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Infectious Mononucleosis

by Kenneth M. Kaye, MD

Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or months. Severe complications, including airway obstruction, splenic rupture, and neurologic syndromes, occasionally occur. Diagnosis is clinical or with EBV serologic testing. Treatment is supportive.

EBV is a herpesvirus that infects 50% of children before age 5. Its host is humans.


After initial replication in the nasopharynx, the virus infects B cells. Morphologically abnormal (atypical) lymphocytes develop, mainly from CD8+ T cells that respond to the infection.

After primary infection, EBV remains within the host, primarily in B cells, for life and undergoes intermittent asymptomatic shedding from the oropharynx. The virus is detectable in oropharyngeal secretions of 15 to 25% of healthy EBV-seropositive adults. Shedding increases in frequency and titer in immunocompromised patients (eg, organ allograft recipients, HIV-infected people).

EBV has not been recovered from environmental sources and is not very contagious. Transmission may occur via transfusion of blood products but much more frequently occurs via kissing between an uninfected and an EBV-seropositive person who is shedding the virus asymptomatically. Only about 5% of patients acquire EBV from someone who has acute infection. Early childhood transmission occurs more frequently among lower socioeconomic groups and in crowded conditions.


EBV is statistically associated with and likely has a causal role in Burkitt lymphoma, certain B-cell tumors in immunocompromised patients, and nasopharyngeal carcinoma. EBV does not cause chronic fatigue syndrome. However, it may occasionally cause a syndrome of fever, interstitial pneumonitis, pancytopenia, and uveitis (ie, chronic active EBV).

Symptoms and Signs

In most young children, primary EBV infection is asymptomatic. Symptoms of infectious mononucleosis develop most often in older children and adults.

The incubation period is about 30 to 50 days. The triad of fever, pharyngitis, and adenopathy is present in most patients. Fatigue can last months but is usually maximal during the first 2 to 3 wk. Fever usually peaks in the afternoon or early evening, with a temperature around 39.5° C, although it may reach 40.5° C. Pharyngitis may be severe, painful, and exudative and may resemble streptococcal pharyngitis. Adenopathy is usually symmetric and may involve any group of nodes, particularly the anterior and posterior cervical chains. Adenopathy may be the only manifestation.

Splenomegaly, which occurs in about 50% of cases, is maximal during the 2nd and 3rd wk and usually results in only a barely palpable splenic tip. Mild hepatomegaly and hepatic percussion tenderness may occur. Patients may have periorbital edema and palatal petechiae. Less frequent findings include maculopapular eruptions and rarely jaundice.


Although recovery is usually complete, complications may be dramatic.

Neurologic complications are rare but may include encephalitis, seizures, Guillain-Barré syndrome, peripheral neuropathy, aseptic meningitis, myelitis, cranial nerve palsies, and psychosis. Encephalitis may manifest with cerebellar dysfunction, or it may be global and rapidly progressive, similar to herpes simplex encephalitis, but is usually self-limited.

Hematologic complications are usually self-limited. They include granulocytopenia, thrombocytopenia, and hemolytic anemia. Transient mild granulocytopenia or thrombocytopenia occurs in about 50% of patients; severe cases, associated with bacterial infection or bleeding, occur less frequently. Hemolytic anemia is often due to anti-i-specific antibodies.

Splenic rupture can have severe consequences. It can result from splenic enlargement and capsular swelling, which are maximal 10 to 21 days after presentation. A history of trauma is present only about half of the time. Rupture is usually painful but occasionally causes painless hypotension. Treatment is Splenic Injury : Treatment.

Respiratory complications include, rarely, upper airway obstruction due to pharyngeal or paratracheal lymphadenopathy; respiratory complications may respond to corticosteroids. Clinically silent interstitial pulmonary infiltrates occur mostly in children and are usually visible on x-rays.

Hepatic complications include elevated aminotransferase levels (about 2 to 3 times normal, returning to baseline over 3 to 4 wk); they occur in about 95% of patients. If jaundice or more severe enzyme elevations occur, other causes of hepatitis should be investigated.

Overwhelming infection with EBV occurs sporadically but may cluster in families, particularly those with X-linked lymphoproliferative syndrome (see also X-linked Lymphoproliferative Syndrome). Survivors of overwhelming primary EBV infection are at risk of developing agammaglobulinemia or lymphoma.


  • Heterophil antibody test

  • Sometimes EBV serologic testing

Infectious mononucleosis should be suspected in patients with typical symptoms and signs. Exudative pharyngitis, anterior cervical lymphadenopathy, and fever may be clinically indistinguishable from those caused by group A β-hemolytic streptococci. However, posterior cervical or generalized adenopathy or hepatosplenomegaly suggests infectious mononucleosis. Moreover, detection of streptococci in the oropharynx does not exclude infectious mononucleosis.

Primary HIV infection (see Human Immunodeficiency Virus (HIV)) can produce a clinical picture resembling acute EBV infection. If patients have risk factors for HIV infection, quantitative HIV RNA viral blood count, p24 antigen assay, and CD4 count, plus EBV serologic testing, should be done. HIV enzyme-linked immunosorbent assay (ELISA)/Western blot is usually negative during the acute infection and thus is not useful in early primary HIV infection.

Pearls & Pitfalls

  • Primary HIV infection can resemble acute EBV infection; patients with risk factors for HIV infection should be tested using quantitative HIV RNA viral count and p24 antigen assay (ELISA/Western blot tests are usually negative during acute HIV infection).

Cytomegalovirus (CMV) may cause a syndrome similar to infectious mononucleosis, with atypical lymphocytosis as well as hepatosplenomegaly and hepatitis but usually not with severe pharyngitis. Toxoplasmosis, hepatitis B, rubella, or atypical lymphocytes associated with adverse drug reactions can also cause infectious mononucleosis–like syndromes. These syndromes can usually be distinguished by their other clinical features or by specific testing.

Laboratory diagnosis usually involves a CBC and EBV serologic testing. Lymphocytes that are morphologically atypical account for up to 30% of the WBCs. Although individual lymphocytes may resemble leukemic lymphocytes, lymphocytes are heterogeneous, which is unlikely in leukemia. Atypical lymphocytes may also be present in HIV or CMV infection, hepatitis B, influenza B, rubella, or other viral illnesses, so diagnosis requires serologic testing. However, very high atypical lymphocyte counts are typically seen only in primary EBV and CMV infection. Two serologic tests are used to diagnose acute EBV infection: heterophil antibody testing and specific EBV antibody testing.

Heterophil antibodies are measured using various card-agglutination (monospot) tests. However, heterophil antibodies are present in only 50% of patients <5 yr and in about 80 to 90% of adolescents and adults. Importantly, the heterophil antibody test may be false-positive in some patients with acute HIV infection. The titer and prevalence of heterophil antibodies rise during the 2nd and 3rd wk of illness. Thus, if the diagnosis is strongly suspected but the heterophil antibody test is negative, repeating the test after 7 to 10 days of symptoms is reasonable. If the test remains negative, antibodies to EBV should be measured. The presence of IgM antibodies to the EBV viral capsid antigen (VCA) indicates primary EBV infection (these antibodies disappear within 3 mo after infection). EBV VCA-IgG antibodies develop later (perhaps after 8 wk) in acute EBV infection and persist for life. If EBV antibody titers are negative or indicate remote infection (ie, positive for IgG antibodies and negative for IgM antibodies), other diagnoses (eg, acute HIV infection, CMV infection) should be considered.


Infectious mononucleosis is usually self-limited. Duration of illness varies; the acute phase lasts about 2 wk. Generally, 20% of patients can return to school or work within 1 wk, and 50% within 2 wk. Fatigue may persist for several more weeks or, in 1 to 2% of cases, for months. Death occurs in < 1%, mostly resulting from complications (eg, encephalitis, splenic rupture, airway obstruction).


  • Supportive care

  • Corticosteroids possibly helpful for severe disease

Treatment is supportive. Patients are encouraged to rest during the acute phase but can resume activity when fever, pharyngitis, and malaise abate. To prevent splenic rupture, patients should avoid heavy lifting and contact sports for 1 mo after presentation and until splenomegaly (which can be monitored by ultrasonography) resolves.

Although corticosteroids hasten defervescence and relieve pharyngitis, they generally should not be used in uncomplicated disease. Corticosteroids can be helpful for complications such as impending airway obstruction, severe thrombocytopenia, and hemolytic anemia. Although oral or IV acyclovir decreases oropharyngeal shedding of EBV, there is no convincing evidence to warrant its clinical use.

Key Points

  • EBV infection is very common; the virus remains within the host for life and is intermittently and asymptomatically shed from the oropharynx.

  • Only about 5% of patients acquire EBV from someone who has acute infection.

  • Typical manifestations include fatigue (sometimes persisting weeks or rarely months), fever, pharyngitis, splenomegaly, and lymphadenopathy.

  • Uncommon severe complications include encephalitis and other neurologic manifestations, splenic rupture, airway obstruction due to tonsillar enlargement, hemolytic anemia, thrombocytopenia, and jaundice.

  • Do heterophil antibody testing and rarely specific EBV antibody testing.

  • Provide supportive care and recommend avoidance of heavy lifting and contact sports; antivirals are not indicated.

  • Consider corticosteroids for complications such as impending airway obstruction, severe thrombocytopenia, and hemolytic anemia.

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