DESCRIPTION

Epstein-Barr virus, frequently referred to as EBV, is a member of the herpes virus family and one of the most common human viruses. The virus occurs worldwide, and most people become infected with EBV sometime during their lives.

In the United States, as many as 95% of adults between 35 and 40 years of age have been infected. Infants become susceptible to EBV as soon as maternal antibody protection (present at birth) disappears. Many children become infected with EBV, and these infections usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. In the United States and in other developed countries, many persons are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence or young adulthood, it causes Infectious Mononucleosis 35% to 50% of the time.

EBV also establishes a lifelong dormant infection in some cells of the body's immune system. A late event in a very few carriers of this virus is the emergence of Burkitt's lymphoma and Nasopharyngeal Carcinoma, two rare cancers that are not normally found in the United States. EBV appears to play an important role in these malignancies, but is probably not the sole cause of disease.

METHOD OF TRANSMISSION

Transmission is by close contact, especially kissing. Periodic reactivation of the virus is linked with shedding of virus in saliva. Most individuals exposed to people with infectious mononucleosis have previously been infected with EBV and are not at risk for infectious mononucleosis. In addition, transmission of EBV requires intimate contact with the saliva (found in the mouth) of an infected person. Transmission of this virus through the air or blood does not normally occur. The incubation period, or the time from infection to appearance of symptoms, ranges from 4 to 6 weeks. Persons with infectious mononucleosis may be able to spread the infection to others for a period of weeks. However, no special precautions or isolation procedures are recommended, since the virus is also found frequently in the saliva of healthy people. In fact, many healthy people can carry and spread the virus intermittently for life. These people are usually the primary reservoir for person-to-person transmission. For this reason, transmission of the virus is almost impossible to prevent.

SYMPTOMS

Symptoms of infectious mononucleosis are fever, sore throat, and swollen lymph glands. Sometimes, a swollen spleen or liver involvement may develop. Heart problems or involvement of the central nervous system occurs only rarely, and infectious mononucleosis is almost never fatal. There are no known associations between active EBV infection and problems during pregnancy, such as miscarriages or birth defects.

Although the symptoms of infectious mononucleosis usually resolve in 1 or 2 months, EBV remains dormant or latent in a few cells in the throat and blood for the rest of the person's life. Periodically, the virus can reactivate and is commonly found in the saliva of infected persons. This reactivation usually occurs without symptoms of illness.

It is important to note that symptoms related to infectious mononucleosis caused by EBV infection seldom last for more than 4 months. When such an illness lasts more than 6 months, it is frequently called chronic EBV infection. However, valid laboratory evidence for continued active EBV infection is seldom found in these patients. The illness should be investigated further to determine if it meets the criteria for chronic fatigue syndrome, or CFS. This process includes ruling out other causes of chronic illness or fatigue.

METHODS OF DIAGNOSIS

When "mono spot" or heterophile test results are negative, additional laboratory testing may be needed to differentiate EBV infections from a mononucleosis-like illness induced by cytomegalovirus, adenovirus, or Toxoplasma gondii. Direct detection of EBV in blood or lymphoid tissues is a research tool and is not available for routine diagnosis. Instead, serologic testing is the method of choice for diagnosing primary infection.

EBV-Specific Laboratory Tests

Laboratory tests for EBV are for the most part accurate and specific. Because the antibody response in primary EBV infection appears to be quite rapid, in most cases testing paired acute- and convalescent-phase serum samples will not demonstrate a significant change in antibody level. Effective laboratory diagnosis can be made on a single acute-phase serum sample by testing for antibodies to several EBV-associated antigens simultaneously. In most cases, a distinction can be made as to whether a person is susceptible to EBV, has had a recent infection, has had infection in the past, or has a reactivated EBV infection. Antibodies to several antigen complexes may be measured. These antigens are the viral capsid antigen, the early antigen, and the EBV nuclear antigen (EBNA). In addition, differentiation of immunoglobulin G and M subclasses to the viral capsid antigen can often be helpful for confirmation. When the "mono spot" test is negative, the optimal combination of EBV serologic testing consists of the antibody titration of four markers: IgM and IgG to the viral capsid antigen, IgM to the early antigen, and antibody to EBNA.

In many people, detection of antibody to the early antigen is a sign of active infection, but 20% of healthy people may have this antibody for years. Antibody to EBNA determined by the standard immunofluorescent test is not seen in the acute phase, but slowly appears 2 to 4 months after onset, and persists for life. This is not true for some EBNA enzyme immunoassays, which detect antibody within a few weeks of onset.

