Etiology

EBV, a member of the γ-herpesviruses, causes >90% of cases of infectious mononucleosis. Two distinct types of EBV, type 1 and type 2 (also called type A and type B), have been characterized and have 70-85% sequence homology. EBV-1 is more prevalent worldwide, although EBV-2 is more common in Africa than in the USA and Europe. Both types lead to persistent, lifelong, latent infection. Dual infections with both types have been documented among immunocompromised persons. EBV-1 induces in vitro growth transformation of B cells more efficiently then EBV-2, but no type-specific disease manifestations or clinical differences have been identified. Co-acquisition of multiple EBV genotypes has been shown by heteroduplex tracking assays to occur commonly in otherwise healthy patients with infectious mononucleosis. Only a single genotype tends to be cultured.

As many as 5-10% of infectious mononucleosis–like illnesses are caused by primary infection with cytomegalovirus, Toxoplasma gondii, adenovirus, viral hepatitis, HIV, and possibly rubella virus. In the majority of EBV-negative infectious mononucleosis–like illnesses, the exact cause remains unknown.

Epidemiology

The epidemiology of infectious mononucleosis is related to the epidemiology and age of acquisition of EBV infection. EBV infects >95% of the world’s population. It is transmitted via penetrative sexual intercourse and in oral secretions such as “deep kissing” and sharing water bottles. Among children, transmission may occur by exchange of saliva from child to child, such as occurs between children in out-of-home child care. Non-intimate contact, environmental sources, and fomites do not contribute to spread of EBV.

EBV is shed in oral secretions consistently for >6 mo after acute infection and then intermittently for life. As many as 20-30% of healthy EBV-infected persons excrete virus at any particular time. Immunosuppression permits reactivation of latent EBV; 60-90% of EBV-infected immunosuppressed patients shed the virus. EBV is also found in male and female genital secretions and, especially type 2, is spread through sexual contact.

Infection with EBV in developing countries and among socioeconomically disadvantaged populations of developed countries usually occurs during infancy and early childhood. In central Africa, almost all children are infected by 3 yr of age. Primary infection with EBV during childhood is usually inapparent or indistinguishable from other infections of childhood; the clinical syndrome of infectious mononucleosis is practically unknown in undeveloped regions of the world. Among more affluent populations in industrialized countries, infection during childhood is also common but occurs less frequently, presumably because of high standards of hygiene, with approximately 30% of infections during adolescence and young adulthood. Primary EBV infection in adolescents and adults manifests in >50% of cases as the classic triad fatigue, pharyngitis, and generalized lymphadenopathy, which constitute the major clinical manifestations of infectious mononucleosis. This syndrome may be seen at all ages but is rarely apparent in children <4 yr of age, when most EBV infections are asymptomatic, or in adults >40 yr of age, of whom most individuals have already been infected by EBV. The true incidence of the syndrome of infectious mononucleosis is unknown but is estimated to occur in 20-70/100,000 persons/year; in young adults, the incidence increases to about 1/1,000 persons/year. The prevalence of serologic evidence of past EBV infection increases with age; almost all adults in the USA are seropositive.

Pathogenesis

After acquisition in the oral cavity, EBV initially infects oral epithelial cells, possibly contributing to the symptoms of pharyngitis. After intracellular viral replication and cell lysis with release of new virions, virus spreads to contiguous structures such as the salivary glands, with eventual viremia and infection of B lymphocytes in the peripheral blood and the entire lymphoreticular system, including the liver and spleen. The atypical lymphocytes that are characteristic of infectious mononucleosis are CD8+ T lymphocytes, which exhibit both suppressor and cytotoxic functions that develop in response to the infected B lymphocytes. This relative as well as absolute increase in CD8+ lymphocytes results in a transient reversal of the normal 2 : 1 CD4+/CD8+ (helper/suppressor) T-lymphocyte ratio. Many of the clinical manifestations of infectious mononucleosis may result, at least in part, from cytokine release from the host immune response, which is effective in reducing the EBV load to <1 copy/10⁵ circulating B lymphocytes, equivalent to <10 copies/µg of DNA from whole blood. The EBV load is more variable among immunocompromised persons and can be >4,000 copies/µg of DNA.

Epithelial cells of the uterine cervix may become infected by sexual transmission of the virus, although local symptoms have not been described after sexual transmission. EBV is consistently found intracellularly in smooth muscle cells of leiomyosarcomas of immunocompromised persons but not in leiomyosarcomas of immunocompetent persons.

