herpesviruses(水痘-带状疱疹病毒).ppt

Herpesviruses AnOverview Propertiesofherpesviruses EnvelopeddoublestrandedDNAviruses Genomeconsisitsoflongandshortfragmentswhichmaybeorientatedineitherdirection givingatotalof4isomers Threesubfamilies Alphaherpesviruses HSV 1 HSV 2 VZVBetaherpesviruses CMV HHV 6 HHV 7Gammaherpesviruses EBV HHV 8SetuplatentorpersistentinfectionfollowingprimaryinfectionReactivationaremorelikelytotakeplaceduringperiodsofimmunosuppressionBothprimaryinfectionandreactivationarelikelytobemoreseriousinimmunocompromisedpatients HerpesvirusParticle HSV 2virusparticle Notethatallherpesviruseshaveidenticalmorphologyandcannotbedistinguishedfromeachotherunderelectronmicroscopy LindaStannard UniversityofCapeTown S A HerpesSimplexViruses Properties BelongtothealphaherpesvirussubfamilyofherpesvirusesDoublestrandedDNAenvelopedviruswithagenomeofaround150kbThegenomeofHSV 1andHSV 2share50 70 homology Theyalsoshareseveralcross reactiveepitopeswitheachother Thereisalsoantigeniccross reactionwithVZV ManistheonlynaturalhostforHSV Epidemiology 1 HSVisspreadbycontact asthevirusisshedinsaliva tears genitalandothersecretions Byfarthemostcommonformofinfectionresultsfromakissgiventoachildoradultfromapersonsheddingthevirus Primaryinfectionisusuallytrivialorsubclinicalinmostindividuals Itisadiseasemainlyofveryyoungchildrenie thosebelow5years Thereare2peaksofincidence thefirstat0 5yearsandthesecondinthelateteens whensexualactivitycommences About10 ofthepopulationacquiresHSVinfectionthroughthegenitalrouteandtheriskisconcentratedinyoungadulthood Epidemiology 2 GenerallyHSV 1causesinfectionabovethebeltandHSV 2belowthebelt Infact 40 ofclinicalisolatesfromgenitalsoresareHSV 1 and5 ofstrainsisolatedfromthefacialareaareHSV 2 Thisdataiscomplicatedbyoralsexualpractices Followingprimaryinfection 45 oforallyinfectedindividualsand60 ofpatientswithgenitalherpeswillexperiencerecurrences Theactualfrequencyofrecurrencesvarieswidelybetweenindividuals Themeannumberofepisodesperyearisabout1 6 Pathogenesis Duringtheprimaryinfection HSVspreadslocallyandashort livedviraemiaoccurs wherebythevirusisdisseminatedinthebody Spreadtothetocraniospinalgangliaoccurs Thevirusthenestablisheslatencyinthecraniospinalganglia Theexactmechanismoflatencyisnotknown itmaybetruelatencywherethereisnoviralreplicationorviralpersistencewherethereisalowlevelofviralreplication Reactivation Itiswellknownthatmanytriggerscanprovokearecurrence Theseincludephysicalorpsychologicalstress infection especiallypneumococcalandmeningococcal fever irradiation includingsunlight andmenstruation ClinicalManifestations HSVisinvolvedinavarietyofclinicalmanifestationswhichincludes 1 Acutegingivostomatitis2 HerpesLabialis coldsore 3 OcularHerpes4 HerpesGenitalis5 Otherformsofcutaneousherpes7 Meningitis8 Encephalitis9 Neonatalherpes Oral facialHerpes AcuteGingivostomatitisAcutegingivostomatitisisthecommonestmanifestationofprimaryherpeticinfection Thepatientexperiencespainandbleedingofthegums 1 8mmulcerswithnecroticbasesarepresent Neckglandsarecommonlyenlargedaccompaniedbyfever Usuallyaselflimitingdiseasewhichlastsaround13days Herpeslabialis coldsore Followingprimaryinfection 45 oforallyinfectedindividualswillexperiencereactivation Theactualfrequencyofrecurrencesvarieswidelybetweenindividuals Herpeslabialis coldsore isarecurrenceoforalHSV Aprodromeoftingling warmthoritchingatthesiteusuallyheraldstherecurrence About12hourslater red nessappearsfollowedbypapulesandthenvesicles Gingivostomatitis OcularHerpes HSVcausesabroadspectrumofoculardisease rangingfrommildsuperficiallesionsinvolvingtheexternaleye toseveresight threateningdiseasesoftheinnereye Diseasescausedincludethefollowing PrimaryHSVkeratitis dendriticulcersRecurrentHSVkeratitisHSVconjunctivitisIridocyclitis chorioretinitisandcataract GenitalHerpes Genitallesionsmaybeprimary recurrentorinitial Manysitescanbeinvolvedwhichincludesthepenis vagina cervix anus vulva bladder thesacralnerveroutes thespinalandthemeninges Thelesionsofgenitalherpesareparticularlypronetosecondarybacterialinfectioneg S aureus Streptococcus TrichomonasandCandidaAlbicans Dysuriaisacommoncomplaint inseverecases theremaybeurinaryretention Localsensorynervesmaybeinvolvedleadingtothedevelopmentofaradiculitis Amildmeningitismaybepresent 60 ofpatientswithgenitalherpeswillexperiencerecurrences RecurrentlesionsintheperianalareatendtobemorenumerousandpersistslongerthantheiroralHSV 1counterparts HerpesSimplexEncephalitis HerpesSimplexencephalitisisoneofthemostseriouscomplicationsofherpessimplexdisease Therearetwoforms Neonatal thereisglobalinvolvementandthebrainisalmostliquefied Themortalityrateapproaches100 Focaldisease thetemporallobeismostcommonlyaffected Thisformofthediseaseappearsinchildrenandadults Itispossiblethatmanyofthesecasesarisefromreactivationofvirus Themortalityrateishigh 70 withouttreatment ItisofutmostimportancetomakeadiagnosisofHSEearly ItisgeneralpracticethatIVacyclovirisgiveninallcasesofsuspectedHSEbeforelaboratoryresultsareavailable NeonatalHerpesSimplex 1 IncidenceofneonatalHSVinfectionvariesinexplicablyfromcountrytocountrye g from1in4000livebirthsintheU S to1in10000livebirthsintheUKThebabyisusuallyinfectedperinatallyduringpassagethroughthebirthcanal Prematurerupturingofthemembranesisawellrecognizedriskfactor Theriskofperinataltransmissionisgreatestwhenthereisafloridprimaryinfectioninthemother Thereisanappreciablysmallerriskfromrecurrentlesionsinthemother probablybecauseofthelowerviralloadandthepresenceofspecificantibodyThebabymayalsobeinfectedfromothersourcessuchasorallesionsfromthemotheroraherpeticwhitlowinanurse NeonatalHerpesSimplex 2 ThespectrumofneonatalHSVinfectionvariesfromamilddiseaselocalizedtotheskintoafataldisseminatedinfection Infectionisparticularlydangerousinprematureinfants Wheredisseminationoccurs theorgansmostcommonlyinvolvedaretheliver adrenalsandthebrain Wherethebrainisinvolved theprognosisisparticularlysevere Theencephalitisisglobalandofsuchseveritythatthebrainmaybeliquefied AlargeproportionofsurvivorsofneonatalHSVinfectionhaveresidualdisabilities AcyclovirshouldbepromptlygiveninallsuspectedcasesofneonatalHSVinfection TheonlymeansofpreventionistooffercaesareansectiontomotherswithfloridgenitalHSVlesions OtherManifestations Disseminatedherpessimplexaremuchmorelikelytooccurinimmunocompromisedindividuals Thewidespreadvesicularresemblesthatofchickenpox Manyorgansotherthantheskinmaybeinvolvede g liver spleen lungs andCNS Othercutaneousmanifestationsincludeeczemaherpeticumwhichispotentiallyaseriousdiseasethatoccursinpatientswitheczema Herpeticwhitlowwhicharisefromimplantationofthevirusintotheskinandtypicallyaffectthefingers zosteriformherpessimplex ThisisararepresentationofherpessimplexwhereHSVlesionsappearinadermatomaldistributionsimilartoherpeszoster LaboratoryDiagnosis DirectDetectionElectronmicroscopyofvesiclefluid rapidresultbutcannotdistinguishbetweenHSVandVZVImmunofluorescenceofskinscrappings candistinguishbetweenHSVandVZVPCR nowusedroutinelyforthediagnosisofherpessimpleencephalitisVirusIsolationHSV 1andHSV 2areamongtheeasiestvirusestocultivate Itusuallytakesonly1 5daysforaresulttobeavailable SerologyNotthatusefulintheacutephasebecauseittakes1 2weeksforbeforeantibodiesappearafterinfection Usedtodocumenttorecentinfection