Finally, even when EBV antibody tests, such as the early antigen test, suggest that reactivated infection is present, this result does not necessarily indicate that a patient's current medical condition is caused by EBV infection. A number of healthy people with no symptoms have antibodies to the EBV early antigen for years after their initial EBV infection. Therefore, interpretation of laboratory results is somewhat complex and should be left to physicians who are familiar with EBV testing and who have access to the entire clinical picture of a person. To determine if EBV infection is associated with a current illness, consult with an experienced physician.

CLINICAL CONDITIONS

Primary clinical conditions associated with EBV infection:

Infectious Mononucleosis

Chronic EBV infection

X-linked lymphoproliferative syndrome

Re-activation Syndromes

Lympho-proliferative disorders in immunocompromised patients

Burkitts Lymphoma

Nasopharyngeal Carcinoma

CONDITIONS LINKED TO EBV

1.Infectious Mononucleosis Illness results from primary infection with EBV. A clinically apparent illness only develops when primary infection occurs in adolescence or adulthood. In most cases of infectious mononucleosis, the clinical diagnosis can be made from the characteristic triad of fever, pharyngitis, and lymphadenopathy lasting for 1 to 4 weeks. Moderate-to-high levels of heterophile antibodies are seen during the first month of illness and decrease rapidly after week 4.

Clinical Features: The incubation period is 4 to 7 weeks. The route of infection is usually close contact. Virus is secreted intermittently in the saliva of asymptomatic carriers. The two main periods when the virus is transmitted are between small children, particularly in day care settings where mouthing of toys is common, and in adolescence where kissing is common.

Signs and symptoms: Fever, sore throat, malaise, tiredness, splenomegaly, hepatomegaly, generalized lymphadenopathy, abnormal liver function tests and atypical lymphocytosis in the peripheral blood. The disease is self-limiting, but convalescence may be prolonged in some cases.

Clinical diagnosis: The diagnosis of infectious mononucleosis is suggested on the basis of the symptoms and the age of the patient. Usually, laboratory tests are needed for confirmation. Serologic test results include a normal to moderately elevated white blood cell count, an increased total number of lymphocytes, greater than 10% atypical lymphocytes, and a positive reaction to a "mono spot" test. In patients with symptoms compatible with infectious mononucleosis, a positive Paul-Bunnell heterophile antibody test result is diagnostic, and no further testing is necessary.

Treatment: There is no specific treatment for infectious mononucleosis, other than treating the symptoms. No antiviral drugs or vaccines are available. Some physicians have prescribed a 5-day course of steroids to control the swelling of the throat and tonsils. The use of steroids has also been reported to decrease the overall length and severity of illness, but these reports have not been published.

2.Burkitt's Lymphoma (BL) A high grade B cell lymphoma that occurs endemically in equatorial Africa and New Guinea, and sporadically worldwide. Almost 100% of equatorial BL tumors are known to be associated with EBV. EBV is believed to be an important co-factor in causing this malignancy, based on the following evidence:

BL is a B cell lymphoma and EBV is known to transform B cells

All patients have high levels of antibodies to EBV antigens

EBV genome can be detected in tumor cells.

Virus particles have been detected in cultured BL cells.

The areas that are endemic for BL are also hyper-endemic for Malaria and it is thought that the malignant change in EBV-transformed B cells might follow infection with Malaria.

3.Nasopharyngeal Carcinoma (NPC) This is a malignant tumor of the squamous epithelium of the nasopharynx. Undifferentiated forms of this tumor are associated with EBV: q Patients have high levels of antibodies to EBV antigens. q EBV genome is present in NPC cells. q Virus can be recovered from cultured NPC cells.

4.X linked Lymphoproliferative syndrome Very rare X-linked recessive disorder in which affected individuals develop a fatal primary infection when exposed to EBV.

5.B cell Latency EBV infects B-lymphocytes and establishes a latent infection. The viral genome enters the nucleus and persists in an episomal form. Six viral genes, termed EBNA 1-6 are expressed during this stage. They transform the B cell into an immortal, continuously dividing cell. A small number of these "EBV-transformed" B cells circulate in the blood of healthy carriers. Their numbers are kept in check by the host's immune response.

6.Lymphoproliferative disorders Immunosuppressed patients may develop a polyclonal proliferation of EBV- transformed B cells.

7.Other Malignancies: EBV has been implicated as a cofactor in a number of other malignancies, including leiomyosarcomas in AIDS patients and Hodgkin’s disease. But the role of EBV in the aetiology of these conditions has yet to be resolved.

SITE LINKS URL:http://www.cdc.gov/ncidod/diseases/ebv.htm

URL:http://www.uct.ac.za/depts/mmi/jmoodie/ebv2.html