1. Pornpimol L.

2. GENERAL CHARACTERISTICS Herpesviruses are amongst the largest human viruses HV infections have been recognised since ancient times “herpein” = “to creep” in ancient Greek (Hippocrates) Herpesviruses are highly disseminated in nature. To date, there are 8 known human Herpesviruses. INTRODUCTION TO THE FAMILY HERPESVIRIDAE

3. ARCHITECTURE

4. Human herpesvirus type 1 (Herpes simplex virus -1) Human herpesvirus type 2 (Herpes simplex virus -2) Human herpesvirus type 3 (Varricella zoster virus) Human herpesvirus type 4 (Epstein-Barr virus) Human herpesvirus type 5 (Cytomegalovirus) Human herpesvirus type 6 Human herpesvirus type 7 Human herpesvirus type 8 Herpes B virus (chimpanzees) may infect humans THE HUMAN HERPESVIRUSES

5. To date, there are 8 known human Herpesviruses. Alphaherpesvirinae: - variable host range, short reproductive cycle, rapid spread in cell culture Simplexvirus human herpesvirus 1, 2 (HSV-1, HSV-2) Varicellovirus human herpesvirus 3 (VZV) Betaherpesvirinae: - restricted host range, long reproductive cycle, enlargement of infected cells Cytomegalovirus human herpesvirus 5 (HCMV) Roseolovirus human herpesvirus 6, 7 (HHV-6, HHV-7) Gammaherpesvirinae: -replicate in lymphoblastoid cells, specific for T or B cells Lymphocryptovirus human herpesvirus 4 (EBV) Rhadinovirus human herpesvirus 8 (HHV-8)

6. Alphaherpesvirinae Simplexvirus (HHV1&2/ HSV1&2) Varicellovirus (HHV3/VZV)

7. First human herpesvirus discovered (1922) Two serotypes recognised – HSV-1 & HSV- 2 (1962) Great deal of polymorphism at genomic level occurs between strains HERPES SIMPLEX VIRUS

8. Herpes Simplex – Two major strains Type I: Oral Herpes Type II: Genital Herpes – Skin lesions form at site of the infection – Virus travels along sensory neurons to ganglia, where it remains – During times of stress or weakened immunity, virus may travel along same neurons to re - infect the initial skin sites Herpes Simplex Viruses

9. PATHOGENESIS HSV-1 infection is generally limited to the oropharynx. Transmission through respiratory droplets HSV-2 infection is usually acquired by sexual transmission Virus must come in contact with mucosal membranes or abraded skin for initiation of infection After primary infection virus is transported to dorsal root ganglia and remains latent Incubation period of 2-12 days, and symptoms last for 2-3 weeks

10. HSV is involved in a variety of clinical manifestations which includes ;- 1. Acute gingivostomatitis 2. Herpes Labialis (cold sore) 3. Ocular Herpes 4. Herpes Genitalis 5. Other forms of cutaneous herpes 6. Meningitis 7. Encephalitis 8. Neonatal herpes Clinical Manifestations

11. HERPES SIMPLEX - Type 1 PRIMARY INFECTION 1. Usually cold sores; sore throat, fever and, rarely, Encephalitis 2. Less frequently found as a genital infection

12. HERPES SIMPLEX - Type 1 LATENT INFECTION 1. Asymptomatic - No virus or virion proteins produced 2. Viral DNA resides in sensory cells of Trigeminal nerve ganglion TRIGEMINAL NERVE

13. HERPES SIMPLEX – Type1 RECURRENT INFECTION 1. Virus replicates and travels down sensory nerve fiber to infect epithelial cells around the nose and mouth 2. Symptoms are usually a milder form of primary infection TRIGEMINAL NERVE

14. HERPES SIMPLEX - Type 2 1. Usually vesicular eruptions on the genitalia 2. Spread by sexual contact 3. Affects both sexes 4. Once associated with cervical carcinoma 5. Less frequently found as Herpes Labialis (cold sores )

15. HSV-2 Acquisition Heterosexual men 1 partner: 0% 2- 10 partners: 20% 11- 50 partners: 35% >50 partners: >70% HSV-2 Acquisition Heterosexual women 1 partner: <10% 2- 10 partners: 40% 11- 50 partners: 62% >50 partners: >80%

