OVERVIEW: What every clinician needs to know

Pathogen name and classification

Epstein-Barr Virus (EBV) belongs to the family Herpesviridae, subfamily Gammaherpesvirinae, genus Lymphocryptovirus.

Mature infectious particles, which are composed of a 172-kb, double-stranded deoxyribonucleic acid (DNA) genome, capsid, protein tegument, and lipid-containing outer envelope, are 150 to 200nm in diameter. The viral capsid is icosahedral and composed of 162 capsomeres. As other herpes virus, EBV is fragile and easily inactivated or degraded.

What is the best treatment?

  • For acute uncomplicated infectious mononucleosis (IM) management consists of supportive care, including rest, fluids, and antipyretics. Acetaminophen and saline gargles usually control the discomfort caused by enlarged lymph nodes and pharyngitis. Several double-blind, controlled studies of corticosteroids for the treatment of IM have shown either no or only modest short-term benefit. Their use should be considered only for the treatment of severe cases characterized by obstruction of airway or thrombocytopenic purpura.

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  • Antiviral agents, such as aciclovir, famciclovir, penciclovir, ganciclovir, and other nucleoside analogues, act on the lytic phase of EBV replication. They are preferentially incorporated into viral DNA through the action of EBV thymidine kinase and inhibit EBV DNA polymerase and subsequent virion production. Ganciclovir can inhibit EBV-induced B-lymphocyte immortalization; its antiviral effect after drug withdrawal is more prolonged than that of aciclovir.

  • There is in vitro activity of the above mentioned drugs; however, there is no clinical benefit when administered to patients with uncomplicated IM. That is, the virus is susceptible in vitro but resistant in vivo.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology

    Most reports have indicated no seasonal predilection.

    Patients from lower socioeconomic groups are at higher risk of acquiring the infection early in life. In these groups of patients, intrafamiliar propagation is frequent. Endemic infectious mononucleosis is frequent in college students living in close contact, such as those living in dorms and frequenting other educational facilities.

    It is an ubiquitous infection. Serologic studies performed in different parts of the world have discovered a high prevalence (80-95%) of past infection in normal adults, with most infections occurring during infancy and childhood. The age at initial (primary) infection varies in different cultural and socioeconomic settings. In developing countries, EBV infection occurs early in life with 80-100% of children becoming infected by 3 to 6 years of age. In higher socioeconomic groups and industrialized countries the infection takes place later in life. An IM case rate of 60 to 75% is associated with primary infection in US college students. A high rate of primary EBV infection has been reported in siblings of a pediatric case of IM. A higher rate of infection has been noted in white persons than in other ethnic groups, and a modest increase of infection in males than in females.

    Primary infections during pregnancy, but not reinfection have been associated with fetal involvement. Transmission via breast milk is unclear.

    There is scarce evidence of EBV transmission and IM illness with sexual intercourse and closely related behaviors. EBV has been detected in genital ulcers, the uterine cervix, and the male reproductive tract. These findings raise the potential for venereal transmission.

    There is no clear evidence of an increasing rate of infection over the last decade.

  • Infection control issues

    EBV is shed regularly in saliva, and, therefore, infection control policies are difficult to develop. In addition, mechanisms for its transmission are not clearly understood. For the hospitalized patient, standard precautions are recommended. Transmission can also occur through blood products and organ transplantation; thus, persons with a recent EBV infection or IM like-illness are urged to refrain from donating blood or organs.

    A safe and efficacious vaccine is not available, although efforts continue on its development. Because of concern over the administration of a vaccine with unknown long-term effects, including malignancy, most vaccine development attempts have focused on development of subunit EBV vaccines. These types of vaccines have shown to be immunogenic and well tolerated; recipients were not protected from EBV infection; however, symptoms of IM were reduced. An effective vaccine is needed for persons at high risk for development of EBV-associated lymphoproliferative diseases (LPD) and cancer, such as patients with acquired immunodeficiency syndrome (AIDS), those with X-linked LPD, and organ transplant recipients.

