Page 1286 - Williams Hematology ( PDFDrive )

1261

CHAPTER 82 of mononuclear leukocytosis in febrile patients. In 1932, Paul and
Bunnell showed that the sera from patients with infectious mononu-
3
MONONUCLEOSIS cleosis agglutinated red cells from sheep and horses, a reaction that was
termed the heterophile antibody test. Paul was investigating heterophile
SYNDROMES antibodies in human sera that reacted with sheep red blood cells. These
antibodies were unrelated by phylogenetic features to the antigen with
which they reacted, the so-called Forssman antigen. He found that the
highest titer had developed in the serum of an individual recovering
Robert F. Betts from infectious mononucleosis. Davidson showed that serum, after
absorption by guinea pig kidney cells, no longer reacted with sheep or
horse cells. This absorption of these antibodies made this test very spe-
4
cific for Epstein Barr virus (EBV) infection. In 1964, Epstein, Ashong,
SUMMARY and Barr reported the isolation of a virus from the cells of a patient with
African Burkitt lymphoma and hence the derivation of its name, EBV.
The defining clinical features of a mononucleosis syndrome are fever and reac- The etiologic role of EBV in infectious mononucleosis was discovered
tive lymphocytes in the blood. The two most common causes of mononucleosis serendipitously in the laboratory of Gertrude and Werner Henle. A
5
are Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection. The clinical technician in their laboratory whose serum had been negative for EBV
manifestations of EBV and CMV mononucleosis depend on a vigorous host antibodies and was used as a seronegative control was discovered to be
response to the viral infection. Patients who become infected without a host EBV antibody-positive after she recovered from infectious mononucle-
response develop antibodies to the virus but no or minimal clinical manifesta- osis. The association later was confirmed in seroepidemiologic studies
tions. Several clinical similarities exist between EBV and CMV mononucleosis. of college students. 6–9
Much of the clinical nature and the incubation period of mono-
Both infections have a febrile prodrome before the mononucleosis phase develops. nucleosis were documented by Hoagland in studies of cadets at West
10
Both infections can induce fever, an enlarged spleen, and an erythematous Point. He established that oral transmission was the principal route of
skin rash—the mononucleosis phase. The disease is self-limited in the vast viral transmission, which led to mononucleosis being dubbed the “kiss-
majority of patients, although resolution may take several weeks, especially in ing disease.” He also noted that cadets developed the disease approxi-
older individuals. In both viral infections, lymphocytes represent greater than mately 6 weeks after they returned from their vacation. 11
50 percent of blood cells, and at least 10 percent are reactive lymphocytes. Although EBV is the most common cause of infectious mononu-
Differences in clinical and laboratory findings are observed. Severe pharyngi- cleosis, other agents produce a febrile syndrome with a blood lympho-
tis and tender lymph node enlargement, often in several lymph node groups, cytosis that mimics some aspects of EBV mononucleosis.
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 mono- ETIOLOGY AND PATHOGENESIS
nucleosis occur in teenagers and young adults, whereas CMV-induced disease
occurs most commonly in adults in their 30s to 60s. A much larger percentage The infectious mononucleosis syndrome is most commonly caused by
of adults have unrecognized primary infection with CMV than with EBV. EBV one of two members of the herpes virus family: EBV or cytomegalo-
results in the development of heterophile antibodies, active against sheep and virus (CMV). Occasionally the HIV and, less commonly, the parasite
Toxoplasma gondii produce a febrile illness with lymphocytosis. Other
horse red cells among others, but this development does not occur in CMV. The viral agents produce a febrile syndrome with a blood lymphocytosis,
pathway leading to lymphocytosis and reactive lymphocytes differs between but only infrequently (Table 82–1). For both EBV and CMV mononu-
the two agents. The B cell is infected in EBV infection which eventually may lead cleosis, the T-lymphocyte response to the infected target cell, resulting
to hematologic malignancy, whereas the macrophage is infected in CMV. This in reactive lymphocytosis, is a hallmark of the disease. The difference
may explain its important role after allogeneic transplantation. In both infec- is that for EBV, the B lymphocyte is the cell that becomes infected and
tions, the T lymphocyte is the reactive cell. Other agents, including Toxoplasma thus the target of the responding T lymphocyte, whereas it is the macro-
gondii, human immune deficiency virus type 1, and several other viruses, can phage/monocyte lineage that is infected by CMV, which engenders the
cause a mononucleosis-like syndrome with reactive lymphocytes in the blood. T-lymphocyte response. 13,14

EPIDEMIOLOGY OF EPSTEIN-BARR
DEFINITION AND HISTORY VIRUS AND CYTOMEGALOVIRUS
The first clinical description of what was probably infectious mononu- Some similar and several distinct epidemiologic and clinical differences
cleosis was published in 1885 when Pfeiffer described a disorder termed exist between EBV and CMV infection. Both EBV and CMV infect
1
Drüsenfieber (glandular fever). In 1920, Sprunt and Evans introduced young children. Those who develop EBV infection at a very young
2
15
the term infectious mononucleosis for an acute, self-limited syndrome age (1 to 5 years) have an illness similar to other illnesses occurring
during their youth. CMV infection presents similarly, but in the young
patients there is low-grade fever, mild elevation in liver function, and,
quite often, lymphadenopathy. The latter seldom occurs in older people
Acronyms and Abbreviations: CMV, cytomegalovirus; EA, early antigen; with primary CMV infection.
EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; NK, natural If an individual escaped EBV infection when he or she was young,
killer; PCR, polymerase chain reaction; PTLD, posttransplantation lymphop- it is very common for the individual to develop infection during the
roliferative disease; VCA, virus capsid antigen. teen and young adult years, that is, between the ages of 12 and 25 years.
8
By contrast, CMV infection is uncommon in that age range but begins

Kaushansky_chapter 82_p1261-1272.indd 1261 9/18/15 10:04 AM