16. Most common complications are extragenital lesions (20%) and aseptic meningitis (10%) Recurrent HSV-2 infection is generally milder,and complications are rare. Herpes keratitis Herpes whitlow

17. Herpes Encephalitis Age :5-30yrs,>50yrs 93-96% HSV-1 Mech : -nasal mucosa/oropharynx  cribiform plate  orbital,temporal -blood stream -recurrent: reactive of HV  trigeminal gg  CN v  anterior, middle fossa Clinical : fever,headache,ataxia,dysarthria,seizure

18. Investigation : –CSF :wbc50-2000 (L),rbc (hemorrhagic necrosis), sugar,protein –Tissue biopsy –DNA-PCR(sense98%,sp94%) –EEG:unilateral or bilateral periodic focal spike –CT brain :low density contrasted temporal Herpes Encephalitis

19. Disseminated HSV Organ transplantation,CA s/p CMT,AIDS,severe burn Liver,kidney,adrenal,spleen,brain,GI, bone marrow Clinical :fever, hemorrhagic vessicle,esophagitis,pneumonitis, renal failure,hepatitis,DIC Ix: –CBC:wbc,plt, –Azothemia,low BS –Abnormal EEG,EKG

20. DIAGNOSIS Both clinical and lab criteria are useful for establishing for diagnosis of HSV infections. Clinical :multiple vesicular lesions on an erythematous base or herpetic ulceration Lab : Wright’s,Giemsa’s,or Papanicolaou’s stain (giant cell or intranuclear inclusions),isolation of the virus in tissue culture or by demonstration of HSV antigen or DNA

21. TREATMENT * Acyclovir Dz.doseDuration (day) Oral,genital200mg x 5times/day 400mg x 3times/day 10-14 Anus400mg x 5times/day10-14 Herpetic whitlow400 mg x 3times/day7 Meningitis5mg/kg v q 8 hrs10-14 Encephalitis10mg/kg v q 8 hrs10-14 Disseminated15mg/kg /day10-14

22. TREATMENT(cont.) Dz.doseDuration(days) Oral,genital500-1000mg x 2times/day 10-14 Recurrent genital 500mg x 2times/day 3-5 keratitis1%Trifuridine ED q 2 hrs 21 * Valacyclovir

23. TREATMENT (cont.) Suppression of Mucocutaneous Herpes Reduction in Transmission of HSV to sexual partners Acyclovir resistance ;foscarnet

24. VARICELLA ZOSTER VIRUS Clinical disease recognised in two forms Primary infection - Varicella (Chicken Pox) Reactivation - Zoster

25. PRIMARY VARICELLA PATHOLOGY Clinical disease is usually benign. Manifests as a viral exanthem (rash) Virus enters via mucosa of URT and oropharynx or via the conjunctiva Viral replication occurs in primary site and virus disseminates via the blood stream. Virus replication then occurs in cells of the reticuloendothelial system (blood mononuclear cells) Virus replication is initially limited by specific and nonspecific immunological responses but in most individuals these are overwhelmed and extensive secondary viremia occurs

26. Secondary viremia is associated with prodromal symptoms (fever) which first appear 14-15 days after initial infection Secondary viremia is usually terminated after 3 days by humoral and cell-mediated factors Fever is followed by a maculopapular rash forming lesions over 2-4 days. These may appear on scalp, trunk, extremities and mucosal surfaces. Vesicles contain fluid with infectious virus, and dry over 1-3 weeks.

27. Chicken Pox

28. SECONDARY ZOSTER PATHOLOGY Virus spreads to the ganglia by systemic virus Sets up latent infection in ganglion without replication or cell damage. Reactivation as herpes zoster involves the ganglia and spinal nerves corresponding to the dermatome involved in the primary infection The areas supplied by the trigeminal nerve (opthalmic) and thoracic ganglia are most often involved

29. Ramsay Hunt :geniculate gg. จะมีอาการ ปวดและตุ่มน้ำใสบริเวณหูส่วนนอกมอัมพาต ใบหน้าซีกเดียวกันและสูญเสียความรู้สึกใน การลิ้มรสของลิ้นส่วนหน้า

