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Pediatric Mononucleosis and Epstein-Barr Virus Infection

Practice Essentials

Infectious mononucleosis is a clinical syndrome caused mostly by Epstein-Barr virus (EBV), or human herpesvirus 4 (HHV-4), which is a γ-herpesvirus. EBV is widely disseminated; it is spread by intimate contact between asymptomatic EBV-infected persons who shed the virus and susceptible persons.

The most common manifestation of primary infection with EBV is acute infectious mononucleosis, which is a self-limiting clinical syndrome that most frequently affects adolescents and young adults. Classic symptoms include malaise, fever, sore throat, fatigue, and generalized adenopathy. Infectious mononucleosis is characterized by atypical-appearing mononuclear lymphocytes. It was known synonymously as “Drüsenfieber,” or glandular fever, owing to pronounced generalized lymphadenopathy.

EBV is the first human virus confirmed to be an oncovirus and may give rise to various lymphoproliferative malignancies in immunocompromised hosts. It is associated with various tumors, including nasopharyngeal carcinoma, gastric carcinoma, lymphoreticular malignancies, and Burkitt lymphoma.

EBV causes 90% of cases of infectious mononucleosis. Primary infection with cytomegalovirus, Toxoplasma gondii, adenovirus, viral hepatitis, HIV, and rubella virus causes an infectious mononucleosis-like illness. The exact cause remains unknown in the majority of cases of EBV-negative infectious mononucleosis.

See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.

Acute infectious mononucleosis was first described in 1889 as acute glandular fever, an illness characterized by lymphadenopathy, fever, hepatosplenomegaly, malaise, and abdominal discomfort in adolescents and young adults. In 1920, Sprunt and associates applied the name infectious mononucleosis to cases of spontaneously resolving acute leukemia associated with blast-like cells in the blood. The distinctive mononuclear lymphocyte cell associated with EBV is known as a “Downey cell,” after Hal Downey, who contributed to the characterization of it in 1923. In 1932, Paul and Bunnell discovered that serum from symptomatic patients had antibodies that agglutinate the red blood cells (RBCs) of unrelated species, the “heterophile antibodies.” This finding allowed enhanced diagnostic accuracy of infectious mononucleosis, even if the exact virus had not been isolated.

In 1958, Denis Burkitt, who was a surgeon posted in Uganda during World War II, reported a specific type of cancer that was common in young children living across central Africa. These aggressive tumors – later named after him as Burkitt lymphoma – were caused by white blood cells multiplying out of control. Later in 1964, UK researcher Antony Epstein and his colleagues Yvonne Barr and Burt Achong collaborated with Denis Burkitt and looked at the Burkitt lymphoma cells from tumor specimens shipped from Uganda. They detected tiny virus particles under the electron microscope in those specimens. In 1965, the newly discovered first human oncovirus was named Epstein-Barr virus.

The EBV DNA was fully sequenced in 1984.

The graph below demonstrates the antibody response to Epstein-Barr virus.

Infectious mononucleosis. Antibody response to Eps

Infectious mononucleosis. Antibody response to Epstein-Barr virus. Adapted with permission from Johnson DH, Cunha BA. Epstein-Barr virus serology. Infect Dis Pract. 1995;19:26-27.

The search for the etiologic agent of infectious mononucleosis was unsuccessful for many years, partly because researchers did not appreciate that most primary infections are asymptomatic and that most adults are seropositive. In 1964, Epstein described the first human tumor virus when he found virus particles in a Burkitt lymphoma cell line.
 Henle et al reported the relationship between acute infectious mononucleosis and EBV in 1968.
 Subsequently, a large prospective study of students at Yale University firmly established EBV as the etiologic agent of infectious mononucleosis.

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