herpesviruses(水痘带状疱疹病毒)课件.ppt

1、HerpesvirusesAn OverviewProperties of herpesvirusesnEnveloped double stranded DNA viruses.nGenome consisits of long and short fragments which may be orientated in either direction,giving a total of 4 isomers.nThree subfamilies:nAlphaherpesviruses-HSV-1,HSV-2,VZVnBetaherpesviruses-CMV,HHV-6,HHV-7nGam

2、maherpesviruses-EBV,HHV-8nSet up latent or persistent infection following primary infectionnReactivation are more likely to take place during periods of immunosuppressionnBoth primary infection and reactivation are likely to be more serious in immunocompromised patients.Herpesvirus ParticleHSV-2 vir

3、us particle.Note that all herpesviruses have identical morphology and cannot be distinguished from each other under electron microscopy.(Linda Stannard,University of Cape Town,S.A.)Herpes Simplex VirusesPropertiesnBelong to the alphaherpesvirus subfamily of herpesvirusesnDouble stranded DNA envelope

4、d virus with a genome of around 150 kbnThe genome of HSV-1 and HSV-2 share 50-70%homology.nThey also share several cross-reactive epitopes with each other.There is also antigenic cross-reaction with VZV.nMan is the only natural host for HSV.Epidemiology(1)nHSV is spread by contact,as the virus is sh

5、ed in saliva,tears,genital and other secretions.nBy far the most common form of infection results from a kiss given to a child or adult from a person shedding the virus.nPrimary infection is usually trivial or subclinical in most individuals.It is a disease mainly of very young children ie.those bel

6、ow 5 years.nThere are 2 peaks of incidence,the first at 0-5 years and the second in the late teens,when sexual activity commences.nAbout 10%of the population acquires HSV infection through the genital route and the risk is concentrated in young adulthood.Epidemiology(2)nGenerally HSV-1 causes infect

7、ion above the belt and HSV-2 below the belt.In fact,40%of clinical isolates from genital sores are HSV-1,and 5%of strains isolated from the facial area are HSV-2.This data is complicated by oral sexual practices.nFollowing primary infection,45%of orally infected individuals and 60%of patients with g

8、enital herpes will experience recurrences.nThe actual frequency of recurrences varies widely between individuals.The mean number of episodes per year is about 1.6.PathogenesisnDuring the primary infection,HSV spreads locally and a short-lived viraemia occurs,whereby the virus is disseminated in the

9、body.Spread to the to craniospinal ganglia occurs.nThe virus then establishes latency in the craniospinal ganglia.nThe exact mechanism of latency is not known,it may be true latency where there is no viral replication or viral persistence where there is a low level of viral replication.nReactivation

10、-It is well known that many triggers can provoke a recurrence.These include physical or psychological stress,infection;especially pneumococcal and meningococcal,fever,irradiation;including sunlight,and menstruation.Clinical ManifestationsHSV is involved in a variety of clinical manifestations which

11、includes;-1.Acute gingivostomatitis2.Herpes Labialis(cold sore)3.Ocular Herpes 4.Herpes Genitalis5.Other forms of cutaneous herpes7.Meningitis8.Encephalitis9.Neonatal herpesOral-facial HerpesnAcute GingivostomatitisnAcute gingivostomatitis is the commonest manifestation of primary herpetic infection

12、.nThe patient experiences pain and bleeding of the gums.1-8 mm ulcers with necrotic bases are present.Neck glands are commonly enlarged accompanied by fever.nUsually a self limiting disease which lasts around 13 days.nHerpes labialis(cold sore)nFollowing primary infection,45%of orally infected indiv

13、iduals will experience reactivation.The actual frequency of recurrences varies widely between individuals.nHerpes labialis(cold sore)is a recurrence of oral HSV.nA prodrome of tingling,warmth or itching at the site usually heralds the recurrence.About 12 hours later,red-ness appears followed by papu

14、les and then vesicles.GingivostomatitisOcular HerpesHSV causes a broad spectrum of ocular disease,ranging from mild superficial lesions involving the external eye,to severe sight-threatening diseases of the inner eye.Diseases caused include the following:-nPrimary HSV keratitis dendritic ulcersnRecu

15、rrent HSV keratitisnHSV conjunctivitis nIridocyclitis,chorioretinitis and cataract Genital HerpesnGenital lesions may be primary,recurrent or initial.nMany sites can be involved which includes the penis,vagina,cervix,anus,vulva,bladder,the sacral nerve routes,the spinal and the meninges.The lesions

16、of genital herpes are particularly prone to secondary bacterial infection eg.S.aureus,Streptococcus,Trichomonas and Candida Albicans.nDysuria is a common complaint,in severe cases,there may be urinary retention.nLocal sensory nerves may be involved leading to the development of a radiculitis.A mild

