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Most EBV infections in infants and young children either are asymptomatic or present as mild pharyngitis with or without tonsillitis. In contrast, ~75% of infections in adolescents present as IM. IM in the elderly often presents with nonspecific symptoms, including prolonged fever, fatigue, myalgia, and malaise. In contrast, pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytes are relatively rare in elderly patients.
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The incubation period for IM in young adults is ~4–6 weeks. A prodrome of fatigue, malaise, and myalgia may last for 1–2 weeks before the onset of fever, sore throat, and lymphadenopathy. Fever is usually low-grade and is most common in the first 2 weeks of the illness; however, it may persist for >1 month. Common signs and symptoms are listed along with their frequencies in Table 90-1. Lymphadenopathy and pharyngitis are most prominent during the first 2 weeks of the illness, while splenomegaly is more prominent during the second and third weeks. Lymphadenopathy most often affects the posterior cervical nodes but may be generalized. Enlarged lymph nodes are frequently tender and symmetric but are not fixed in place. Pharyngitis, often the most prominent sign, can be accompanied by enlargement of the tonsils with an exudate resembling that of streptococcal pharyngitis. A morbilliform or papular rash, usually on the arms or trunk, develops in ~5% of cases (Fig. 90-1). Many patients treated with ampicillin develop a macular rash; this rash is not predictive of future adverse reactions to penicillins. Erythema nodosum and erythema multiforme also have been described. The severity of the disease correlates with the levels of CD8+ T cells and EBV DNA in the blood. Most patients have symptoms for 2–4 weeks, but nearly 10% have fatigue that persists for ≥6 months.
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The white blood cell count is usually elevated and peaks at 10,000–20,000/μL during the second or third week of illness. Lymphocytosis is usually demonstrable, with >10% atypical lymphocytes. The latter cells are enlarged lymphocytes that have abundant cytoplasm, vacuoles, and indentations of the cell membrane (Fig. 90-2). CD8+ cells predominate among the atypical lymphocytes. Low-grade neutropenia and thrombocytopenia are common during the first month of illness. Liver function is abnormal in >90% of cases. Serum levels of aminotransferases and alkaline phosphatase are usually mildly elevated. The serum concentration of bilirubin is elevated in ~40% of cases.
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Most cases of IM are self-limited. Deaths are very rare and are most often due to central nervous system (CNS) complications, splenic rupture, upper airway obstruction, or bacterial superinfection.
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When CNS complications develop, they usually do so during the first 2 weeks of EBV infection; in some patients, especially children, they are the only clinical manifestations of IM. Heterophile antibodies and atypical lymphocytes may be absent. Meningitis and encephalitis are the most common neurologic abnormalities, and patients may present with headache, meningismus, or cerebellar ataxia. Acute hemiplegia and psychosis also have been described. The cerebrospinal fluid contains mainly lymphocytes, with occasional atypical lymphocytes. Most cases resolve without neurologic sequelae. Acute EBV infection has also been associated with cranial nerve palsies (especially those involving cranial nerve VII), Guillain-Barré syndrome, acute transverse myelitis, and peripheral neuritis.
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Autoimmune hemolytic anemia occurs in ~2% of cases during the first 2 weeks. In most cases, the anemia is Coombs-positive, with cold agglutinins directed against the red blood cell antigen. Most patients with hemolysis have mild anemia that lasts for 1–2 months, but some patients have severe disease with hemoglobinuria and jaundice. Nonspecific antibody responses may also include rheumatoid factor, antinuclear antibodies, anti–smooth muscle antibodies, antiplatelet antibodies, and cryoglobulins. IM has been associated with red-cell aplasia, severe granulocytopenia, thrombocytopenia, pancytopenia, and hemophagocytic lymphohistiocytosis. The spleen ruptures in <0.5% of cases. Splenic rupture is more common among male than female patients and may manifest as abdominal pain, referred shoulder pain, or hemodynamic compromise.
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Hypertrophy of lymphoid tissue in the tonsils or adenoids can result in upper airway obstruction, as can inflammation and edema of the epiglottis, pharynx, or uvula. About 10% of patients with IM develop streptococcal pharyngitis after their initial sore throat resolves.
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Other rare complications associated with acute EBV infection include hepatitis (which can be fulminant), myocarditis or pericarditis, pneumonia with pleural effusion, interstitial nephritis, genital ulcerations, and vasculitis.
