Epstein-Barr Virus (Mononucleosis and Lymphoproliferative Disorders)

Epstein-Barr virus (EBV), a ubiquitous herpesvirus of humans, was discovered in 1964. The causal relationship between EBV and infectious mononucleosis (IM) was observed in 1968. The spectrum of associated infections ranges from asymptomatic to self-limited mononucleosis in healthy hosts to progressive infections in patients with acquired or inherited disorders of immunity.

Description Of The Pathogen

EBV is a γ-herpesvirus. Mature, infectious particles are 150–200 nm in diameter and are composed of a 172-kb, double-stranded DNA genome, capsid, protein tegument, and lipid-containing outer envelope. The viral capsid has icosahedral symmetry and is composed of 162 capsomeres. The entire nucleotide sequence of several strains is known. EBV, like other herpesviruses, is easily degraded and has a latent and a lytic life cycle.

Latent and Lytic Life Cycles

Cells that are latently infected with EBV replicate continuously, the viral genome is maintained as a circle (plasmid), a limited number of regions of the EBV genome are transcribed, and a relatively small number of viral proteins are synthesized. One latent protein, Epstein-Barr nuclear antigen-1 (EBNA-1), is necessary for plasmid maintenance. Cells that are permissive to the lytic life cycle (some differentiated plasma cells and differentiated epithelial cells) linearize the EBV genome, transcribe a larger portion of the genome than latently infected cells, synthesize more proteins, release infectious EBV, and perish. The switch between latency and replication is tightly regulated and is initiated by two EBV early proteins termed BZLF1 or ZEBRA and BRLF1. Another EBV protein, BCRF1, is homologous to IL-10 and stimulates B-cell proliferation while suppressing T-cell proliferation.

In vitro, the virus has a narrow host range and infects B lymphocytes of humans and other primates. In vivo, the virus also can be found in epithelial cells, T lymphocytes, or natural killer (NK) cells.

B-Lymphocyte Immortalization and Activation

Generally, EBV infects B lymphocytes and confers on them the ability to grow continuously in cell culture, a process termed immortalization. B-lymphocyte immortalization is the hallmark of EBV infection. EBV latent membrane protein (LMP)-1 mimics B-lymphocyte activation antigen CD40, promoting B-lymphocyte activation and immortalization by preventing programmed cell death (apoptosis). LMP-2 prevents EBV from reactivating in latently infected B cells. The role played by EBV latent proteins in the immortalization process has been reviewed.

Epstein-Barr Virus Antigens

Up to 11 messenger RNAs (mRNAs) and 9 EBV antigens are expressed during latency. EBNA, the classic EBV-induced latent neoantigen defined by immunofluorescence microscopy, is composed of 6 proteins (including EBNA-1). About 60 mRNAs are produced when the virus replicates lytically. Early antigens (EAs) are lytic proteins produced by the virus before viral DNA replication; these antigens consist mainly of viral enzymes necessary for genome replication. The classic EA complex, also defined by immunofluorescence microscopy, consists of diffuse (EA-D) and restricted (EA-R) components. The viral capsid antigen (VCA) is the classic EBV late antigen and is synthesized after EBV DNA replication. Genes encoding some of these classic EBV lytic antigens have been identified.

Epidemiology

In developing countries and in lower socioeconomic populations in industrialized nations, up to 90% of children contract EBV infection by 8 years of age. In contrast, in higher socioeconomic groups, from 30% to 75% of adolescents are EBV seronegative ( Fig. 208.1 ).

FIGURE 208.1, Differences in rates of acquisition of Epstein-Barr virus (EBV) by socioeconomic status. In Connecticut, by 8 years of age, only 30% of children are EBV seropositive, whereas in Barbados, by the age of 8 years, 90% have been infected with the virus.

Young children who acquire primary EBV infection usually do so asymptomatically or with only mild, nonspecific symptoms. IM occurs mainly in adolescents and young adults of higher socioeconomic groups who escaped primary EBV infection when younger. Approximately 1%–5% of susceptible adolescents and adults contract EBV infection annually, about one-half of whom develop symptomatic IM. Many of the symptoms of IM are secondary to the immune response directed at EBV. The annual incidence of IM in the US is about 500 per 100,000; peak ages affected are 15–24 years.

EBV is shed in oropharyngeal secretions during acute infection and intermittently thereafter; these secretions are the major source of infectious viruses. It is not clear how EBV transitions between B lymphocytes and oral epithelium; however, because patients with X-linked agammaglobulinemia do not contract EBV infection, B lymphocytes must play a critical role in this process. ^,

Infection usually is transmitted through close personal contact. EBV also can be transmitted sexually. ^, ^, Infection is only modestly communicable, and secondary attack rates are low. Rarely, the transmission of IM has been documented after blood transfusion.

