医学文献翻译(中英对照)

Theclinicalandcost-effectivenessofPharmalgen®forthetreatmentofbeeandwaspvenomallergy1TITLEOFPROJECTTheclinicalandcosteffectivenessofPharmalgen®forthetreatmentofbeeandwaspvenomallergy2TARTEAMLiverpoolReviewsandImplementationGroup(LRiG),UniversityofCorrespondenceto:RumonaDickson,MsDirector,LRiGUniversityofRoom2.12WhelanTheQuadrangleBrownlowHillLiverpoolL693GBTel:+44(0)1517945682Fax:+44(0)1517945585Email:R.Dickson@liv.ac.ukFordetailsofexpertisewithintheTARteam,seesection7.3PLAINENGLISHSUMMARYAllergicreactionstobeeandwaspvenommayoccurinvenom-sensitivepatientsimmediatelyfollowingasting,andcanvaryinseverity,withinitiallymildsymptomssometimesprogressingtocriticalconditionswithinseconds.Themostseveresystemicallergicreactions(generalisedreactions)areknownasanaphylaxis,areactioncharacterisedbyabnormallylowbloodpressure,faintingorcollapse,andinextremereactionsthesesymptomscancausedeath.EachyearintheUKtherearebetweentwoandninedeathsfromanaphylaxiscausedbybeeandwaspvenom.Theimmediatetreatmentforsevereallergicreactionstobeeandwaspvenomconsistsofemergencytreatmentwithdrugstodecreasethepatient’sresponsetothevenomandsupportbreathing,ifrequired.Toavoidfurtherreactions,theuseofsensitisationtobeeandwaspvenom,throughaprocessknownasvenomimmunotherapy(VIT),hasbeeninvestigated.Venomimmunotherapyconsistsofsubcutaneousinjectionsofincreasingamountsofvenomintopatientswithahistoryofanaphylaxistobeeandwaspvenom.Pharmalgen®hashadUKmarketingauthorisationforthediagnosisandtreatment(usingVIT)ofallergytobeevenom(usingPharmalgen®BeeVenom)andwaspvenom(usingPharmalgen®WaspVenom)sinceMarch1995,anditisusedbymorethan40centresacrosstheUK.ThisreviewaimstoassesswhetherusingPharmalgen®inVITisclinicallyusefulwhentreatingpeoplewithahistoryofseverereactiontobeeandwaspstings.ThereviewwillcomparepreventativetreatmentwithPharmalgen®toothertreatmentoptions,includinghighdoseantihistamines,adviceontheavoidanceofbeeandwaspstingsandadrenalineauto-injectorprescriptionandtraining.Ifsuitabledataareavailable,thereviewwillalsoconsiderthecosteffectivenessofusingPharmalgen®forVITandothersubgroupsincludingchildrenandpeopleathighriskoffuturestingsorsevereallergicreactionstofuturestings.4DECISIONPROBLEM4.1ClarificationofresearchquestionandscopePharmalgen®isusedforthediagnosisandtreatmentofimmunoglobinE(IgE)-mediatedallergytobeeandwaspvenom.TheaimofthisreportistoassesswhethertheuseofPharmalgen®isofclinicalvaluewhenprovidingVITtoindividualswithahistoryofseverereactiontobeeandwaspvenomandwhetherdoingsowouldbeconsideredcosteffectivecomparedwithalternativetreatmentoptionsavailableintheNHS.4.2BackgroundBeesandwaspsformpartoftheorderHymenoptera(whichalsoincludesants),andwithinthisorderthespeciesthatcausethemostfrequentallergicreactionsaretheVespidae(wasps,yellowjacketsandhornets),andtheApinae(honeybees).1Beeandwaspstingscontainallergenicproteins.Inwasps,thesearepredominantlyphospholipaseA1,2hyaluronidase2andantigen5,3andinbeesarephospholipaseA2andhyaluronidase.4Followinganinitialsting,atype1hypersensitivityreactionmayoccurinsomeindividualswhichproducestheIgEantibody.Thissensitisescellstotheallergen,andanysubsequentexposuretotheallergenmaycausetheallergentobindtotheIgEmolecules,whichresultsinanallergicreaction.Theseallergenstypicallyproduceanintense,burningpainfollowedbyerythema(redness)andasmallareaofoedema(swelling)atthesiteofthesting.Thesymptomsproducedfollowingastingcanbeclassifiedintonon-allergicreactions,suchaslocalreactions,andallergicreactions,suchasextensivelocalreactions,anaphylacticsystemicreactionsanddelayedsystemicreactions.5-6Systemicallergicreactionsmayoccurinvenom-sensitivepatientsimmediatelyfollowingasting,7andcanvaryinseverity,withinitiallymildsymptomssometimesprogressingtocriticalconditionswithinseconds.1Themostseveresystemicallergicreactionisknownasanaphylaxis.Anaphylacticreactionsareofrapidonset(typicallyupto15minutespoststing)andcanmanifestindifferentways.Initialsymptomsareusuallycutaneousfollowedbyhypotension,withlight-headedness,faintingorcollapse.Somepeopledeveloprespiratorysymptomsduetoanasthma-likeresponseorlaryngealoedema.Inseverereactions,hypotension,circulatorydisturbances,andbreathingdifficultycanprogresstofatalcardio-respiratoryarrest.Anaphylaxisoccursmorecommonlyinmalesandinpeopleunder20yearsofageandcanbesevereandpotentiallyfatal.84.3EpidemiologyItisestimatedthattheprevalenceofwaspandbeestingallergyisbetween0.4%and3.3%.9Theincidenceofsystemicreactionstowaspandbeevenomisnotreliablyknown,butestimatesrangefrom0.15-3.3%,10-11Systemicallergicreactionsarereportedbyupto3%ofadults,andalmost1%ofchildrenhaveamedicalhistoryofseverestingreactions.9,12Afteralargelocalreaction,5–15%ofpeoplewillgoontodevelopasystemicreactionwhennextstung.13Inpeoplewithamildsystemicreaction,theriskofsubsequentsystemicreactionsisthoughttobeabout18%.13HymenopteravenomareoneofthethreemaincausesoffatalTable1:InclusioncriteriaIntervention(s)Pharmalgen®forthetreatmentofbeeandwaspvenomallergy,Population(s)Peoplewithahistoryoftype1IgE-mediatedsystemicallergicreactionsto:waspvenomand/orbeevenomComparatorsAlternativetreatmentoptionsavailableintheNHS,withoutvenomimmunotherapyincluding:adviceontheavoidanceofbeeandwaspvenom,high-doseantihistamines,adrenalineauto-injectorprescriptionandtrainingStudydesignRandomisedcontrolledtrialsSystematicreviewsOutcomesOutcomemeasurestobeconsideredinclude:numberandseverityoftype1IgE-mediatedsystemicallergicreactionsmortalityanxietyrelatedtothepossibilityoffutureallergicreactionsadverseeffectsoftreatmenthealth-relatedqualityoflifeOtherconsiderationsIftheevidenceallows,considerationswillbegiventosubgroupsofpeople,accordingtotheir:riskoffuturestings(asdetermined,forexample,byoccupationalexposure)riskofsevereallergicreactionstofuturestings(asdeterminedbysuchfactorsasbaselinetryptaselevelsandco-morbidities)Iftheevidenceallows,theappraisalwillconsiderseparatelypeoplewhohaveacontraindicationtoadrenaline.Iftheevidenceallows,theappraisalwillconsiderchildrenseparately.Tworeviewerswillindependentlyscreenalltitlesandabstractsofpapersidentifiedintheinitialsearch.Discrepancieswillberesolvedbyconsensusandwherenecessaryathirdreviewerwillbeconsulted.Studiesdeemedtoberelevantwillbeobtainedandassessedforinclusion.Wherestudiesdonotmeettheinclusioncriteriatheywillbeexcluded.5.1.2DataextractionstrategyDatarelatingtostudydesign,findingsandqualitywillbeextractedbyonereviewerandindependentlycheckedforaccuracybyasecondreviewer.Studydetailswillbeextractedusingastandardiseddataextractionform.Iftimepermits,attemptswillbemadetocontactauthorsformissingdata.Datafromstudiespresentedinmultiplepublicationswillbeextractedandreportedasasinglestudywithallrelevantotherpublicationslisted.5.1.3QualityassessmentstrategyThequalityoftheclinical-effectivenessstudieswillbeassessedaccordingtocriteriabasedontheCRD’sguidanceforundertakingreviewsinhealthcare.33-34Thequalityoftheindividualclinical-effectivenessstudieswillbeassessedbyonereviewer,andindependentlycheckedforagreementbyasecond.Disagreementswillberesolvedthroughconsensusandifnecessaryathirdreviewerwillbeconsulted.5.1.4Methodsofanalysis/synthesisTheresultsofthedataextractionandqualityassessmentforeachstudywillbepresentedinstructuredtablesandasanarrativesummary.Thepossibleeffectsofstudyqualityontheeffectivenessdataandreviewfindingswillbediscussed.Allsummarystatisticswillbeextractedforeachoutcomeandwherepossible,datawillbepooledusingastandardmeta-analysis.35HeterogeneitybetweenthestudieswillbeassessedusingtheI2test.34Bothfixedandrandomeffectsresultswillbepresentedasforestplots.6METHODSFORSYNTHESISINGCOSTEFFECTIVENESSEVIDENCETheeconomicsectionofthereportwillbepresentedintwoparts.Thefirstwillincludeastandardreviewofrelevantpublishedeconomicevaluations.Ifappropriateanddataareavailable,thesecondwillincludethedevelopmentofaneconomicmodel.ThemodelwillbedesignedtoestimatethecosteffectivenessofPharmalgen®forVITinindividualswithahistoryofanaphylaxistobeeandwaspvenom.ThissectionofthereportwillalsoconsiderbudgetimpactandwilltakeaccountofavailableinformationoncurrentandanticipatedpatientnumbersandserviceconfigurationforthetreatmentofthisconditionintheNHS.6.1SystematicreviewofpublishedeconomicliteratureTheliteraturereviewofeconomicevidencewillidentifyanyrelevantpublishedcost-minimisation,cost-effectiveness,cost-utilityand/orcost-benefitanalyses.Economicevaluations/modelsincludedinthemanufacturersubmission(s)willbeincludedinthereviewandcritiquedasappropriate.6.1.1SearchstrategyThesearchstrategiesdetailedinsection5willbeadaptedaccordinglytoidentifystudiesexaminingthecosteffectivenessofusingPharmalgen®forVITinpatientswithahistoryofallergicreactionstobeeorwaspvenom.Othersearchingactivities,includingelectronicsearchingofonlinehealtheconomicjournalsandcontactingexpertsinthefieldwillalsobeundertaken.Fulldetailsofthesearchprocesswillbepresentedinthefinalreport.Thesearchstrategywillbedesignedtomeettheprimaryobjectiveofidentifyingeconomicevaluationsforinclusioninthecost-effectivenessliteraturereview.Atthesametime,thesearchstrategywillbeusedtoidentifyeconomicevaluationsandotherinformationsourceswhichmayincludedatathatcanbeusedtopopulateadenovoeconomicmodelwhereappropriate.SearchingwillbeundertakeninMEDLINEandEMBASEaswellasintheCochraneLibrary,whichincludestheNHSEconomicEvaluationDatabase(NHSEED).6.1.2InclusionandexclusionInadditiontotheinclusioncriteriaoutlinedinTable1,specificcriteriarequiredforthecost-effectivenessreviewaredescribedinTable2.Inparticular,onlyfulleconomicevaluationsthatcomparetwoormoreoptionsandconsiderbothcostsandconsequenceswillbeincludedinthereviewofpublishedliterature.Anyeconomicevaluations/modelsincludedinthemanufacturersubmission(s)willbeincludedasappropriate.Studiesthatdonotmeetallofthecriteriawillbeexcludedandtheirbibliographicdetailslistedwithreasonsforexclusion.Table2:Additionalinclusioncriteria(costeffectiveness)StudydesignFulleconomicevaluationsthatconsiderbothcostsandconsequences(cost-effectivenessanalysis,cost-utilityanalysis,cost-minimisationanalysisandcostbenefitanalysis)OutcomesIncrementalcostperlifeyeargainedIncrementalcostperqualityadjustedlifeyeargained6.1.3DataextractionstrategyDatarelatingtobothstudydesignandqualitywillbeextractedbyonereviewerandindependentlycheckedforaccuracybyasecondreviewer.Disagreementwillberesolvedthroughconsensusand,ifnecessary,athirdreviewerwillbeconsulted.Iftimeconstraintsallow,attemptswillbemadetocontactauthorsformissingdata.Datafrommultiplepublicationswillbeextractedandreportedasasinglestudy.6.1.4QualityassessmentstrategyThequalityofthecost-effectivenessstudies/modelswillbeassessedaccordingtoachecklistupdatedfromthatdevelopedbyDrummondetal.36ThischecklistwillreflectthecriteriaforeconomicevaluationdetailedinthemethodologicalguidancedevelopedbyNICE.37Thequalityoftheindividualcost-effectivenessstudies/modelswillbeassessedbyonereviewer,andindependentlycheckedforagreementbyasecond.Disagreementswillberesolvedthroughconsensusand,ifnecessary,athirdreviewerwillbeconsulted.Theinformationwillbetabulatedandsummarisedwithinthetextofthereport.6.2Methodsofanalysis/synthesis6.2.1CosteffectivenessreviewofpublishedliteratureIndividualstudydataandqualityassessmentwillbesummarisedinstructuredtablesandasanarrativedescription.Potentialeffectsofstudyqualitywillbediscussed.Tosupplementfindingsfromtheeconomicliteraturereview,additionalcostandbenefitinformationfromothersources,includingthemanufacturersubmission(s)toNICE,willbecollatedandpresentedasappropriate.6.2.2DevelopmentofadenovoeconomicmodelbytheAGa.CostdataTheprimaryperspectivefortheanalysisofcostinformationwillbetheNHS.Costdatawillthereforefocusonthemarginaldirecthealthservicecostsassociatedwiththeintervention.Quantitiesofresourcesusedwillbeidentifiedfromconsultationwithexperts,primarydatafromrelevantsourcesandthereviewedliterature.Wherepossible,unitcostdatawillbeextractedfromtheliteratureorobtainedfromotherrelevantsources(drugpricelists,NHSreferencecostsandCharteredInstituteofPublicFinanceandAccountingcostdatabases).Whereappropriatecostswillbediscountedat3.5%perannum,theraterecommendedinNICEguidancetomanufacturersandsponsorsofsubmissions.37b.AssessmentofbenefitsAbalancesheetwillbeconstructedtolistbenefitsandcostsarisingfromalternativetreatmentoptions.LRiGanticipatesthatthemainmeasuresofbenefitwillbeincreasedQALYs.Whereappropriate,effectivenessandothermeasuresofbenefitwillbediscountedat3.5%,theraterecommendedinNICEguidancetomanufacturersandsponsorsofsubmissions.37b.ModellingTheabilityofLRiGtoconstructaneconomicmodelwilldependonthedataavailable.Wheremodellingisappropriate,asummarydescriptionofthemodelandacriticalappraisalofkeystructures,assumptions,resources,dataandsensitivityanalysis(seeSectiond)willbepresented.Inaddition,LRiGwillprovideanassessmentofthemodel’sstrengthsandweaknessesanddiscusstheimplicationsofusingdifferentassumptionsinthemodel.Reasonsforanymajordiscrepanciesbetweentheresultsobtainedfromassessmentgroupmodelandthemanufacturermodel(s)willbeexplored.Thetimehorizonwillbeapatient’slifetimeinordertoreflectthechronicnatureofthedisease.Aformalcombinationofcostsandbenefitswillalsobeperformed,althoughthetypeofeconomicevaluationwillonlybechoseninlightofthevariationsinoutcomeidentifiedfromtheclinical-effectivenessreviewevidence.Ifdataareavailable,theresultswillbepresentedasincrementalcostperQALYratiosforeachalternativeconsidered.Ifsufficientdataarenotavailabletoconstructthesemeasureswithreasonableprecision,incrementalcost-effectivenessanalysisorcost-minimisationanalysiswillbeundertaken.Anyfailuretomeetthereferencecasewillbeclearlyspecifiedandjustified,andthelikelyimplicationswill,asfaraspossible,bequantified.d.SensitivityanalysisIfappropriate,sensitivityanalysiswillbeappliedtoLRiG’smodelinordertoassesstherobustnessoftheresultstorealisticvariationsinthelevelsoftheunderlyingparametervaluesandkeyassumptions.Wheretheoverallresultsaresensitivetoaparticularvariable,thesensitivityanalysiswillexploretheexactnatureoftheimpactofvariations.Imprecisionintheprincipalmodelcost-effectivenessresultswithrespecttokeyparametervalueswillbeassessedbyuseoftechniquescompatiblewiththemodellingmethodologydeemedappropriatetotheresearchquestionandtothepotentialimpactondecisionmakingforspecificcomparisons(e.g.multi-waysensitivityanalysis,cost-effectivenessacceptabilitycurvesetc).7HANDLINGTHEMANUFACTURERSUBMISSION(S)Alldatasubmittedbythedrugmanufacturersarrivingbefore22ndMarch2011andmeetingthesetinclusioncriteriawillbeconsideredforinclusioninthereview.Dataarrivingafterthisdatewillonlybeconsiderediftimeconstraintsallow.Anyeconomicevaluationsincludedinthemanufacturersubmission(s)willbeassessed.Thiswillincludeadetailedanalysisoftheappropriatenessoftheparametricandstructuralassumptionsinvolvedinanymodelsinthesubmissionandanassessmentofhowrobustthemodelsaretochangesinkeyassumptions.Clarificationonspecificaspectsofthemodelmaybesoughtfromtherelevantmanufacturer.Any'commercialinconfidence'datatakenfromamanufacturersubmissionwillbeclearlymarkedintheNICEreportaccordingtoestablishedNICEpolicyandremovedfromthesubsequentsubmissiontotheHTA8EXPERTISEINTHISTARTEAMANDCOMPETINGINTERESTSOFAUTHORSThisTARteamwillbemadeupofthefollowingindividuals:Teamlead/clinicalsystematicreviewerJulietHockenhullSenioreconomicmodellerProfessorAdrianBagustSystematicreviewer(clinical)GemmaCherrySystematicreviewer(economics)DrAngelaBolandEconomicmodellerDrCarlosMartinSaboridoInformationspecialistDrYenalDundarMedicalstatisticianJamesOyeeDirectorMsRumonaDicksonClinicaladvisorAteamofclinicalexpertswillbeestablishedtoaddressclinicalquestionsrelatedtothetechnologyandtoprovidefeedbackondraftsofthefinalreport9REFERENCES1.FreemanT.Hypersensitivitytohymenopterastings.NEJM.2004;351:1978-84.2.KingT,LuG,GonzalezM,QianN,SoldatovaL.Yellowjacketvenomallergens,hyaluronidaseandphospholipase:sequencesimilarityandantigeniccross-reactivitywiththeirhornetandwasphomologsandpossibleimplicationsforclinicalallergy.JAllergyClinImmunol.1996;98:588-600.3.LuG,VillalbaM,CosciaM,HoffmanD,KingT.Sequenceanalysisandantigeniccross-reactivityofavenomallergen,antigen5,fromhornets,wasps,andyellowjackets.JImmunol.1993;150:2823-30.4.Muller5.GoldenDB,TracyJM,FreemanTM,HoffmanDR,InsectCommitteeoftheAmerican6.IncorvaiaC,PucciS,PastorelloE.ClinicalaspectsofHymenopteravenomallergy..Allergy.1999;54(Suppl58):50-2.7.BurnsT,BreathnachS,CoxN,GriffithsC,editors.Rook'stextbookofdermatology.7ed.Oxford:BlackwellScience;2004.8.DemainJ,MinaeiA,TracyJ.Anaphylaxisandinsectallergy.CurrOpinAllergyClinImmunol.2010;10(4):318-22.9.GoldenDB.Epidemiologyofallergytoinsectvenomsandstings.AllergyAsthmaProc.1989;10(2):103-7.10.CharpinD,BimbaumJ,VervloetD.Epidemiologyofhymenopteraallergy.ClinExpAllergy.1994;24:1010-5..11.MoffittJ,GoldenD,ReismanR,etal.Stinginginsecthypersensitivity:apracticeparameterupdateJAllergyClinImmunol.2004;114(4):869-86.12.SettipaneG,NewsteadG,BoydG.FrequencyofHymenopteraallergyinanatopicandnormalpopulation.JAllergy.1972;50:146-50.13.BiloB,RueffF,MosbechH,BonifaziF,Oude-ElberinkJ,theEAACIInterestGrouponInsectVenomHypersensitivity.DiagnosisofHymenopteravenomallergy.Allergy.2005;60(11):1339-49.14.JohanssonB,ErikssonA,OrnehultL.HumanfatalitiescausedbywaspandbeestingsinSweden.IntJLegalMed.1991;104:99-103.15.GoldenD.Insectstinganaphylaxis.ImmunolAllergyClinNorthAm.2007;27(261-272).16.PumphreyR,StanworthS.Theclinicalspectrumofanaphylaxisinnorth-westEngland.ClinExpAllergy.1996;26:1364-70.17.TheAnaphylaxisCampaign.Allergytobeeandwaspstings.TheAnaphylaxisCampaign.2005.18.PumphreyR,RobertsI.Postmortemfindingsafterfatalanaphylacticreactions.JClinPath.2000;53:273-619.PumphreyR.FatalanaphylaxisintheUK,1992-2001.In:NovartisFoundation,editor.AnaphylaxisChichester:Wiley;200420.AdkisC,BleskenT,AkdisM.Roleofinterleukin10inspecificimmunotherapy