30. Lab findings Isolation of VZV in susceptible tissue culture cell line Tzank smear Detection of antibodies:IFA,ELISA,FAMA

31. VZV Encephalitis 1:1,000 Children>adult Clinical:headahe,vomitting,siffneck,siezure,oculomotor,facial palsy Dx: –CSF:wbc,(L),prot,sugar,Ab positive Cpx:transverse myelitis,peripheral neuritis,optic neuritis

32. Herpes Zoster ophthalmicus Occur after zoster eruption in any branch of trigeminal n.(V1) Produce corneal dendrite Common sequelae: stromal kerratitis,anterior uveitis,ocular motor n.palsy,acute retinal nerosis,post herpetic neuralgia

33. Treatment Normal host Chicken pox –prevention of avoidable cpx.,acyclovir therapy is recommend for adolescents and adult with chicken pox <24hrs(acyclovir 20mg/kg 4times/day x 5) Herpes zoster –Acyclovir 800mg five times daily for7-10 days Immunocompromised host Should be treat with intravenous acyclovir(10- 12.5mg/kg v q8hrs 7days

34. Acute neuritis and/or postherpetic neuralgia :gabapentin,amitryptyline,lidocainpatches and fluphenazine hydrochloride Prevention :Varicella vaccine (active immunization),VZIg (passive immunization) Treatment

35. Betaherpesvirinae Cytomegalovirus (HHV5/CMV) Roseolovirus (HHV6 & 7)

36. HUMAN HERPESVIRUS - 6 First isolated from PBMC of patients in 1986 during attempts to isolate HIV Later isolated from patients in Africa and the UK and subsequently was found to be ubiquitous. Genetic similarity and growth cycle to CMV led to classification as a beta-herpesvirus Two variants of HHV-6 have been identified on basis of genetic and biological properties (variants A and B)

37. Primary Infection HHV-6 causes exanthem subitum (Roseola) in children - Benign disease - Fever, rash - Complications include febrile convulsions - 60-70% of infections are unapparent - Variant B is predominant cause

38. Immunocompromised :organ transplantation –Solid organ,bone marrow transplant –Fever,headache,confusion,seizure,abnormal movement and behavior change –CSF ;PCR

39. DIAGNOSIS Children(primary infection) :antiHHV-6,fourfold rise of antiHHV-6 IgG Clinical & HHV-6 in PBMC and plasma,high viral load

40. TREATMENT ในเด็กที่ภูมิคุ้มกันปกติมักหายได้เอง immunocompromisid : ganciclovir,foscarnet,cidofovir

41. Gamma herpesvirinae Epstein Barr Virus Kaposi’s sarcoma associated herpesvirus (KSHV)

42. KSHV Human herpes virus 8(HHV-8) or Kaposi’s sarcoma associated herpes virus (KSHV) Associate with multicentric Castleman’s dz. and primary effusion lymphoma “Rhadinovirus” Risk in AIDS>normal population 20,000x Homosexual

43. PATHOGENESIS Oral transmission (saliva), fecal-oral sexual contact and parenteral transmission

44. Clinical manifestation Classic KS : “Kaposi’s sarcoma” Endemic or African KS Iatrogenic KS AIDS-associated KS

45. AIDS-Associated KS AIDS defining illness Skin lesion; รูปร่างรี เรียงตัวตาม skin tension line symmetrical ตามหน้า, ขาและอวัยวะเพศ (macule  pappules/nodules) Pulmonary KS Gastrointestinal KS

46. Kaposi’s sarcoma

47. Staging of AIDS associated KS

48. Disease associate with HHV-8 Pemphigus Interstitial pneumonitis Hemophagocytic syndrome Multiple myeloma Kikuchi’s dz.( Histtocytic necrotizing lymphadenitis)

49. DIAGNOSIS Molecular –PCR –In situ hybridization –immunohistochemistry Serology –IFA –ELISA

50. TREATMENT Palliation –Localized dz :radiation, vinblastin,  - interferon, tumor necrotic factor –Systemic therapy: extensive mucocutaneous dz., visceral organ dz., lympedema,painful local lesion >>bleomycin,doxorubicin,daunorubicin, etoposide,paclitaxel * (cidofovir,foscarnet and gancyclovir)