Pathogenesis Of Infectious Mononucleosis In Previously Healthy Children

Infection in a susceptible person probably begins in the epithelial cells of the buccal mucosa or salivary glands. Subsequently, the virus gains access to B lymphocytes (probably memory B lymphocytes, the primary site of EBV persistence) in the lymphoid tissue of the pharynx and disseminates to the entire lymphoid system ( Fig. 208.2 ). CD21, the major B-lymphocyte receptor for EBV, binds to the viral glycoprotein gp350. Various HLA molecules can act as coreceptors, and other viral glycoproteins allow the virus to penetrate the cell. ^,

FIGURE 208.2, Pathogenesis and control (or lack thereof) of primary Epstein-Barr virus (EBV) infection. (Figure not drawn to scale.) SAP, signal lymphocyte activation molecule (SLAM)-associated protein. CAEBVI, chronic active EBV infection; HLH, hemophagocytic lymphohistiocytosis; XLPS, X-linked lymphoproliferative syndrome.

Early in the course of primary EBV infection, up to 20% of circulating B lymphocytes are infected and immortalized, with EBV DNA present within their nuclei. Most of the characteristic atypical lymphocytes of IM are activated, EBV-specific cytotoxic/suppressor T lymphocytes, which account for up to 30% of the CD8 ⁺ T cells in the blood of patients with IM. These cells can kill EBV-infected B lymphocytes and are themselves subject to enhanced apoptosis. ^, NK lymphocytes that lyse EBV-infected B lymphocytes also are produced. Probably because of this CD8 ⁺ T-lymphocyte and NK-cell activity, a transient general depression in cellular immunity can occur during acute IM, with anergy to skin test antigens and decreased lymphocyte responses to plant mitogens, soluble antigens, and mixed leukocyte culture. ^, Infection ultimately is brought under control by a combination of neutralizing antibodies, cytotoxic T lymphocytes, NK cells, and their secreted products (e.g., lymphokines).

Clinical Aspects Of Infectious Mononucleosis

Clinical Manifestations

EBV causes almost all cases of heterophil-positive and most cases of heterophil-negative IM. Other causes of heterophil-negative mononucleosis include cytomegalovirus, toxoplasmosis, HIV; rubella; hepatitis A and B viruses; human herpesviruses 6, 7, and 8; and adenovirus. Pharyngitis, lymphadenopathy, hepatitis, and splenomegaly tend to be more common and more severe in EBV-induced IM.

The incubation period for IM is approximately 4–6 weeks. Infection often is heralded by 3–5 days of mild headache, malaise, and fatigue. Major clinical manifestations include fever, sore throat or pharyngitis, and lymphadenopathy. Hepatosplenomegaly, jaundice, and rash also can be present. Recurrence is rare.

Body temperature usually rises to 39.4°C and gradually falls over about 6 days. In severe cases, the temperature can remain >40°C for 2 weeks or longer. ^,

Generalized lymphadenopathy is a hallmark of IM. Involvement of anterior and posterior cervical nodes is most common. Enlarged nodes usually are single, firm, tender, 2–4 cm in diameter, and not matted. Massive mediastinal and hilar lymph node enlargement leading to airway obstruction can occur. Mesenteric lymphadenopathy can mimic acute appendicitis symptoms. Lymphadenopathy gradually subsides over days to weeks. ^,

Pharyngitis can be indistinguishable from that caused by group A streptococci. The tonsils are enlarged, erythematous, and covered with exudate in >50% of cases. Petechiae appear on the palate, characteristically at the junction of the hard and soft palate, between days 5 and 17 of illness in up to 25% of patients.

Moderate enlargement of the spleen occurs in about 20% of cases between the second and third weeks of illness and usually is asymptomatic. After splenomegaly is detected, repeated splenic examination should be avoided because of the rare possibility of precipitating splenic rupture. Splenic rupture, leading to hemorrhage, shock, and even death, can follow trauma or can occur spontaneously (1 per 500 to 1 per 1600 cases of IM). ^, Splenic rupture should be suspected in any patient with IM and abdominal pain, especially if there are signs of peritoneal irritation, shock, tachycardia, or shoulder pain. Most cases of splenic rupture occur within 3 weeks of the diagnosis of IM, although rupture can occur as late as 7 weeks into the illness. ^, Splenic infarction also has been reported.

