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Epstein-Barr Virus Infections Updated November, 2009 Sankar Swaminathan, M.D., Fred Wang, M.D.
GENERAL DESCRIPTION Epstein-Barr virus (EBV; Human herpesvirus-4) is a human gammaherpesvirus that establishes lifelong infection in B lymphocytes with predilection for latent, rather than lytic, infection. EBV replicates during lytic infection by mechanisms common to all herpesviruses, and EBV lytic infection is inhibited by nucleoside analogues such as acyclovir, ganciclovir, and foscarnet. However, diseases induced by EBV are frequently associated with latent infection, and nucleoside analogues active against lytic replication may not be effective clinically. Currently, treatment of EBV-associated diseases is more often directed against virus-induced tumors or disease symptoms and less frequently against viral replication. Pharmacologic intervention in pathways important for latent infection, vaccines and other immunologic therapies to prevent infection or attenuate disease are potential areas for therapeutic development. Virology Guided Medline Search Epstein-Barr virus is a double-stranded DNA virus (reviewed in (69, 70). Human and primate B lymphocytes and to a lesser degree, epithelial cells can be infected in vitro with EBV. After adsorption to the cell surface receptor and virion entry, several Epstein Barr nuclear antigens (EBNAs) and latent membrane proteins are expressed (1). Infected B lymphocytes become immortalized and proliferate indefinitely in culture. The molecular mechanisms by which EBV latent infection gene products immortalize B cell growth are currently being delineated. In general these involve viral proteins usurping normal cell signaling pathways involved in cell growth, such as the Tumor Necrosis Factor Receptor and Notch ligand receptor pathways. Determining how latent EBV genes function to affect cell growth is an active area for investigation and may provide novel opportunities for pharmacologic intervention in EBV latent infection and associated malignancies. In vitro, only a small fraction of infected cells reactivates lytic infection to produce infectious virions. In latently EBV-infected cells, the virus exists as a circular DNA molecule, or episome, in the nucleus, and viral DNA is replicated in unison with cell DNA and cell doubling. Epidemiology Guided Medline Search Infection with EBV is ubiquitous, with 90-95% of all adults displaying serological evidence of past infection (32). In the United States, approximately 50% of children are seropositive by age five, with a second period of seroconversion occurring in early adulthood (64). Infection occurs earlier in developing countries and in certain areas of the United States. Most cases of EBV infection are transmitted by the presence of virus in oropharyngeal secretions of asymptomatic shedders. Blood transfusions and transplantation of solid organs or bone marrow may also be associated with EBV transmission. Infectious Mononucleosis: Infectious mononucleosis, the syndrome characterized by a classic triad of fever, sore throat and lymphadenopathy (see Clinical Manifestations below) is most commonly caused by primary EBV infection. Infectious mononucleosis is most frequently diagnosed in industrialized countries in young adults. When infection is delayed beyond childhood, the incidence of symptomatic infectious mononucleosis has been estimated to be between 25-75% (59, 77). The higher incidence in this demographic group most likely reflects a later age of primary infection as well as greater access to health care and availability of specific diagnostic tests. Although racial differences in the incidence of infectious mononucleosis have been noted, these are likely to be related to differences in the age at which primary infection occurs (31). Genetic polymorphisms in the interleukin-10 gene have been linked to severe symptomatic EBV infection (30). A recent study also found a significant association of type 1 EBV with infectious mononucleosis, suggesting that viral determinants may also influence the host response that results in symptomatic infection (14). In a large study of students entering college in the United Kingdom, EBV infection was significantly more common among women than men. A history of sexual intercourse was also significantly associated with prior infection as well as with symptomatic infectious mononucleosis (15). EBV is found in the saliva for extended periods after recovery from infection, and has been detected at high titers for median period of 32 weeks after primary infection (5), suggesting that healthy convalescent patients may be a common source of infection among young adults. It has been suggested that larger infectious doses of EBV that may be transmitted in saliva during kissing are responsible for the association of infectious mononucleosis with a history of sexual activity (14). Katz BZ, Shiraishi Y, et al. Chronic Fatigue Syndrome After Infectious Mononucleosis in Adolescents. Pediatrics. 