    Adults and children at high risk for developing post-transplant LPD (e.g., EBV seronegative persons and infants aged less than 12 months) are generally given prophylactic anti-Cytomegalovirus (CMV) IG (e.g., Cytogam) and an antiviral, such as aciclovir, ganciclovir, famciclovir, penciclovir, and other nucleoside analogues, following transplantation. There are data from North America and Europe suggesting a beneficial effect of anti-CMV-IG for the prevention of B-cell lymphomas in adult renal transplant recipients.

What host factors protect against this infection?

  • EBV is a herpetic lymphotropic microorganism; latently infected B-cells are its primary reservoir in the body, although monocytes may also play a role in its latency. In the acute phases of the infection, proliferating EBV-infected B-cells are controlled primarily by natural killer (NK) T-cells, helper (cluster of differentiation [CD]4+) T-cells, and cytotoxic-suppressor (CD8+) NK T-cells. After this T-cell response, the number of EBV infected cells drops significantly during the next 4 to 6 weeks. During convalescence, human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes maintain EBV under control by targeting the latently expressed Epstein-Barr nuclear antigen (EBNA)-3 protein.

  • The histopathology will vary according to the clinical syndrome or disease caused by EBV. Most cases of acute IM are benign, and the diagnosis is based on clinical and serologic findings, thus, histopathology examination of tissues is rarely required. There is information on tissues, such as lymph nodes, tonsils, and spleen, from patients with unusual disease that requires surgery. Most histopathologic changes due to EBV infection have been attained from patients with LPD and other serious complications.

    The lymph nodes show active lymphoid follicles with lymphoid proliferation of the sinuses, blood vessels, trabecula, and capsule (this latter one usually remains intact). The response is mediated mainly by T and B immunoblasts with a pleomorphic pattern and mitosis indicative of rapid cell turnover. Small and large atypical lymphocytes can be seen, as well as plasma cells, eosinophils, histiocytes, and micronecrosis.

    The tonsils also contain an active lymphoproliferative response with more prominent follicles and extensive necrosis.

    The spleen is enlarged two to three times its normal size and weight during the acute stage of the infection because of hyperplasia of the red pulp. As in lymph nodes, the cells are primarily immunoblasts with pleomorphism; subcapsular hemorrhage is commonly encountered.

    The liver shows minimal disease with infiltration by lymphocytes and monocytes in the portal area and minor degeneration of the hepatocytes.

    The bone marrow can appear normal during acute IM; however, there have been reports of hypercellularity and small granulomas.

    The central nervous system (CNS) shows, when involved, lymphocytic infiltration of the meninges. Less commonly, there can be demyelinization, degenerative changes, focal hemorrhages, congestion, and edema.

  • Histology of EBV-associated malignancies

    Non-Hodgkin lymphoma (NHL): Its most common form is Burkitt lymphoma (BL), which has uniform layers of small noncleaved cells. Most CNS NHL tumors are composed of large cells containing monoclonal EBV DNA. In EBV-related LPD syndromes and B-cell lymphomas (collectively named post-transplantation lymphoproliferative disorder [PTLD]), the histologic findings range from benign lymphoid hyperplasia with normal tissue architecture and a pleomorphic response (polyclonality) to well defined malignant lymphomas.

    Hodgkin disease (HD): As few as 1% of the tumor cells are neoplastic in nature. There are diffuse inflammatory cell infiltrates; some of the neoplastic cells have classically been termed Red-Sternberg cells and mononuclear Hodgkin cells (collectively termed as H-RS cells). These cells are large, and their multinucleated pattern is evidence derived from germinal centers of B-cells. Their nucleoli are strongly stained and surrounded by a clear area resembling a halo. The World Health Organization (WHO) has recently redefined the classification system into two groups: nodular lymphocytic-predominant HD and classic HD. The classic HD includes four categories: lymphocyte rich; nodular sclerosis; mixed cellularity; and lymphocyte depleted. EBV DNA can be found in as much as 40% of HD tissues. The sclerosing variety is most commonly found in children with HD.

    Epithelial tumors of the nasopharynx: In children, the most common type of epithelial cells is the undifferentiated variety characterized by undifferentiated squamous cells with multiple copies of monoclonal EBV DNA.

    Other EBV virus-associated diseases: Tissues of patients with hemophagocytic lymphohistiocytosis (HLH), such as bone marrow, spleen, lymph nodes, brain, and skin can be affected. The bone marrow shows hypocellularity, mainly activated macrophages with engulfment of all bone marrow elements, their precursors, or fragments, including erythrocytes, platelets, and leukocytes.