Hepatomegaly is present in 10%–35%, hyperbilirubinemia (typically direct) in up to 25%, and moderately elevated serum concentrations of hepatic transaminases in >65% of patients with IM. ^, Hepatitis can be associated with anorexia, nausea, and vomiting.

An exanthem occurs in about 5%–20% of cases. ^, The rash usually is located on the trunk and arms; rarely, palmar dermatitis occurs. The rash appears during the first few days of illness, lasts 1–6 days, and can be erythematous, macular, papular, or morbilliform. Sometimes an urticarial or scarlatiniform eruption or acrocyanosis is observed. Rarely, the rash is petechial, vesicular, umbilicated, or hemorrhagic. Rashes can resemble those of Gianotti-Crosti syndrome and secondary syphilis. ^, Eyelid edema occurs in up to 50% of patients, and presternal edema is not infrequent.

In 1967, Pullen and colleagues and Patel observed an increased incidence of rash in hospitalized patients with IM who received ampicillin. The copper-colored exanthem is mainly over the trunk but can progress into an extensive, confluent, maculopapular pruritic eruption that includes the palms and soles. It usually occurs within 3 days of administration and can persist for up to 1 week, with subsequent desquamation. The rash also has been reported with other antibiotics, occurring in ≥30% of patients with IM treated with antibiotics; however, the magnitude of the association has recently been questioned. ^, Exanthems do not represent hypersensitivity to the antibiotic, which can be used safely when the infection subsides.

Paroxysmal cough and radiographic findings of patchy alveolar and interstitial pneumonia develop in a small percentage of patients. Pleural effusion and empyema also have been reported. ^,

Neurologic complications occur in 1%–5% of patients with IM. Meningoencephalitis is most common. Other reported neurologic complications include aseptic meningitis, Guillain-Barré syndrome, optic neuritis, cranial nerve palsy, transverse myelitis, acute cerebellitis (ataxia or cognitive syndromes), dysautonomia, subacute sclerosing panencephalitis, peripheral neuritis, optic neuritis, psychosis, Parkinson-like syndrome, acute disseminated encephalomyelitis, and central nervous system (CNS) lymphoma. These can occur as the singular manifestation of EBV or in association with typical IM.

Hematologic complications generally are mild and occur in about 25% of cases. Transient thrombocytopenic purpura and hemolytic anemia are most common. Rare hematologic complications include aplastic anemia, agranulocytosis, agammaglobulinemia, hemolytic uremic syndrome, and disseminated intravascular coagulation.

Unilateral or bilateral orchitis lasting 2–4 weeks and scrotal edema can occur. Renal insufficiency can be present in up to 15% of cases, but renal complications occur <2% of the time and include interstitial nephritis, acute renal failure, and glomerulonephritis. Electrocardiographic abnormalities, as well as pericarditis and myocarditis, have been reported. Endocrinopathies include thyroiditis and polyglandular syndrome. ^, Arthritis, pancreatitis, proctitis, ocular involvement, lacrimal gland inflammation, genital ulcerations, necrotizing epiglottitis, hyperuricemia, cholecystitis, extrahepatic biliary obstruction, and hydrops of the gallbladder also have been observed.

Death from IM in previously healthy individuals is rare. In a review of the literature from 1932 to 1970, only 20 deaths were attributable to IM. Causes of death, in decreasing frequency, included neurologic complications, secondary infections, splenic rupture, hepatic failure, and myocarditis. The mortality rate was estimated to be <1 per 3000 cases.

Laboratory Findings and Diagnosis

IM usually is diagnosed based on typical clinical features, hematologic abnormalities, and a positive heterophil antibody agglutination test. Antibodies to specific EBV antigens can be used to confirm the diagnosis. Younger children often experience primary EBV infection in the absence of characteristic symptoms, hematologic abnormalities, and heterophil antibody response; a specific antibody response to EBV antigens is present, however. ^, Histology of lymph nodes can resemble that of a lymphoma.

During the first week of illness, leukopenia or leukocytosis can be so prominent that leukemia is suspected. An absolute increase in the number of atypical lymphocytes is characteristic during the second week of illness. Atypical lymphocytes (Downey cells) are a hallmark of IM. Cells vary markedly in size and shape, and after Wright staining, the cytoplasm is dark blue and vacuolated, with a foamy appearance. Nuclei are round, bean-shaped, or lobulated and contain no nucleoli. The presence of >10% atypical lymphocytes is characteristic, although not specific, for IM.

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