Pornpimol L.

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 FAMILYHERPESVIRIDAE

ARCHITECTURE

-1 1Human herpesvirus type (Herpes simplex virus ) -2 ( 2 )Human herpesvirus type Herpes simplex virus 3 ( )Human herpesvirus type Varricella zoster virus - 4 ( )Human herpesvirus type Epstein Barr virus 5 ( )Human herpesvirus type Cytomegalovirus

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THE HUMAN HERPESVIRUSES

8To date, there are known human Herpesviruses.

Alphaherpesvirinae:- rrrrrr rrrrr rrrrrrrrrrrr rrrrrr rrrrr rrrr, ,

ad in cell culture Simplexvirus human - -1 , 2 ( 1 ,herpesvirus HSV HSV

2) Varicellovirus human 3 ( )herpesvirus VZV

Betaherpesvirinae:- restricted host range, long reproductive cycle, enlargemrrr rr rrrrrrrr rrrrrCytomegalovirus 5 ( )human herpesvirus HCMVRoseolovirus - -6 , 7 ( 6 , 7human herpesvirus HHV HHV)

Gammaherpesvirinae:- replicate in lymphoblastoid cells, specific for T or B cellsLymphocryptoviru 4 ( )s human herpesvirus EBVRhadinovirus -8 8human herpesvirus (HHV )

Alphaherpesvirinae

1 2Simplexvirus (H H V & / H SV1&2)

Varicellovirus (HHV3/VZV)

• First human herpesvirus discovered (1922)

• - Two serotypes recognised – HSV 1 & H-SV 2 (1962)

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HERPES SIMPLEX VIRUS

• 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

PATHOGENESIS

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• - 2HSV infection is usually acquired by vvvvvv vvvvvvvvvvvv

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• v vvvv vvvv vvv vvvvvvvvv vvvvv vv vvvvvvvvvvv vv vvvvvv vvvv vvvvvvv vvv vvvvvvv vvvvvv• - 212 2Incubation period of days, and symptoms last for-3 weeks

• 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

HERPES SIMPLEX - Type 1

PRIMARY INFECTION

1. Usually cold sores; sorethroat, fever and, rarely,Encephalitis

2. Less frequently found asa genital infection

HERPES SIMPLEX - Type 1

LATENT INFECTION

1. Asymptomatic - No virus orvirion proteins produced

2. Viral DNA resides in sensorycells of Trigeminal nerveganglion

TRIGEMINAL NERVE

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RECURRENT INFECTION

1. Virus replicates and travrrr

down sensory nerve fiber to infect epithelial cells around

the nose and mouth 2. Symptoms are usually a

milder form of primaryinfection

TRIGEMINAL NERVE

- HERPES SIMPLEX Type2

1. Usually vesicular erupti ons on the genitalia 2. Spread by sexual contac

r 3. Affects both sexes 4. Once associated with ce

rrrrrr carcinoma

5. Less frequently found ar Herpes Labialis (cold sorer)

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%

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

Herpes Encephalitis

• Age :5-30yrs,>50yrs• 93-96% HSV-1• Mech : -nasal mucosa/oropharynx

cribiform plateorbital,temporal-blood stream-recurrent: reactive of HV

trigeminal gg CN v anterior, middle fossa

Clinical : fever,headache,ataxia,dysarthria,seizure

• 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

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

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

TREATMENT

* Acyclovir

Dz. dose Duration (day)Oral ,genital 200mg x 5times/day

400mg x 3times/day10-1410-14

Anus 400mg x 5times/day 10-14

Herpetic whitlow

400 mg x 3times/day 7

Meningitis 5mg/kg v q 8 hrs 10-14

Encephalitis 10mg/kg v q 8 hrs 10-14

Disseminated 15mg/kg /day 10-14

TREATMENT(cont.)

Dz. dose Duration(days)

Oral,genital 500-1000mg x 2times/day

10-14

Recurrent genital

500mg x 2times/day

3-5

keratitis 1%Trifuridine ED q 2 hrs

21

* Valacyclovir

TREATMENT (cont.)

• Suppression of Mucocutaneous Herpes

• Reduction in Transmission of HSV to sexual partners

• Acyclovir resistance ;foscarnet

VARICELLA ZOSTER VIRUS

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v vvv vvv vvvvvvvvv - Varicella (Chicken Pox)

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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 indi

viduals these are overwhelmed and extensive secondary viremia occurs

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.

Chicken Pox

SECONDARY ZOSTER PATHOLOGY

Virus spreads to the gangl ia 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

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Lab findings

• Isolation of VZV in susceptible tissue culture cell line

• Tzank smear• Detection of

antibodies:IFA,ELISA,FAMA

VZV Encephalitis

• 1:1,000• Children>adult• Clinical:headahe,vomitting,siffneck,si

ezure,oculomotor,facial palsy• Dx:

– CSF:wbc ,(L) ,prot ,sugar ,Ab positive

• Cpx:transverse myelitis,peripheral neuritis,optic neuritis

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

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

• Acute neuritis and/or postherpetic neuralgia :gabapentin,amitryptyline,lidocainpatches and fluphenazine hydrochloride

• Prevention :Varicella vaccine (active immunization) ,VZIg (passive immunization)

Treatment

Betaherpesvirinae

• Cytomegalovirus (HHV5/CMV)

• Roseolovirus (HHV6 & 7)

HUMAN HERPESVIRUS - 6

198First isolated from PBM C of patients in 6 during

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UK and subsequently was found to be ubiquitous.v vvvvvv vvv vvvvvvv vvv vvvv vv vvvvv vv v v v

vvv vv -classification as a beta herpesvirus

- Two variants of HHV 6 have been identified on basis of genetic and biological properties

(variants A and B)

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

• Immunocompromised :organ transplantation– Solid organ,bone marrow transplant– Fever,headache,confusion,seizure,abno

rmal movement and behavior change– CSF ;PCR

DIAGNOSIS

• Children(primary infection) :antiHHV-6,fourfold rise of antiHHV-6 IgG

• Clinical & HHV-6 in PBMC and plasma,high viral load

TREATMENT

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ganciclovir,foscarnet,cidofovir

Gamma herpesvirinae• Epstein Barr Virus• Kaposi’ s sarcoma associated

herpesvirus(KSHV)

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

PATHOGENESIS

• Oral transmission (saliva), fecal-oral sexual contact and parenteral transmission

Clinical manifestation

• Classic KS : “Kaposi’s sarcoma”

• Endemic or African KS• Iatrogenic KS• AIDS-associated KS

AIDS-Associated KS

• AIDS defining illness• Skin lesion;ร�ปร�างร� เร�ยงตุ่�วตุ่ามีskin

tension line symmetrical ตุ่ามีหูน้ำ!า,ขาและอว�ยวะเพศ (maculepappules/nodules)

• Pulmonary KS• Gastrointestinal KS

Kaposi’s sarcoma

Staging of AIDS associated KS

Disease associate with HHV-8

• Pemphigus• Interstitial pneumonitis• Hemophagocytic syndrome• Multiple myeloma• Kikuchi’s dz.( Histtocytic necrotizing

lymphadenitis)

DIAGNOSIS

• Molecular – PCR– In situ hybridization– immunohistochemist

ry• Serology

– IFA– ELISA

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)