醫(yī)學(xué)文獻(xiàn)翻譯(中英對照)

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?治療蜜蜂和黃蜂的毒液過敏的臨床和成本效益1課題題目Pharmalgen?治療蜜蜂和黃蜂的毒液過敏的臨床和成本效益3純英文摘要對毒素敏感的患者可能會在被蜜蜂和黃蜂的毒針刺中后立即發(fā)生毒液的過敏反應(yīng)，嚴(yán)重程度會有很大差異。最初癥狀輕微，有時在幾秒鐘內(nèi)發(fā)展到危急的狀況，最嚴(yán)重的全身過敏反應(yīng)（廣義反應(yīng)）被稱為過敏性休克，一個特征性的反應(yīng)就是異常的低血壓，昏厥或跌倒，在極端的反應(yīng)發(fā)生時，這些癥狀可導(dǎo)致死亡。在英國，每年有2－9人死于蜜蜂和黃蜂的毒液引起的過敏反應(yīng)。對蜜蜂和黃蜂的毒液引起的嚴(yán)重的過敏反應(yīng)應(yīng)立即采取的治療措施包括用藥物來減輕病人對毒液的反應(yīng)和必要情況下的呼吸支持。為了避免更嚴(yán)重的反應(yīng)，已經(jīng)開始對蜜蜂和黃蜂毒液導(dǎo)致過敏的免疫過程進行研究。毒液免疫過程包括增加對蜜蜂和黃蜂毒液有過敏史的患者皮下注射的毒液量。從1995年3月至今，擁有英國上市許可的用于診斷和治療蜜蜂（使用Pharmalgen?蜜蜂毒液）和胡蜂（使用Pharmalgen?胡蜂毒液）蜂毒過敏的藥物Pharmalgen?（使用毒液免疫），已經(jīng)在英國的40多個醫(yī)療中心中使用。這次回顧分析的目的是評估Pharmalgen?在治療蜜蜂和胡蜂蜇傷嚴(yán)重反應(yīng)史的人的蜂毒過敏方面的臨床作用。這次回顧分析將對比使用Pharmalgen?進行預(yù)防性治療的方案和其它治療方案，包括稿劑量的抗組胺藥，避免被蜜蜂和黃蜂蜇傷的建議，腎上腺素藥自動注射的處方和訓(xùn)練。如果有合適的數(shù)據(jù)可用，這次回顧性分析也將考慮在蜂毒過敏者和遭到蜂蜇風(fēng)險較高或被蜂蜇會發(fā)生嚴(yán)重過敏反應(yīng)的兒童和其他人群中使用Pharmalgen?的成本效益。4決策問題4.1關(guān)于研究的問題及范圍的說明Pharmalgen?是用于診斷和治療免疫球蛋白E（IgE）介導(dǎo)的蜜蜂和黃蜂的毒液過敏的藥物。本報告的目的是評估對有蜜蜂和黃蜂的毒液嚴(yán)重反應(yīng)史的個人使用Pharmalgen以提供毒液免疫是否具有臨床應(yīng)用價值，這樣做和NHS提供的替代治療方案相比是否更符合成本效益，更劃算。4.2背景蜜蜂和黃蜂是膜翅目昆蟲的一部分（同樣也包括螞蟻），在這一類昆蟲中最常見的導(dǎo)致過敏反應(yīng)的是黃蜂和蜜蜂。蜜蜂和馬蜂刺含有過敏的蛋白質(zhì)。黃蜂的致過敏蛋白主要是磷脂酶A1，透明質(zhì)酸酶和抗原5，而蜜蜂的致過敏蛋白主要是磷脂酶A2和透明質(zhì)酸。在被某個蜂刺蜇了后，某些個體可能會發(fā)生1型過敏反應(yīng)并產(chǎn)生IgE抗體。這類對過敏原敏感的細(xì)胞和任何對過敏原的再次接觸都可能導(dǎo)致IgE抗體分子和過敏原結(jié)合，這會導(dǎo)致過敏性反應(yīng)。這些過敏原通常會產(chǎn)生強烈的燒灼樣疼痛，在刺痛部位會有小面積的紅斑（發(fā)紅）和水腫（腫脹）。這些被蜇后產(chǎn)生的癥狀可以分為非過敏性反應(yīng)如局部反應(yīng)，還有過敏反應(yīng)，如廣泛的局部反應(yīng)，全身過敏性反應(yīng)和遲發(fā)性全身反應(yīng)。對毒液敏感的患者在被蜂刺蜇了之后可能會立即發(fā)生系統(tǒng)性的過敏反應(yīng)，在嚴(yán)重的程度上會有所差異，最初癥狀輕微，有時在幾秒鐘內(nèi)發(fā)展到危急的狀況。最嚴(yán)重的全身過敏性癥狀被稱為過敏反應(yīng)。過敏反應(yīng)起效迅速（通常在被蜂刺蜇后15分鐘），并能以不同的方式體現(xiàn)。最初的癥狀通常是皮膚其次是低血壓，頭暈，昏厥或暈倒。有些人發(fā)展致哮喘樣反應(yīng)如喉頭水腫，呼吸道癥狀。嚴(yán)重的低血壓，循環(huán)系統(tǒng)障礙，呼吸困難等反應(yīng)，可以進展到致命的心跳呼吸驟停。過敏反應(yīng)較為普遍發(fā)生在男性和未滿20歲的人，可以是嚴(yán)重和潛在致命的。4.3流行病學(xué)據(jù)估計，黃蜂和蜜蜂蜇傷后過敏的發(fā)生率是0.4％和3.3％之間。黃蜂和蜜蜂毒液的全身性反應(yīng)的發(fā)生率是不可靠的，但估計范圍從0.15-3.3％。據(jù)報道，有嚴(yán)重的刺痛反應(yīng)的病史的患者，會導(dǎo)致成年人的全身性過敏反應(yīng)升高達(dá)3％，兒童的全身性過敏反應(yīng)升高達(dá)1％。