Epstein-Barr virus (EBV) is the cause of heterophile-positive infectious mononucleosis (IM), which is characterized by fever, sore throat, lymphadenopathy, and atypical lymphocytosis. EBV is also associated with several human tumors, including nasopharyngeal carcinoma, Burkitt's lymphoma, Hodgkin's disease, and (in patients with immunodeficiencies) B cell lymphoma. The virus is a member of the family Herpesviridae. The two types of EBV that are widely prevalent in nature are not distinguishable by conventional serologic tests.
EBV infections occur worldwide. These infections are most common in early childhood, with a second peak during late adolescence. By adulthood, more than 90% of individuals have been infected and have antibodies to the virus. IM is usually a disease of young adults. In lower socioeconomic groups and in areas of the world with deficient standards of hygiene (e.g., developing regions), EBV tends to infect children at an early age, and IM is uncommon. In areas with higher standards of hygiene, infection with EBV is often delayed until adulthood, and IM is more prevalent.
EBV is spread by contact with oral secretions. The virus is frequently transmitted from asymptomatic adults to infants and among young adults by transfer of saliva during kissing. Transmission by less intimate contact is rare. EBV has been transmitted by blood transfusion and by bone marrow transplantation. More than 90% of asymptomatic seropositive individuals shed the virus in oropharyngeal secretions. Shedding is increased in immunocompromised patients and those with IM.
EBV is transmitted by salivary secretions. The virus infects the epithelium of the oropharynx and the salivary glands and is shed from these cells. While B cells may become infected after contact with epithelial cells, studies suggest that lymphocytes in the tonsillar crypts can be infected directly. The virus then spreads through the bloodstream. The proliferation and expansion of EBV-infected B cells along with reactive T cells during IM result in enlargement of lymphoid tissue. Polyclonal activation of B cells leads to the production of antibodies to host-cell and viral proteins. During the acute phase of IM, up to 1 in every 100 B cells in the peripheral blood is infected by EBV; after recovery, 1–50 in every 1 million B cells is infected. During IM, there is an inverted CD4+/CD8+ T cell ratio. The percentage of CD4+ T cells decreases, while there are large clonal expansions of CD8+ T cells; up to 40% of CD8+ T cells are directed against EBV antigens during acute infection. Memory B cells, not epithelial cells, are the reservoir for EBV in the body. When patients are treated with acyclovir, shedding of EBV from the oropharynx stops but the virus persists in B cells.
The EBV receptor (CD21) on the surface of B cells is also the receptor for the C3d component of complement. EBV infection of epithelial cells results in viral replication and production of virions. When B cells are infected by EBV in vitro, they become transformed and can proliferate indefinitely. During latent infection of B cells, only the EBV nuclear antigens (EBNAs), latent membrane proteins (LMPs), and small EBV RNAs are expressed in vitro. EBV-transformed B cells secrete immunoglobulin; only a small fraction of cells produce virus.
Cellular immunity is more important than humoral immunity in controlling EBV infection. In the initial phase of infection, suppressor T cells, natural killer cells, and nonspecific cytotoxic T cells are important in controlling the proliferation of EBV-infected B cells. Levels of markers of T cell activation and serum interferon (IFN) γ are elevated. Later in infection, human leukocyte antigen–restricted cytotoxic T cells that recognize EBNAs and LMPs and destroy EBV-infected cells are generated. Studies have shown that one of the late proteins expressed during EBV replication, BCRF1, is a homologue of interleukin 10 and can inhibit the production of IFN-γ by mononuclear cells in vitro.
If T cell immunity is compromised, EBV-infected B cells may begin to proliferate. When EBV is associated with lymphoma, virus-induced proliferation is but one step in a multistep process of neoplastic transformation. In many EBV-containing tumors, LMP-1 mimics members of the tumor necrosis factor receptor family (e.g., CD40), transmitting growth-proliferating signals.
Most EBV infections in infants and young children either are asymptomatic or present as mild pharyngitis with or without tonsillitis. In contrast, up to 75% of infections in adolescents present as IM. IM in the elderly presents relatively often as nonspecific symptoms, including prolonged fever, fatigue, myalgia, and malaise. In contrast, pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytes are relatively rare in elderly patients.
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 181–1. 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. 181-1). Most patients treated with ampicillin develop a macular rash; this rash is not predictive of future adverse reactions to penicillins. Erythema nodosum and erythema multiforme have also been described (Chap. 53). Most patients have symptoms for 2–4 ...