Cytomegalovirus CMV, EBV Herpes 6,7,8

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Herpesviridae CMV. EBV, Herpes 6,7,8 Lecture 2 ( basics ) :

Herpesviridae CMV. EBV, Herpes 6,7,8 Lecture 2 ( basics ) Dr.T.V.Rao MD Dr.T.V.Rao MD 1

Cytomegalovirus :

Cytomegalovirus Dr.T.V.Rao MD 2

Cytomegalovirus :

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 Herpesvirida e , Dr.T.V.Rao MD 3

Cytomegalovirus :

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

Cytomegalovirus :

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

Properties of Virus.:

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


CMV Dr.T.V.Rao MD 7

Replication of the virus.:

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

Transmission :

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

Pathogenesis and Pathology.:

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 weeks Manifest as Infectious mononucleosis syndrome Dr.T.V.Rao MD 10


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

Typical appearance of cells Infected with CMV:

Typical appearance of cells Infected with CMV Dr.T.V.Rao MD 12

Congenital and Perinatal Infections.:

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

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Part of the To RCH panel:

Part of the To R C H 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

Clinical Findings,:

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

Events in CMV Infections:

Events in CMV Infections Dr.T.V.Rao MD 17

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CMV and AIDS Dr.T.V.Rao MD 19

CMV Retinitis:

CMV Retinitis Dr.T.V.Rao MD 20

Mother to Child Transmission:

Mother to Child Transmission Dr.T.V.Rao MD 21

Congenital / Perinatal Infections.:

Congenital / Perinatal Infections . Death, CNS Respiratory Involvement. Growth retardation. Jaundice Hepato splenomegaly, Microcephaly, Mental retardation, Deafness, Dr.T.V.Rao MD 22

A New Born Child with CMV:

A New Born Child with CMV Dr.T.V.Rao MD 23

Laboratory Diagnosis. :

Laboratory Diagnosis. Cell cultures Too slow, PCR, Replication of virus, Isolation of virus- Human Fibroblasts, Serology, Ig M current infection Ig G Potential reactivation, past infection Dr.T.V.Rao MD 24

Laboratory Tests:

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

CMV infected cell In Urine. Observe the Cytomegaly:

CMV infected cell In Urine. Observe the Cytomegaly Dr.T.V.Rao MD 26

Treatment and Control.:

Treatment and Control. Ganciclovir, in Retinitis, esophagitis, colitis, Other Drugs, Acyclovir, Valaciclovir Screening of Blood, and organ donors, Passive Immunization with CMV hyper immune globulin, Dr.T.V.Rao MD 27

Ganciclovir :

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

Passive immunization:

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

Alone or in combination with an antiviral agent, :

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


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

Epstein Barr Virus DNA Group ds DNA :

Epstein Barr Virus DNA Group ds DNA Commonly Called as Kissing Disease Dr.T.V.Rao MD 32

Properties of EB Virus:

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

Properties of Virus.:

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

EPSTEIN BARR Virus Herpes Group Of Viruses.:

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

The kiss of cancer:

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 ag ent. Dr.T.V.Rao MD 36

EBV Viral Structure:

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

EBV Viral Structure:

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 surfa ce . Dr.T.V.Rao MD 38

Primary Infection Diseases:

Primary Infection Diseases Infectious Mononucleosis (glandular fever) - fever, lymphadenopathy, and pharyngitis X-Linked Lymph proliferative Disease - inherited disease of males, absence of functional SAP gene impairs the normal interaction of T and B cells resulting in unregulated growth of EBV-infected B cells. Chronic active EBV infection - severe illness of more than six months, histologic evidence of organ disease, and demonstration of EBV antigens or EBV DNA in tissue (mimics chronic fatigue syndrome) Dr.T.V.Rao MD 39

EBV infection leads to:

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 3 Uterine cervix Dr.T.V.Rao MD 40

EBV replication occurs in :

EBV replication occurs in Epithelial cells of Oropharynx. Parotid Gland. Uterine cervix Nasopharynx. Dr.T.V.Rao MD 41

Pathology and Pathogenesis.:

