ICS-formoterol reliever therapy stepwise treatment algorithm ...

The proposed anti-inflammatory ICS/formoterol reliever therapy-based algorithm is based on budesonide/formoterol, due to the extensive evidence of its efficacy ... Skiptomaincontent ICS-formoterolrelievertherapystepwisetreatmentalgorithmforadultasthma RichardBeasley,IreneBraithwaite,AlexSemprini,CiléinKearns,MarkWeatherall,TimW.Harrison,AlbertoPapi,IanD.Pavord EuropeanRespiratoryJournal202055:1901407;DOI:10.1183/13993003.01407-2019 RichardBeasley1MedicalResearchInstituteofNewZealand,Wellington,NewZealand2CapitalandCoastDistrictHealthBoard,Wellington,NewZealandFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforRichardBeasleyForcorrespondence: richard.beasley@mrinz.ac.nzIreneBraithwaite1MedicalResearchInstituteofNewZealand,Wellington,NewZealand2CapitalandCoastDistrictHealthBoard,Wellington,NewZealandFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforIreneBraithwaiteAlexSemprini1MedicalResearchInstituteofNewZealand,Wellington,NewZealand2CapitalandCoastDistrictHealthBoard,Wellington,NewZealandFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforAlexSempriniCiléinKearns1MedicalResearchInstituteofNewZealand,Wellington,NewZealand2CapitalandCoastDistrictHealthBoard,Wellington,NewZealandFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforCiléinKearnsMarkWeatherall2CapitalandCoastDistrictHealthBoard,Wellington,NewZealand3UniversityofOtagoWellington,Wellington,NewZealandFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforMarkWeatherallTimW.Harrison4NottinghamNIHRBiomedicalResearchCentre,UniversityofNottingham,Nottingham,UKFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforTimW.HarrisonAlbertoPapi5RespiratoryMedicineUnit,DeptofMedicalSciences,UniversitàdiFerrara,Ferrara,ItalyFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforAlbertoPapiIanD.Pavord6OxfordRespiratoryNIHRBRC,NuffieldDeptofMedicine,UniversityofOxford,Oxford,UKFindthisauthoronGoogleScholarFindthisauthoronPubMedSearchforthisauthoronthissiteORCIDrecordforIanD.Pavord 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AbstractApractical“anti-inflammatoryrelievertherapy”-basedalgorithmbasedontheGINA2019updateispresented,togetherwithaprototypeactionplantofacilitateitsimplementation.http://bit.ly/33C2s5uIntroductionAstepwiseapproachtothepharmacologicaltreatmentofasthmaisakeyfeatureofcurrentasthmaguidelines[1–4].Throughalgorithms,treatmentintensityis“steppedup”toobtainasthmacontrolandreducetheriskofexacerbations,and“steppeddown”afteraperiodofprolongedcontrolandabsenceofexacerbations.Traditionalalgorithmsadvocatedshort-actingβ2-agonist(SABA)relievertherapyforalllevelsofseverity,initiallyassoletherapyatStep1,togetherwithmaintenance“lowdose”inhaledcorticosteroids(ICS)atStep2,withmaintenanceICS/long-actingβ2-agonist(LABA)at“low”,“moderate”or“high”dosesatSteps3and4,andfinallywith“add-on”therapiesatStep5.Inaparadigmshiftinthestepwiseapproach,the2019updateoftheGINAguidelinesnowrecommendsICS/formoterolrelievertherapyasthepreferredrelieveroptionacrossallstepsofthetreatmentalgorithm[5].ThispropositionisbasedonstrongevidencethatICS/formoterolrelievertherapyismoreeffectiveandsaferthanSABArelievertherapyforalllevelsofasthmaseverity[6–9],assummarisedinfigure1.ICS/formoterolrelievertherapycanbedefinedas“anti-inflammatoryrelievertherapy”,aterminologythatprobablyalsoappliestocombinedICS/SABArelievertherapy,whichismoreeffectiveatreducingexacerbationsthanSABArelievertherapyalone[10].DownloadfigureOpeninnewtabDownloadpowerpointFIGURE1Traditionaltreatmentstepsusingshort-actingβ2-agonist(SABA)relievertherapyversusanti-inflammatoryreliever(AIR)treatmentstepsandriskofsevereexacerbationsinpublishedrandomisedcontrolledtrials.ICS:inhaledcorticosteroid;LABA:long-actingβ2-agonist.Thefollowingstudiescontainedinclusioncriteriathatrequiredahistoryofanexacerbationinthe12 