Epstein-Barr Virus Infection

Definition

Epstein-Barr virus (EBV), a member of the gamma human herpesvirus family, is the etiologic agent of infectious mononucleosis and of a diverse assortment of neoplastic and lymphoproliferative syndromes.

Epidemiology

Ubiquitous in the human population, EBV is found in 90 to 95% of adults throughout the world. As in the case of other herpesviruses, infection with EBV is lifelong. The virus resides in B lymphocytes and is intermittently shed asymptomatically in oropharyngeal secretions, which accounts for the bulk of its transmission in the human population. The virus is usually acquired during early childhood by sharing of saliva-bearing fomites or during adolescence by kissing, although it can be acquired at any decade of life. In addition to oropharyngeal spread, the virus can be transmitted by blood transfusion or by organ and tissue donation.

Most childhood EBV infections are clinically silent, but infection of adolescents and adults results in the clinical syndrome of infectious mononucleosis between 25 and 50% of the time, depending on the setting. The incidence of infectious mononucleosis is highest in the 15- to 24-year-old age group. Incidence rates in men and women are equal, but the peak incidence is 2 years earlier in women than in men. Incidence rates are lower in lower socioeconomic populations, due to the likelihood of acquisition of EBV during early childhood rather than during adolescence.

Pathobiology

EBV infects B lymphocytes preferentially but also infects epithelial cells. For B lymphocytes, the receptor is CD21, whereas for epithelial cells, cellular entry is less well defined. Infection of B cells typically results in two pathways: lytic destruction of B lymphocytes owing to viral replication, and latency within lymphocytes. Once inside the cell, the virus expresses several nuclear proteins (termed Epstein-Barr nuclear antigens [EBNAs]) that activate EBV-encoded latent membrane proteins and other gene products responsible for regulation of B-cell growth. These events are associated with the transformation or immortalization of the B cell that is the phenotypic hallmark of B-cell infection. EBV-transformed B cells have the potential to proliferate vigorously but are prevented from doing so in the normal host due to surveillance by T lymphocytes.

The host response to acute EBV infection consists of a vigorous and coordinated cellular and humoral immune response. The humoral immune response includes IgM and IgG antibodies directed at the viral capsid (VCA) and to EBNA, as well as “heterophile” antibodies to surface antigens of sheep red blood cells. Heterophile antibodies are useful diagnostically and are present at some point in up to 90% of adolescents and adult cases but are often not detected in children younger than 4 years of age. These antibodies are an epiphenomenon in host defense and are not cross-reactive with any known viral antigens.

The cellular immune response includes both natural killer and EBV-specific CD4 ⁺ and CD8 ⁺ T lymphocytes. The expansion of the CD8 ⁺ subset of T lymphocytes during acute EBV infection includes a subset of large, activated cells demonstrable on standard peripheral blood smears as “atypical” lymphocytes. This vigorous cellular immune response is associated with an outpouring of cytokines, including tumor necrosis factor, interleukin-1, and interleukin-6, that are responsible for many of the symptoms and signs of infectious mononucleosis. Over a period of 4 to 6 weeks after initial evaluation in most patients, adaptive immune mechanisms gain control of the EBV-driven B-cell proliferation and the virus enters into a lifelong period of symbiosis with the host. The virus is asymptomatically shed in the oropharyngeal fluids of healthy human immunodeficiency virus type 1 (HIV-1)–seronegative adolescents and adults and is shed even more often in individuals with T-cell defects, such as occur with HIV-1 infection or immunosuppression associated with organ allografts. Shedding is increased among healthy persons during periods of transient immune dysregulation.

Acute Infection

Clinical Manifestations

Most cases of acute EBV infection are clinically silent. The syndrome of infectious mononucleosis consists of the clinical triad of fever, sore throat ( Chapter 397 ), and lymphadenopathy, in association with an atypical lymphocytosis ( Fig. 348-1 ) and the transient appearance of heterophile antibodies.

