Herpes CMV, EBV Herpes 6,7,8


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Cytomegalovirus CMV, EBV Herpes 6,7,8

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Herpes CMV, EBV Herpes 6,7,8

  1. 1. Herpesviridae CMV. EBV, Herpes 6,7,8 Lecture 2 ( basics ) Dr.T.V.Rao MD Dr.T.V.Rao MD 1
  2. 2. Cytomegalovirus Dr.T.V.Rao MD 2
  3. 3. Cytomegalovirus• Cytomegalovirus (from the Greek cyto-, "cell", and -megalo-, "large") is a herpes viral genus of the Herpesviruses group: in humans it is commonly known as HCMV or Human Herpesvirus 5 (HHV-5).[1] CMV belongs to the Betaherpesvirinae subfamily of Herpesviridae, Dr.T.V.Rao MD 3
  4. 4. Cytomegalovirus• HCMV infections are frequently associated with salivary glands, though they may be found throughout the body. HCMV infection can also be life threatening for patients who are immunocompromised (e.g. patients with HIV, organ transplant recipients, or neonates). Dr.T.V.Rao MD 4
  5. 5. Cytomegalovirus• HCMV is found throughout all geographic locations and socioeconomic groups, and infects between 50% and 80% of adults in the United States (40% worldwide as indicated by the presence of antibodies in much of the general population. Seroprevalence is age-dependent: 58.9% of individuals aged 6 and older are infected with CMV while 90.8% of individuals aged 80 and older are positive for HCMV. Dr.T.V.Rao MD 5
  6. 6. Properties of Virus.• Spherical in shape.• 150-200 nm in diameter.• Genome ds DNA.• Species specific.• Cell type specific. Dr.T.V.Rao MD 6
  7. 7. CMVDr.T.V.Rao MD 7
  8. 8. Replication of the virus.• Human Fibroblasts,• Can be isolated from Epithelial cells,• Slow growth on culturing,• CMV produce cytopathic effects• Infected cells are greatly enlarged. Dr.T.V.Rao MD 8
  9. 9. Transmission• Transmission of HCMV occurs from person to person through bodily fluids. Infection requires close, intimate contact with a person excreting the virus in their saliva, urine, or other bodily fluids. CMV can be sexually transmitted and can also be transmitted via breast milk, transplanted organs, and rarely from blood transfusions. Dr.T.V.Rao MD 9
  10. 10. Pathogenesis and Pathology.• Spreads because of close contact between human to human.• Isolated from Lungs, Liver, oesophagus, colon kidney, Monocytes, T and B lymphocytes, Salivary glands Cell mediate immunity is depressed.Incubation period 4 – 8 weeksManifest as Infectious mononucleosis syndrome Dr.T.V.Rao MD 10
  11. 11. Pathogenesis• Sub clinical infections are common• Latent infections are common• Virus are shed from Pharynx, and excreted in urine.• Produce severe infections in Immunosuppressed patients.• Pneumonia most important complication. Dr.T.V.Rao MD 11
  12. 12. Typical appearance of cells Infected with CMV Dr.T.V.Rao MD 12
  13. 13. Congenital and Perinatal Infections.• 1% are infected congenitally in USA.• Produce birth defects,• 1% maternal transmission,• Genital tract helps in spread during delivery.• Blood transfusion can spread to virus to recipient. Dr.T.V.Rao MD 13
  14. 14. Dr.T.V.Rao MD 14
  15. 15. Part of the To RCH panel• HCMV is one of the TORCH infections that lead to congenital abnormalities. These are: toxoplasmosis, rubella, herpes simplex, and cytomegalovirus. Congenital HCMV infection occurs when the mother suffers a primary infection (or reactivation) during pregnancy. Dr.T.V.Rao MD 15
  16. 16. Clinical Findings,• Asymptomatic in majority,• Infectious Mononucleosis.• Fever, Myalgia and Liver dysfunction,• In Immune compromised, Increased Morbidity, and Mortality, Pneumonia, Bone marrow transplantation,Disseminate Disease in AIDS.Gastro Enteritis and Chorioretinitis,lead to Blindness Dr.T.V.Rao MD 16