2009 Jul;124:189-93. Oral Hairy Cell Leukoplakia: Oral hairy leukoplakia is an irregular white oral lesion that is almost exclusively seen in patients with advanced HIV infection or immunosuppression. The major risk factor is low CD4 counts (<200) and the incidence of oral hairy leukoplakia has declined with highly active antiretroviral therapy. EBV-Associated-Lymphoproliferative Diseases: EBV-associated lymphoproliferative disease occurs after both solid organ and hematopoietic stem cell transplantation and is most common in the first year post-transplant (23). Post-transplant lymphoproliferative disease (PTLD) occurs in as many as 10% of solid organ transplant recipients and is the leading cause of post-transplant mortality in many settings. The risk is highest with prolonged and intense immunosuppression and in EBV seronegative recipients of organs from EBV-positive donors.. Small bowel, lung, and heart transplant recipients are at highest risk. PTLD after hematopoietic stem cell transplantation occurs almost exclusively in allogeneic transplants. Risk factors include T cell depletion, treatment with anti-thymocyte globulin and HLA-mismatched donor-recipient pairs. Diffuse large B cell lymphoma in AIDS patients is also associated with more prolonged immunosuppression manifested by low CD4 counts. Virtually 100% of primary CNS lymphomas that develop in the setting of HIV infection are EBV-positive versus approximately 75% of peripheral lymphomas. Review Article: Sun HY, et al. Pharmacotherapy of post-transplant viral infections. Expert Opin Pharmacother 2008;9(14):2409-2421. X-Linked Lymphoproliferative Disease: X-linked lymphoproliferative syndrome (XLP) is associated with a rare genetic disorder which occurs with a frequency of less than 1 in 1 million. Approximately 50% of cases appear to represent spontaneous mutations without a familial history. EBV-Associated Malignancies (Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s lymphoma): The endemic form of Burkitt lymphoma originally identified in sub-Saharan Africa is associated with EBV infection in >90% of cases. Sporadic Burkitt lymphoma in the United States is less frequently EBV-associated (<25%) and is relatively rare with an age-adjusted incidence of approximately 0.3 per 100,000 person-years (55). Burkitt’s lymphoma occurs more often in males and in children than in adults. Hodgkin’s lymphoma is a lymphoma of B cell origin that occurs worldwide. Specific subtypes of Hodgkin’s lymphoma, (mixed cellularity and lymphocyte-depleted), are associated with EBV infection. It is now clear that not only is infectious mononucleosis a risk factor (RR=4.0) for the development of Hodgkin’s lymphoma, but that infectious mononucleosis does not increase the risk of EBV-negative Hodgkin’s disease. The median interval to the diagnosis of Hodgkin’s disease after symptomatic infectious mononucleosis was 4.1 years in a large recent study (35). Nasopharyngeal carcinoma is rare worldwide, with an incidence of less than one per 100,000, but occurs commonly in localized geographic regions in Southeast Asia and Africa with an incidence as high as 50 per 100,000 in some regions of Southern China (63). In addition to complex genetic susceptibility patterns, epidemiologic evidence implicates dietary factors such as the consumption of salted fish in the etiology of nasopharyngeal carcinoma (40, 90). Chronic Active EBV Infection: EBV infection rarely causes an aggressive syndrome with persistent lytic replication and widespread organ involvement. This rare manifestation most likely represents an inability of the host to adequately contain the primary infection and may reflect underlying specific immune deficits. Chronic Fatigue Syndrome: EBV has also been implicated as a cause of the much more common chronic fatigue syndrome. However, seroepidemiologic studies have argued against a pathogenic role for EBV in chronic fatigue syndrome (36, 37). Clinical Manifestations Guided Medline Search Epstein-Barr virus is associated with a variety of clinical disorders arising from different pathogenic mechanisms (reviewed in (69). Infection during childhood is often asymptomatic or associated with nonspecific symptoms. Infectious Mononucleosis: Infection during adolescence or adulthood more commonly results in the syndrome of acute infectious mononucleosis, characterized by a vigorous humoral and cellular immune response to rapidly proliferating EBV-infected B cells. Epidemiologic evidence suggests that the incubation period of infectious mononucleosis is greater than 4 weeks. The most common symptoms are sore throat, fever and lymphadenopathy. The exudative pharyngitis is often severe and associated tonsillar swelling can