經(jīng)過大量的局部反應(yīng)，有5-15％的人會在下次被蜂蜇時的發(fā)生一種全身反應(yīng)。發(fā)生溫和的全身性反應(yīng)的人，隨后的全身性反應(yīng)的風(fēng)險被認(rèn)為是18％左右。蜂毒液是在美國和英國的三個主要的致命過敏反應(yīng)的原因之一。昆蟲叮咬的醫(yī)療環(huán)境以外的第二個最常見的過敏的原因在英國，每年有兩到九人死于由于黃蜂和蜜蜂蜇刺引起的過敏反應(yīng)。一個人一旦經(jīng)歷了過敏反應(yīng)，經(jīng)常性發(fā)作過敏反應(yīng)的風(fēng)險大約是60％和79％之間。在2000年，由龐弗里報道的從1992年起在英國的致命的過敏性反應(yīng)的記錄確定致命過敏反應(yīng)的典型表現(xiàn)的頻率。根據(jù)56份過敏反應(yīng)者的驗尸報告，我們知道，有19人死于蜂毒液的反應(yīng)（33.9％）?；仡?004年的研究在英國1992年和2001年之間的所有過敏死亡，估計22.19％是蜂毒液的反應(yīng)（47/212）。進一步分析發(fā)現(xiàn)29/212（13.68％）是馬蜂蜇傷，4/212（1.89％）是蜜蜂蜇傷。余下的14/212（6.62％）是被不明蜂蜇傷4.4目前的診斷方法目前，個人可以進行測試，以確定他們是否處于易發(fā)蜜蜂和黃蜂毒液的全身性反應(yīng)的風(fēng)險中。蜜蜂和/或馬蜂蜇傷的全身反應(yīng)診斷的主要方法是毒液的皮膚測試。皮膚測試的方法是在皮內(nèi)注射五種蜂毒液的蛋白提取物，其的濃度范圍在0.001到1.0微克/毫升。這是可以得出陽性的結(jié)果（在個體發(fā)生的反應(yīng)）的規(guī)定的最低濃度。當(dāng)毒液測試表現(xiàn)為不明原因的變異超時，或陰性的皮膚測試結(jié)果可能會發(fā)生以下最近的過敏反應(yīng)，建議1到6個月后重復(fù)測試。過敏反應(yīng)的病人其他的診斷方法，包括放射變應(yīng)性吸附法（RAST），一種檢測血清中的過敏原特異性IgE抗體的方法。這個測試方法沒有皮膚測試敏感，但在皮膚測試不能進行時可以使用該方法，比如被測試者有皮膚病時。4.5目前的治療方法預(yù)防性治療包括如何避免蜜蜂和黃蜂的毒液，高劑量抗組胺藥處方的教育。應(yīng)該為有溫和的局部反應(yīng)病史的患者應(yīng)提供急救包，包內(nèi)含有抗組胺藥H1阻斷劑和外用皮質(zhì)類固醇，可以在被蜇后立即使用。應(yīng)為過敏癥病史的患者提供包含快速長效抗組胺藥H1阻斷劑，口服皮質(zhì)類固醇和自我管理的自動注射器，含腎上腺素套件。注射腎上腺素（一種交感神經(jīng)藥物，作用于α和β受體）被視為例急性過敏反應(yīng)，如蜂蜇緊急治療的首選。對于成年人來說，推薦劑量為0.30毫克/毫升和0.50毫克/毫升的I.M,兒童的推薦劑量為0.01毫升/千克I.M。有過敏反應(yīng)史的個體應(yīng)該帶著含有腎上腺素的自動注射器。（常見的有EpiPen?,Adrenaclick?,Anapen?orTwinject?）。這些都是用于有蜂蜇傷和其他過敏原過敏史的個體的及時的自我治療。繼成功治療蜂毒液的全身過敏性反應(yīng)的預(yù)防措施，包括避免過敏原或特定的過敏原免疫療法，比如眾所周知的VIT。毒液免疫治療被認(rèn)為是一種安全有效的治療。目前，VIT可以在多個國家使用，包括Pharmalgen?（由ALKAbello生產(chǎn)，在英國獲得許可）Aquagen?andAlutardSQ?(都是由ALKAbello生產(chǎn)，未在英國獲得許可，但在歐洲的部分國家獲得許可)VENOMENHAL?(由新西蘭的HALAllergy,Leiden,生產(chǎn)，未在英國獲得許可)Alyostal?（法國Stallergenes,AntonyCedex生產(chǎn)，未在英國獲得許可），andVenomil?(霍利斯特的公牛實驗室有限責(zé)任公司,未在英國獲得許可).為防止未來的系統(tǒng)免疫反應(yīng)，毒液免疫是必需的。據(jù)建議，VIT被認(rèn)為是“特異性IgE抗體的檢測結(jié)果呈陽性和可以觸發(fā)器及病人的暴露是相關(guān)的”。毒液免疫包括皮下注射劑量逐漸增加的毒液，治療將分為兩個階段：建立階段和維護階段。毒液免疫治療是目前治療蜂蜇過敏的標(biāo)準(zhǔn)，也是過敏原特異性治療模式，在一些研究報告中治療成功率98％以上（患者仍然是無過敏性的）。目前有44個英國中心為被蜜蜂和馬蜂蜇過敏