rupture, which usually occurs within 3 weeks of onset of IM but has been reported as late as 7 weeks into the illness.
Complications of acute IM can be neurologic (seizures, cranial nerve palsies, aseptic meningitis, encephalitis, optic neuritis, transverse myelitis, infectious polyneuritis [Guillain-Barré syndrome], psychosis, Alice in Wonderland syndrome, or acute cerebellar ataxia), hematologic (hemolytic or aplastic anemia, thrombocytopenic purpura, agranulocytosis, or agammaglobulinemia), cardiac (pericarditis or myocarditis), pulmonary (cough or atypical pneumonia), renal (glomerulonephritis, acute kidney failure, or acute interstitial nephritis), or ophthalmologic (conjunctivitis) in nature. In about 10% of adolescents and young adults, fatigue can persist for 6 months or longer, and many of these patients meet the criteria for chronic fatigue syndrome.
Rare patients have very high titers of EBV antibodies, and a chronic active EBV infection associated with unusual clinical manifestations such as uveitis or lymphoma can occur. EBV is also associated with lymphoproliferative disorders in persons with underlying abnormal immune responses. These include X-linked lymphoproliferative syndrome, in which affected males usually die of acute EBV infection, and the related infection-associated hemophagocytic syndrome, which is most commonly (about 75% of the time) triggered by EBV and seems to be due to an overly exuberant macrophage response to EBV- infected lymphocytes. Transplant recipients can acquire EBV- associated lymphoproliferative disease that can range from an asymptomatic infection to fatal IM or lymphoma. Patients with AIDS are susceptible to several serious complications of EBV infection, including lymphocytic interstitial pneumonitis, oral leukoplakia, leiomyosarcoma, and lymphoma.
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2. Cohen J.I., Jaffe E.S., Dale J.K., et al. Characterization and treatment of chronic active Epstein–Barr virus disease: A 28- year experience in the United States. Blood. 2011;117:5835– 5849.
3. Katz B.Z. Commentary on “Steroids for symptom control in infectious mononucleosis (Review)” by B Candy and M Hotopf. Evid Based Child Health. 2012;7:447–449.
4. Katz B.Z., Shiraishi Y., Mears C.J., et al. Chronic fatigue syndrome following infectious mononucleosis in adolescents. Pediatrics. 2009;124:189–193.
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7. Soltys K., Green M. Posttransplant lymphoproliferative disease. Pediatr Infect Dis J. 2005;24:1107–1108.
1 Not FDA approved for this indication.