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1264 Part IX: Lymphocytes and Plasma Cells Chapter 82: Mononucleosis Syndromes 1265

cells and B cells are not increased. In EBV mononucleosis, the nota- Chronic Progressive Epstein-Barr Virus Infections, T-Cell or
ble populations increased are CD8+CD57– and CD3+γδ+ T cells. If Natural Killer–Cell Lymphoproliferation, Lymphoma, and Hemo-
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β-streptococcal infection accompanies the EBV infection segmented phagocytic Syndrome Chronic EBV infection is a rare outcome of
neutrophils may be present in the tonsillar exudate. primary EBV infection, notable in persons with an immunodeficiency
state. 76,77 In chronic EBV infection, fever, marrow hypoplasia, inter-
Other Blood Test Abnormalities stitial pneumonia, hepatosplenomegaly, persistent hepatitis often to
Liver function abnormalities are common, especially elevated serum the point of hepatic failure, lymphadenitis, and uveitis are frequent
alkaline phosphatase and γ-aminotransferase. There is no or only slight clinical manifestations. These findings may persist for months or years
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elevation of bilirubin. Studies in Israel have found a higher frequency and eventuate in a high fatality rate. EBV antibodies may be very
of hyperbilirubinemia (15 percent), a lower incidence of leukocytosis elevated (VCA in excess of 1:5120, anti-EA greater than 1:640) but
(46 percent), and elevated liver enzymes (58 percent) than previously with no detectable EBNA-1 antibody. A persistently elevated blood
reported. The differences may be geographical or genetic. 29 PCR for EBV is a feature. The more-severe form of this manifestation
may evolve into a natural killer (NK)- or T-cell lymphoproliferative
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COURSE AND PROGNOSIS disease that ranges from chronic to fulminant. Alternatively, EBV
hemophagocytic syndrome may develop. The latter is a severe mul-
Complications of Epstein-Barr Virus Mononucleosis tiorgan, inflammatory disease provoked by massive cytokine elabo-
Hematologic Virtually all subjects with acute mononucleosis develop ration. In some case, clonal proliferation induced by EBV develops
a mildly decreased platelet count (see Table 82–2). More-severe hema- (Chap. 71). 78–81
tologic complications occur infrequently, but include severe immune
thrombocytopenia with petechiae, immune hemolytic anemia, OTHER EPSTEIN-BARR VIRUS–ASSOCIATED
immune-mediated granulocytopenia, and aplastic anemia. 52–60 Uncom-
monly, the splenomegaly that accompanies the lymphoid proliferation DISEASE PROCESSES
accentuates an underlying, previously undiagnosed, hereditary sphero- Neoplastic Potential of Epstein-Barr Virus
cytosis. Splenic rupture is estimated to occur in 1 to 5 per 1000 cases. EBV was the first human tumor virus identified from the cultured cells
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It is the leading cause of death from EBV mononucleosis. 61,62 Avoidance of a patient with African Burkitt lymphoma. EBV can confer unlim-
of athletic activities is prudent until the signs of the disease have disap- ited proliferative potential of infected B lymphocytes in culture. EBV
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peared and the spleen has returned to normal size. 62 has since been associated with tumors other than Burkitt lymphoma,
Neurologic Neurologic complication include Guillain-Barré including some patients with Hodgkin lymphoma (Chap. 97). Although
syndrome, acute encephalitis, acute disseminated encephalomyelitis proof of causality still eludes investigators, there is an intriguing rela-
(Alice-in-Wonderland syndrome), acute cerebellar ataxia, viral men- tionship between EBV and Hodgkin lymphoma. 84–87 EBV is detectable
ingitis, transverse myelitis, and cranial nerve palsies. 57,58,63–65 There is in the neoplastic B cells (Reed-Sternberg cells) of a significant percent
evidence that antibody to gangliosides plays a role in the pathogene- of patients with Hodgkin lymphoma. The etiologic role of EBV in this
sis of Guillain-Barré syndrome Neurologic complications may occur setting is unknown. 84–87
in the absence of clinical mononucleosis. Diagnosis of EBV-induced There is also a relationship between EBV and lymphoma in
neurologic disease requires obtaining specific antibodies to EBV (see immune-deficient individuals including the posttransplantation lym-
“Antibody Responses” above) and a positive PCR for EBV in the cere- phoproliferative disease (PTLD). Recipient PTLD is a more serious
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brospinal fluid. Neurologic disease can be associated with primary problem than donor PTLD and investigators avoid certain immu-
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infection, reactivated infection or chronic EBV infection. Table 82–2 nosuppressive programs if there is a risk of PTLD. Use of positron
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lists other complications. emission tomography helps determine who of those at risk for PTLD
Chronic Fatigue Fatigue is a very prominent feature of acute have evidence for disease. X-chromosome–linked lymphoproliferative
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infectious mononucleosis. Most recover from this fatigue fairly quickly disease, T-cell and NK-cell lymphomas that follow chronic EBV infec-
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but a few remain fatigued for a very long period of time. The source tion, 93–95 nasopharyngeal carcinoma in patients in the Far East, the
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of this fatigue is not certain but there is evidence that dysfunction of latter disease generating efforts to develop a vaccine, leiomyoma and
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the midbrain plays a role. 68,69 Furthermore, there are genetic factors that leiomyosarcoma in patients with HIV infection or immunodeficiency
are present in those who remain fatigued. Limited information suggests posttransplantation, and a small fraction of cases of gastric carci-
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improvement in some with antiviral treatment. 69 noma are each associated with EBV infection (Table 82–4). In three
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Multiple Sclerosis There are reports indicating that EBV infec- types of lymphomas, Burkitt, Hodgkin, and PTLD, the cell that mutates
tion is linked to the development of multiple sclerosis. 70,71 Further stud- to produce the clonal disease is a germinal center B cell with a circular
ies to clarify which molecular mechanisms link the immune response to viral genome in the tumor cells that expresses the EBV-encoded latent
a natural infection of humans with EBV to the subsequent development genes. 100
of chronic inflammatory damage to the CNS are required to explain this In the case of PTLD, the most characteristic clinical setting involves
relationship an EBV seronegative person receiving an organ from an EBV seropos-
Systemic Lupus Erythematosus and Rheumatoid Arthritis There itive donor. EBV is latent in the B lymphocytes of the transplanted
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are epidemiologic links between previous infection with EBV and marrow or solid organ. Immunosuppression allows reactivation of the
development of systemic lupus erythematosus (SLE). Not unex- latent virus. Because basiliximab, calcineurin inhibitor, sirolimus, and
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pectedly, virtually everyone with SLE has had previous infection with glucocorticoids seem to increase the frequency of PTLD, that regi-
EBV. Therefore, the link may be fortuitous. Alternatively, a history men is avoided where the potential for PTLD is present. Because the
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of infection with EBV might lead to induction of autoimmunity. 73,74 recipient is not immune, there is no T-cell response and the B cells
There has also been a suggested relationship between increased viral may proliferate unchecked, sometimes eventuating in PTLD. In the
load in rheumatoid arthritis leading to expansion of CD8+ cells and EBV-seronegative recipient who develops PTLD posttransplantation,
its consequences. 75 this disease usually develops within the first posttransplantation year

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