monthspriortorandomisation[18,19,21–23,25,27–29].Theriskofsevereexacerbation(AIRversustraditionalalgorithm)wasreportedasrelativerate[6,15,16,19,21,23–25,27,29],relativerisk[7,17,28]andhazardratio[18,22],respectively.Studiesprescribedrelievertherapyasfollows;budesonide/formoterol(B/F)200/6 μg,oneactuationasrequiredforreliefofsymptoms[6,7,15,16,19,21,22,24,25,27–29];B/F100/6 μg,oneactuationasrequiredforreliefofsymptoms[17,18];ultrafinebeclometasonedipropionate/formoterol100/6 μg(BDP/F),oneactuationasrequiredforreliefofsymptoms[23].Thishigh-qualityevidencehasledtorecommendationsthatSABArelievertherapybereplacedbyICS/formoterolrelievertherapyinadultswithasthma[11–14].However,forthisfundamentalchangeinpracticetooccur,apracticalstepwisetreatmentalgorithmincorporatingICS/formoterolrelievertherapyisnowneeded.Thetreatmentstepsforsuchaprototypeanti-inflammatoryrelievertherapyalgorithmarerelativelystraightforward(figure2),ifbasedontheclinicaltrialprogrammesofbudesonide/formoterolrelievertherapyregimens,whichcontributealmostalltheevidenceoftheefficacyandsafetyofanti-inflammatoryrelievertherapy,acrossthespectrumofasthmaseverity.DownloadfigureOpeninnewtabDownloadpowerpointFIGURE2Prototypeanti-inflammatoryrelievertherapyalgorithmforclinic-basedreviewinadultasthmabasedonbudesonide/formoterol200/6 µgTurbuhaler.Alternativecutpointscouldbeusedtoguidetransitionbetweensteps(seetext).GP:generalpractitioner.Step1Step1intheanti-inflammatoryrelieveralgorithmisbudesonide/formoterol200/6 µgoneactuationas-neededviatheTurbuhalerasrelievermonotherapyinmildasthma.ThisissuperiortothetraditionalStep1treatment,eitheras-neededSABArelievermonotherapywithterbutaline[6]orsalbutamol[7],inreducingsevereexacerbationriskandimprovingasthmacontrol(figure1).Theclinicaltrialevidencealsoshowsthatthebudesonide/formoterolrelievermonotherapyregimenreducesairwaysinflammation(asmeasuredbyexhalednitricoxidefraction),therebyconfirmingitsdesignationasan“anti-inflammatoryrelievertherapy”[7].Step1treatmentwithbudesonide/formoterolrelievertherapyresultsinasimilar[6,15]orgreaterreduction[7,16]insevereexacerbationriskthantraditionalStep2maintenance“lowdose”ICSandSABArelievertherapy,withnoclinicallyimportantdifferenceinasthmacontrolfigure1).Step2Step2intheanti-inflammatoryrelievertherapyalgorithmis“lowdose”budesonide/formoterolmaintenanceandrelievertherapy,whichissuperiortoboththetraditionalStep2treatmentofmaintenance“lowdose”ICStogetherwithSABArelievertherapy[17],andoneofthealternativeStep3treatmentoptions,maintenance“medium/highdose”ICStogetherwithSABArelievertherapy(figure1)[18,19].Fourdosingoptionshavesupportiveevidencefromclinicaltrials:budesonide/formoterol200/6 µgTurbuhalertwoactuationsoncedailyasmaintenancetogetherwithoneactuationas-neededforsymptomrelief[19],budesonide/formoterol200/6 µgoneactuationtwicedailyasmaintenancetogetherwithoneactuationas-needed[20–22],budesonide/formoterol100/6 µgTurbuhalertwoactuationsoncedailyasmaintenancetogetherwithoneactuationasneeded[17],andbudesonide/formoterol100/6 