17、meningitis may be present.n60%of patients with genital herpes will experience recurrences.Recurrent lesions in the perianal area tend to be more numerous and persists longer than their oral HSV-1 counterparts.Herpes Simplex EncephalitisnHerpes Simplex encephalitis is one of the most serious complica

18、tions of herpes simplex disease.There are two forms:nNeonatal there is global involvement and the brain is almost liquefied.The mortality rate approaches 100%.nFocal disease the temporal lobe is most commonly affected.This form of the disease appears in children and adults.It is possible that many o

19、f these cases arise from reactivation of virus.The mortality rate is high(70%)without treatment.nIt is of utmost importance to make a diagnosis of HSE early.It is general practice that IV acyclovir is given in all cases of suspected HSE before laboratory results are available.Neonatal Herpes Simplex

20、(1)nIncidence of neonatal HSV infection varies inexplicably from country to country e.g.from 1 in 4000 live births in the U.S.to 1 in 10000 live births in the UKnThe baby is usually infected perinatally during passage through the birth canal.nPremature rupturing of the membranes is a well recognized

21、 risk factor.nThe risk of perinatal transmission is greatest when there is a florid primary infection in the mother.nThere is an appreciably smaller risk from recurrent lesions in the mother,probably because of the lower viral load and the presence of specific antibody nThe baby may also be infected

22、 from other sources such as oral lesions from the mother or a herpetic whitlow in a nurse.Neonatal Herpes Simplex(2)nThe spectrum of neonatal HSV infection varies from a mild disease localized to the skin to a fatal disseminated infection.nInfection is particularly dangerous in premature infants.nWh

23、ere dissemination occurs,the organs most commonly involved are the liver,adrenals and the brain.nWhere the brain is involved,the prognosis is particularly severe.The encephalitis is global and of such severity that the brain may be liquefied.nA large proportion of survivors of neonatal HSV infection

24、 have residual disabilities.nAcyclovir should be promptly given in all suspected cases of neonatal HSV infection.nThe only means of prevention is to offer caesarean section to mothers with florid genital HSV lesions.Other ManifestationsnDisseminated herpes simplex are much more likely to occur in im

25、munocompromised individuals.The widespread vesicular resembles that of chickenpox.Many organs other than the skin may be involved e.g.liver,spleen,lungs,and CNS.nOther cutaneous manifestations include neczema herpeticum which is potentially a serious disease that occurs in patients with eczema.nHerp

26、etic whitlow which arise from implantation of the virus into the skin and typically affect the fingers.n“zosteriform herpes simplex.This is a rare presentation of herpes simplex where HSV lesions appear in a dermatomal distribution similar to herpes zoster.Laboratory DiagnosisnDirect DetectionnElect

27、ron microscopy of vesicle fluid-rapid result but cannot distinguish between HSV and VZVnImmunofluorescence of skin scrappings-can distinguish between HSV and VZVnPCR-now used routinely for the diagnosis of herpes simple encephalitisnVirus Isolation nHSV-1 and HSV-2 are among the easiest viruses to c

28、ultivate.It usually takes only 1-5 days for a result to be available.nSerologynNot that useful in the acute phase because it takes 1-2 weeks for before antibodies appear after infection.Used to document to recent infection.Cytopathic Effect of HSV in cell culture:Note the ballooning of cells.(Linda

29、Stannard,University of Cape Town,S.A.)Positive immunofluorescence test for HSV antigen in epithelial cell.(Virology Laboratory,New-Yale Haven Hospital)ManagementAt present,there are only a few indications of antiviral chemo-therapy,with the high cost of antiviral drugs being a main consideration.Gen

30、erally,antiviral chemotherapy is indicated where the primary infection is especially severe,where there is dissemination,where sight is threatened,and herpes simplex encephalitis.Acyclovir this the drug of choice for most situations at present.It is available in a number of formulations:-nI.V.(HSV i

31、nfection in normal and immunocompromised patients)nOral(treatment and long term suppression of mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients)nCream(HSV infection of the skin and mucous membranes)nOphthalmic ointmentFamciclovir and valacyclovir oral only,more expensive tha

32、n acyclovir.Other older agents e.g.idoxuridine,trifluorothymidine,Vidarabine(ara-A).n These agents are highly toxic and is suitable for topical use for opthalmic infection only Varicella-Zoster VirusPropertiesnBelong to the alphaherpesvirus subfamily of herpesvirusesnDouble stranded DNA enveloped vi

33、rusnGenome size 125 kbp,long and short fragments with a total of 4 isometric forms.nOne antigenic serotype only,although there is some cross reaction with HSV.EpidemiologynPrimary varicella is an endemic disease.Varicella is one of the classic diseases of childhood,with the highest prevalence occurr