CytopathicEffectofHSVincellculture Notetheballooningofcells LindaStannard UniversityofCapeTown S A PositiveimmunofluorescencetestforHSVantigeninepithelialcell VirologyLaboratory New YaleHavenHospital Management Atpresent thereareonlyafewindicationsofantiviralchemo therapy withthehighcostofantiviraldrugsbeingamainconsideration Generally antiviralchemotherapyisindicatedwheretheprimaryinfectionisespeciallysevere wherethereisdissemination wheresightisthreatened andherpessimplexencephalitis Acyclovir thisthedrugofchoiceformostsituationsatpresent Itisavailableinanumberofformulations I V HSVinfectioninnormalandimmunocompromisedpatients Oral treatmentandlongtermsuppressionofmucocutaneousherpesandprophylaxisofHSVinimmunocompromisedpatients Cream HSVinfectionoftheskinandmucousmembranes OphthalmicointmentFamciclovirandvalacyclovir oralonly moreexpensivethanacyclovir Otherolderagents e g idoxuridine trifluorothymidine Vidarabine ara A Theseagentsarehighlytoxicandissuitablefortopicaluseforopthalmicinfectiononly Varicella ZosterVirus Properties BelongtothealphaherpesvirussubfamilyofherpesvirusesDoublestrandedDNAenvelopedvirusGenomesize125kbp longandshortfragmentswithatotalof4isometricforms Oneantigenicserotypeonly althoughthereissomecrossreactionwithHSV Epidemiology Primaryvaricellaisanendemicdisease Varicellaisoneoftheclassicdiseasesofchildhood withthehighestprevalenceoccurringinthe4 10yearsoldagegroup Varicellaishighlycommunicable withanattackrateof90 inclosecontacts Mostpeoplebecomeinfectedbeforeadulthoodbut10 ofyoungadultsremainsusceptible Herpeszoster incontrast occurssporadicallyandevenlythroughouttheyear Pathogenesis Thevirusisthoughttogainentryviatherespiratorytractandspreadsshortlyaftertothelymphoidsystem Afteranincubationperiodof14days thevirusarrivesatitsmaintargetorgan theskin Followingtheprimaryinfection thevirusremainslatentinthecerebralorposteriorrootganglia In10 20 ofindividuals asinglerecurrentinfectionoccursafterseveraldecades Thevirusreactivatesintheganglionandtracksdownthesensorynervetotheareaoftheskininnervatedbythenerve producingavaricellaformrashinthedistributionofadermatome Varicella Primaryinfectionresultsinvaricella chickenpox Incubationperiodof14 21daysPresentsfever lymphadadenopathy awidespreadvesicularrash Thefeaturesaresocharacteristicthatadiagnosiscanusuallybemadeonclinicalgroundsalone Complicationsarerarebutoccursmorefrequentlyandwithgreaterseverityinadultsandimmunocompromisedpatients Mostcommoncomplicationissecondarybacterialinfectionofthevesicles Severecomplicationswhichmaybelifethreateningincludeviralpneumonia encephalititis andhaemorrhagicchickenpox RashofChickenpox HerpesZoster Shingles HerpesZostermainlyaffectasingledermatomeoftheskin Itmayoccuratanyagebutthevastmajorityofpatientsaremorethan50yearsofage Thelatentvirusreactivatesinasensoryganglionandtracksdownthesensorynervetotheappropriatesegment Thereisacharacteristiceruptionofvesiclesinthedermatomewhichisoftenaccompaniedbyintensivepainwhichmaylastformonths postherpeticneuralgia Herpeszosteraffectingtheeyeandfacemayposegreatproblems Aswithvaricella herpeszosterinafargreaterprobleminimmunocompromisedpatientsinwhomthereactivationoccursearlierinlifeandmultipleattacksoccuraswellascomplications Complicationsarerareandincludeencephalitisanddisseminatedherpeszoster Shingles CongenitalVZVInfection 90 ofpregnantwomenalreadyimmune thereforeprimaryinfectionisrareduringpregnancy Primaryinfectionduringpregnancycarriesagreaterriskofseveredisease inparticularpneumonia First20weeksofPregnancyUpto3 chanceoftransmissiontothefetus recognisedcongenitalvaricellasyndrome