HERPESVIRUSES

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Information about HERPESVIRUSES
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Published on March 9, 2014

Author: Raghunathreddy

Source: authorstream.com

HERPESVIRUSES: HERPESVIRUSES Dr. Pendru Raghunath Reddy PowerPoint Presentation:  Introduction Herpes viruses are a leading cause of human viral diseases, second only to influenza and cold viruses Are capable of causing overt disease or remaining silent for many years only to be reactivated Name Herpes comes from the Latin herpes which, in turn, comes from the Greek word herpein which means to creep PowerPoint Presentation:  Morphology 100 – 200 nm in diameter, contains an icosahedral capsid containing linear double stranded DNA genome Surrounded by a lipid envelope containing peplomers Between capsid and envelope is tegument PowerPoint Presentation: Subfamily Scientific name Common name Alphaherpesvirinae Human herpesvirus 1 Human herpesvirus 2 Human herpesvirus 3 Herpes simplex virus type 1 Herpes simplex virus type 2 Varicella -zoster virus Betaherpesvirinae Human herpesvirus 5 Human herpesvirus 6 Human herpesvirus 6a Human herpesvirus 7 Cytomegalovirus - - - Gammaherpesvirinae Human herpesvirus 4 Human herpesvirus 8 Epstein-Barr (EB) virus Kaposi’s sarcoma associated virus Classification of Human Herpesviruses PowerPoint Presentation:  Herpes Simplex Virus (HSV) These are very large viruses and their genome (150 kb) encodes at least 80 proteins Almost any human cell type can be affected by HSV The genome of HSV-1 and HSV-2 share 50 - 70% homology Man is the only natural host HSV-1 is usually associated with oral and occular lesions HSV-2 is responsible for the majority of genital infections PowerPoint Presentation: Pathogenesis Source of infection Saliva, skin lesions or respiratory secretions from patients or carriers Mode of transmission Direct contact with virus containing secretions or with lesions HSV 1: Kissing or saliva contaminated fingers HSV 2 : Sexual intercourse, congenital infection PowerPoint Presentation:  HSV is shed in saliva, tears, genital and other secretions The primary infection occurs through the skin, oral mucous membranes, or eyes resulting in a vesicle formation The virus spreads to draining lymphnodes producing lymphadenitis After primary infection the virus travels by retrograde intra-axonal flow to sensory root ganglia They settle within the neurons in the ganglia (trigeminal-HSV-1; sacral-HSV-2) The Herpesvirus DNA gets integrated into the host cell genome These get reactivated when provoked by various stimuli (common cold, fever, pneumonia, stress, exposure to sunlight etc) PowerPoint Presentation: Diseases caused by HSV-1 Acute gingivostomatitis Herpes labialis Keratoconjunctivitis Eczema herpeticum Encephalitis Dendritic keratitis PowerPoint Presentation: Gingivostomatitis Acute gingivostomatitis is the commonest manifestation of primary herpetic infection The patient experiences pain and bleeding of the gums 1 - 8 mm ulcers with necrotic bases are present Neck glands are commonly enlarged accompanied by fever Usually a self limiting disease which lasts around 13 days PowerPoint Presentation: Herpes labialis (cold sore) Following primary infection, 45% of orally infected individuals will experience reactivation Herpes labialis (cold sore) is a recurrence of oral HSV A prodrome of tingling, warmth or itching at the site usually heralds the recurrence About 12 hours later, red­ness appears followed by papules and then vesicles PowerPoint Presentation: Eczema herpeticum This is found in children with active eczema The virus can spread to other organs such as the liver and adrenals PowerPoint Presentation: Diseases caused by HSV-2 Genital herpes (penis, urethra, cervix, vulva, vagina) Neonatal herpes Aseptic meningitis Note: Besides above mentioned primary infections, herpesviruses may present as latent infection, reactivation and recrudescence PowerPoint Presentation: Herpes Simplex Viruses (HSV) PowerPoint Presentation: HSV-1 and HSV-2 cross react serologically. They can be differentiated by the following features By using specific monoclonal antibodies HSV-2 forms larger pocks on chick embryo CAM HSV-2 replicates well in chick embryo fibroblast cells HSV-2 is more neurovirulent in laboratory animals The infectivity of HSV-2 is more temparature sensitive than that of HSV-1 HSV-2 is more resistant to antiviral agents Restriction endonuclease analysis of viral DNA PowerPoint Presentation: Laboratory diagnosis Specimens Vesicle fluid, skin swab, saliva, corneal scrapings, brain biopsy and CSF according to the site of invovlement 1. Direct examination Smears prepared from base of vesicles are stained with toludine blue. multinucleated giant cells with faceted nuclei and homogeneously stained chromatin (Tzanck cells) are present in a positive smear PowerPoint Presentation: Cowdry type A intranuclear inclusion bodies may be seen in Giemsa stained smears Herpes virions may be demonstrated in specimens by electron microscopy Viral antigens can also be demonstrated in the scrapings from the base of the lesions and tissue preparation by immunofluorescence PowerPoint Presentation: 