    Oral hairy leukoplakia: Tissues of patients (usually adults with AIDS) with this disorder show keratin or parakeratin projections, acanthosis, ballooning, hyperparakeratosis, and hyperplasia of the prickle cell layer. Mild inflammatory cell infiltrates in the connective tissue can be seen.

What are the clinical manifestations of infection with this organism?

  • Infectious mononucleosis (IM): It is the most common illness associated with infection by EBV.

    Clinical manifestations

    The incubation period is approximately 4 to 6 weeks, whether acquired through contact with infected secretions or after a blood transfusion. The prodrome lasts 3 to 5 days and is that of mild headache, malaise, and fatigue. These symptoms are usually followed by the onset of fever with body temperature of 39ºC, which falls gradually over the next 6 days. In severe cases, temperature may remain greater than 40ºC for 2 weeks of longer.

    Younger children are more likely to be afebrile.

    Generalized lymphadenopathy is a hallmark of IM; any group of lymph nodes can be involved; however, those of the anterior and posterior cervical chains are the most frequent. They are tender, firm, usually single, 2 to 4cm in diameter, and not matted. Massive mediastinal and hilar lymph nodes can cause respiratory distress. Mesenteric lymphadenopathy can mimic acute appendicitis. Lymph node enlargement tends to subside over a period of days to weeks.

    Pharyngitis characterized by sore throat is the cardinal symptom of IM. Tonsils are enlarged, can cause obstruction of the airway, and are reddened, tender, and covered with an exudate in over 50% of patients. Petechiae in the junction of the hard to the soft palate are present in 25% of the patients between days 5 and 17. Pharyngitis caused by EBV is clinically indistinguishable of that caused by group A streptococci.

    The spleen is enlarged in up to 50% of patients by the second and third weeks of illness. Rarely, spontaneous or trauma-induced rupture of the spleen can lead to hemorrhage, shock, and death. Once splenomegaly is detected, repeated splenic examination should be avoided. The triad of lympadenomegaly, splenomegaly, and exudative pharyngitis in a febrile patient is typical but not pathognomonic of IM caused by EBV.

    Hepatomegaly is present in 10 to 15% and hyperbilirubinemia in 25%; moderate elevation of hepatic transaminases can be found in 80% of the cases. Jaundice develops in less than 5% and is usually mild and direct.

    Hepatitis can occur with anorexia and vomiting.

    Dermatologic manifestations

    3 to 19% of the patients with IM develop dermatitis. The rash involves mainly the trunk and arms and rarely palmar and solar regions. It appears during the first few days of illness and lasts 1 to 6 days. It can be erythematous, macular, papular, or morbilliform. Sometimes, it can be urticarial or scarlatiniform or acrocyanotic. Rarely, it is petechial, vesicular, umbilicated, or hemorrhagic. Rashes resembling those of Gianotti-Crosti syndrome and secondary syphilis have been described.

    An increased incidence and severity of rash can occur in patients with EBV IM who are prescribed beta-lactam antibiotics, mainly ampicillin or amoxicillin. It is copper-colored, appears mainly in the trunk, and it can develop into an extensive, confluent, maculopapular pruritic eruption that extends to palms and soles. It can persist for up to 1 week, with desquamation taking place over several more days. Rash does not represent hypersensitivity to beta-lactams. Similar rashes have been described in EBV infected individuals following the use of azithromycin and cefprozil.

    Eyelid edema occurs in up to 50% of cases early in the disease, probably as a result of lymphatic obstruction.

    Pulmonary manifestations

    A small percentage of the patients can develop paroxysmal cough and radiographic findings of patchy alveolar and interstitial pneumonia.

    Nervous system manifestations

    Neurologic disorders can occur in association with clinical findings typical of IM. These include aseptic meningitis, encephalitis, Guillain-Barré syndrome, optic neuritis, cranial nerve palsy, transverse myelitis, acute cerebellar ataxia, dysautonomia, subacute sclerosing panencephalitis, psychosis, Parkinson-like syndrome, and CNS lymphoma.