ScarringofskinHypoplasiaoflimbsCNSandeyedefectsDeathininfancynormal NeonatalVaricella VZVcancrosstheplacentainthelatestagesofpregnancytoinfectthefetuscongenitally Neonatalvaricellamayvaryfromamilddiseasetoafataldisseminatedinfection Ifrashinmotheroccursmorethan1weekbeforedelivery thensufficientimmunitywouldhavebeentransferredtothefetus Zosterimmunoglobulinshouldbegiventosusceptiblepregnantwomenwhohadcontactwithsuspectedcasesofvaricella Zosterimmunoglobulinshouldalsobegiventoinfantswhosemothersdevelopvaricelladuringthelast7daysofpregnancyorthefirst14daysafterdelivery LaboratoryDiagnosis Theclinicalpresentationsofvaricellaorzosteraresocharacteristicthatlaboratoryconfirmationisrarelyrequired Laboratorydiagnosisisrequiredonlyforatypicalpresentations particularlyintheimmunocompromised VirusIsolation rarelycarriedoutasitrequires2 3weeksforaresults Directdetection electronmicroscopymaybeusedforvesiclefluidsbutcannotdistinguishbetweenHSVandVZV Immunofluorescenseonskinscrappingscandistinguishbetweenthetwo Serology thepresenceofVZVIgGisindicativeofpastinfectionandimmunity ThepresenceofIgMisindicativeofrecentprimaryinfection CytopathicEffectofVZVincellculture Notetheballooningofcells CoutesyofLindaStannard UniversityofCapeTown S A CytopathicEffectofVZV Management Uncomplicatedvaricellaisaselflimiteddiseaseandrequiresnospecifictreatment However acyclovirhadbeenshowntoacceleratetheresolutionofthediseaseandisprescribedbysomedoctors Acyclovirshouldbegivenpromptlyimmunocompromisedindividualswithvaricellainfectionandnormalindividualswithseriouscomplicationssuchaspneumoniaandencephalitis herpeszosterinahealthyindividualisnotnormallyacauseforconcern Themainproblemisthemanagementofthepostherpeticneuralgia TheInternationalHerpesManagementForumrecommendsthatantiviraltherapyshouldbeofferedroutinelytoallpatientsover50yearsofagepresentingwithherpeszoster Threedrugscanbeusedforthetreatmentofherpeszoster acyclovir valicyclovir andfamciclovir Thereappearstobelittledifferenceinefficacybetweenthem Prevention Preventivemeasuresshouldbeconsideredforindividualsatriskofcontractingseverevaricellainfectione g leukaemicchildren neonates andpregnantwomenWhereurgentprotectionisneeded passiveimmunizationshouldbegiven Zosterimmunoglobulin ZIG isthepreparationofchoicebutitisveryexpensive WhereZIGisnotavailable HNIGshouldbegiveninstead Aliveattenuatedvaccineisavailable Therehadbeengreatreluctancetouseitinthepast especiallyinimmunocompromisedindividualssincethevaccineviruscanbecomelatentandreactivatelateron However recentdatasuggeststhatthevaccineissafe eveninchildrenwithleukaemiaprovidedthattheyareinremission Itishighlydebatablewhetheruniversalvaccinationshouldbeofferedsincechickenpoxandshinglesarenormallymilddiseases Cytomegalovirus Properties BelongtothebetaherpesvirussubfamilyofherpesvirusesdoublestrandedDNAenvelopedvirusNucleocapsid105nmindiameter 162capsomersThestructureofthegenomeofCMVissimilartootherherpesviruses consistingoflongandshortsegmentswhichmaybeorientatedineitherdirection givingatotalof4isomers Alargeno ofproteinsareencodedfor theprecisenumberisunknown Epidemiology CMVisoneofthemostsuccessfulhumanpathogens itcanbetransmittedverticallyorhorizontallyusuallywithlittleeffectonthehost Transmissionmayoccurinutero perinatallyorpostnatally Onceinfected thepersoncarriesthevirusforlifewhichmaybeactivatedfromtimetotime duringwhichinfectiousvirionsappearintheurineandthesaliva Reactivationcanalsoleadtoverticaltransmission ItisalsopossibleforpeoplewhohaveexperiencedprimaryinfectiontobereinfectedwithanotherorthesamestrainofCMV thisreinfectiondoesnotdifferclinicallyfromreactivation