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EBV-associated diseases other than IM
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EBV-associated lymphoproliferative disease has been described in patients with congenital or acquired immunodeficiency, including those with severe combined immunodeficiency, patients with AIDS, and recipients of bone marrow or organ transplants who are receiving immunosuppressive drugs (especially cyclosporine). Proliferating EBV-infected B cells infiltrate lymph nodes and multiple organs, and patients present with fever and lymphadenopathy or gastrointestinal symptoms. Pathologic studies show B cell hyperplasia or poly- or monoclonal lymphoma.
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X-linked lymphoproliferative disease is a recessive disorder of young boys who have a normal response to childhood infections but develop fatal lymphoproliferative disorders after infection with EBV. The protein associated with most cases of this syndrome (SAP) binds to a protein that mediates interactions of B and T cells. Most patients with this syndrome die of acute IM. Others develop hypogammaglobulinemia, malignant B cell lymphomas, aplastic anemia, or agranulocytosis. Disease resembling X-linked lymphoproliferative disease has also been associated with mutations in XIAP. Mutations in ITK, MagT1, or CD27 are associated with inability to control EBV and lymphoma. Moreover, IM has proved fatal to some patients with no obvious preexisting immune abnormality.
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Oral hairy leukoplakia (Fig. 90-3) is an early manifestation of infection with HIV in adults (Chap. 97). Most patients present with raised, white corrugated lesions on the tongue (and occasionally on the buccal mucosa) that contain EBV DNA. Children infected with HIV can develop lymphoid interstitial pneumonitis; EBV DNA is often found in lung tissue from these patients.
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Patients with chronic fatigue syndrome may have titers of antibody to EBV that are elevated but are not significantly different from those in healthy EBV-seropositive adults. While some patients have malaise and fatigue that persist for weeks or months after IM, persistent EBV infection is not a cause of chronic fatigue syndrome. Chronic active EBV infection is very rare and is distinct from chronic fatigue syndrome. The affected patients have an illness lasting >6 months, with elevated levels of EBV DNA in the blood, high titers of antibody to EBV, and evidence of organ involvement, including hepatosplenomegaly, lymphadenopathy, and pneumonitis, uveitis, or neurologic disease.
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EBV is associated with several malignancies. About 15% of cases of Burkitt’s lymphoma in the United States and ~90% of those in Africa are associated with EBV. African patients with Burkitt’s lymphoma have high levels of antibody to EBV, and their tumor tissue usually contains viral DNA. Malaria in African patients may impair cellular immunity to EBV and induce polyclonal B cell activation with an expansion of EBV-infected B cells. These changes may enhance the proliferation of B cells with elevated EBV DNA in the bloodstream, thereby increasing the likelihood of a c-myc translocation—the hallmark of Burkitt’s lymphoma. EBV-containing Burkitt’s lymphoma also occurs in patients with AIDS.
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Anaplastic nasopharyngeal carcinoma is common in southern China and is uniformly associated with EBV; the affected tissues contain viral DNA and antigens. Patients with nasopharyngeal carcinoma often have elevated titers of antibody to EBV. High levels of EBV plasma DNA before treatment or detectable levels of EBV DNA after radiation therapy correlate with lower rates of overall survival and relapse-free survival among patients with nasopharyngeal carcinoma.
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Worldwide, the most common EBV-associated malignancy is gastric carcinoma. About 9% of these tumors are EBV-positive.
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EBV has been associated with Hodgkin’s disease, especially the mixed-cellularity type. Patients with Hodgkin’s disease often have elevated titers of antibody to EBV. In about half of cases in the United States, viral DNA and antigens are found in Reed-Sternberg cells. The risk of EBV-positive Hodgkin’s disease is significantly increased in young adults for several years after EBV-seropositive IM. About 50% of non-Hodgkin’s lymphomas in patients with AIDS are EBV-positive.
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EBV is present in B cells of lesions from patients with lymphomatoid granulomatosis. In some cases, EBV DNA has been detected in tumors from immunocompetent patients with angiocentric nasal NK/T cell lymphoma, T cell lymphoma, and CNS lymphoma. Studies have demonstrated viral DNA in leiomyosarcomas from AIDS patients and in smooth-muscle tumors from organ transplant recipients. Virtually all CNS lymphomas in AIDS patients are associated with EBV. Studies have found that a history of IM and higher levels of antibodies to EBV before the onset of disease is more common in persons with multiple sclerosis than in the general population; additional research on a possible causal relationship is needed.