µgTurbuhaleroneactuationtwicedailyasmaintenancetogetherwithoneactuationas-needed[18].Itmaybepreferabletousethebudesonide/formoterol200/6 µgTurbuhaler,asthisreducestreatmentcomplexityandenablesstandardisationofthe200/6 µgdoseperactuationacrossthedifferentstepsofthisproposedalgorithm.The“lowdose”budesonide/formoterolmaintenanceandrelievertherapyregimenismoreeffectivethanthetraditionalStep3treatment,maintenance“lowdose”ICS/LABAtogetherwithSABArelievertherapy(figure1)[18,21,22].Thisisconsistentwithclinicaltrialevidencethat“lowdose”beclometasone/formoterolmaintenanceandrelieverregimenissuperiorto“lowdose”beclometasone/formoteroltogetherwithSABArelievertherapy[23].The“lowdose”budesonide/formoterolmaintenanceandrelievertherapyregimenisalsomoreeffectivethanthetraditionalStep4treatment,“mediumdose”maintenanceICS/LABAtogetherwithSABArelievertherapy,inreducingsevereexacerbationrisk(figure1)[24,25].Inconsideringthisevidenceofcomparativeefficacy,itisnecessarytorecognisethatinsixoftheeightstudiesofanti-inflammatoryrelievertherapyatStep2,thestudies'inclusioncriteriarequiredahistoryofanexacerbationinthe12 monthspriortorandomisation,therebyenhancingthepowerofthestudy,althoughreducingthegeneralisabilityofthefindingstopatientsatlowerlevelsofexacerbationrisk.Insummary,Step2oftheanti-inflammatoryrelievertherapyalgorithm,“lowdose”budesonide/formoterolmaintenanceandrelievertherapyismoreeffectivethanthetraditionalICSandICS/LABAregimensincorporatingSABArelievertherapyatSteps2,3andpartof4intraditionalguidelines.ThisisconsistentwiththepropositionthatfromStep2to4,thechoiceofrelievertherapyisamajordeterminantoftherapeuticefficacyinadultasthma[26].Step3Step3oftheanti-inflammatoryrelievertherapyalgorithmis“mediumdose”budesonide/formoterolmaintenanceandrelievertherapy,whichismoreeffectivethanthetraditionalStep4treatment,maintenance“mediumdose”ICS/LABAtogetherwithSABArelievertherapy(figure1)[27,28].Instudiesofthisregimen,whichrequiredahistoryofanexacerbationinthe12 monthspriortorandomisation,budesonide/formoterol200/6 µghasbeenself-administeredfrombothaTurbuhalerandapressurisedmetereddoseinhaler(pMDI)device.However,asbudesonide/formoterolpMDIdeviceshavenotyetbeenassessedattheotherstepsinthealgorithm,theydonotrepresentanoptionforuseinanalgorithmwhichincorporatesthesamebudesonide/formoterol200/6 µginhalerdeviceacrossthespectrumofasthmaseverity.Furtherresearchofthebudesonide/formoterol200/6 µgand100/3 µgpMDIproductsisaprioritytoprovidetheevidencebaserequiredforthisoption,notleastbecausemostpatientsareusedtotakingSABArelievertherapythroughapMDI.The“mediumdose”budesonide/formoterolmaintenanceandrelieverregimenisalsomoreeffectivethan“highdose”ICS/LABAtogetherwithSABArelievertherapy,whichisnowdesignatedasoneoftheStep5treatmentoptions(figure1)[29].Thistrialevidenceisbasedoncomparisonwithbothbudesonide/formoterolandfluticasonepropionate/salmeterolataboutdoubletheequivalentmaintenanceICSdose,togetherwithSABArelievertherapy.Thisindicatesthatthegreaterefficacyisduetobudesonide/formoterolcomparedwithSABAuseasrelievertherapy,ratherthanthespecificICS/LABAproductusedformaintenancetherapy.Step4Step4oftheanti-inflammatoryrelievertherapy-basedalgorithmwouldbesimilartoStep5ofthealgorithmsrepresentedintraditionalguidelines,inwhichadd-ontherapiessuchaslongactingmuscarinicantagonists,leukotrienereceptorantagonists,macrolidesandbiologicsareconsidered,togetherwithspecialistreview.Insummary,thethreetreatmentlevelsbasedonasinglebudesonide/formoterol200/6 