Transcript HUMAN HERPESVIRUS

Pornpimol L.
INTRODUCTION TO THE FAMILY
HERPESVIRIDAE
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.
ARCHITECTURE
THE HUMAN HERPESVIRUSES
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
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)
Alphaherpesvirinae
Simplexvirus (HHV1&2/
HSV1&2)
Varicellovirus (HHV3/VZV)
HERPES SIMPLEX VIRUS
• First human herpesvirus discovered (1922)
• Two serotypes recognised – HSV-1 & HSV2 (1962)
• Great deal of polymorphism at genomic
level occurs between strains
Herpes Simplex Viruses
• 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
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
Clinical Manifestations
• 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
HERPES SIMPLEX - Type
1
PRIMARY INFECTION
1. Usually cold sores; sore
throat, fever and, rarely,
Encephalitis
2. Less frequently found as
a genital infection
HERPES SIMPLEX - Type 1
TRIGEMINAL
NERVE
LATENT INFECTION
1. Asymptomatic - No virus or
virion proteins produced
2. Viral DNA resides in sensory
cells of Trigeminal nerve
ganglion
HERPES SIMPLEX – Type1
TRIGEMINAL
NERVE
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
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)
HSV-2 Acquisition
HSV-2 Acquisition
• Heterosexual men
• Heterosexual women
• 1 partner: 0%
• 2- 10 partners: 20%
• 11- 50 partners: 35%
• >50 partners: >70%
• 1 partner: <10%
• 2- 10 partners: 40%
• 11- 50 partners: 62%
• >50 partners: >80%
Herpes
whitlow
Herpes keratitis
Most common complications are extragenital
lesions (20%) and aseptic meningitis (10%)
Recurrent HSV-2 infection is generally milder,and
complications are rare.
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
Herpes Encephalitis
• 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
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/day
10-14
10-14
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.)
* Valacyclovir
Dz.
Oral,genital
Recurrent
genital
keratitis
dose
500-1000mg x
2times/day
Duration(days)
10-14
500mg x
2times/day
3-5
1%Trifuridine
ED q 2 hrs
21
TREATMENT (cont.)
• Suppression of
Mucocutaneous Herpes
• Reduction in
Transmission of HSV to
sexual partners
• Acyclovir resistance
;foscarnet
VARICELLA ZOSTER VIRUS
Clinical disease recognised in two forms
Primary infection
- Varicella (Chicken Pox)
Reactivation
- Zoster
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
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 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
• Ramsay Hunt :geniculate gg. จะมีอาการปวด
และตุ่มน้ าใสบริ เวณหูส่วนนอกมอัมพาตใบหน้าซีกเดียวกันและ
สู ญเสี ยความรู ้สึกในการลิ้มรสของลิ้นส่ วนหน้า
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,siezure
,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(1012.5mg/kg v q8hrs 7days
Treatment
• Acute neuritis and/or postherpetic neuralgia
:gabapentin,amitryptyline,lidocainpatches
and fluphenazine hydrochloride
• Prevention :Varicella vaccine
(active immunization) ,VZIg (passive
immunization)
Betaherpesvirinae
• Cytomegalovirus (HHV5/CMV)
• Roseolovirus (HHV6 & 7)
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)
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,abnormal
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
• ในเด็กที่ภูมิคุม้ กันปกติมกั หายได้เอง
• immunocompromisid :
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;รู ปร่ างรี เรี ยงตัวตามskin tension line
symmetrical ตามหน้า,ขาและอวัยวะเพศ
(maculepappules/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
– immunohistochemistry
• 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)