EBV.ppt
- 2. o Epstein-Barr virus (EBV), is a member of the herpesvirus family and one of the most common human viruses. o The virus occurs worldwide, and most people become infected with EBV sometime during their lives.
- 3. o Infants become susceptible to EBV as soon as maternal antibody protection disappears. o Many children become infected with EBV, and these infections usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood.
- 4. When infection with EBV occurs during adolescence or young adulthood, it causes infectious mononucleosis 35% to 50% of the time.
- 5. The virus infects oral epithelium where a productive infection takes place and B-cells, where infection is non-productive.
- 6. The virus is shed in the throat during the illness and for up to a year after infection. After the initial infection, the virus tends to become dormant for a prolonged period and can later reactivate and be shed from the throat again.
- 7. The virus is spread by person-to-person contact, via saliva through intimate contact (kissing) and in young children through transfer of saliva.
- 8. In rare instances, the virus has been transmitted by blood transfusion or transplacentally.
- 9. There are no known associations between active EBV infection and problems during pregnancy, such as miscarriages or birth defects.
- 10. 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.
- 11. Periodically, the virus can reactivate and is commonly found in the saliva of infected persons. This reactivation usually occurs without symptoms of illness.
- 12. Epstein Barr Virus is also associated with: Nasopharyngeal carcinoma, Burkitts lymphoma, Hodgkin's Disease, B cell lymphoma.
- 14. EBV infected B-lymphocytes express a variety of “new” antigens encoded by the virus. Infection with EBV results in expression of: 1. Viral Capsid Antigen (VCA) 2. Early Antigen (EA) 3. Nuclear Antigen (NA) Each antigen expression has corresponding antibody responses.
- 15. Epstein-Barr Virus (VCA) Viral capsid antigen (VCA) is produced by infected B cells and can be found in the cytoplasm. Anti-VCA IgM is usually detectable early in the course of infection, 4 to 7 days after onset of signs and symptoms, but it is low in concentration and disappears within 2 to 4 months.
- 16. Epstein-Barr Virus (EA) Early antigen (EA) is a complex of two components, early antigen-diffuse (EA-D), which is found in both the nucleus and cytoplasm of the B cells, and early antigen- restricted (EA-R), which is usually found as a mass only in the cytoplasm.
- 17. Anti-EA-D of the IgG type is highly indicative of acute infection, but it is not detectable in 10% to 20% of patients with IM. EA-D disappears in about 3 months; however, a rise in titer is demonstrated during reactivation of a latent EBV infection.
- 18. Anti-EA-R IgG is not usually found in young adults during the acute phase. Anti-EA-R IgG appears transiently in the later convalescent phase. In general, anti-EA-D and anti-EA-R IgG are not consistent indicators of the disease stage.
- 19. Epstein-Barr Virus (EBNA) Epstein-Barr nuclear antigen (EBNA) is found in the nucleus of all EBV-infected cells. Although the synthesis of NA precedes EA synthesis during the infection of B cells, EBV- NA does not become available for antibody stimulation until after the incubation period of Infectious Mono, when activated T lymphocytes destroy the EBV genome- carrying B cells.
- 20. As a result, antibodies to NA are absent or barely detectable during acute IM.
- 21. Anti-EBNA IgG does not appear until a patient has entered the convalescent period. EBV-NA antibodies are almost always present in sera containing IgG antibodies to VCA of EBV unless the patient is in the early acute phase of IM. Patients with severe immunologic defects or immunosuppressive disease may not have EBV-NA antibodies, even if antibodies to VCA are present.
- 22. Epstein-Barr Virus (EBNA) Under normal conditions, antibody titers to NA gradually increase through convalescence and reach a plateau between 3 and 12 months postinfection. The antibody titer remains at a moderate, measurable level indefinitely because of the persistent viral carrier state established following primary EBV infection.
- 23. Test results of antibodies to EBV- NA should be evaluated in relationship to patient symptoms, clinical history, and antibody response patterns to EBV-VCA and EA to establish a diagnosis.
- 24. Signs and Symptoms of Infectious Mononucleosis
- 25. Mononucleosis is characterized by fever, sore throat, fatigue, malaise, and loss of appetite. Patients generally have swelling of the lymph nodes in the neck and often have an enlarged spleen. No treatment, other than rest, is needed in the vast majority of cases and there is no vaccine available to prevent IM.