µgTurbuhalertakenasareliever,eitherasmonotherapyortogetherwith“low”or“medium”dosemaintenancebudesonide/formoteroltherapyaresuperiortothecorrespondingfivetreatmentstepsbasedonSABArelievertherapy,eitherasmonotherapy,ortogetherwithICSorICS/LABAmaintenancetherapy.TransitionbetweenstepsAnimportantissueishowtoenablepatientstomovebetweenthetreatmentstepsrecommendedbytheanti-inflammatoryrelievertherapyalgorithm.Asimplestepup/stepdownsystemcouldbeused,basedonthefrequencyofrelieveruseoveraperiodofamonth,andwhethertherehasbeenarecentsevereexacerbation.Thepointoftransitionfromas-neededrelievertoregularmaintenanceandrelieverusemaynotneedtobestandardised,andcouldbebasedonpatientandprescriberpreferences.Highβ2-agonistrescuemedicationuseisamarkerofpoorasthmacontrolandexacerbationrisk[30,31],bothofwhichrespondtohigherdosesofregularICStherapy[32].Forthisreason,ifapatientusestheirbudesonide/formoterolTurbuhaleras-neededforreliefonaveragemorethansevenactuationsperweek,thenthelogicalstepupapproachwouldbetoaddtwoadditionaldailymaintenanceactuationstothemaintenanceregimen,withthepatienttherebymovingupastep,however,notbeyondStep3.Forpatientswhousetheirbudesonide/formoterolasrelieveronaveragebetweentwoandsevenactuationsperweek,thentheirmaintenancedosecouldbeleftunchanged.Forpatientswithbudesonide/formoterolrelieveruseonaveragenomorethantwooccasionsperweek,thentheirmaintenancedosecouldbereducedbyastep,butnotbeyondStep1.Analternative,lessconservativeapproachwouldbetousecutpointsofbudesonide-formoterolrelieveruseoftwoormoreactuationsperdaytostepup;aroundonceadayonaveragetoremainatthesamelevel,andlessthanonceadayonaveragetostepdown.Asevereexacerbationshouldpromptmedicalreviewforconsiderationofanincreaseintreatmentlevel,asthiseventwouldbeassociatedwithamarkedincreaseintheriskoffuturesevereexacerbations[30,31,33,34].Thistransitionsystemwouldresultintreatmentdefinedbyaspecificstepbeingtakenfortheperiodbetweenclinicreviews,orforperiodsofatleastamonthwhenself-managedbythepatient.ImplementationThroughtheuseofasthmaactionplans,apromptandsmoothtransitionbetweenthelevelsoftreatmentcouldbeachieved,whichaftereducationbyhealthprofessionalsmaythenbeundertakenwithoutclinic-basedmedicalreview.Aprototypeactionplanthathasbeendevelopedfromtheactionplansusedinstudiesofbudesonide/formoterolrelievertherapyisproposedforusebypatientsintheirself-management(figure3)[7,27].Afterthepatientbecomesfamiliarwiththesystem,patientswouldthenbeabletotransitionbetweenstepsthemselves,withoutrequirementtoseekclinicalreviewpriortotreatmentstepdecisions.DownloadfigureOpeninnewtabDownloadpowerpointFIGURE3Prototypeadultasthmaactionplanfortheanti-inflammatoryrelievertherapystepwisetreatmentalgorithmdevelopedfromtheactionplansusedinthestudiesofbudesonide/formoterolrelievertherapythatdemonstratedefficacyandsafetyofthisregimen[7,25].Onthereversesideoftheplanadditionalinformationandguidancecanbeprovided,butnotlimitedtoinhalerandspacertechnique,medicationuseandthefrequencyofrecommendedmedicalreview.ConcludingcommentsTheproposedanti-inflammatoryICS/formoterolrelievertherapy-basedalgorithmisbasedonbudesonide/formoterol,duetotheextensiveevidenceofitsefficacyandsafetywhenusedinthisway,acrosstherangeofasthmaseverityinadultasthma.However,itseemslikelythatthealgorithmcouldbebasedonotherICS/formoterolproducts,suchasbeclometasonedipropionate/formoterol,orICS/SABAproducts,suchasbeclometasonedipropionate/salbutamol,forwhichthereisevidenceofefficacyatonestep,butnotacrosstherangeofasthmaseverity,aswouldberequiredfortheirincorporationinanalgorithm[12,26].Thisnovelanti-inflammatoryrelievertherapy-basedalgorithmandassociatedactionplanswillneedassessment,inparticularbycomparisonwiththetraditionalSABArelievertherapy-basedalgorithms,coveringefficacy,safety,steroidburden,patientpreferenceandeconomiccost.Thiswoulddeterminewhethertheproposedanti-inflammatoryrelievertherapyalgorithmissuperiortothetraditionalalgorithms,asissuggestedbycomparisonsofthedifferentregimensattheindividualstepsofthealgorithms,anditsplaceinasthmamanagementincountriesinwhichbudesonide/formoterolproductsareavailable.ShareablePDFSupplementaryMaterialThisone-pagePDFcanbesharedfreelyonline.ShareablePDFERJ-01407-2019.Shareable FootnotesAuthorcontributions:R.Beasleywrotethefirstdraftofthemanuscriptandallauthorscontributedtoitsreviewandredrafting.R.Beasleyhadfinalresponsibilityforthedecisiontosubmitforpublication.Noexternalwritingassistancewassoughtforthismanuscript.Conflictofinterest:R.BeasleyreportsgrantsfromHealthResearchCouncilofNewZealand,personalfeesforconsultancyfromAstraZeneca,duringtheconductofthestudy;grantsandpersonalfeesforadvisoryboardwork,consultancyandtraveltomeetingsfromAstraZeneca,grantsfromGlaxoSmithKlineandGenentech,personalfeesforadvisoryboardworkfromTheravanceBiopharma,outsidethesubmittedwork.Conflictofinterest:I.BraithwaitereportsgrantsfromHealthResearchCouncilofNewZealand,duringtheconductofthestudy;grantsfromGenentech,outsidethesubmittedwork.Conflictofinterest:A.SemprinireportsgrantsfromHealthResearchCouncilofNewZealand,duringtheconductofthestudy.Conflictofinterest:C.Kearnshasnothingtodisclose.Conflictofinterest:M.Weatherallhasnothingtodisclose.Conflictofinterest:T.W.HarrisonreportspersonalfeesforconsultancyfromAstraZeneca,duringtheconductofthestudy;personalfeesforconsultancyandlectures,andtravelexpensesreimbursementfromAstraZeneca,personalfeesforadvisoryboardworkfromGSK,outsidethesubmittedwork.Conflictofinterest:A.Papireportspersonalfeesforboardmembership,consultancyandlectures,grantsforresearch,andtravelexpensesreimbursementfromChiesi,AstraZeneca,GlaxoSmithKline,BoehringerIngelheim,MundipharmaandTEVA,personalfeesforlecturesandtravelexpensesreimbursementfromMenarini,NovartisandZambon,personalfeesforboardmembershipandconsultancyfromSanofi/Regeneron,outsidethesubmittedwork.Conflictofinterest:I.D.Pavordreportspersonalfeesforlecturesandadvisoryboardwork,andtravelexpensesfromAstraZeneca,GSK,BoehringerIngelheimandTEVA,grantsandpersonalfeesforlecturesandadvisoryboardwork,andtravelexpensesfromChiesi,personalfeesforadvisoryboardworkfromSanofi/Regeneron,Merck,Novartis,KnoppandRoche/Genentech,personalfeesforlecturesfromCircassiaandMundipharma,grantsandpersonalfeesforadvisoryboardworkfromAfferent,outsidethesubmittedwork.Supportstatement:TheMRINZreceivesHealthResearchCouncilofNewZealandIndependentResearchOrganisationfunding.Nootherfundingwasreceivedforthismanuscript.FundinginformationforthisarticlehasbeendepositedwiththeCrossrefFunderRegistry.ReceivedMay28,2019.AcceptedNovember5,2019.Copyright©ERS2020https://www.ersjournals.com/user-licenceReferences↵GlobalStrategyforAsthmaManagementandPrevention,GlobalInitiativeforAsthma(GINA)Update2018.www.ginasthma.org/BeasleyR,HancoxRJ,HarwoodM,etal.AsthmaandRespiratoryFoundationNZadultasthmaguidelines:aquickreferenceguide.NZMedJ2016;129:83–102.OpenUrlBritishThoracicSociety/SIGN.BritishGuidelineontheManagementofAsthma:aNationalClinicalGuideline,2016.www.brit-thoracic.org.uk↵NationalAsthmaEducationandPreventionProgram.ExpertPanelReport3:GuidelinesfortheDiagnosisandManagementofAsthma.Bethesda,NationalHeartLungandBloodInstitute,2007.