The incubation period between exposure and the onset of symptoms is generally 30 to 50 days. The onset of symptoms may be abrupt, or it may be heralded by a several-day nonspecific prodrome of malaise and low-grade fever. Although the classic syndrome includes fever, sore throat, and adenopathy, the findings may be dominated by only one or any combination of these symptoms. Other common clinical manifestations include headache, malaise, and anorexia. On physical examination, patients are usually febrile. Pharyngeal erythema, tonsillar enlargement (see Fig. 397-4 in Chapter 397 ), and cervical adenopathy are generally present. Mild periorbital edema may also be observed. Abdominal findings may include splenomegaly or hepatomegaly, or both. Splenomegaly can be demonstrated by ultrasonographic examination in virtually all patients with infectious mononucleosis, although palpable splenomegaly is present in only about 20% of patients. Splenic enlargement is usually maximal in the second or third week of illness and might not be detectable at the initial presentation. Adenopathy may be observed in noncervical regions, but it is usually much less prominent than in cervical regions.

More serious primary infections can occur in individuals over age 30 years. Approximately 5% of patients will exhibit a rash that may be macular, scarlatiniform, or urticarial in nature. Ampicillin or its derivatives evoke a pruritic maculopapular eruption in 15 to 30% of patients with acute EBV infection in recent series, compared with a reported 80 to 100% in earlier reports. Patients with an ampicillin-induced rash during acute EBV infection generally tolerate the drug and other penicillin products when administered later in life.

Complications

Most patients have self-limited disease EBV, but a number of complications may arise. In some patients, these complications dominate the clinical findings, and seroconversion to EBV may be the only evidence of acute EBV infection.

Patients should be specifically warned about splenic rupture, a complication attributable to splenomegaly ( Chapter 154 ) and associated stretching of the splenic capsule that occurs most frequently in the second or third week of the illness, when other symptoms of the disease are abating. It may be accompanied by trauma but may also occur without an obvious antecedent event. Left upper quadrant pain, especially pain radiating to the subscapular region, should raise this diagnostic consideration. As with other complications of acute EBV infection, splenic rupture may occur occasionally in patients without other prominent clinical manifestations of acute EBV infection. Other hematologic complications, which usually arise from a combination of self-reactive antibodies and hypersplenism, include autoimmune hemolytic anemia ( Chapter 146 ), thrombocytopenia ( Chapter 158 ), and neutropenia ( Chapter 153 ).

Neurologic complications can also occur during acute EBV infection. EBV DNA has been detected in brain tissue from rare patients with clinical manifestations compatible with herpes simplex encephalitis ( Chapter 383 ). Other neurologic complications include aseptic meningitis ( Chapter 381 ), cerebellitis, mononeuritis multiplex ( Chapter 388 ), Bell palsy ( Chapter 388 ), Guillain-Barré syndrome ( Chapter 388 ), transverse myelitis ( Chapters 369 and 380 ), and a higher risk of multiple sclerosis. ^,

Mild hepatomegaly is common in acute infectious mononucleosis, and biochemical evidence of hepatitis ( Chapter 134 ) is to be expected in virtually every case of acute infection. More severe hepatic complications are uncommon, however. Renal, cardiac, pulmonary, and skeletal muscle complications are rare.

X-Linked Lymphoproliferative Syndrome

The most serious complication of acute EBV infection arises in individuals with the X-linked lymphoproliferative syndrome. This syndrome occurs in males with mutations in the signaling lymphocyte activation molecule (SLAM)–associated protein (SAP) that regulates T-cells and natural killer (NK) cells. These previously healthy individuals who become immune dysregulated upon encountering EBV have severe clinical symptoms, a pronounced lymphocytosis consisting of T and B cells, and severe hepatitis. If patients survive the acute infection, the syndrome may evolve into progressive agammaglobulinemia or lymphoma in the following months. The genetic defect associated with this syndrome can be diagnosed in utero, and early bone marrow transplantation has been recommended for the prevention of the devastating clinical syndrome associated with the acquisition of EBV infection.

