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Infectious Mononucleosis

By Kenneth M. Kaye, MD, Brigham and Women’s Hospital, Harvard Medical School

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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. Over 90% of adults are seropositive for EBV. Its host is humans.

EBV infection is usually asymptomatic.

Pathophysiology

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

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.

Associated disorders

EBV is statistically associated with and likely has a causal role in

  • Burkitt lymphoma

  • Certain B-cell tumors in immunocompromised patients

  • 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. Fatigue can last for months but is usually maximal during the first 2 to 3 wk.

Most patients have the triad of

  • Fever

  • Pharyngitis

  • Adenopathy

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.

Other symptoms include

  • Splenomegaly

  • Mild hepatomegaly and hepatic percussion tenderness

  • Periorbital edema and palatal petechiae

  • Less frequently maculopapular eruptions

  • Rarely jaundice

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.

Complications

Although recovery is usually complete, complications may be dramatic.

Neurologic complications are rare but may include encephalitis, seizures, Guillain-Barré syndrome, peripheral neuropathy, viral 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

  • 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 cold-agglutinin 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. For treatment, see 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. Survivors of overwhelming primary EBV infection are at risk of developing agammaglobulinemia or lymphoma.

Diagnosis

  • Heterophile 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.

Differential diagnosis

Primary HIV infection can produce a clinical picture resembling acute EBV infection. If patients have risk factors for HIV infection, the following should be done:

  • Quantitative HIV RNA viral blood count

  • Combination antibody immunoassay and p24 antigen assay

HIV enzyme-linked immunosorbent assay (ELISA)/Western blot is usually negative during the acute infection and thus should not be used alone to diagnose early primary HIV infection. Quantitative HIV RNA and p24 antigen detection are more sensitive for diagnosing acute HIV infection because HIV RNA and p24 antigen are present in blood before HIV antibodies develop

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 combination antibody immunoassay and p24 antigen testing.

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 tests

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:

  • Heterophile antibody testing

  • Specific EBV antibody testing

Heterophile antibodies are measured using various agglutination card (monospot) tests. However, heterophile antibodies are present in only 50% of patients <5 yr and in about 80 to 90% of adolescents and adults with infectious mononucleosis. Importantly, the heterophile antibody test may be false-positive in some patients with acute HIV infection. The titer and prevalence of heterophile antibodies rise during the 2nd and 3rd wk of illness. Thus, if the diagnosis is strongly suspected but the heterophile 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). IgG VCA (EBV VCA-IgG) also develops early in primary EBV infection, but these antibodies persist for life. EBV nuclear antigen (EBNA-IgG) antibodies develop later (perhaps after 8 wk) in acute EBV infection and also 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.

Prognosis

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).

Treatment

  • 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 heterophile antibody testing and sometimes 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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* This is the Professional Version. *