    Cardiac manifestations

    Electrocardiographic and echocardiographic abnormalities, as well as pericarditis and myocarditis, have been reported.

    Hematologic manifestations

    Occasionally, patients develop transient thrombocytopenic purpura.

    Other rare complications are hemolytic anemia, aplastic anemia, agranulocytosis, and agammaglobulinemia.

    Miscellaneous manifestations

    Protean complications include unilateral or bilateral orchitis, interstitial nephritis, acute renal failure, and glomerulonephritis.

    Pancreatitis, ocular involvement, arthritis, proctitis, genital ulcers, extrahepatic biliary obstruction, and hydrops of the gallbladder have been reported.

    Mortality

    Deaths from IM in otherwise healthy individuals are rare. Causes of death, in decreasing order of frequency, are neurologic complications, secondary infections, splenic rupture, hepatic failure, and myocarditis. The mortality rate has been estimated to be less than 1 per 3,000 cases in England and Wales.

  • Congenital infection: There are scant reports of infants with birth defects attributed to congenital infection following maternal primary EBV infections. These defects have included cataracts, cryptorchidism, hypotonia, and mild micrognathia. Also, radiological findings of a “celery stalk” appearance of long bones, similar to that of congenital rubella, have been noted. One prospective study of 700 pregnant women with serologic evidence of EBV primary infection during pregnancy showed that they were several times more likely to result in early fetal death and premature labor or delivery. Whether these various conditions are associated with EBV is unknown. Another prospective study of 4,000 pregnant women failed to document intrauterine EBV infection.

What common complications are associated with infection with this pathogen?

  • Disseminated EBV Infection in X-linked LPD (XLP): Overwhelming EBV infection occurs rarely in immunocompetent patients. It is more frequent in children with primary immunodeficiencies, mainly in boys with XLP. The initial clinical presentation can be that of IM; however, fulminant disease subsequently develops and can lead to death due to uncontrolled lymphoproliferation, acute hemorrhage, meningoencephalitis, liver failure, and bacterial suprainfection. Survivors often have hypogammaglobulinemia, and later on they can develop B-cell lymphomas.

  • Hemophagocytic lymphohistiocytosis (HLH): HLH, also called hemophagocytic syndrome, consists of engulfment of bone marrow elements and their precursors by activated macrophages. Patients present with fever, splenomegaly, pancytopenia, and hemophagocytosis in lymphoproliferatve tissue or reticuloendothelial system organs, such as lymph nodes, spleen, and bone marrow. HLH has been associated with viral infections, mainly with EBV infection. It can be hereditary, mainly in children with XLP; these patients present a disseminated EBV infection with features of HLH. Primary EBV infection in patients with HLH leads to an EBV-driven T-cell proliferation and release of proinflammatory cytokines, whereas, IM involves infection of B-cells. Children who are HLH carriers and develop EBV infection have high mortality rates if the disease is not treated.

  • Chronic active disease: EBV chronic active disease (CAEBV) shares with HLH the proliferation of non-B-cells. It has been more frequently described in Japan and in children. There are two recognized clinical forms of the disease. One involves EBV-infected T-cells and the second affects NK cells.

    The most severe presentation can be regarded clinically as a chronic form of HLH; the prognosis is similarly poor. After classical acute IM disease, these patients do not recover completely because of persistent infection of their peripheral T cells (CD4+, CD8+, or both). The clinical course of the disease involves persistent signs and symptoms, such as fever, lymphadenopathy, hepatosplenomegaly, headache, fatigue, and malaise that can last for 3 months or longer. More severe forms of the disease include CNS involvement (encephalitis most commonly); malignancies, such as lymphoma or leukemia; hematologic disease, such a hemophagocytosis; hepatic failure; pneumonitis; myocarditis; and peritonitis. These patients show high antibody titers against EBV replicative antigens, such VCA (viral capsid antigen), EA (early antigen), and low or nil EBNA (Epstein Barr nuclear antigen) antibodies. The prognosis worsens as the age and the viral loads increase. Patients with CAEBV infection should be differentiated from those with chronic fatigue disorder, which has not been demonstrated to be related to EBV infection.

