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Herpesviridae HSV1,2,VZV,CMV&EBV By: Dr.Malak El-Hazmi Assistant Professor & Consultant Virologist College of Medicine & KKUH

Herpesviridae 1- Herpes simplex virus type -1 HSV-1 3- Varicella –Zoster virus VZV 4- Epstein- Barr virus EBV 5- Cytomegalovirus CMV 6- Human herpes virus type-6 HHV-6 7- Human herpes virus type-7 HHV-7 8- Human herpes virus type-8 HHV-8

dsDNA, Enveloped, Icosahedral Virus HERPESVIRVS dsDNA, Enveloped, Icosahedral Virus

Features of herpesviruses Herpesviridae Features of herpesviruses All herpesviruses are structurally identical Replicate in nucleus Intranuclear inclusions Envelope from nuclear mb Latent infection Cause high morbidity and mortality in immuno ed patients Some herpesviruses Associated with cancers e.g. EBV & HHV8

Sub family Virus Target cell Latency Alpha HHV1 HHV2 HHV3 HSV1 HSV2 VZV Neuron Mucoepithelial Monocyte Lymphocyte&Epithelial cells Beta Mono & lymphocyte CMV HHV5 Gamma B lymphocyte, Epithelial cells HHV4 EBV B lymphocyte

HERPES SIMPLEX VIRUS HSV Location of lesions

Immunity Not Completed Pathogenesis HSV-1 becomes latent in trigeminal g HSV-2 becomes latent in lumber & sacral g Typical Lesion Immunity Not Completed

Epidemiology HSV1 HSV2 Transmission Direct contact with lesions & Contaminated secretions Saliva Sexual contact during birth [perinatal] Age Children Adolescent& adults Source Herpetic lesions Asymptomatic shedding

HSV-1 Infections Asymptomatic Diseases of HSV-1 Oral infections 1ْGingivostomatitis / herpetic stomatitis Pharyngitis / tonsillitis Herpes labialis (cold sores) – R

Diseases of HSV-1 Keratoconjunctivitis: Herpetic whitlow: 1o & R Keratitis R dendritic ulcer may cause blindness Herpetic whitlow: 1o & R Toddlers Nurses & dentists

Diseases of HSV -1 Oral infections Herpetic whitlow : 1o & R Gingivostomatitis / herpetic stomatitis Pharyngitis / tonsillitis Herpes labialis (cold sores} – R Herpetic whitlow : 1o & R Nurses & dentists Toddlers Keratoconjunctivitis: Keratitis dendritic ulcer may cause blindness Encephalitis Disseminated disease Immuno ed patients 1o or R R R

Diseases of HSV2 Neonatal herpes Aseptic meningitis Genital herpes: STD 1o or R Neonatal herpes Aseptic meningitis

Comparison of Diseases Caused by HSV-1 and HSV-2 Site Disease Caused By HSV-1 Disease Caused by HSV-2 Skin Vesicular lesions above the waist Vesicular lesions below the waist (especially genitals) Mouth Gingivostomatitis Rare Eye Keratoconjunctivitis Central nervous system Encephalitis (temporal lobe) Meningitis Neonate Skin lesions and disseminated infection Dissemination to viscera in immunocompromised patients Yes

Diagnosis Clinically Lab Dx. Direct ex: Serological test: HSV Clinically Lab Dx. Direct ex: Vesicular fluid for E/M & virus isolation Cells scraping from the base of vesicles ImmunoFluorescent test (Ag)** Tzanck smear (Giemsa stain) CSF for DNA-HSV by PCR in HE Serological test: IgM AB* ≥ 4 fold increase in AB titers b/t acute & convalescent sera.

Treatment Prevention Acyclovir Foscarnet HSV Acyclovir Severe diseases Systemic diseases Immuno ed patients Foscarnet Acyclovir resistant strains of HSV Prevention Avoid contact with herpetic lesions & its secretions Gloves & hand washing C/S for pregnant lady with infected birth canal Sex education No vaccine

Varicella - Zoster Virus VZV Varicella : Chickenpox: 1o illness Generalized vesicular rash Zoster: Shingles: Recurrent form Localized VR

Varicella Zoster Adults & immuno ed host Children VZV Varicella Children Late winter & early spring highly infectious disease (communicable) Epidemic Respiratory droplets Direct & Indirect contact Transplacental Zoster Adults & immuno ed host No seasonal distribution Sporadic Age Incidence Transmission Rarely May give V in s-host

Pathogenesis Immunity : to Varicella, not to zoster VZV Pathogenesis VZV remains latent in trigeminal ganglia, or in dorsal root ganglia. Immunity : to Varicella, not to zoster

Varicella Complications IP = 2 -3 wks Vesicular rash VZV IP = 2 -3 wks Vesicular rash Starts on trunk , spread to face & limbs Appears in successive waves Healing without scarring Mild in children, Severe in adults & immuno ed patients Complications Secondary bacterial infection of skin lesions Reye’s syndrome Pneumonia Encephalitis

Varicella in Pregnancy VZV Varicella in Pregnancy Severe disease in pregnant women e.g. pneumonia Intrauterine infections Congenital varicella syndrome Neonatal varicella < 7 days of delivery severe disease > 7 days before delivery mild disease

zoster A localized unilateral VR & pain Post-herpetic neuralgia VZV A localized unilateral VR & pain Thoracic zoster R dorsal root g Ophthalmic zoster R trigeminal g Ramsay-Hunt syndrome rare Post-herpetic neuralgia Dissemination of zoster in immuno ed patients

Diagnosis Clinically Lab Dx. Direct ex: Serological test: VZV Diagnosis Clinically Lab Dx. Direct ex: Vesicular fluid for E/M & virus isolation Cells scraping from the base of vesicles ImmunoFluorescent test (Ag)** Tzanck smear (Giemsa stain) CSF for DNA-VZV by PCR in encephalitis Serological test: IgM AB* ≥ 4 fold increase in AB titers b/t acute & convalescent sera.

Treatment: Indications Antiviral drugs: VZV Treatment: Indications Neonates Immuno ed patients Adults with moderate to severe disease Patients with complications Ophthalmic zoster Antiviral drugs: Acyclovir Valacyclovir Famicilovir A acyclovir resistant strains of VZV Foscarnet

Prevention Infection control practice VZV Prevention Infection control practice Live -attenuated Varicella vaccine Two doses Immunocompetent children & Adults VZIG Immuno ed patient & non-immune pregnant& neonate born to mother who acquired varicella around delivery <4 days after exposure

Epstein – Barr Virus EBV HHV-4 , gammaherpesvirinae Special features It is lymphotropic It has oncogenic properties Its antigenic composition

Epidemiology Distribution :worldwide Transmission: Age: EBV Epidemiology Distribution :worldwide Transmission: Saliva [kissing disease] Blood [rarely] Age: Socio-economic status: SE Low SE class early childhood High SE class adolescence

Clinical Features: Immunocompetent host Chronic EBV infection Asymptomatic Infectious mononucleosis [glandular fever] Mainly in teenagers & young adults IP = 4-7 weeks Fever, pharyngitis, malaise, LAP, hepatosplenomegaly & abnormal LFT Rash may follow ampicillin Last 2- 3 weeks Complications ( acute air way obstruction, splenic rupture, CNS inf) Chronic EBV infection

Immunocompromised host EBV Clinical Features : Immunocompromised host Lymphoproliferative disease ( LD) Patients with decrease CMI Transplant recipients PTLD Oral hairy leukoplakia (OHL) Non-malignant lesion HIV-infectedpatients immuno ed patients

EBV – Associated Malignancies Burkitt’s lymphoma A tumor of lymphoid tissue African children Malaria can act as a cofactor Nasopharyngeal carcinoma A tumor of epithelial origin Adults China

EBV Diagnosis: Hematology: WBC lymphocytosis Atypical lymphocytes

Diagnosis: Serology: EBV Ags & EBV-DNA in lymphoid & other tissues Non-specific AB test Heterophile Abs +ve Paul-Bunnell or mono-spot test EBV-specific AB test: IgM Abs to EBVirus capsid antigen Serology is not reliable in immuno ed patients EBV Ags & EBV-DNA in lymphoid & other tissues

EBV

Prevention: Management: Treatment: EBV Management: Treatment: Antiviral drug is not effective in IMN Acyclovir is used in treating OHL Prevention: No vaccine

Cytomegalovirus CMV Betaherpesvirinae – HHV-5 Special features Its replication cycle is longer Infected cell enlarged with multinucleated [cyto=cell, megalo=big] Resistant to acyclovir Latent in monocyte & lymphocyte & other

Epidemiology Distribution: worldwide Transmission Early in life: CMV Epidemiology Distribution: worldwide Transmission Early in life: Transplacenta Birth canal Breast milk Young children: saliva Later in life: sexual contact Blood transfusion & organ transplant

Acquired Infection Immunocompetent host Immunocompromised host CMV Acquired Infection Immunocompetent host Asymptomatic Self-limited illness Hepatitis Infectious mononucleosis like syndrome [Heterophile AB is –ve] Immunocompromised host 1o or R Pneumonia, Hepatitis, Encephalitis Retinitis, Esophagitis, Colitis

Congenital Infections: CMV Congenital Infections: Clinically normal 15% Hearing defect mental retardation 4% Cytomegalic inclusion disease 1% death

Lab. Diagnosis [Owl’s –eye] CMV Histology: Intranuclear inclusion bodies [Owl’s –eye]

Lab. Diagnosis Culture: In human fibroblast 1-4 wks CPE CMV Lab. Diagnosis Culture: In human fibroblast 1-4 wks CPE Shell Vial Assay 1-3 days Serology: AB IgM: 1 or R inf. IgG: previous exposure Ag CMV pp65 Ag by IFA PCR

Treatment Ganciclovir Foscarnet: the 2nd drug of choice CMV Treatment Ganciclovir is effective in the Rx of severe CMV inf. e.g. CMV retinitis, pneumonia Foscarnet: the 2nd drug of choice

Prevention: Screening Leukocyte-depleted blood CMV Prevention: Screening organ donors Organ recipients Blood donors Leukocyte-depleted blood Chemoprophylaxis: Ganciclovir Immunoprophylaxis: CMVIG No vaccine

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