- 26. The most important and most characteristic symptom of IM is a sore throat. This usually develops a few days after the onset of the illness, increases in severity during the first week, and then rapidly subsides during the next five to seven days. In many young adults sore throat is the first indication of sickness and in some it is the only major symptom throughout the entire illness.
- 27. Tongue and palate of patient with infectious mononucleosis.
- 28. A conjunctival hemorrhage of the right eye of this patient with infectious mononucleosis.
- 29. Although anorexia may persist for as long as there is fever, its intensity and duration are more directly related to the severity of sore throat and dysphagia. Gross tonsillar and pharyngeal edema may cause virtually complete pharyngeal obstruction with harsh-sounding breathing and complete inability to swallow either food or fluids. In some patients the soreness of the throat is so severe that swallowing water becomes extremely painful.
- 30. The headaches of early IM are often retro- orbital in location but have no characteristic features. They may be moderately severe for one or two days but usually they are mild and rarely last for more than three or four days. Ocular symptoms may be in the form of photophobia, and ocular muscle aching .
- 31. Lymphadenopathy, is sometimes accidentally discovered or detected during self-examination following the development of systemic symptoms. In about 3 percent of all cases of IM, the gross cervical lymphadenopathy imparts a “bull neck” appearance.
- 32. Enlargement of lymph nodes usually begins two or three days after the onset of the first symptoms and, by the end of the week, palpable lymphadenopathy is present in 70-80 percent of all patients.
- 33. Jaundice is a moderately important symptom of infectious mono as 8-10 percent of patients eventually become visibly jaundiced. In most instances, however, it is not noticed since it consists of only a transient icteric tint to the sclera and mucous membranes, lasting for a few days.
- 34. Complications Most cases of IM are self-limited. Deaths are very rare and most often are due to central nervous system (CNS) complications, splenic rupture, upper airway obstruction, or bacterial superinfection.
- 35. Pathogenesis & Immunity The infection first occurs in the oropharynx (epithelium/ lymphoid tissue) and then spreads to the blood, where it infects B lymphocytes. Cytotoxic T lymphocytes react against the infected B cells. The T cells are the "atypical lymphs" seen in the blood smear.
- 36. EBV remains latent within B lymphocytes. A few copies of EBV DNA are integrated into the cell genome; many copies of circular EBV DNA are found in the cytoplasm.
- 37. The immune response to EBV infection consists first of IgM antibody to the VCA. IgG antibody to the VCA follows and persists for life. The IgM response is therefore useful for diagnosing acute infection, whereas the IgG response is best for revealing prior infection. Lifetime immunity against second episodes of infectious mononucleosis is based on antibody to the viral membrane antigen.
- 38. In addition to the EBV specific antibodies, nonspecific heterophil antibodies are found. The term "heterophil" refers to antibodies that are detected by tests using antigens different from the antigens that induced them.
- 39. The heterophil antibodies formed in infectious mononucleosis agglutinate sheep or horse red blood cells in the laboratory. (Cross-reacting Forssman antibodies in human serum are removed by adsorption with guinea pig kidney extract prior to agglutination.)
- 40. Note that these antibodies do not react with any component of EBV. It seems likely that EBV infection modifies a cell membrane constituent such that it be- comes antigenic and induces the heterophil antibody. Heterophil antibodies usually disappear within 6 months after recovery.
- 42. Examination of the blood usually shows an increase in the white blood cells, due to the appearance of many atypical lymphocytes in the blood. Blood serum in IM often contains heterophil antibody that agglutinates, or clumps, the red blood cells of sheep.
- 43. Heterophil antibodies are antibodies that are stimulated by one antigen and react with an entirely unrelated surface antigen present on cells from different mammalian species.
- 44. Heterophil antibody titers rise during the first two or three weeks with half or more developing a significant titer during the first week of illness. The level of antibody gradually declines and usually disappears in eight to twelve weeks following the onset.
- 45. Elevated titers sometimes linger for four to six months up to a year or more. Heterophil antibody most commonly used in the serological diagnosis of IM is an IgM antibody which agglutinates sheep red blood cells.
- 46. The diagnosis of EBV infection is summarized as follows: Susceptibility: If antibodies to the viral capsid antigen are not detected, the patient is susceptible to EBV infection.
- 47. Primary Infection: Primary EBV infection is indicated if IgM antibody to the viral capsid antigen is present and antibody to EBV nuclear antigen, or EBNA, is absent.