cause difficulty swallowing. Fever is almost universal, and lymphadenopathy is present in approximately 90% of patients at some point during the course of the illness. Headache, anorexia, malaise and fatigue are common. Less common symptoms present in less than 25% of cases include parotitis, conjunctivitis and myalgias. Lymphadenopathy is most commonly cervical but can also be generalized. The enlarged nodes are mobile and only mildly tender. A rash that is usually non-pruritic is seen in less than 10% of patients. Administration of ampicillin during the course of illness leads to a typical pruritic, maculopapular eruption that can be diffuse. Splenic enlargement is common and has been reported to be detectable by physical examination in 15-50% of patients in various studies. However, based on ultrasound examination, splenic enlargement is probably universal. Hepatic enlargement is less common and less prominent. Palatal enanthems and jaundice occur in less than 10-15% of patients. Asymptomatic elevations in transaminases occur in the majority of patients. Many aspects of this clinical syndrome, e.g. fever, lymphadenopathy, splenomegaly, atypical lymphocytosis, are due to the vigorous NK and T cell proliferation and cytokine response of the immune system rather than direct viral infection, replication, and cytolysis. The syndrome of mononucleosis with atypical lymphocytosis can also be seen during primary infection with several other viruses including human cytomegalovirus, HIV, and human herpesvirus 6 (HHV-6), with CMV being the most common. Toxoplasmosis is another less common cause of a mononucleosis-like syndrome with lymphadenopathy. Occasional serious and life-threatening complications of EBV infection occur and include autoimmune hemolytic anemia, erythrophagocytic syndrome, thrombocytopenia, splenic rupture and neurologic syndromes (81). The latter, although rare, include encephalitis and Guillain Barre syndrome. Oral Hairy Leukoplakia: Oral hairy leukoplakia is a benign white lesion most commonly seen on the lateral surface of the tongue. Oral hairy leukoplakia is almost exclusively seen in patients with HIV infection and occasionally in patients with other types of chronic immunosuppression. The lesions are not friable and the main differential diagnosis is oral candidiasis. The diagnosis is usually made clinically based on the appearance of the lesion. Biopsies are positive for EBV genomes by in situ hybridization and immunofluorescent staining. EBV-Induced Lymphoproliferation: The clinical presentation of PTLD is highly variable (For review see (23). Most cases occur within the first year although cases have been reported nine years after transplantation. Symptoms are similar to those of primary EBV infection and include fever, malaise, and lymphadenopathy. The disease can progress rapidly, underscoring the need for a high index of clinical suspicion in high-risk patients. The lymphoproliferations can range from a polyclonal lymphoproliferation to frank lymphoma. Lymphoma developing in the setting of PTLD is usually of diffuse large-cell type. Chronic Active EBV Infection: Rare patients have an unusual clinical course following infectious mononucleosis and develop a chronic active infection characterized by ongoing lytic EBV replication and multiple organ system disease, such as pneumonitis, hepatitis, pancytopenia and iritis (78). These patients typically have extremely high antibody responses to EBV early antigens, lack antibodies to EBNA-1, and exhibit severe disease with end organ involvement or evidence of increased viral load in affected tissues (50, 78, 83). X-Linked Lymphoproliferative Disease: Individuals with a rare, inherited X-linked immunodeficiency known as X-linked lymphoproliferative syndrome or Duncan’s syndrome, are at risk for overwhelming lethal primary infection with Epstein-Barr virus (6, 66). The clinical presentation is that of a fulminant infectious mononucleosis syndrome with typical and severe symptoms of infectious mononucleosis. In addition, patients often develop a severe hepatitis usually culminating in fatal hepatic failure. Patients may also develop erythrophagocytic syndrome. Survivors are at risk for the subsequent development of lymphoma and dysgammaglobulinemia. The genetic defect in these patients has been mapped to a small cytoplasmic protein SAP, implicated in regulation of T and NK cell signaling (9). Genetic defects in the SAP gene lead to a defect in the development of NKT cells in both mice and humans, suggesting a mechanism for the development of deficient antiviral responses (8, 58). EBV Associated Malignancies (Burkitt’s lymphoma, Nasopharyngeal carcinoma, Hodgkin’s lymphoma): Burkitt’s lymphoma usually presents with lymphadenopathy or an abdominal mass and is much more common in children than in adults . Burkitt lymphoma is an extremely