↵GlobalStrategyforAsthmaManagementandPrevention,GlobalInitiativeforAsthma(GINA)Update2019.www.ginasthma.org/↵O'ByrnePM,FitzGeraldJM,BatemanED,etal.Inhaledcombinedbudesonide–formoterolasneededinmildasthma.NEnglJMed2018;378:1865–1876.doi:10.1056/NEJMoa1715274OpenUrl↵BeasleyR,HollidayM,ReddelHK,etal.Controlledtrialofbudesonide-formoterolas-neededformildasthma.NEnglJMed2019;380:2020–2030.doi:10.1056/NEJMoa1901963OpenUrlEdwardsSJ,vonMaltzahnR,NayaIP,etal.Budesonide/formoterolformaintenanceandrelievertherapyofasthma:ametaanalysisofrandomisedcontrolledtrials.IntJClinPract2010;64:619–627.doi:10.1111/j.1742-1241.2009.02320.xOpenUrlCrossRefPubMed↵SobierajDM,WeedaER,NguyenE,etal.Associationofinhaledcorticosteroidsandlong-actingβ-agonistsascontrollerandquickrelieftherapywithexacerbationsandsymptomcontrolinpersistentasthmaasystematicreviewandmeta-analysis.JAMA2018;319:1485–1496.doi:10.1001/jama.2018.2769OpenUrl↵PapiA,CanonicaGW,MaestrelliP,etal.Rescueuseofbeclomethasoneandalbuterolinasasingleinhalerformildasthma.NEnglJMed2007;356:2040–2052.doi:10.1056/NEJMoa063861OpenUrlCrossRefPubMedWebofScience↵O'ByrnePM,JenkinsC,BatemanED.Theparadoxesofasthmamanagement:timeforanewapproach?EurRespirJ2017;50:1701103.doi:10.1183/13993003.01103-2017OpenUrlAbstract/FREEFullText↵BeasleyR,BirdG,HarperJ,etal.Thefurtherparadoxesofasthmamanagement:timeforanewapproachacrossthespectrumofasthmaseverity.EurRespirJ2018;52:1800694.doi:10.1183/13993003.00694-2018OpenUrlAbstract/FREEFullTextMartinMJ,HarrisonTW.Isittimetomoveawayfromshort-actingbeta-agonistsinasthmamanagement?EurRespirJ2019;53:1802223.doi:10.1183/13993003.02223-2018OpenUrlAbstract/FREEFullText↵PavordI,BeasleyR,AgustiA,etal.Afterasthma:redefiningairwaysdiseases.Lancet2018;391:350–400.doi:10.1016/S0140-6736(17)30879-6OpenUrlCrossRefPubMed↵BatemanED,ReddelHK,O'ByrnePM,etal.As-neededbudesonide-formoterolversusmaintenancebudesonideinmildasthma.NEnglJMed2018;378:1877–1887.doi:10.1056/NEJMoa1715275OpenUrl↵HardyJ,BaggottC,FingletonJ,etal.Budesonide-formoterolrelievertherapyversusmaintenancebudesonideplusterbutalinerelievertherapyinadultswithmil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Print CitationTools ICS-formoterolrelievertherapystepwisetreatmentalgorithmforadultasthma RichardBeasley,IreneBraithwaite,AlexSemprini,CiléinKearns,MarkWeatherall,TimW.Harrison,AlbertoPapi,IanD.Pavord EuropeanRespiratoryJournalJan2020,55(1)1901407;DOI:10.1183/13993003.01407-2019 CitationManagerFormats BibTeXBookendsEasyBibEndNote(tagged)EndNote8(xml)MedlarsMendeleyPapersRefWorksTaggedRefManagerRISZotero Share ICS-formoterolrelievertherapystepwisetreatmentalgorithmforadultasthma RichardBeasley,IreneBraithwaite,AlexSemprini,CiléinKearns,MarkWeatherall,TimW.Harrison,AlbertoPapi,IanD.Pavord EuropeanRespiratoryJournalJan2020,55(1)1901407;DOI:10.1183/13993003.01407-2019 ShareThisArticle: Copy FullText(PDF) JumpTo ArticleAbstractIntroductionStep1Step2Step3Step4TransitionbetweenstepsImplementationConcludingcommentsShareablePDFFootnotesReferencesFigures&DataInfo&MetricsPDF TweetWidgetFacebookLikeGooglePlusOne MoreinthisTOCSection IsBPDinadultageanovelCOPDendotype? 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