Infectious Mononucleosis

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 (1).

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 patients who are immunocompromised

• Certain forms of Hodgkin lymphoma

• Nasopharyngeal carcinoma

• Certain gastric cancers

• Multiple sclerosis

EBV does not cause chronic fatigue syndrome. However, it rarely causes a syndrome that may include fever, interstitial pneumonitis, pancytopenia, hepatitis, or uveitis (ie, chronic active EBV).

1. 1. Johannsen EC, Kaye KM: Epstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases). In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Ninth Edition), Elsevier, 2020, pp. 138, 1872-1890, 2020 . ISBN: 9996119890, 9789996119897

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 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.

Respiratory complications include, rarely, upper airway obstruction due to pharyngeal or paratracheal lymphadenopathy; respiratory complications may respond rapidly to corticosteroids.

Hepatic complications include elevated aminotransferase levels (about 2 to 3 times normal, returning to baseline over 3 to 4 weeks); they occur in about 90% of patients (1). 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 with lymphoproliferative syndrome are at risk of developing agammaglobulinemia or lymphoma.

1. 1. Johannsen EC, Kaye KM: Epstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases). In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Ninth Edition), Elsevier, 2020, pp. 138, 1872-1890, 2020 . ISBN: 9996119890, 9789996119897

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 load in blood

• 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.

Cytomegalovirus (CMV) may also cause a mononucleosis syndrome, with atypical lymphocytosis as well as hepatosplenomegaly and hepatitis but usually not with severe pharyngitis.

Toxoplasmosis may cause a syndrome similar to infectious mononucleosis with fever and lymphadenopathy but usually not with pharyngitis.

Laboratory diagnosis usually involves a complete blood count and EBV serologic testing. Lymphocytes that are morphologically atypical account for up to 30% of the white blood cells. 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 years 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 week of illness. Thus, if the diagnosis is suspected and the heterophile antibody test is negative early in clinical illness (in the first week), testing can be repeated approximately 7 days later. Due to the potential for false positive or negative results, the Centers for Disease Control and Prevention (CDC) does not recommend heterophile antibodies to diagnose primary EBV infection (see CDC: Laboratory Testing). However, a positive heterophile antibody test in the appropriate clinical situation is generally sufficient to confirm the diagnosis of primary EBV. Alternatively, EBV antibody testing can be performed.

EBV-specific antibody testing is highly sensitive. The presence of IgM antibodies to the EBV viral capsid antigen (VCA) indicates primary EBV infection (these antibodies disappear within 3 months 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 (after 2 to 4 months ) 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 that can present with similar symptoms (eg, acute HIV infection, CMV infection) should be considered.