rapidly-growing tumor and disseminated disease involving bone marrow and CNS is common. It should be emphasized that rapid diagnosis and treatment of Burkitt lymphoma is extremely important as the response and cure rate is greater than 70% with appropriate initial therapy whereas salvage therapy is markedly less successful. Hodgkin’s lymphoma usually presents as lymphadenopathy. Mediastinal adenopathy occurs in over 50% of patients and B symptoms such as fever and weight loss are common. Hodgkin’s lymphoma has also been associated with a large variety of unusual paraneoplastic manifestations including skin or CNS abnormalities, nephrotic syndrome, hemolytic anemia and thrombocytopenia. Hodgkin’s lymphoma has a very high cure rate and relapses have been successfully treated with intensive chemotherapy and stem cell transplantation. Nasopharyngeal carcinoma of the undifferentiated type is essentially 100% EBV-associated. As mentioned earlier, this type of nasopharyngeal carcinoma is common in Southeast Asia and is also found in Northern African and Inuit populations but is rare in other geographic areas. Diagnosis is often delayed and patients may present with metastatic head and neck masses. Serological screening or high-risk populations for IgA antibodies against VCA and early antigen allows identification of early cases for close monitoring. Definitive diagnosis requires endoscopic biopsy and demonstration of EBV antigen or Epstein-Barr virus-encoded RNA (EBER) expression in malignant tissue. Endoscopic brushing with measurement of EBV DNA load and specific EBV mRNAs expressed in tumors may allow less invasive diagnostic testing and follow-up (80). Laboratory Diagnosis Guided Medline Search Laboratory confirmation of EBV infection is primarily achieved by serological testing. Heterophile antibodies directed against sheep erythrocyte agglutinins are positive in about 90% during the primary infection. Commercially available Monospot testing for heterophile antibodies is less sensitive in children, and sequential Monospot testing or determination of EBV-specific antibodies is indicated when the clinical findings are suggestive of EBV infection but the initial Monospot is negative. In the clinical setting in which the young adult patient has typical infectious mononucleosis, a Monospot will confirm the diagnosis in more than 90% of cases. Unless the history suggests the possibility of other infections such as HIV, a battery of viral serologies is not routinely necessary. If the presentation is atypical but suggestive of infectious mononucleosis, and the Monospot is negative, EBV serology can confirm the diagnosis or indicate whether testing for other pathogens such as CMV, toxoplasmosis may be appropriate, based on the clinical presentation and history. The presence of IgM antibodies to viral capsid antigen (VCA) is the most sensitive and specific indicator of acute infection (Table 1). These are usually detectable at the initial presentation, along with IgG VCA Abs. IgM VCA antibodies, however, decline and are absent by 4-8 weeks, whereas IgG VCA Abs persist for life (18, 37). Therefore, IgG VCA antibodies are not usually useful in diagnosing infectious mononucleosis since virtually all patients are IgG positive by the time they seek medical attention. Antibodies to EBNAs do not develop until approximately 4 weeks after onset of symptoms, and persist for life (33). Seroconversion to anti-EBNA positivity is therefore indicative of recent EBV infection. Although antibodies to EBV early antigens are often elevated during acute infection, they may persist for variable periods and are occasionally detectable in healthy convalescent patients many years after infection, and are therefore of limited utility in diagnosing acute infection (37). At the time of presentation, VCA IgM antibodies are positive, and VCA IgG and early antigens are also usually positive. As convalescence proceeds, EBNA antibodies become detectable and VCA IgM disappears. EBNA and VCA IgG antibodies remain detectable for life and early antigen antibodies are also usually detectable though at low titers. Hurt C, et al. Diagnostic Evaluation of Mononucleosis-Like Illnesses. Am J Med 2007;120:911.e1-8. Post Transplant Lymphoproliferative Disease (PTLD): Quantifying peripheral blood EBV DNA load by polymerase chain reaction is used to identify immunosuppressed patients with or at high risk for developing EBV-associated B cell lymphomas. Although an elevated blood EBV DNA load is clearly associated with the development of PTLD, the predictive value of such a finding is not uniformly high, since only approximately 50% of hematopoietic stem cell transplantation patients with an elevated EBV DNA develop PTLD. An increasing EBV DNA load may be predictive of the development of PTLD, underscoring the need for serial monitoring in high-risk