34、ing in the 4-10 years old age group.nVaricella is highly communicable,with an attack rate of 90%in close contacts.nMost people become infected before adulthood but 10%of young adults remain susceptible.nHerpes zoster,in contrast,occurs sporadically and evenly throughout the year.PathogenesisnThe vir

35、us is thought to gain entry via the respiratory tract and spreads shortly after to the lymphoid system.nAfter an incubation period of 14 days,the virus arrives at its main target organ,the skin.nFollowing the primary infection,the virus remains latent in the cerebral or posterior root ganglia.In 10-

36、20%of individuals,a single recurrent infection occurs after several decades.nThe virus reactivates in the ganglion and tracks down the sensory nerve to the area of the skin innervated by the nerve,producing a varicellaform rash in the distribution of a dermatome.VaricellanPrimary infection results i

37、n varicella(chickenpox)nIncubation period of 14-21 daysnPresents fever,lymphadadenopathy.a widespread vesicular rash.nThe features are so characteristic that a diagnosis can usually be made on clinical grounds alone.nComplications are rare but occurs more frequently and with greater severity in adul

38、ts and immunocompromised patients.nMost common complication is secondary bacterial infection of the vesicles.nSevere complications which may be life threatening include viral pneumonia,encephalititis,and haemorrhagic chickenpox.Rash of Chickenpox Herpes Zoster(Shingles)nHerpes Zoster mainly affect a

39、 single dermatome of the skin.nIt may occur at any age but the vast majority of patients are more than 50 years of age.nThe latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment.nThere is a characteristic eruption of vesicles in the dermatome whi

40、ch is often accompanied by intensive pain which may last for months(postherpetic neuralgia)nHerpes zoster affecting the eye and face may pose great problems.nAs with varicella,herpes zoster in a far greater problem in immunocompromised patients in whom the reactivation occurs earlier in life and mul

41、tiple attacks occur as well as complications.nComplications are rare and include encephalitis and disseminated herpes zoster.ShinglesCongenital VZV Infectionn90%of pregnant women already immune,therefore primary infection is rare during pregnancy.nPrimary infection during pregnancy carries a greater

42、 risk of severe disease,in particular pneumonia.First 20 weeks of PregnancynUp to 3%chance of transmission to the fetus,recognised congenital varicella syndrome;nScarring of skinnHypoplasia of limbsnCNS and eye defectsnDeath in infancy normalNeonatal VaricellanVZV can cross the placenta in the late

43、stages of pregnancy to infect the fetus congenitally.nNeonatal varicella may vary from a mild disease to a fatal disseminated infection.nIf rash in mother occurs more than 1 week before delivery,then sufficient immunity would have been transferred to the fetus.nZoster immunoglobulin should be given

44、to susceptible pregnant women who had contact with suspected cases of varicella.nZoster immunoglobulin should also be given to infants whose mothers develop varicella during the last 7 days of pregnancy or the first 14 days after delivery.Laboratory DiagnosisThe clinical presentations of varicella o

45、r zoster are so characteristic that laboratory confirmation is rarely required.Laboratory diagnosis is required only for atypical presentations,particularly in the immunocompromised.nVirus Isolation-rarely carried out as it requires 2-3 weeks for a results.nDirect detection-electron microscopy may b

46、e used for vesicle fluids but cannot distinguish between HSV and VZV.Immunofluorescense on skin scrappings can distinguish between the two.nSerology-the presence of VZV IgG is indicative of past infection and immunity.The presence of IgM is indicative of recent primary infection.Cytopathic Effect of

47、 VZV in cell culture:Note the ballooning of cells.(Coutesy of Linda Stannard,University of Cape Town,S.A.)Cytopathic Effect of VZVManagementnUncomplicated varicella is a self limited disease and requires no specific treatment.However,acyclovir had been shown to accelerate the resolution of the disea

48、se and is prescribed by some doctors.nAcyclovir should be given promptly immunocompromised individuals with varicella infection and normal individuals with serious complications such as pneumonia and encephalitis.nherpes zoster in a healthy individual is not normally a cause for concern.The main pro

49、blem is the management of the postherpetic neuralgia.nThe International Herpes Management Forum recommends that antiviral therapy should be offered routinely to all patients over 50 years of age presenting with herpes zoster.nThree drugs can be used for the treatment of herpes zoster:acyclovir,valic

50、yclovir,and famciclovir.There appears to be little difference in efficacy between them.PreventionnPreventive measures should be considered for individuals at risk of contracting severe varicella infection e.g.leukaemic children,neonates,and pregnant womennWhere urgent protection is needed,passive im