2. Cell culture Virus can be isolated on human fibroblasts, HEp-2 cells, Vero cells and CAM of embryonated egg Swollen, rounded cells may appear within 1-5 days Diagnosis can be confirmed by immunofluorescent staining of infected cell culture Cytopathic effect of HSV in cell culture: Note the ballooning of cells PowerPoint Presentation: 3. Serology Primary infection can be diagnosed by detection of virus specific IgM antibody or by a rising titre of antibody Various tests like CFT, neutralisation, immunofluorescence, ELISA and RIA have been employed for antibody detection 4. PCR Chemotherapy HSV infection can be treated with acyclovir (acycloguanosine) Valaciclovir and famciclovir are more effective oral agents When resistance to these drugs develop, drugs like trisodium -phosphonoformate (Foscarnet) may be useful PowerPoint Presentation: Varicella-Zoster Varicella (chickenpox) and herpes zoster (shingles) are caused by a single virus Chickenpox follows primary infection in a non-immune individual, whereas herpes zoster is a reactivation of the latent virus VZV is similar to the HSV in its morphology Only one antigenic type of VZV is known PowerPoint Presentation:  Epidemiology Primary varicella is an endemic disease. Varicella is one of the classic diseases of childhood, with the highest prevalence occurring in the 4 - 10 years old age group Varicella is highly communicable, with an attack rate of 90% in close contacts Most people become infected before adulthood but 10% of young adults remain susceptible Herpes zoster, in contrast, occurs sporadically and evenly throughout the year PowerPoint Presentation: Varicella Pathogenesis Source of infection Patient with varicella or zoster Mode of transmission Inhalation of respiratory droplets Sometimes through conjunctiva PowerPoint Presentation:  Pathogenesis The virus is thought to gain entry via the respiratory tract and spreads shortly after to the lymphoid system After an incubation period of 14 days, the virus arrives at its main target organ, the skin Following the primary infection, the virus remains latent in the cerebral or posterior root ganglia. In 10 - 20% of individuals, a single recurrent infection occurs after several decades The virus reactivates in the ganglion and tracks down the sensory nerve to the area of the skin innervated by the nerve, producing a varicellaform rash in the distribution of a dermatome PowerPoint Presentation:  Primary infection results in varicella (chickenpox) Incubation period of 7-23 days Presents fever, a widespread vesicular rash mostly on the trunk The features are so characteristic that a diagnosis can usually be made on clinical grounds alone Complications are rare but occurs more frequently and with greater severity in adults and immunocompromised patients Most common complication is secondary bacterial infection of the vesicles Severe complications which may be life threatening include viral pneumonia, encephalititis, and haemorrhagic chickenpox Rash of Chickenpox : Rash of Chickenpox PowerPoint Presentation: Congenital Varicella Infection 90% of pregnant women already immune, therefore primary infection is rare during pregnancy Primary infection during pregnancy carries a greater risk of severe disease, in particular pneumonia First 20 weeks of Pregnancy Up to 3% chance of transmission to the fetus, recognised congenital varicella syndrome; Scarring of skin Hypoplasia of limbs CNS and eye defects Death in infancy normal PowerPoint Presentation: Herpes Zoster (Shingles) Herpes Zoster mainly affect a single dermatome of the skin It may occur at any age but the vast majority of patients are more than 50 years of age The latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment The reactivation is associated with the inflammation of the nerve which leads to neuritic pain that often precedes the skin lesions There is a characteristic eruption of vesicles in the dermatome which is often accompanied by intensive pain which may last for months (postherpetic neuralgia) PowerPoint Presentation:  Herpes zoster affecting the eye (ophthalmic zoster) and face (Ramsay Hunt syndrome affecting the facial nerve) may pose great problems As with varicella, herpes zoster in a far greater problem in immunocompromised patients in whom the reactivation occurs earlier in life and multiple attacks occur as well as complications Complications are rare and include encephalitis and disseminated herpes zoster Shingles PowerPoint Presentation: Laboratory diagnosis The clinical presentations of varicella or zoster are so characteristic that laboratory confirmation is rarely required. Laboratory diagnosis is required only for atypical presentations, particularly in the immunocompromised Direct Microscopy Toludine blue or Giemsa stained smears from the base of early vesicles show multinucleated giant cells and type A intranuclear inclusion bodies under light microscope Eelectron microscopy may be used but cannot distinguish between HSV and VZV Immunofluorescense using monoclonal antibody on skin scrappings can distinguish between the two PowerPoint Presentation: 2. Virus isolation VZV isolated in human fibroblast cells, human amnion, HeLa or Vero cells Cytopathic effect is focal with refractile ballooned cells Virus antigen can be demonstrated in nuclear inclusions by immunofluorescence using monoclonal antibody Cytopathic effect of VZV PowerPoint Presentation: 3. PCR 4. Serology Varicella-zoster specific IgM antibody in patient’s serum can be detected by ELISA Other methods such as CFT, neutralisation test and immunofluorescence can be used for detection of VZV-specific antibodies Treatment Acyclovir and vidarabine are effective in the treatment of severe varicella and zoster Cytomegalovirus: Cytomegalovirus Belong to the betaherpesvirus subfamily of herpesviruses Double stranded DNA enveloped virus and 150-200 nm in size The virus exhibits strict host-specificity Cytomegalovirus infections are almost always inapparent, leading to prolonged latency, with occasional reactivation Cytomegalovirus disease is rare but infection with the virus is extremely common Pathogenesis: Pathogenesis Mode of transmission The virus may be transmitted from person to person in several ways (in utero, perinatally, or postnatally) Perinatal infection is acquired mainly through infected genital secretions, or breast milk. Overall, 2 - 10% of infants are infected by the age of 6 months worldwide. Perinatal infection is thought to be 10 times more common than congenital infection Postnatal infection mainly occurs through saliva. Sexual transmission may occur as well as through blood and blood products and transplanted organ PowerPoint Presentation: Initial replication of the virus occurs in the epithelial cells of the respiratory and GI tracts which is followed by viraemia resulting in infections of all organs of the body In symptomatic cases, renal tubular epithelium, liver and CNS are also affected The virus establishes lifelong latent infection in monocytes, B lymphocytes, epithelial cells and stromal cells of bone marrow and in some organs like kidneys and heart Once infected, the virus remains in the person for life and may be reactivated from time to time, especially in immunocompromised individuals Clinical Manifestations: Clinical Manifestations Congenital infection - may remain inapparent at birth or may lead to cytomegalic inclusion disease which is often fatal The disease is characterised by hepatosplenomegaly, jaundice, thrombocytopenic purpura, microcephaly and chorioretinitis Perinatal infection - usually asymptomatic Postnatal infection - usually asymptomatic. However, in a minority of cases, the syndrome of infectious mononucleosis may develop which consists of fever, malaise, fatigue, and splenomegaly. The heterophil antibody test is negative although atypical lymphocytes may be found in the blood PowerPoint Presentation:  Immunocompromised patients such as transplant recipients and AIDS patients are prone to severe cytomegalic inclusion disease characterised by hepatosplenomegaly, jaundice, thrombocytopenic purpura, pneumonia and micro cephaly Reactivation or reinfection with CMV is usually asymptomatic except in immunocompromised patients PowerPoint Presentation: Laboratory diagnosis Specimens CMV can be isolated from urine, saliva, breast milk, semen, cervical secretions and blood leucocytes Demonstration of Cytomegalic cells Enlarged cells with large intranuclear “owl’s eye” appearance inclusions (cytomegalic cells) can be demonstrated in the centrifuged deposits from urine or saliva PowerPoint Presentation: Isolation of virus Virus can be grown in human fibroblast cultures The virus replicates very slowly, therefore, cytopathic effects (swollen refractile cells with cytoplasmic granules) may take 2-3 weeks to appear For precise identification, these cultures may be stained by immunofluorescence using monoclonal antibody Cytopathic effect of CMV PowerPoint Presentation: Antigen detection CMV antigen can be detected from blood leucocytes using monoclonal antibodies PCR Serology CMV-specific IgM can be detected in the serum by ELISA PowerPoint Presentation:  Treatment For treatment of severe CMV infections, ganciclovir is the drug of choice Prophylaxis Indicated only in high risk cases such as organ transplants, premature infants, immunodeficient persons Screening of blood and organ donors Administration of CMV immunoglobulins and Acyclovir No vaccine is available PowerPoint Presentation: Epstein-Barr virus Belong to the gammaherpesvirus subfamily of herpesviruses EBV has affinity for lymphoid tissue. The B lymphocytes of human beings have receptors (CD21 molecules) for EBV EBV infected B lymphocytes are transformed in such a way that they multiply continuously PowerPoint Presentation: Pathogenesis Source of infection Saliva of infected persons Mode of transmission Intimate oral contact, as in kissing appears to be main mode of transmission PowerPoint Presentation:  The virus enters the pharyngeal epithelial cell through CD21 (or CR2) receptors It multiplies locally, enters the blood stream and infects B lymphocytes In most cases, the virus remains latent inside the lymphocytes, which become transformed The activated B lymphoblast, along with the antigen of EBV, matures into a long-lived memory lymphocyte in the germinal centre of the lymph node This leads to polyclonal activation of the infected B