patients. Pathogenesis Guided Medline Search After resolution of primary infection, EBV persists for life as a latent infection in B cells and as a lytic infection in the oropharynx. Persistent EBV infection is controlled by a virus-specific immune response and is asymptomatic in most humans. However, immunosuppression associated with HIV infection, transplantation, or congenital immunodeficiencies can result in uncontrolled oligoclonal or monoclonal B cell proliferation of latently infected cells. Uncontrolled lytic infection in the oropharynx is manifested as oral hairy leukoplakia in immunosuppressed hosts (24). Persistent, latent EBV infection is also associated with development of Burkitt’s lymphoma, nasopharyngeal carcinoma, certain types of Hodgkin’s lymphoma, gastric adenocarcinoma, and leiomyosarcomas in immunosuppressed hosts (38). Infection of NK cells by EBV has recently been associated with hypersensitivity to mosquito bites and the development of NK cell leukemia (41). Patients who experience infectious mononucleosis as a consequence of primary infection may have a long-lasting and possibly permanent down-regulation of the IL-15 receptor IL15Rα on T and NK cells (75). Since IL-15 is involved in the generation and maintenance of memory CD8+ T cell populations, it is possible that symptomatic EBV infection may have long-term effects on immunologic function. The pathogenesis of EBV-associated disease is closely correlated with the proliferative stimulus of EBV on the infected cell and the immune status of the host. Thus, EBV causes lymphoproliferative lesions that range from Burkitt’s lymphoma to Hodgkin’s lymphoma or transplant-associated lymphomas. Infection of nasopharyngeal epithelium can lead to nasopharyngeal carcinoma or to hairy leukoplakia in the immunosuppressed host. The pattern of EBV latent infection gene expression in each of these diseases is distinct (1). Many of the proteins expressed by EBV have been identified as having either growth-promoting, anti-apoptotic or immune evasion function. Vaccination, immunomodulation, or pharmacologic intervention of important cell-signaling pathways usurped by viral gene products might provide more effective therapeutic strategies against EBV-associated malignancies than traditional anti-viral drugs designed to block viral replication. Review Article: Macsween KF, Crawford DH. Epstein-Barr virus-recent advances. Lancet Infect Dis. 2003 Mar;3:131-40. Review Article: Funk GA, et al. Viral dynamics in transplant patients: implications for disease. Lancet Infect Dis 2007;7:460-472.
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo Because EBV infection typically results in latent infection, rather than a lytic infection associated with plaque formation, EBV sensitivity to conventional antiviral drugs cannot be assayed by conventional plaque reduction assays. Instead, latently infected cell lines are used in which cells can be induced for lytic viral replication in the presence or absence of potential antiviral agents. Antiviral activity is measured by quantifying viral DNA and is expressed as the concentration of drug required to inhibit 50% of viral DNA replication induced by lytic infection (IC50). Using these types of assays, acyclovir has an IC50 of 0.3 uM for EBV, and ganciclovir has an IC50 of 0.05 uM for EBV (11, 42, 47). It was originally hypothesized that acyclovir was effective against EBV in the absence of an EBV-specified thymidine kinase (61), but EBV does encode a thymidine kinase (BXLF1) that was belatedly discovered due to the difficulties of inducing EBV lytic replication in vitro (48). The EBV thymidine kinase shares approximately 50% amino acid similarity with the HSV thymidine kinase and can utilize acyclovir and ganciclovir as substrates. Similarly, the EBV DNA polymerase shares approximately 70% amino acid similarity with the HSV DNA polymerase reflecting the common heritage of lytic replication mechanisms. The conserved mechanisms of lytic replication among herpesviruses suggests that other antiviral drugs developed against herpes simplex or cytomegalovirus replication may have activity against EBV lytic infection. Despite the effectiveness of acyclovir against EBV lytic replication, acyclovir has no inhibitory activity on replication of the episomal EBV genomes present in latent infection. Thus, acyclovir will inhibit production of linear genomes in the minority of cells entering lytic infection in an EBV-infected B cell line, but episomal DNA is replicated by cell DNA polymerases and is unaffected by acyclovir in the majority of EBV-infected B cells that are latently infected. Once acyclovir is removed, lytic replication can resume from the latent EBV genomes (10, 61). Thus, immortal B cell growth induced by latent EBV infection is unaffected by acyclovir treatment in vitro, and these in vitro studies are consistent with the clinical experience that nucleoside analogues have little effect on EBV-induced malignancies associated with latent EBV infection.