  17. 17. Events in CMV Infections Dr.T.V.Rao MD 17
  18. 18. Dr.T.V.Rao MD 18
  19. 19. CMV and AIDS Dr.T.V.Rao MD 19
  20. 20. CMV Retinitis Dr.T.V.Rao MD 20
  21. 21. Mother to Child Transmission Dr.T.V.Rao MD 21
  22. 22. Congenital / Perinatal Infections.• Death,• CNS Respiratory Involvement.• Growth retardation.• Jaundice Hepato splenomegaly,• Microcephaly,• Mental retardation, Deafness, Dr.T.V.Rao MD 22
  23. 23. A New Born Child with CMV Dr.T.V.Rao MD 23
  24. 24. Laboratory Diagnosis.• Cell cultures Too slow,• PCR, Replication of virus,• Isolation of virus- Human Fibroblasts,• Serology, Ig M current infection Ig G Potential reactivation, Dr.T.V.Rao MD 24 past infection
  25. 25. Laboratory Tests• The enzyme-linked immunosorbent assay (or ELISA) is the most commonly available serologic test for measuring antibody to CMV. The result can be used to determine if acute infection, prior infection, or passively acquired maternal antibody in an infant is present. Other tests include various fluorescence assays, indirect haemagglutination, (PCR) and latex agglutination. Dr.T.V.Rao MD 25
  26. 26. CMV infected cell In Urine.Observe the Cytomegaly Dr.T.V.Rao MD 26
  27. 27. Treatment and Control.• Ganciclovir, in Retinitis, esophagitis, colitis,Other Drugs, Acyclovir, ValaciclovirScreening of Blood, and organ donors,Passive Immunization with CMV hyper immune globulin, Dr.T.V.Rao MD 27
  28. 28. Ganciclovir• Ganciclovir treatment is used for patients with depressed immunity who have either sight-related or life-threatening illnesses. Valganciclovir (Valcyte®) is an antiviral drug that is also effective and is given orally. Dr.T.V.Rao MD 28
  29. 29. Passive immunization• Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV) is an immunoglobulin G (IgG) containing a standardized amount of antibody to Cytomegalovirus (CMV). It may be used for the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas, and heart.• Alone or in combination with an antiviral agent, it has been shown to: Dr.T.V.Rao MD 29
  30. 30. Alone or in combination with an antiviral agent,• Reduce the risk of CMV-related disease and death in some of the highest-risk transplant patients• Provide a measurable long-term survival benefit• Produce minimal treatment-related side effects and adverse events Dr.T.V.Rao MD 30
  31. 31. Epidemiology.• Endemic world wide.• Developing countries 90%.• Person to Person spread.• Urine, Saliva, Semen,• Breast Milk Cervical secretions,• Mother to Child spread congenital infections.• Risk with Blood transfusions 1-5% Dr.T.V.Rao MD 31
  32. 32. Epstein Barr VirusDNA Group ds DNA Commonly Called as Kissing Disease Dr.T.V.Rao MD 32
  33. 33. Properties of EB Virus• Contain 100 genes• Two types EBV 1 and EBV 2• Targets B lymphocytes• B cells can become continuous cell line• Immortalized by Virus• EBV virus attaches to viral receptor on C3d component of Complement. Dr.T.V.Rao MD 33
  34. 34. Properties of Virus.• Size 150 -200 nm• Ds DNA• Two antigenic types EBV1,and EBV2.• Targets B lymphocytes.• Causes Immortalization of B lymphocytes.• Binds on B lymphocytes,• Causes viral persistence. Dr.T.V.Rao MD 34
  35. 35. EPSTEIN BARR Virus Herpes Group Of Viruses.• Causative Agent 1. Acute Infections Mononucleosis. 2. Nasopharyngeal Carcinoma. 3.Lymphoma. 4.Burkitts Lymphoma. 5.Lymphoproliferative disorders.(Immunosuppressed)‫‏‬ Transplant recipients AIDS Patients Dr.T.V.Rao MD 35