Indevelopedcountrieswithahighstandardofhygiene 40 ofadolescentsareinfectedandultimately70 ofthepopulationisinfected Indevelopingcountries over90 ofpeopleareultimatelyinfected Pathogenesis Onceinfected thevirusremainsinthepersonforlifeandmybereactivatedfromtimetotime especiallyinimmunocompromisedindividuals Thevirusmaybetransmittedinutero perinatally orpostnatally Perinataltransmissionoccurs Perinatalinfectionisacquiredmainlythroughinfectedgenitalsecretions orbreastmilk Overall 2 10 ofinfantsareinfectedbytheageof6monthsworldwide Perinatalinfectionisthoughttobe10timesmorecommonthancongenitalinfection Postnatalinfectionmainlyoccursthroughsaliva Sexualtransmissionmayoccuraswellasthroughbloodandbloodproductsandtransplantedorgan ClinicalManifestations Congenitalinfection mayresultincytomegalicinclusiondiseasePerinatalinfection usuallyasymptomaticPostnatalinfection usuallyasymptomatic However inaminorityofcases thesyndromeofinfectiousmononucleosismaydevelopwhichconsistsoffever lymphadenopathy andsplenomegaly Theheterophilantibodytestisnegativealthoughatypicallymphocytesmaybefoundintheblood ImmunocompromisedpatientssuchastransplantrecipientsandAIDSpatientsarepronetosevereCMVdiseasesuchaspneumonitis retinitis colitis andencephalopathy ReactivationorreinfectionwithCMVisusuallyasymptomaticexceptinimmunocompromisedpatients CongenitalInfection DefinedastheisolationofCMVfromthesalivaorurinewithin3weeksofbirth Commonestcongenitalviralinfection affects0 3 1 ofalllivebirths ThesecondmostcommoncauseofmentalhandicapafterDown ssyndromeandisresponsibleformorecasesofcongenitaldamagethanrubella TransmissiontothefetusmayoccurfollowingprimaryorrecurrentCMVinfection 40 chanceoftransmissiontothefetusfollowingaprimaryinfection Maybetransmittedtothefetusduringallstagesofpregnancy Noevidenceofteratogenecity damagetothefetusresultsfromdestructionoftargetcellsoncetheyareformed CytomegalicInclusionDisease CNSabnormalities microcephaly mentalretardation spasticity epilepsy periventricularcalcification Eye choroidoretinitisandopticatrophyEar sensorineuraldeafnessLiver hepatosplenomegalyandjaundicewhichisduetohepatitis Lung pneumonitisHeart myocarditisThrombocytopenicpurpura HaemolyticanaemiaLatesequelaeinindividualsasymptomaticatbirth hearingdefectsandreducedintelligence IncidenceofCytomegalicDisease LaboratoryDiagnosis 1 DirectdetectionbiopsyspecimensmaybeexaminedhistologicallyforCMVinclusionantibodiesorforthepresenceofCMVantigens However thesensitivitymaybelow Thepp65CMVantigenaemiatestisnowroutinelyusedfortherapiddiagnosisofCMVinfectioninimmunocompromisedpatients PCRforCMV DNAisusedinsomecentersbuttheremaybeproblemswithinterpretation CMVpp65antigenaemiatest VirologyLaboratory New YaleHavenHospital LaboratoryDiagnosis 2 VirusIsolationconventionalcellcultureisregardedasgoldstandardbutrequiresupto4weeksforresult MoreusefularerapidculturemethodssuchastheDEAFFtestwhichcanprovidearesultin24 48hours SerologythepresenceofCMVIgGantibodyindicatespastinfection ThedetectionofIgMisindicativeofprimaryinfectionalthoughitmayalsobefoundinimmunocompromisedpatientswithreactivation CytopathicEffectofCMV CourtesyofLindaStannard UniversityofCapeTown S A DEAFFtestforCMV VirologyLaboratory New YaleHavenHospital SpecimensforLaboratoryDiagnosis Treatment Congenitalinfections itisnotusuallypossibletodetectcongenitalinfectionunlessthemotherhassymptomsofprimaryinfection Ifso thenthemothershouldbetoldofthechancesofherbabyhavingcytomegalicinclusiondiseaseandperhapsofferedthechoiceofanabortion Perinatalandpostnatalinfection itisusuallynotnecessarytotreatsuchpatients Immunocompromisedpatients itisnecessaryt