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 over the body Dr.T.V.Rao MD 42


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

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Kissing Disease – EB virus Infection Dr.T.V.Rao MD 44

Modes of Transmission Kissing can be dangerous:

Modes of Transmission Kissing can be dangerous Intimate Contact kissing, sharing food, coughing Dr.T.V.Rao MD 45

CMV can manifest and progress:

Sub clinical infection in Majority of children. ADULTS May manifest as Infectious Mononucleosis Polyclonal stimulation of Lymphocytes, Synthesizes Immunoglobulin's. Heterophile Antibodies Agglutinate Sheep Erythrocytes, ( Paul Bunnel Test ) ‏ CMV can manifest and progress Dr.T.V.Rao MD 46

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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


TUMOURS Burkett's Lymphoma Nasopharyngeal Carcinoma. Hodgkin's Diseases Other Lymphomas. Complicates immune suppressed Dr.T.V.Rao MD 49

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Burkitt's Lymphoma:

Burkitt's 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

Other Clinical Manifestations:

Other Clinical Manifestations Asymptomatic Adults and Adolescents Infectious Mononucleosis. Infectious Mononucleosis Incubation 30-50Days Head ache, fever, Malaise Fatigue. Sore throat. Enlargement of Lymph nodes and Spleen Hepatitis,Lymphocytosis.Large Large Atypical T Lymphocytes Dr.T.V.Rao MD 53

Diseases resulting from EBV in reduced immunity patients:

Diseases resulting from EBV in reduced immunity patients PTLD (Post-transplant lymphoproliferative disease) - a tumor often found in organ transplant patients Oral Hairy Leukoplakia Nonmalignant hyperplastic lesion of epithelial cells Oral Hairy Leukoplakia Dr.T.V.Rao MD 54

Can transform to Malignant conditions :

Can transform to Malignant conditions Oral Hairy Leukoplakia, Hodgkins disease. Burkett's 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

Cancers Associated with EBV:

Cancers Associated with EBV Nasopharyngeal Carcinoma Southern China, Northern Africa, and Alaskan Eskimos Elevated titers of IgA antibody to EBV structural proteins Burkitt's Lymphoma Found in equatorial Africa and associated with malaria which doesn’t allow T-cells to control proliferation of EBV-infected B cells Tumors present in jaw Hodgkin's 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

Infectious mononucleosis:

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 months. Dr.T.V.Rao MD 57

Infectious mononucleosis:

Infectious mononucleosis Dr.T.V.Rao MD 58

Nasopharyngeal Carcinoma:

Nasopharyngeal Carcinoma Common in persons of Chinese origin Genetic and environmental factors are important. Other diseases - 1 All central nervous system Non Hodgkin's lymphomas are associated with EBV _ DNA Dr.T.V.Rao MD 59


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

Laboratory Diagnosis:

Laboratory Diagnosis Nucleic Acid Hybridization. Saliva, Peripheral Blood Cells. PCR Serology ELISA Ig M , Ig g HeterophileAgglutination tests Paul Bunnell Test uses sheep cells. Titers are estimated Dr.T.V.Rao MD 61

Diagnosis of EBV:

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

Other optimal options in Diagnosis:

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

Paul Bunnell Test.:

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

Differential Absorption test for Paul-Bunnell antibody.:

Differential Absorption test for Paul-Bunnell antibody. Result of Absorption on Guinea pig Ox red cells. Normal serum Absorbed Not absorbed After serum Absorbed . Infectious Mononucleosis Not absorbed Absorbed Dr.T.V.Rao MD 65


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

Treatment of EBV:

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

Epidemiology. :

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


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

Understating of CMV :

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

Human Herpes Viruses 6 &7:

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

Roseola Modes of transmission:

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 signs that the child is infected with the virus. Dr.T.V.Rao MD 72


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


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 . Dr.T.V.Rao MD 74

Diagnosis and Treatment:

Diagnosis and Treatment PCR assays. ELISA Use of Foscarnet, Ganciclovir Associated with AIDS patients Dr.T.V.Rao MD 75

For Articles of Interest on Microbiology follow me on:

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