  36. 36. The kiss of cancer• Named after its discoverers, Epstein–Barr virus (EBV) was first isolated in 1964 from patients with hematologic pathology. It is a lymphocytic human herpesvirusthat is carried, like some other pathogenic herpesviruses, by the majority of the world’s population as a persistent, latent contagious agent. Dr.T.V.Rao MD 36
  37. 37. EBV Viral Structure• An icosahedral capsid, approximately 100-110 nm in diameter, containing 162 capsomeres with a hole running down the long axis. Dr.T.V.Rao MD 37
  38. 38. EBV Viral Structure• A core containing a linear, dsDNA molecule of about 175 kbp.• An amorphous, sometimes asymmetric material that surrounds the capsid, designated as the tegument• An envelope containing viral glycoprotein spikes on its surface. Dr.T.V.Rao MD 38
  39. 39. Primary Infection Diseases• Infectious Mononucleosis (glandular fever) - fever, lymphadenopathy, and pharyngitis• Chronic active EBV infection - severe illness ofmore than six months, histologic evidence of organdisease, and demonstration of EBV antigens or EBVDNA in tissue (mimics chronic fatigue syndrome)• X-Linked Lymph proliferative Disease -inherited disease of males, absence of functional SAPgene impairs the normal interaction of T and B cells Dr.T.V.Rao MD 39resulting in unregulated growth of EBV-infected B cells.
  40. 40. EBV infection leads to• Viral persistence• Restricted viral expressions• Potential for reactivation• Lytic replication• Majority of viral DNA is immortalised• Cells existence as circular episodes• EBV can also replicate in vivo in epithelial cell of• 1 Oropharynx• 2 Parotid gland Dr.T.V.Rao MD 40• 3 Uterine cervix
  41. 41. EBV replication occurs in• Epithelial cells of Oropharynx.• Parotid Gland.• Uterine cervix• Nasopharynx.Dr.T.V.Rao MD 41
  42. 42. Pathology and Pathogenesis.• Primary Infection.• Saliva Oropharynx, epithelial cells, Cervical Lymphadenitis. Pharynx Salivary Glands.Shedding of Virus From weeks and months.Infected B lymphocytes spread infection all Dr.T.V.Rao MD 42 over the body
  43. 43. Pathogenesis• In some individuals most viral infected cell are eliminated• Latency persists for life of host• One in 10/5 to 10/6 B cells• Reactivation – is evidenced by increased levels of virus in saliva and of DNA in the blood cells.• Immunosuppression will reactivated the infection Dr.T.V.Rao MD 43
  44. 44. Kissing Disease – EB virus Infection Dr.T.V.Rao MD 44
  45. 45. Modes of Transmission Kissing can be dangerous• Intimate Contact –kissing, sharing food, coughing Dr.T.V.Rao MD 45
  46. 46. CMV can manifest and progress•Sub clinical infection in Majority of children. ADULTSMay manifest as Infectious MononucleosisPolyclonal stimulation of Lymphocytes,Synthesizes Immunoglobulins.Heterophile Antibodies Agglutinate SheepErythrocytes, ( Paul Bunnel Test )‫‏‬ Dr.T.V.Rao MD 46
  47. 47. Dr.T.V.Rao MD 47
  48. 48. Symptoms Other symptoms include: • Fatigue and malaise • Rash (associated with the use of ampicillin) • Headache • Muscle aches • Abdominal pain • Occasional jaundice • Enlargement of the spleen and liver Dr.T.V.Rao MD 48
  49. 49. TUMOURS• Burketts Lymphoma• Nasopharyngeal Carcinoma.• Hodgkins Diseases• Other Lymphomas.• Complicates immune suppressed Dr.T.V.Rao MD 49
  50. 50. Dr.T.V.Rao MD 50
  51. 51. Dr.T.V.Rao MD 51
  52. 52. Burkitts Lymphoma• A tumour of jaw. In African children and young adults.• African tumours contain > 90% EB DNA• Express EBNA 1 antigen• Malaria is a cofactor• Chromosomal translocations• That involve immunoglobulin genes result in deregulation. Dr.T.V.Rao MD 52