ANTIVIRAL THERAPY Guided Medline Search Smart search Infectious Mononucleosis The issue of whether nucleoside analogues might be effective during primary gammaherpesvirus infection, where viral replication is more likely to play an important pathogenic role, has been extensively studied in infectious mononucleosis. In 6 different studies involving a total of approximately 320 patients, oral or intravenous acyclovir therapy consistently reduced or eliminated lytic EBV infection during therapy as detected by virus shedding in oropharyngeal secretions but had no effect on clinical outcome, duration of symptoms, or establishment of persistent infection in the oropharynx or peripheral blood B lymphocytes (2, 3, 62, 86, 87, 89). Thus, acyclovir can effectively inhibit lytic EBV replication in vivo, but acyclovir treatment initiated after the onset of symptoms has no clinical benefit in infectious mononucleosis most likely because latent infection has already been established and the vigorous host immune response to virus infection responsible for the majority of symptoms has been triggered. In rare, complicated cases of primary EBV infection and infectious mononucleosis where the patient is immunosuppressed or severely ill, acyclovir or ganciclovir treatment may be rational given the safety profile of these drugs, its ability to inhibit EBV replication in vitro and in vivo, and anecdotal reports of clinical response in unusual cases where excessive EBV replication may have been pathogenic (16, 39, 60, 78). Oral Hairy Leukoplakia Oral hairy leukoplakia is an unusual lesion of the tongue found in HIV-infected patients. Vigorous EBV lytic replication is present in the excessively proliferating epithelium. This is the only instance where disease appears to be a direct consequence of lytic EBV replication, and oral acyclovir therapy (3.2 gm/day) can temporarily reverse the lesions (68). However, recurrence could be due to reactivation of persistent infection or reinfection lytic EBV replication and oral hairy leukoplakia frequently recur upon withdrawal of therapy. EBV-Induced Lymphoproliferations Associated With Immunosuppression EBV-infected monoclonal or polyclonal B cell proliferations can arise during immunosuppression associated with congenital immunodeficiencies, transplantation, or HIV infection. Since latent EBV infection is responsible for driving uncontrolled B cell growth, nucleoside analogues generally are not effective against such lymphoproliferative disease. While there are case reports that early, polyclonal EBV-induced B cell proliferations may respond to nucleoside analogues (27, 29) more aggressive or monoclonal EBV-induced B cell lymphoproliferations are generally not responsive to acyclovir (28, 29, 82). Some have suggested that a more active nucleoside analogue such as ganciclovir might be more effective against EBV-induced B cell lymphoproliferations. However, there is limited evidence to support this hypothesis, and it is counter-intuitive to the underlying pathogenesis of latent EBV infection. Phase II/III clinical trials are underway to assess the feasibility of chemically inducing lytic gene expression in the proliferating EBV-infected cells in lymphoproliferative disease and killing the induced cells with ganciclovir. Specifically, EBV thymidine kinase expression may be induced in EBV-infected cells by treatment with arginine butyrate, rendering the cells susceptible to killing by ganciclovir (19). There are no currently available antiviral agents that have been clinically demonstrated to be effective against latent EBV infection. Chronic Active EBV Infection and Chronic Fatigue Syndrome Both clinical responses and failures with acyclovir or corticosteroids have been noted in anecdotal reports of these rare patients with chronic active EBV infection (78, 84). A placebo controlled study with acyclovir has shown no efficacy for patients with chronic fatigue syndrome (85). EBV-Associated Malignancies (Burkitt’s Lymphoma, Nasopharyngeal Carcinoma, Hodgkin’s lymphoma) There is no effective antiviral therapy for the Burkitt’s lymphomas, nasopharyngeal carcinoma, and Hodgkin’s lymphoma associated with EBV infection, and treatment is usually based upon cancer chemotherapy. Adoptive transfer of EBV-specific cytotoxic T lymphocytes may also be useful for treating these types of EBV-associated malignancies (73). Boosting of the immune response to EBV latent antigens by expressing these genes in dendritic cells may offer promise for treatment of relapsed Hodgkin’s lymphoma (21). Novel pharmacologic approaches against latent EBV infection may be another approach for treating these diseases. Antisense oligonucleotides may be used to disrupt specific essential latent gene functions, such as EBNA-1 binding and maintenance of the latent EBV episome (43). Delineation of the cell signaling pathways used by EBV latent genes, such as the Tumor Necrosis Factor Receptor pathway by LMP1 (56), may provide unique opportunities to block virus induced cell proliferation or to induce apoptosis of virus infected cells.