    The form affecting NK cells has most commonly been described in Japanese patients and is milder. It presents with a milder form of acute IM disease and lower serum antibody titers against the above mentioned antigens, and they have granular lymphocytosis and high IgE titers. These patients usually have an unusually high skin hypersensitivity to insect bites. CD56+ NK cells can be seen in peripheral blood and in the skin lesions.

  • There are other complications associated with EBV infection. Seroepidemiologic data suggests a correlation between EBV infection and the development of autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, among others, in children and adults. Careful research is required to establish the true correlation between EBV infection and its evolution to the above mentioned autoimmune disorders.

How should I identify the organism?

  • The diagnosis of EBV infection is based mainly on general laboratory findings, antibodies to specific antigens, EBV DNA, ribonucleic acid (RNA) and proteins identification, virus culture, and electron microscopy identification of whole virions representing replicative infection. Pathology can sometimes resemble that of a lymphoma; immune complex disease can also be seen.

    Hematologic abnormalities: During the first week of acute IM, leukopenia or leukocytosis can be so marked that leukemia might be suspected. An absolute increase, or greater than 10% in the number of atypical lymphocytes or Downey cells, is a characteristic finding usually occurring during the second week of illness. Their size and shape are variable. Under Wright staining, their cytoplasm looks dark blue and vacuolated with a foamy appearance. The nuclei are round, bean-shaped, or lobulated with no nucleoli. Downey cells are less common in young children and infants.

    Heterophil antibodies: It is principally IgM. It is detected during the first or second week of illness and disappears over the following 6 months. Usually, serum from patients with acute IM causes agglutination of sheep red blood cells after absorption with guinea pig kidney antigens, but not after absorption with beef red blood cells. Young children and infants with acute EBV infection unusually will be heterophil antibody positive. Rapid heterophil slide tests show a high correlation with standard Paul-Brunnell heterophil test results; the specificity of this test has a 90 to 98% correlation with EBV infection; however, false positivity can occur with rubella, CMV, adenovirus, HIV, malaria infections, hepatitis C, as well as with systemic lupus erythematosus, leukemia, and lymphoma.

    Antibodies against specific EBV antigens: The serologic diagnosis of EBV-associated primary infection includes three types of serum antibodies. These are IgG and IgM against the EBV capsid (VCA IgG and VCA IgM) and IgG against the EBV nuclear antigen (EBNA IgG). The latter is a complex of six nuclear antigens or proteins, mainly EBNA-1, and is referred to as EgG to EBNA, or EBNA IgG.

    There are commercial immunofluorescent kits for the detection of all three types of antibodies or by means of enzyme immunoassays. For most episodes of classic acute IM, the serum detection of IgG to EBV early antigen EA is not deemed necessary. Because of the differing kinetics of antibodies elicited during EBV infection, the diagnosis can usually be confirmed with a single serum sample. The presence of IgG antibody against VCA along with lack of antibody to EBNA is diagnostic of primary infection. IgM antibody to VCA also denotes acute infection; however, this assay is technically difficult and can yield false-positive reactions caused by the presence of rheumatoid factors in the blood. Highly elevated titers of antibody against VCA or EA, along with the presence of antibody to EBNA, is very suggestive of secondary or reactivated infection. High titers to EBNA usually rule out primary infection. Evolution of the serologic response to EBV antigens after a prototypic EBV-associated IM episode is depicted in Figure 1.

    Autoantibodies: Autoantibodies, including antinuclear antibody and rheumatoid factor, are occasionally present during IM; they usually have no clinical significance. Also, false-positive mumps and rubella IgM tests, and false-positive reagin test for syphilis can be found. EBV can also induce production of antibodies of clinical relevance, such as antiplatelet antibodies of the IgG and IgM isotypes, which can lead to thrombocytopenia; and anti-I, anti-i, and anti-HLA class I antibodies that can be associated with severe hemolytic disease. Hypogammaglobulinemia or isolated IgA deficiency can also occur.

