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Some will make you sick. Some will give you a new start. Pills that make you sick. And pills that make you well. We have to have them. Or we feel like hell!
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ȱ ȱ ȱ ȱ ȱ DevelopmentȱandȱValidationȱofȱtheȱInhaledȱCorticosteroidȱQuestionnaire:ȱȱ AȱmodelȱforȱtheȱmeasurementȱofȱpatientȬperceivedȱsideȱeffectsȱ ȱbyȱselfȬreportȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ JulietȱM.ȱFosterȱ ȱ

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RIJKSUNIVERSITEITȱGRONINGENȱ ȱ DevelopmentȱandȱValidationȱofȱtheȱInhaledȱCorticosteroidȱQuestionnaire:ȱ ȱAȱmodelȱforȱtheȱmeasurementȱofȱpatientȬperceivedȱsideȱeffectsȱȱ byȱselfȬreportȱ ȱ ȱ

Proefschriftȱ ȱ ȱ terȱverkrijgingȱvanȱhetȱdoctoraatȱinȱdeȱ MedischeȱWetenschappenȱ aanȱdeȱRijksuniversiteitȱGroningenȱ opȱgezagȱvanȱdeȱ RectorȱMagnificus,ȱdr.ȱF.ȱZwarts,ȱ inȱhetȱopenbaarȱteȱverdedigenȱopȱ woensdagȱ12ȱdecemberȱ2007ȱ omȱ16.15ȱuurȱ ȱ doorȱ ȱ JulietȱMichelleȱFosterȱ ȱ

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ȱ ȱ ȱ ȱ ȱ ȱ Beoordelingscommissie:ȱȱ

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Promotores:ȱ ȱ ȱ

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Prof.ȱdr.ȱT.ȱvanȱderȱMolenȱ Prof.ȱdr.ȱP.ȱHannafordȱȱ Prof.ȱdr.ȱR.ȱSandermanȱ ȱ

Prof.ȱdr.ȱE.D.ȱBatemanȱȱ Prof.ȱdr.ȱP.N.R.ȱDekhuijzenȱ Prof.ȱdr.ȱA.A.ȱKapteinȱ ȱ ȱ

Paranimfen:ȱ

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SamanthaȱLouwȱ GiorgioȱBarbareschi

ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ Foster,ȱJ.M.ȱ DevelopmentȱandȱValidationȱofȱtheȱInhaledȱCorticosteroidȱQuestionnaire:ȱAȱmodelȱ forȱtheȱmeasurementȱofȱpatientȬperceivedȱsideȱeffectsȱbyȱselfȬreport.ȱ ȱ ThesisȱUniversityȱofȱGroningenȱwithȱsummaryȱinȱDutch.ȱ ȱ PrintedȱbyȱPrintPartnersȱIpskamp,ȱEnschede,ȱTheȱNetherlands.ȱ ȱ Theȱstudiesȱinȱthisȱthesisȱwereȱfinanciallyȱsupportedȱbyȱanȱunrestrictedȱgrantȱfromȱ NycomedȱGmbH.ȱȱ ȱ PrintingȱofȱthisȱthesisȱwasȱsponsoredȱbyȱAstraZenecaȱBV,ȱBelbezet,ȱBoehringerȬ Ingelheim/Pfizer,ȱGlaxoSmithKline,ȱMedaȱPharmaȱBV,ȱMerckȱSharpