Herpesviridae By: Dr.Malak El-Hazmi Assistant Professor & Consultant Virologist College of Medicine & KKUH

Herpesviridae 1-Herpes simplex type -1 HSV-1 1-Herpes simplex virus type -1 HSV-1 2-Herpes simplex virus type -2 HSV-2 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

HERPESVIRVS dsDNA, Enveloped, Icosahedral Virus

  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 Herpesviridae

Short, cytolytic Muco- Neurons Simplex 1 Herpes simplex virus-1 Short, cytolytic Muco- Neurons Simplex 1 Herpes simplex virus-1 Alpha epithelial Alpha epithelial 2 Herpes simplex virus-2 2 Herpes simplex virus-2 Varicello 3 Varicella-zoster virus Varicello 3 Varicella-zoster virus Long, cytomegalic Epithelial cells ? Cytomegalo 5 Cytomegalovirus Long, cytomegalic Epithelial cells ? Cytomegalo 5 Cytomegalovirus Beta M,L cells Beta M,L cells Long, lympho- lympho- Lymphoid Roseolo 6 Human herpesvirus-6 Long, lympho- lympho- Lymphoid Roseolo 6 Human herpesvirus-6 proliferative cytes tissue proliferative cytes tissue 7 Human herpesvirus-7 7 Human herpesvirus-7 Variable, lympho Epithelial Lymphoid Lymphocrypto 4 Epstein-Barr virus Variable, lympho Epithelial Lymphoid Lymphocrypto 4 Epstein-Barr virus Gamma proliferative lympho- tissue Gamma proliferative lympho- tissue cytes Rhadino 8 Kaposi’s sarcoma- cytes Rhadino 8 Kaposi’s sarcoma- associated herpesvirus associated herpesvirus ? = monocytes,leucocytes,kidney& gland ? = monocytes,leucocytes,kidney& gland Subfamily Growth Cycle & Target Latency Genus Official Name (“-virinae”) Cytopathology cell (‘virus”) (“Human Common herpesvirus”) Name Biologic Properties Examples Classification of Human Herpesviruses

HERPES SIMPLEX VIRUS HSV  Location of lesions

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

Transmission Direct contact with lesions & Contaminated secretions SalivaSexual contact during birth [perinatal] AgeChildren Adolescent & adults Source Herpetic lesions Asymptomatic shedding EpidemiologyHSV1 HSV2

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

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

1. 1.Oral infections   Gingivostomatitis / herpetic stomatitis   Pharyngitis / tonsillitis   Herpes labialis (cold sores( – R 2. 2.Herpetic whitlow : 1 o & R   Nurses & dentists   Toddlers 3. 3.Keratoconjunctivitis:   Keratitis dendritic ulcer may cause blindness 4. 4.Encephalitis 5. 5.Disseminated disease   Immuno ed patients   1 o or R Diseases of HSV -1 RR

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

Comparison of Diseases Caused by HSV-1 and HSV-2 SiteDisease Caused By HSV-1Disease Caused by HSV-2 SkinVesicular lesions above the waist Vesicular lesions below the waist (especially genitals) MouthGingivostomatitisRare EyeKeratoconjunctivitisRare Central nervous systemEncephalitis (temporal lobe)Meningitis NeonateRareSkin lesions and disseminated infection Dissemination to viscera in immunocompromised patients YesRare

  Clinically   Lab Dx. A. A.Direct ex: 1. 1.Vesicular fluid for E/M & virus isolation 2. 2.Cells scraping from the base of vesicles ImmunoFluorescent test (Ag)** Tzanck smear (Giemsa stain) 3. 3.CSF for DNA-HSV by PCR in HE B. B.Serological test: 1. 1.IgM AB* 2. 2.≥ 4 fold increase in AB titers b/t acute & convalescent sera. Diagnosis 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 Treatment HSV

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

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

Pathogenesis  VZV remains latent in trigeminal ganglia, or in dorsal root ganglia.  Immunity : to Varicella, not to zoster 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 Varicella Complications  Secondary bacterial infection of skin lesions  Reye’s syndrome  Pneumonia  Encephalitis VZV

  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 Varicella in Pregnancy 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 zoster VZV

  Clinically   Lab Dx. A. A.Direct ex: 1. 1.Vesicular fluid for E/M & virus isolation 2. 2.Cells scraping from the base of vesicles ImmunoFluorescent test (Ag)** Tzanck smear (Giemsa stain) 3. 3.CSF for DNA-VZV by PCR in encephalitis B. B.Serological test: 1. 1.IgM AB* 2. 2.≥ 4 fold increase in AB titers b/t acute & convalescent sera. Diagnosis VZV

  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 VZVFoscarnet Treatment: VZV

  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 Prevention VZV

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

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

  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 Clinical Features: Immunocompetent host Immunocompetent host EBV

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

  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 – Associated Malignancies EBV

  Hematology:   WBC lymphocytosis Atypical lymphocytes Diagnosis : EBV

  Serology:   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 Diagnosis : EBV

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

  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 Cytomegalovirus CMV

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

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

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

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

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

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

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

  Betaherpesvirinae   Latent infection in lymphoid tissue   Transmitted by saliva   Most infections are asymptomatic Human Herpes Virus Type 6

  Exanthem subitum = Roseola infantum   Fever followed by maculopapular rash on the trunk &neck   Young children   Mononucleosis with cervical LAP   Adults   Reactivation may occur in immuno ed patients Disease HHV6

Human Herpes Virus Type 7   It is closely related to HHV6   Roseola Infantum   Diseases remain to be established

Human Herpes Virus Type 8   Gammaherpesvirinae   Kaposi’s sarcoma   Transmitted by Sexual contact (mainly) Saliva (possible) Organ transplants