Diagnosis

Because clinical manifestations of acute EBV infection are variable and other organisms may cause similar clinical syndromes, laboratory tools are required to confirm an etiologic diagnosis. Heterophile antibodies to sheep red blood cells are classically used to diagnose EBV-induced infectious mononucleosis. Although ultimately demonstrable in approximately 90% of symptomatic acute EBV infections, these antibodies are present in only about two thirds of patients at initial encounter. If antibodies are negative at the outset and clinical suspicion is high, repeat testing in the second or third week of the illness is warranted. EBV-specific antibodies remain the “gold standard” for the diagnosis of acute EBV infection, but if heterophile antibodies are demonstrated in a straightforward case of infectious mononucleosis, EBV-specific serologic studies are not generally required. Testing for IgM antibodies to the EBV capsid antigen (VCA) is the most useful serologic study in the diagnosis of acute EBV infection. Relatively high titers of IgG antibodies to VCA persist for life after initial infection and are not useful in making the diagnosis of acute EBV infection. Antibodies to EBNA are slower to arise than those to capsid antigens, and acute infection may be diagnosed by demonstration of seroconversion to this antigen.

Among pathogens causing clinical syndromes that can be mistaken for acute EBV infection, cytomegalovirus ( Chapter 347 ) is the most frequent. Patients with cytomegalovirus infection are less likely to have an acute onset of illness, and pharyngitis is less frequently a prominent manifestation of the illness. Toxoplasma gondii ( Chapter 320 ) infection can also present as a nonspecific febrile illness that can be confused with infectious mononucleosis. Streptococcal pharyngitis ( Chapter 269 ), primary herpes stomatitis ( Chapter 345 ), and adenovirus infection ( Chapter 333 ) may occasionally cause symptoms that are mistaken for acute EBV infection. None of these syndromes is associated with heterophile antibodies or with other serologic evidence of acute EBV infection. The differential diagnosis is generally made by serologic studies directed at these organisms or by culture. Nonetheless, physicians should be cognizant that organisms such as group A β-hemolytic streptococci ( Chapter 269 ) and herpes simplex virus are also common in the human population and may be demonstrated in people whose symptoms are nonetheless due to acute EBV infection.

Treatment and Prevention

The clinical course is generally self-limited and does not usually require specific therapeutic intervention beyond the use of aspirin or acetaminophen for antipyresis and mild pain relief, except in the presence of specific complications such as when lymphadenopathy threatens the airway or in certain cases of autoimmune hemolytic anemia ( Chapter 146 ) or thrombocytopenia ( Chapter 158 ). To reduce the risk of splenic rupture, patients should be counseled against activities that might result in abdominal trauma for 6 to 8 weeks after the onset of symptoms.

Short courses of corticosteroids have been used to hasten symptomatic recovery in cases in which the symptoms are severe or refractory. For example, corticosteroids may be of benefit in more severe cases of autoimmune hemolytic anemia ( Chapter 146 ) or thrombocytopenia ( Chapter 158 ). Corticosteroids should not, however, be used routinely and should consist of no more than a 10- to 14-day tapering course that begins at a dose equivalent to 0.5 to 1 mg/kg of prednisone. Although EBV replication can be inhibited in vitro or in vivo by acyclovir and related antiviral agents, the symptoms of infectious mononucleosis are primarily driven by the immune response to the virus and follow the time of maximal viral replication. Antiviral agents have not been demonstrated to accelerate resolution of symptoms significantly or prevent complications of the disease. However, patients with encephalitis may be treated with parenteral ganciclovir (10 mg/kg/day intravenously for 3 weeks followed by valganciclovir 900 mg/day orally for another 3 weeks until the virus is cleared; Chapter 328 ).

Because the virus is usually transmitted by asymptomatic oral shedders and is so common in the human population, epidemiologic interventions directed at patients with acute infection are not warranted to prevent spread. No vaccine yet has been developed for clinical use.

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