lymphocytes resulting in production of many kinds of antibodies to many antigens -accompanied by nonspecific increase in total IgM, IgG and IgA PowerPoint Presentation:  EB virus antigens are expressed on the surface of infected B lymphocytes. T lymphocytes will be activated in response to such neoantigens In immunocompetent persons, proliferation of transformed B lymphocytes is kept in check by activated T lymphocytes In the immunodeficient persons, lymphomas may occur because of unchecked replication of B lymphocyte clones PowerPoint Presentation: Clinical manifestations Most EBV infections are inapparent Once infected, the virus is present in the individual for life The following clinical manifestations may result from EBV infection Infectious mononucleosis Infections in immunocompromised hosts EBV-associated malignancies PowerPoint Presentation: Infectious Mononucleosis (Glandular fever) It is an acute self-limiting disease of children and young adults characterised by fever, sore throat, lymphadenopathy and splenomegaly In some patients jaundice may be seen which is due to hepatitis Abnormal lymphocytes are present in the blood The incubation period is 4-7 weeks and infection is believed to occur through respiratory route by close contact with patients Complications occur rarely but may be serious e.g. splenic rupture, meningoencephalitis, and pharyngeal obstruction PowerPoint Presentation: In some patients, chronic IM may occur where eventually the patient dies of lymphoproliferative disease or lymphoma EBV activates B lymphocytes and leads to secretion of immunoglobulins (IgM antibodies) 2. Infections in immunocompromised hosts EBV may cause progressive lymphoproliferative disease in immunodeficient children, transplant recipients and AIDS patients PowerPoint Presentation: 3. EBV-associated malignancies Burkitt’s lymphoma It is a malignant neoplasm of B-lymphocytes ( tumour of jaw) which occurs in regions of Africa and New Guinea The disease occurs in endemic or sporadic type Cells of Burkitt’s lymphoma carry multiple copies of EBV genome b) Nasopharyngeal carcinoma c) B-cell lymphoma PowerPoint Presentation: Burkitt's lymphoma showing disruption of teeth and partial obstruction of airway Burkitt’s lymphoma affecting jaw PowerPoint Presentation: Laboratory diagnosis White blood cell count During the initial phase, patient develops leucopenia Later there is leucocytosis with a predominance of abnormal or atypical lymphocytes 2. Paul- Bunnell test During infectious mononucleosis, heterophile antibodies ( IgM ) appear in the serum of the patient These antibodies agglutinate sheep erythrocytes These antibodies appear in 85-90% of patients sera during the acute phase of illness PowerPoint Presentation:  Procedure Inactivated serum in doubling dilutions is mixed with equal volumes of 1% sheep erythrocytes suspension These tubes incubated at 37 0 C for 4 h and examined for agglutination A titre of 100 or above is suggestive of infectious mononucleosis PowerPoint Presentation: Absorption with Guinea pig kidney Ox red cells Normal serum Absorbed Not absorbed Antibody after serum injections Absorbed Absorbed Infectious mononucleosis Not absorbed Absorbed Confirmation Absorption test for Paul – Bunnell antibody PowerPoint Presentation: 3. EBV – specific antibodies The IgM antibody to EBV viral capsid antigen (VCA) appears soon after primary infection and disappears in 1 – 2 weeks The IgG antibody to VCA persists throughout life and is an indication of past or recent infection These can be demonstrated by indirect immunofluorescence or ELISA Antibody to the EBV nuclear antigen (EBNA) is also a reliable marker for primary infection Antibodies to early antigens (EA) can be demonstrated in EB – associated lymphomas PowerPoint Presentation: 4. Antigen detection EBV antigen can be detected by immunofluorescence using monoclonal antibodies EBNA1 is very important antigen 5. Virus isolation Saliva or throat washings and peripheral blood cells can be inoculated onto lymphocytes If specimen contains EBV, it produces a lymphoblastoid cell line 6. Nucleic acid hybridisation 7. PCR PowerPoint Presentation:  Human Herpesvirus 6 HHV – 6 infects dividing CD4 + T lymphocytes Saliva is the main route of transmission Most HHV – 6 infections appear to be asymptomatic They may, however cause exanthem subitum or roseola infantum and infectious mononucleosis – like disease with cervical lymphadenopathy HHV – 6 can be isolated from peripheral blood mononuclear cells in early febrile stage of the illness by co – cultivation with lymphocytes PowerPoint Presentation:  Primary HHV-6 or HHV-7 infection is associated with Roseola Infantum, which is a classical disease of childhood Most cases occur in infants between the ages of 4 months and two years A spiking fever develops over a period of 2 days followed by a mild rash The fever is high enough to cause febrile convulsions There are reports that the disease may be complicated by encephalitis Roseola infantum PowerPoint Presentation:  Human Herpesvirus 8 is associated with Kaposi’s sarcoma, which is the commonest tumour in HIV infected individuals Kaposi’s sarcoma

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