  53. 53. Other Clinical Manifestations• Asymptomatic• Adults and Adolescents Infectious Mononucleosis. Infectious Mononucleosis Incubation 30-50DaysHead ache, fever, Malaise Fatigue.Sore throat. Enlargement of Lymph nodes and Spleen Hepatitis,Lymphocytosis.LargeLarge Atypical T Lymphocytes Dr.T.V.Rao MD 53
  54. 54. Diseases resulting from EBV in reduced immunity patients• PTLD (Post-transplant Oral Hairy Leukoplakia lymphoproliferative disease) -a tumor often found in organ transplant patients• Oral Hairy Leukoplakia – Nonmalignant hyperplastic lesion of epithelial cells Dr.T.V.Rao MD 54
  55. 55. Can transform to Malignant conditions • Oral Hairy Leukoplakia, Hodgkins disease. • Burketts Lymphoma. A tumour of Jaw in Africans. Lymphomas. Tumour tissue contain EBV DNA Express limited number of viral genes B lymphomas are complication of Immunodeficient hosts Nasopharyngeal Carcinoma Malaria has some contribution Chromosomal Translocation Dr.T.V.Rao MD 55
  56. 56. Cancers Associated with EBV• Nasopharyngeal Carcinoma – Southern China, Northern Africa, and Alaskan Eskimos – Elevated titers of IgA antibody to EBV structural proteins• Burkitts Lymphoma – Found in equatorial Africa and associated with malaria which doesn’t‫‏‬allow‫‏‬T-cells to control proliferation of EBV-infected B cells – Tumors present in jaw• Hodgkins Disease – EBV DNA detected in tumors• Lymphoproliferative Disease – Impaired T-cell immunity and cannot control proliferation of EBV-infected B cells Dr.T.V.Rao MD 56
  57. 57. Infectious mononucleosis• After an incubation of 30 -50 days• Head ache, Fever, Malaise Fatigue• Sore throat• Enlarged lymph nodes• Spleen,• Hepatitis• Self limited• Lasts for 2-4 weeks• Increased lymphocytes, low grade fever,• May persist for weeks to MD Dr.T.V.Rao months. 57
  58. 58. Infectious mononucleosis Dr.T.V.Rao MD
  59. 59. Nasopharyngeal Carcinoma• Common in persons of Chinese origin• Genetic and environmental factors are important.• Other diseases -• 1 All central nervous system Non Hodgkins lymphomas are associated with EBV _ DNA Dr.T.V.Rao MD 59
  60. 60. Diagnosis• Isolation of infectious virus from peripheral blood mononuclear cells is the most definitive method of diagnosing primary infection. However special cell culture techniques need to be applied. Not often performed. Dr.T.V.Rao MD 60
  61. 61. Laboratory Diagnosis• Nucleic Acid Hybridization.• Saliva, Peripheral Blood Cells.• PCR Serology ELISA Ig M , Ig gHeterophileAgglutination testsPaul Bunnell Test uses sheep cells.Titers are estimated Dr.T.V.Rao MD 61
  62. 62. Diagnosis of EBV• Clinical diagnosis- Classic triad of symptoms lasting 1-4 weeks• Serologic test- Shows elevate white blood cell count, an increased number of lymphocytes, greater than 10% atypical lymphocytes, and a positive reaction to a mono spot test• Someone who appears to have infectious mono, a positive Paul-Bunnell Heterophile antibody test can be done• Serologic testing is the method of choice for primary infection• EBV specific lab tests can be performed, testing patient for EBV antibodies. Dr.T.V.Rao MD 62
  63. 63. Other optimal options in Diagnosis• Diagnosis of IM is best accomplished by examining the IgM and IgG antibody reactivity pattern to a number of EBV proteins. These include the viral capsid (VCA), nuclear protein (EBNA) and the leader protein (EBNA LP)• •Virus in tumour biopsy specimens is detected by direct immunofluorescence or by PCR amplification Dr.T.V.Rao MD 63
  64. 64. Paul Bunnell Test.• Test done with inactivated serum ( 56 c- 30mt)‫‏‬• The dilution of serum add 1% sheep cell• >100 titer indicates positive test.• Differential absorption with Guinea pig kidney cell. Ox red cells. Dr.T.V.Rao MD 64