ADJUNCTIVE THERAPY Guided Medline Search General Treatment of EBV-associated diseases is closely linked to the underlying pathogenesis of the disease. Infectious Mononucleosis Supportive treatment is generally indicated since more than 95% of infectious mononucleosis cases resolve uneventfully without specific therapy. Acetaminophen can be used to reduce fever. Use of concomitant antibiotics for possible bacterial pharyngitis should be judicious and supported by positive culture results due to the high incidence of allergic reactions to antibiotics such as ampicillin during acute infectious mononucleosis. The use of corticosteroids for uncomplicated infectious mononucleosis is still controversial. Corticosteroids have been shown to reduce fever and shorten the duration of constitutional symptoms (7, 12, 45, 65, 79). However, adverse drug complications can arise from even short courses of corticosteroid use (12, 88), and corticosteroid use is probably best avoided for routine infectious mononucleosis, a self-limited disease. Corticosteroid use is generally reserved for infectious mononucleosis cases complicated by potential airway obstruction from enlarged tonsils, severe thrombocytopenia, or severe hemolytic anemia (13, 65, 81). These complications result from the excessive immune response to virus infection rather than uncontrolled viral infection, and a short course of corticosteroids at 1 mg/kg/day of prednisone with tapering over 1-2 weeks can be effective for treating the excessive tonsillar proliferation or autoimmune symptoms. Corticosteroids might also be used for other autoimmune complications rarely associated with infectious mononucleosis such as CNS involvement, myocarditis or pericarditis (49). Unless contraindicated, it is our general practice to administer acyclovir concurrently with corticosteroids. Splenic rupture is a rare but potentially fatal complication of infectious mononucleosis and occurs in approximately 0.1% of cases of infectious mononucleosis (4, 20). Splenic rupture is more common in males and approximately half the cases are spontaneous (not associated with trauma or other contributory factors). In one review of 55 cases of infectious mononucleosis-associated splenic rupture, all cases occurred within three weeks after the beginning of illness. Another case-control study which combined physical, ultrasound and laboratory examinations of infectious mononucleosis patients found that physical examination was an insensitive method of detecting splenomegaly (17%), but all patients were found to have splenomegaly for the first 20 days, and the severity of laboratory abnormalities did not correlate with splenic enlargement (17). Although various strategies to minimize the risk of splenic rupture have been advanced, incorporating the results of physical exam and ultrasound imaging, no studies have validated the utility of such approaches. It therefore seems prudent to recommend avoidance of contact sports or activities that raise intra-abdominal pressure such as weight lifting for a minimum of four weeks after the onset of illness. Patients recovering from infectious mononucleosis may shed virus in saliva for periods of several months after recovery despite being clinically well (See Epidemiology above). Furthermore, it is clear that all latently infected humans may intermittently shed EBV in saliva. It is therefore difficult for seronegative subjects to avoid the risk of acquiring EBV infection. It appears that intimate sexual contact is more likely to transmit EBV infection. EBV-Induced Lymphoproliferation If possible, the treatment of choice is to reduce the level of immunosuppression (82). However, in hematopoietic stem cell transplantation, this is rarely possible since patients have received immune-ablative therapy. Anti-B lymphocyte monoclonal antibodies specific for the B cell antigen CD20 (rituximab) are commonly used as therapy for imminent or active PTLD (46). Although impressive success rates in excess of 70% have been reported, the long term effects of profound global B cell depletion are unknown. Recently, investigators have successfully treated EBV-induced lymphoproliferative disease by augmenting the host’s immune response through adoptive transfer of EBV-specific cytotoxic T cells grown in vitro (72, 73, 74). In PTLD arising in the setting of hematopoietic stem cell transplantation, the donor’s T cells are harvested prior to transplantation and stimulated in vitro with an EBV-infected B cell line which can also be