    Detection of the virus: The most specific method for demonstrating EBV in pathologic material is nucleic acid hybridization. There are two techniques commonly used: 1-in-situ hybridization, which identifies the cells that contain EBV nucleic acid; and 2-polymerase chain reaction (PCR), which amplifies a segment of DNA. The probes for these techniques are made of cloned EBV DNA or synthetic oligonucleotides, labeled by radioactive or nonisotopic techniques. PCR is more sensitive than immortalization assays. In most cases of acute infection, EBV DNA can be detected in blood by PCR. The EBV plasma DNA loads show a direct correlation with the severity of the disease and the degree of the infectivity of the patient. In-situ hybridization for the abundant EBV-encoded small RNAs (EBERs), which can play a role in the B-cell immortalization, is a specific and sensitive technique for the detection of EBV-infected cells in pathologic samples or specimens.

Figure 1.

Schematic representation of the evolution of antibodies to various Epstein-Barr virus antigens in patients with infectious mononucleosis.

How does this organism cause disease?

  • Infection in susceptible hosts probably begins in the epithelial cells of the buccal mucosa or salivary gland. Following this, the virus gains access to B lymphocytes in the lymphoid tissue of the pharynx and disseminates to the entire lymphoid system and to other susceptible human subjects. The major receptor for EBV on B lymphocytes binds to the glycoprotein gp350. HLA molecules may act as co-receptors, and other viral glycoproteins allow the penetration of the virus into the cell.

  • In the primary stages of the infection, up to 20% of circulating B lymphocytes may be infected. Many of them are immortalized, and EBV DNA is present within their nucleus. Most of the atypical lymphocytes are activated, EBV-specific cytotoxic/suppressor T lymphocytes. At the time of acute EBV infection, these cells may account for up to 30% of the CD8+ cells in the blood. These HLA-restricted cytotoxic CD8+ T lymphocytes kill EBV-infected B lymphocytes, thus, inhibiting the secretion of immunoglobulin. CD4+ T lymphocytes inhibit proliferation of EBV-infected cells. NK lymphocytes that lyse EBV-infected B-cells are produced.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Supportive therapy

Antila, V, Makela, TE, Klemola, E. “Corticotropin in the treatment of infectious mononucleosis”. Acta Medic Scand. vol. 171. 1962. pp. 345-48.

Bender, CE. “The value of corticosteroids in the treatment of infectious mononucleosis”. JAMA. vol. 199. 1967. pp. 97-9.

Bolden, KJ. “Corticosteroids in the treatment of infectious mononucleosis: an assessment using a double blind trial”. J R Coll Gen Pract. vol. 22. 1972. pp. 87-95.

Brandfonbrenner, A, Epstein, A, Wu, S. “Corticosteroid therapy in Epstein–Barr virus infection: effect on lymphocyte class, subset, and response to early antigen”. Arch Intern Med. vol. 146. 1986. pp. 337-9.

Klein, E, Cochran, JF, Buck, RL. “The effects of short-term corticosteroid therapy on the symptoms of infectious mononucleosis pharyngotonsillitis: a double-blind study”. J Am Coll Health Assoc. vol. 17. 1969. pp. 446-52.

Prout, C, Dalrymple, W. “A double blind study of eighty-two cases of infectious mononucleosis treated with corticosteroids”. J Am Coll Health Assoc. vol. 15. 1966. pp. 62-6.

Antiviral therapy

Andersson, J, Britton, S, Ernberg, I. “Effect of acyclovir on infectious mononucleosis: a double-blind, placebo-controlled study”. J Infect Dis. vol. 153. 1986. pp. 283-90.

Crumpacker, CS. “Ganciclovir”. N Engl J Med. vol. 335. 1996. pp. 721-9.

Lin, JC, Smith, MC, Pagano, JS. “Prolonged inhibitory effect of 9-(1,3-dihydroxy-2-propoxymethyl) guanine against replication of Epstein–Barr virus”. J Virol. vol. 50. 1984. pp. 50-5.

Oertel, SH, Ruhnke, MS, Anagnostopoulos, I. “Treatment of Epstein–Barr virus-induced post-transplantation lymphoproliferative disorder with foscarnet alone in an adult after simultaneous heart and renal transplantation”. Transplantation. vol. 67. 1999. pp. 765-7.

Tynell, E, Aurelius, E, Brandell, A. “Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study”. J Infect Dis. vol. 174. 1996. pp. 324-31.

Van der Horst, C, Joncas, J, Ahronheim, G. “Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis”. J Infect Dis. vol. 164. 1991. pp. 788-92.

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