EBV, like the other herpesviruses, establishes lifelong latent infection after the primary illness. The latent virus is carried in oropharyngeal epithelial cells and systemically in memory B lymphocytes as multiple episomes in the nucleus. The viral episomes replicate with cell division and are distributed to both daughter cells. Viral integration into the cell genome is not typical. Only a few viral proteins, including the EBV-determined nuclear antigens (EBNAs), are produced during latency. These proteins are important in maintaining the viral episome during the latent state. Progression to viral replication begins with production of EBV early antigens (EAs), proceeds to viral DNA replication, is followed by production of viral capsid antigen (VCA), and culminates in cell death and release of mature virions. Reactivation with viral replication occurs at a low rate in populations of latently infected cells and is responsible for intermittent viral shedding in oropharyngeal secretions of infected individuals. Reactivation is apparently asymptomatic and is not recognized to be accompanied by distinctive clinical symptoms.

Oncogenesis

EBV was the first human virus to be associated with malignancy. EBV infection may result in a spectrum of proliferative disorders ranging from self-limited, usually benign disease such as infectious mononucleosis to aggressive, nonmalignant proliferations such as the virus-associated hemophagocytic syndrome to lymphoid and epithelial cell malignancies. Benign EBV-associated proliferations include oral hairy leukoplakia, primarily in adults with AIDS, and lymphoid interstitial pneumonitis, primarily in children with AIDS. Malignant EBV-associated proliferations include nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin disease, lymphoproliferative disorders, and leiomyosarcoma in immunodeficient states, including AIDS. There is no firm evidence of development of EBV quasispecies that would contribute to the pathogenesis of EBV-positive malignancies.

Nasopharyngeal carcinoma occurs worldwide but is 10 times more common in persons in southern China, where it is the most common malignant tumor among adult men. It is also common among whites in North Africa and Inuit in North America. Patients usually present with cervical lymphadenopathy, eustachian tube blockage, and nasal obstruction with epistaxis. All malignant cells of undifferentiated nasopharyngeal carcinoma contain a high copy number of EBV episomes. Persons with undifferentiated and partially differentiated, nonkeratinizing nasopharyngeal carcinomas have elevated EBV antibody titers that are both diagnostic and prognostic. High levels of immunoglobulin A (IgA) antibody to EA and VCA may be detected in asymptomatic individuals and can be used to follow response to tumor therapy (Table 246-1). Cells of well-differentiated, keratinizing nasopharyngeal carcinoma contain a low number of or no EBV genomes; people with this disease have EBV serologic patterns similar to those of the general population.

Table 246-1 CORRELATION OF CLINICAL STATUS AND SEROLOGIC RESPONSES TO EPSTEIN-BARR VIRUS INFECTION^*

CT and MRI are helpful in both identifying and defining masses in the head and neck. The diagnosis is established by biopsy of the mass or of a suspicious cervical lymph node. Surgery is important for staging and diagnosis. Radiation therapy is effective for control of the primary tumor and regional nodal metastases. Chemotherapy with 5-fluorouracil, cisplatin, and methotrexate is effective but not always curative. The prognosis is good if the tumor is localized.

Endemic (African) Burkitt lymphoma, often found in the jaw, is the most common childhood cancer in equatorial East Africa and New Guinea (Chapter 490.2). The median age at onset is 5 yr. These regions are holoendemic for Plasmodium falciparum malaria and have a high rate of EBV infection early in life. The constant malarial exposure acts as a B-lymphocyte mitogen that contributes to the polyclonal B-lymphocyte proliferation with EBV infection, impairs T-lymphocyte surveillance of EBV-infected B lymphocytes, and increases the risk for development of Burkitt lymphoma. Approximately 98% of cases of endemic Burkitt lymphoma contain the EBV genome, compared with only 20% of cases of nonendemic (sporadic or American) Burkitt lymphoma. Individuals with Burkitt lymphoma have unusually and characteristically high levels of antibody to VCA and EA that correlate with the risk for developing tumor (see Table 246-1).

All cases of Burkitt lymphoma, including those that are EBV negative, are monoclonal and demonstrate chromosomal translocation of the c-myc proto-oncogene to the constant region of the immunoglobulin heavy-chain locus, t(8;14), to the κ constant light-chain locus, t(2;8), or to the λ constant light-chain locus, t(8;22). This translocation results in the deregulation and constitutive transcription of the c-myc gene with overproduction of a normal c-myc product that autosuppresses c-myc production on the untranslocated chromosome.

The incidence of Hodgkin disease peaks in childhood in developing countries and in young adulthood in developed countries. Levels of EBV antibodies are consistently elevated preceding development of Hodgkin disease; only a small minority of patients with the disease is seronegative for EBV. Infection with EBV appears to increase the risk for Hodgkin disease by a factor of 2-4. EBV is associated with more than 50% of cases of mixed cellularity Hodgkin disease and approximately 25% of cases of the nodular sclerosing subtype and is rarely associated with lymphocyte-predominant Hodgkin disease. Immunohistochemical studies have localized EBV to the Reed-Sternberg cells and their variants, the pathognomonic malignant cells of Hodgkin disease.

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