generated from the donor. Cytotoxic T cells specific for EBV antigens are stimulated and expanded in vitro. After transplantation, patients are monitored for EBV viral load by polymerase chain reaction for viral DNA in peripheral blood lymphocytes. If the viral load begins to increase beyond acceptable levels or if EBV-infected tumors are detected, the EBV-specific cytotoxic T lymphocytes are infused. These cytotoxic T lymphocytes amplify in vivo and persist long-term. Adoptive transfer of EBV-specific cytotoxic T lymphocytes has been shown to reduce the incidence of EBV-associated lymphoproliferative disease and to induce regression of established EBV-infected lymphoproliferations (34, 76). Complications due to the inflammatory response associated with cytotoxic T lymphocyte treatment in sensitive anatomic locations such as the airway or gastrointestinal tract have been observed. In addition, tumors infected with escape mutants of EBV that are not recognized by the epitope-specific cytotoxic T lymphocytes have also arisen (22). The risk for such mutants is particularly high where the tumor burden is large. Infusion of EBV-specific cytotoxic T lymphocytes, although an attractive form of specific therapy, requires two to three months and the expertise in cytotoxic T lymphocytes generation. In patients with solid organ transplants, reduction in immunosuppression is ideal but often carries the risk of endangering graft and/or patient survival. Adjunctive therapy, including interferon, IL-6, and cytotoxic T lymphocytes have been used, but must be considered unproven therapy although favorable results have been reported. As in the case of hematopoietic stem cell transplantation, rituximab has been used with varying degrees of success. X-Linked Lymphoproliferative Disease Hematopoietic stem cell transplantation performed during childhood with HLA-identical sibling donors, regardless of EBV serologic status, offers potentially curative therapy for X-linked lymphoproliferative disease (25). EBV-Associated Malignancies (Burkitt’s Lymphoma, Nasopharyngeal Carcinoma, Hodgkin’s lymphoma) The usual treatment for EBV-associated malignancies is based on cancer chemotherapy and radiation therapy as opposed to antiviral strategies. As mentioned above, the progression of some of these malignancies can be extremely rapid and referral to a specialized oncology center is essential for prompt diagnosis, staging, and appropriate initial therapy.
VACCINES Guided Medline Search Potential strategies for EBV vaccination include prophylactic approaches (to prevent infection or attenuate morbidity associated with primary infection/infectious mononucleosis), post-infection approaches (to reduce or eliminate persistent EBV infection and risk of EBV-associated malignancies), and therapeutic approaches (to treat established EBV-infected malignancies). Most work has focused on the EBV major membrane glycoprotein, gp350, as a potential EBV vaccine (54). EBV binding to the cellular receptor, CD21, is mediated by gp350 (57), and a gp350 subunit vaccine can prevent the development of lymphomas after injection of EBV in a cotton-top tamarin animal model for EBV infection (52, 53, 67). A small trial with a recombinant gp350 vaccinia virus vaccine showed that it can induce EBV neutralizing antibodies in human volunteers. However, 3/9 vaccinated volunteers with neutralizing antibody were subsequently infected with EBV by natural routes of transmission (26). A recently completed phase II trial showed that the EBV gp350 subunit vaccine was associated with a decreased risk of infectious mononucleosis in a cohort of students. More studies will be required to determine the role of humoral versus cellular immunity, the importance of mucosal immunity, the optimal adjuvant and delivery system for gp350 vaccines, and whether a gp350 vaccine will decrease the increased risk of malignancy associated with EBV infection. In this regard, attenuation rather than prevention of infectious mononucleosis by the vaccine may be sufficient to decrease the risk of malignancy associated with severe primary infection. It remains to be shown whether gp350 represents the optimal candidate for an EBV vaccine. Vaccines that induce cytotoxic T cell activity against EBV latent genes have also been proposed as a potentially effective vaccine strategy. Preliminary trials in volunteers using synthetic peptides of multiple fused EBV cytotoxic T lymphocyte epitopes are also underway (44). An animal model in rhesus monkeys that reproduces the natural route of oral transmission and other aspects of acute and persistent EBV infection has recently been established and the complete sequence of the rhesus EBV homolog has been determined (51, 71). These advances should be useful for the development of effective EBV vaccine strategies.
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