.JClinInvest.1998;102:98.21.NasserSM,YingS,MengQ,KayAB,EwanPW.Interleukin-10levelsincreaseincutaneousbiopsiesofpatientsundergoingwaspvenomimmunotherapy.EurJImmunol.2001;31(12):3704-13.22.O'GarraA,VieiraP.RegulatoryTcellsandmechanismsofimmunesystemcontrol.NaturalMedicine.2004;10:801-5.23.BellinghausenI,KnopJ,SalogaJ.Roleofinterleukin10-producingTcellsinspecific(allergen)immunotherapy.JAllergyClinImmunol.2000;12:20-5.24.WorkingGroupoftheResuscitationCouncil(UK).Emergencytreatmentofanaphylacticreactions:Guidelinesforhealthcareproviders2008.ReportNo.:.uk/pages/reaction.pdf.25.MüllerU,MosbechH,AbererW,DreborgS,EwanP,KunkelG,etal.EAACIPositionPaper.Adrenalineforemergencykits.Allergy.1995;50:783-7.26.ReportfromtheCommitteeonInsects.ThediscontinuationofHymenopteravenomimmunotherapy.JAllergyClinImmunol.1998;101(5):573-5.27.JointTaskForceonPracticeParameters,AmericanAcademyofAllergyAsthmaandImmunology,American28.RossR,NelsonH,FinegoodI.Effectivenessofspecificimmunotherapyinthetreatmentofhymenopteravenomhypersensitivity:ametaanalysis.ClinicalTherapy.2000;22:351-8.29.GoldenD.Insectstingallergyandvenomimmunotherapy:amodelandamystery..JAllergyClinImmunol.2005;115(3):439-47.30.MullerU,MosbechH.Immunotherapywithhymenopteravenoms:EAACIpositionpaper.Allergy.1993;48:36-46.31.KingT,HoffmanD,LowensteinH,MarshD,Platts-MillsT,ThomasW.Allergennomenclature.BulletinoftheWorldHealthOrganisation.1994;72:797-806.32.ALKAbello.PharmalgenSummaryofProductCharacteristics.[08/11/2010];Availablefrom:/UK/products/pharma/Lists/Pharmalgen/Pharmalgen%20Wasp%20Venom%20SmPC.pdf.33.CentreforReviewsandDissemination.SystematicReviews:CRDsguidanceforundertakingreviewsinhealthcare.[cited2009December];Availablefrom:http://www.york.ac.uk/inst/crd/darefaq.htm.34.HigginsJPT,ThompsonSG,DeeksJJ,AltmanDG.Measuringinconsistencyinmeta-analysis.BritMedJ.2003;327:557-60.35.EggerM,SmithGD,AltmanDG.Systematicreviewsinhealthcare–Meta-analysisincontext:BMJbooks;2001.36.DrummondMF,JeffersonTO.GuidelinesforauthorsandpeerreviewersofeconomicsubmissionstotheBMJ.BritMedJ.1996;313(7052):275-83.37.NationalInstituteforHealthandClinicalExcellence.Guidetothemethodsoftechnologyappraisal.London:NICE;2008[cited2009July];Availablefrom:.uk/media/B52/A7/TAMethodsGuideUpdatedJune2008.pdfAppendix1DetailsofMEDLINEclinicaleffectivenesssearchstrategies:1.expwasps/orexpbees/2.*Hymenoptera/3.(wasp$orhoneybee$orbeesoryellowhornet$oryellowjacket$orwhitehornet$orpoliste$).tw.4.*hypersensitivity,delayed/or*hypersensitivity,immediate/5.((wasp$orbees)adj(venomorsting)adj(hypersensitivit$orallerg$oranaphylax$orsystemicreaction$)).tw.6.or/1-57.Pharmalgen.af.8.*Immunotherapy/orimmunotherap$.ti,ab.9.*Desensitization,Immunologic/10.or/7-911.6and1012.limit11to(englishlanguageandhumans)Pharmalgen®治疗蜜蜂和黄蜂的毒液过敏的临床和成本效益1课题题目Pharmalgen®治疗蜜蜂和黄蜂的毒液过敏的临床和成本效益3纯英文摘要对毒素敏感的患者可能会在被蜜蜂和黄蜂的毒针刺中后立即发生毒液的过敏反应，严重程度会有很大差异。最初症状轻微，有时在几秒钟内发展到危急的状况，最严重的全身过敏反应（广义反应）被称为过敏性休克，一个特征性的反应就是异常的低血压，昏厥或跌倒，在极端的反应发生时，这些症状可导致死亡。