- 48. A rising or high IgG antibody to the viral capsid antigen and negative antibody to EBNA after at least 4 weeks of illness is also strongly suggestive of primary infection. In addition, 80% of patients with active EBV infection produce antibody to early antigen.
- 49. Past Infection If antibodies to both the viral capsid antigen and EBNA are present, then past infection (from 4 to 6 months to years earlier) is indicated. Since 95% of adults have been infected with EBV, most adults will show antibodies to EBV from infection years earlier. High or elevated antibody levels may be present for years and are not diagnostic of recent infection.
- 50. Reactivation In the presence of antibodies to EBNA, an elevation of antibodies to early antigen suggests reactivation. However, when EBV antibody to the early antigen test is present, this result does not automatically indicate that a patient's current medical condition is caused by EBV.
- 51. A number of healthy people with no symptoms have antibodies to the EBV early antigen for years after their initial EBV infection. Many times reactivation occurs subclinically.
- 52. Chronic EBV Infection Reliable laboratory evidence for continued active EBV infection is very seldom found in patients who have been ill for more than 4 months. When the illness lasts more than 6 months, it should be investigated to see if other causes of chronic illness or CFS are present.
- 53. EBV is only a minor problem for immunocompetent persons, but it can become a major one for immunologically compromised patients After primary exposure a person is considered to be immune and generally no longer susceptible to overt reinfection.
- 54. Treatment Unlike herpes simplex virus, there are no drugs available to treat Epstein-Barr virus. This may reflect the absence of a thymidine kinase encoded by this virus (drugs such as acyclovir that are active against herpes simplex are activated by the viral thymidine kinase). A vaccine is being developed.
- 55. 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.
- 56. Burkitt's lymphoma The association between Epstein-Barr virus and Burkitt's lymphoma has long been established. This is a tumor of the jaw and face found in children.
- 58. The tumor cells show evidence of EBV DNA and tumor antigens and patients show a much higher level of anti-EBV antibodies than other members of the population.
- 59. Biopsy tissue shows large multinucleated cells . Further evidence that implicates EBV in Burkitt's lymphoma is the observation that EBV can transform B lymphocytes in culture and can produce B cell lymphomas in primates.
- 60. Burkitt's lymphoma histological stain. Notice the large multinucleated cells
- 61. This lymphoma is endemic in equatorial Africa but only occurs rarely elsewhere. Why this is so is unclear but there is probably a genetic reason possibly involving an association with malaria. Persons who are resistant to malaria appear to be susceptible to progression to the lymphoma.
- 62. Nasopharyngeal cancer This disease, which occurs in a number of areas (south China, Alaska, Tunisia, east Africa), is also associated with EBV. There may be a genetic predisposition to the development of EBV cancers in these populations or there may be an environmental cofactor involved.
- 63. The disease is a tumor of the epithelium of the upper respiratory tract and the cells contain EBV DNA. The titer of anti-EBV antibodies alter as the tumor progresses.
- 64. Oral hairy leukoplakia: This EBV-associated disease results in lesions in the mouth and has increased in frequency recently as it is an opportunistic infection of HIV- infected patients
- 65. Oral hairy leukoplakia of tongue in AIDS
- 66. Human herpes virus 6
- 67. Primary infection: Ubiquitous and most children infected by age 2.Causes roseola, or Exanthem subitum characterized by fever for 2-3 days, followed 48 hours later by a maculopapular rash. Tropism: Infects T-cells. It also infects cells of the central nervous system and possibly other cells too.
- 68. Latency: Remains latent for life. Consequences of latency are unclear, although it can be pathogenic in immunocompromised individuals (persons with AIDS, allograft recipients), in whom it can cause pneumonitis. It is also a cause of bone marrow failure in bone marrow transplant recipients.
- 69. Treatment: Gancyclovir since it is a beta herpes virus.
- 70. HUMAN HERPESVIRUS 7 (HHV-7): Closely related to HHV-6, with similar properties. Ubiquitous and most children infected by age 3 (slightly later than HHV-6). May cause some cases of roseola, and can reactivate HHV-6. Infects T-cells also, and remains latent for life.
- 71. HUMAN HERPESVIRUS 8 (HHV-8): First detected in 1994 in Kaposi’s sarcoma (KS) cells; subsequently isolated and sequenced within 3 years. Appears to the causative agent of KS, and has also been linked to some B cell tumors found in persons with AIDS. Tropism: The virus is tropic for B-cells and possibly for other cells too.