  65. 65. Differential Absorption test for Paul-Bunnell antibody.Result of Absorption on Guinea pig Ox red cells.Normal serum Absorbed Not absorbedAfter serum Absorbed .InfectiousMononucleosis Not absorbed Absorbed Dr.T.V.Rao MD 65
  66. 66. Serology• ELISA• Immunoblot assay• Indirect immunofloresecent tests• Early Infection• Ig M acute infection• Ig G persist for life• Spot tests like Paul Bunell test Dr.T.V.Rao MD 66
  67. 67. Treatment of EBV• Infectious Mononucleosis – No specific therapy just nonaspirins and rest• Oral Hairy Leukoplakia – Acyclovir – inhibits EBV replication• EBV Lymphoproliferative Disease – reduction in the dose of immunosuppressive medication – Surgical removal or irradiation of localized lymphoproliferative lesions Dr.T.V.Rao MD 67
  68. 68. Epidemiology.• Prevalent in all parts of the World• In all parts of the world 90% of the Adults are seropositive.• In developing countries > 90% of the children are infected by 6 years of age Dr.T.V.Rao MD 68
  69. 69. EPSTEIN-BARR VIRUS EPIDEMIOLOGY• EBV persists in the population through sporadic shedding via the oropharynx into saliva.• •Infection normally occurs after 10 yrs. of age.• •Infection during adolescence usually results in IM• •40 –65% of adults have antibodies to EBV Dr.T.V.Rao MD 69
  70. 70. Understating of CMV• As many as 95% of adults between 35 and 40 years old have been infected.• Many children become infected with EBV but do not usually show symptoms.• When EBV occurs during adulthood it causes infectious mononucleosis 35-50% of the time.• Causes lifelong, persistent infections - majority are benign Dr.T.V.Rao MD 70
  71. 71. Human Herpes Viruses 6 &7• T-lymphotropic viruses of world wide distribution• Found in most of adults saliva• Infection is acquired by the age of 2 years• HHV-6 infects T cells, epithelial cells, NK cells & monocytes• Causes childhood disease – Exanthem subitum (Roseola infantum or Sixth disease)• Primary infection in adults can result in hepatitis, mononucleosis, Lnpathy• No disease has been established with HHV-7 Dr.T.V.Rao MD 71
  72. 72. Roseola Modes of transmission• Roseola is spread from person to person via respiratory fluids or saliva of infected individuals.• The incubation period for roseola is approximately 9-10 days after exposure.• The exact period an infected person is contagious for is unclear but it is most likely spread during the febrile phase of the illness when there are no outward signs72 Dr.T.V.Rao MD that the child is infected with the virus.
  73. 73. HUMAN HERPESVIRUS - 8• First detected in 1995 in Kaposi sarcoma biopsies from AIDS patients.• •DNA sequences detected by differential PCR. Virus was not isolated or visualised.• •Genome sequence analysis identified a new herpesvirusclassified as a gamma-herpesvirus• •Contains a “piratedoncogeniccluster”of cellular genes Dr.T.V.Rao MD 73
  74. 74. HUMAN HERPESVIRUS - 8• Closely associated with KS, but now shown to be more widespread. Found in biopsies of body cavity lymphomas(Castleman’s Disease).• •Castleman’sdisease is a rare B cell lympho- proliferative disorder related to excess IL-6 activity.• •HHV-8 encodes for a cytokine IL- 6homologue which leads to B cell lymphoproliferation.• •Diagnosis by PCR using specific primers. 74 Dr.T.V.Rao MD
  75. 75. Diagnosis and TreatmentPCR assays. ELISAUse of Foscarnet, GanciclovirAssociated with AIDS patients Dr.T.V.Rao MD 75
  76. 76. For Articles of Interest onMicrobiology follow me on Dr.T.V.Rao MD 76
  77. 77. • Programme created by Dr.T.V.Rao MD as ‘e’‫‏‬learning‫‏‬resource‫‏‬for‫‏‬Medical‫‏‬Students‫‏‬ in Developing World. • Email • doctortvrao@gmail.com Dr.T.V.Rao MD 77