在英国，每年有2－9人死于蜜蜂和黄蜂的毒液引起的过敏反应。对蜜蜂和黄蜂的毒液引起的严重的过敏反应应立即采取的治疗措施包括用药物来减轻病人对毒液的反应和必要情况下的呼吸支持。为了避免更严重的反应，已经开始对蜜蜂和黄蜂毒液导致过敏的免疫过程进行研究。毒液免疫过程包括增加对蜜蜂和黄蜂毒液有过敏史的患者皮下注射的毒液量。从1995年3月至今，拥有英国上市许可的用于诊断和治疗蜜蜂（使用Pharmalgen®蜜蜂毒液）和胡蜂（使用Pharmalgen®胡蜂毒液）蜂毒过敏的药物Pharmalgen®（使用毒液免疫），已经在英国的40多个医疗中心中使用。这次回顾分析的目的是评估Pharmalgen®在治疗蜜蜂和胡蜂蜇伤严重反应史的人的蜂毒过敏方面的临床作用。这次回顾分析将对比使用Pharmalgen®进行预防性治疗的方案和其它治疗方案，包括稿剂量的抗组胺药，避免被蜜蜂和黄蜂蜇伤的建议，肾上腺素药自动注射的处方和训练。如果有合适的数据可用，这次回顾性分析也将考虑在蜂毒过敏者和遭到蜂蜇风险较高或被蜂蜇会发生严重过敏反应的儿童和其他人群中使用Pharmalgen®的成本效益。4决策问题4.1关于研究的问题及范围的说明Pharmalgen®是用于诊断和治疗免疫球蛋白E（IgE）介导的蜜蜂和黄蜂的毒液过敏的药物。本报告的目的是评估对有蜜蜂和黄蜂的毒液严重反应史的个人使用Pharmalgen以提供毒液免疫是否具有临床应用价值，这样做和NHS提供的替代治疗方案相比是否更符合成本效益，更划算。4.2背景蜜蜂和黄蜂是膜翅目昆虫的一部分（同样也包括蚂蚁），在这一类昆虫中最常见的导致过敏反应的是黄蜂和蜜蜂。蜜蜂和马蜂刺含有过敏的蛋白质。黄蜂的致过敏蛋白主要是磷脂酶A1，透明质酸酶和抗原5，而蜜蜂的致过敏蛋白主要是磷脂酶A2和透明质酸。在被某个蜂刺蜇了后，某些个体可能会发生1型过敏反应并产生IgE抗体。这类对过敏原敏感的细胞和任何对过敏原的再次接触都可能导致IgE抗体分子和过敏原结合，这会导致过敏性反应。这些过敏原通常会产生强烈的烧灼样疼痛，在刺痛部位会有小面积的红斑（发红）和水肿（肿胀）。这些被蜇后产生的症状可以分为非过敏性反应如局部反应，还有过敏反应，如广泛的局部反应，全身过敏性反应和迟发性全身反应。对毒液敏感的患者在被蜂刺蜇了之后可能会立即发生系统性的过敏反应，在严重的程度上会有所差异，最初症状轻微，有时在几秒钟内发展到危急的状况。最严重的全身过敏性症状被称为过敏反应。过敏反应起效迅速（通常在被蜂刺蜇后15分钟），并能以不同的方式体现。最初的症状通常是皮肤其次是低血压，头晕，昏厥或晕倒。有些人发展致哮喘样反应如喉头水肿，呼吸道症状。严重的低血压，循环系统障碍，呼吸困难等反应，可以进展到致命的心跳呼吸骤停。过敏反应较为普遍发生在男性和未满20岁的人，可以是严重和潜在致命的。4.3流行病学据估计，黄蜂和蜜蜂蜇伤后过敏的发生率是0.4％和3.3％之间。黄蜂和蜜蜂毒液的全身性反应的发生率是不可靠的，但估计范围从0.15-3.3％。据报道，有严重的刺痛反应的病史的患者，会导致成年人的全身性过敏反应升高达3％，儿童的全身性过敏反应升高达1％。经过大量的局部反应，有5-15％的人会在下次被蜂蜇时的发生一种全身反应。发生温和的全身性反应的人，随后的全身性反应的风险被认为是18％左右。蜂毒液是在美国和英国的三个主要的致命过敏反应的原因之一。昆虫叮咬的医疗环境以外的第二个最常见的过敏的原因在英国，每年有两到九人死于由于黄蜂和蜜蜂蜇刺引起的过敏反应。一个人一旦经历了过敏反应，经常性发作过敏反应的风险大约是60％和79％之间。在2000年，由庞弗里报道的从1992年起在英国的致命的过敏性反应的记录确定致命过敏反应的典型表现的频率。根据56份过敏反应者的验尸报告，我们知道，有19人死于蜂毒液的反应（33.9％）。回顾2004年的研究在英国1992年和2001年之间的所有过敏死亡，估计22.19％是蜂毒液的反应（47/212）。进一步分析发现29/212（13.68％）是马蜂蜇伤，4/212（1.89％）是蜜蜂蜇伤。余下的14/212（6.62％）是被不明蜂蜇伤4.4目前的诊断方法目前，个人可以进行测试，以确定他们是否处于易发蜜蜂和黄蜂毒液的全身性反应的风险中。蜜蜂和/或马蜂蜇伤的全身反应诊断的主要方法是毒液的皮肤测试。皮肤测试的方法是在皮内注射五种蜂毒液的蛋白提取物，其的浓度范围在0.001到1.0微克/毫升。这是可以得出阳性的结果（在个体发生的反应）的规定的最低浓度。当毒液测试表现为不明原因的变异超时，或阴性的皮肤测试结果可能会发生以下最近的过敏反应，建议1到6个月后重复测试。过敏反应的病人其他的诊断方法，包括放射变应性吸附法（RAST），一种检测血清中的过敏原特异性IgE抗体的方法。这个测试方法没有皮肤测试敏感，但在皮肤测试不能进行时可以使用该方法，比如被测试者有皮肤病时。4.5目前的治疗方法预防性治疗包括如何避免蜜蜂和黄蜂的毒液，高剂量抗组胺药处方的教育。应该为有温和的局部反应病史的患者应提供急救包，包内含有抗组胺药H1阻断剂和外用皮质类固醇，可以在被蜇后立即使用。应为过敏症病史的患者提供包含快速长效抗组胺药H1阻断剂，口服皮质类固醇和自我管理的自动注射器，含肾上腺素套件。注射肾上腺素（一种交感神经药物，作用于α和β受体）被视为例急性过敏反应，如蜂蜇紧急治疗的首选。对于成年人来说，推荐剂量为0.30毫克/毫升和0.50毫克/毫升的I.M,儿童的推荐剂量为0.01毫升/千克I.M。有过敏反应史的个体应该带着含有肾上腺素的自动注射器。（常见的有EpiPen®,Adrenaclick®,Anapen®orTwinject®）。这些都是用于有蜂蜇伤和其他过敏原过敏史的个体的及时的自我治疗。继成功治疗蜂毒液的全身过敏性反应的预防措施，包括避免过敏原或特定的过敏原免疫疗法，比如众所周知的VIT。毒液免疫治疗被认为是一种安全有效的治疗。目前，VIT可以在多个国家使用，包括Pharmalgen®（由ALKAbello生产，在英国获得许可）Aquagen®andAlutardSQ®(都是由ALKAbello生产，未在英国获得许可，但在欧洲的部分国家获得许可)VENOMENHAL®(由新西兰的HALAllergy,Leiden,生产，未在英国获得许可)Alyostal®（法国Stallergenes,AntonyCedex生产，未在英国获得许可），andVenomil®(霍利斯特的公牛实验室有限责任公司,未在英国获得许可).为防止未来的系统免疫反应，毒液免疫是必需的。据建议，VIT被认为是“特异性IgE抗体的检测结果呈阳性和可以触发器及病人的暴露是相关的”。毒液免疫包括皮下注射剂量逐渐增加的毒液，治疗将分为两个阶段：建立阶段和维护阶段。毒液免疫治疗是目前治疗蜂蜇过敏的标准，也是过敏原特异性治疗模式，在一些研究报告中治疗成功率98％以上（患者仍然是无过敏性的）。目前有44个英国中心为被蜜蜂和马蜂蜇过敏