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The defining clinical features of a mononucleosis syndrome are fever and reactive lymphocytes in the blood. The two most common causes of mononucleosis are Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection. The clinical manifestations of EBV and CMV mononucleosis depend on a vigorous host response to the viral infection. Patients who become infected without a host response develop antibodies to the virus but no or minimal clinical manifestations. Several clinical similarities exist between EBV and CMV mononucleosis. Both infections have a febrile prodrome before the mononucleosis phase develops. Both infections can induce fever, an enlarged spleen, and an erythematous skin rash—the mononucleosis phase. The disease is self-limited in the vast majority of patients, although resolution may take several weeks, especially in older individuals. In both viral infections, lymphocytes represent greater than 50% of blood cells, and at least 10% are reactive lymphocytes. Differences in clinical and laboratory findings are observed. Severe pharyngitis and tender lymph node enlargement, often in several lymph node groups, occur in infection with EBV and perhaps with some unknown agents but not to the same degree in infections with CMV. The majority of cases of EBV mononucleosis occur in teenagers and young adults, whereas CMV-induced disease occurs most commonly in adults in their 30s–60s. A much larger percentage of adults have unrecognized primary infection with CMV than with EBV. EBV results in the development of heterophile antibodies, active against sheep and horse red cells (among others), but this development does not occur in CMV. The pathway leading to lymphocytosis and reactive lymphocytes differs between the two agents. The B cells are infected in EBV infection, which eventually may lead to hematologic malignancy, whereas the macrophages are infected in CMV. This may explain its important role after allogeneic transplantation. In both infections, T and natural killer lymphocytes are the reactive cells that contribute to the leukocytosis observed in the blood. Other agents, including Toxoplasma gondii, human immune deficiency virus type 1, and several other viruses, can cause a mononucleosis-like syndrome with reactive lymphocytes in the blood.

Acronyms and Abbreviations

IM, infectious mononucleosis; CMV, cytomegalovirus; EA, early antigen; EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; NK, natural killer; PCR, polymerase chain reaction; PTLD, posttransplantation lymphoproliferative disease; VCA, virus capsid antigen.


The first clinical description of what was probably infectious mononucleosis (IM) was published in 1885 when Pfeiffer described a disorder termed Drüsenfieber (glandular fever), although some aspects of these cases were not typical of IM.1 In 1920, Sprunt and Evans introduced the term infectious mononucleosis for an acute, self-limited syndrome of mononuclear leukocytosis in febrile patients.2 In 1932, Paul and Bunnell showed that the sera from patients with IM agglutinated red cells from sheep and horses, a reaction that was termed the heterophile antibody test.3 Paul and Bunnell were investigating heterophile antibodies in human sera that reacted with sheep ...

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