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Infectious mononucleosis is a clinical syndrome classically defined by the presence of fever, lymphadenopathy, pharyngitis, and fatigue. The illness was first recognized in the late 19th century and termed “glandular fever” or “Drusenfieber” by German physicians who noted its frequent occurrence in the context of family outbreaks.1,2 In a 1920 Johns Hopkins Medical Bulletin, Sprunt and Evans described 6 previously healthy young adults with a febrile illness similar to glandular fever, and noted the presence of atypical lymphocytes in the peripheral blood smear; because of the predominance of these unusual mononuclear cells, they termed the syndrome “infectious mononucleosis.”3 Twelve years later while investigating rheumatic disease, Paul and Bunnell4 serendipitously noted that the serum of patients with symptoms of infectious mononucleosis contained high titers of antibodies that agglutinated sheep red blood cells, thus the detection of these “heterophile antibodies” became the first laboratory marker available to diagnose the illness. The association of Epstein-Barr virus (EBV) with infectious mononucleosis followed in the late 1960s when a laboratory technician working with specimens from patients with Burkitt's lymphoma, a condition which had recently been shown to be associated with EBV, accidentally became infected and developed clinical infectious mononucleosis.5,6


We now know that the majority of patients with infectious mononucleosis have an acute EBV infection; the symptoms are caused by another infectious agent in up to 10% of patients. This chapter will concentrate on EBV, the major infectious cause, but other important diagnostic considerations will also be addressed.


More than 95% of adults worldwide are EBV-seropositive.7,8 In lower socioeconomic classes and in underdeveloped countries, most children acquire the infection before the age of 5.9 Fewer than 10% of children younger than the age of 4, develop clinically apparent symptoms of EBV infection.10 This parallels the epidemiology of several of the other differential etiologies of infectious mononucleosis, including cytomegalovirus (CMV) and hepatitis A infections. Therefore, patients who present with symptomatic infectious mononucleosis are most often older children, adolescents, and young adults of middle to upper socioeconomic status.11


EBV is transmitted primarily by direct contact with oral secretions. Transmission via aerosol or fomites is uncommon given the virus’ poor ability to survive outside host body fluids. The incubation period, during which the virus may be communicated but the patient is asymptomatic, is approximately 4–6 weeks.12 Epidemics of viral spread have not been reported, suggesting fairly low transmission rates, and no seasonal predominance has been identified. Transmission by blood product transfusion has occasionally been documented. Additionally, the presence of the virus in cervical secretions suggests that sexual transmission may also occur. As is characteristic of the other members of the herpesvirus family, EBV exhibits the property of latency in the host, so that those who have been previously infected, often continue to intermittently shed virus, further contributing to the transmission of EBV. Immunosuppression in the host from any etiology will increase ...

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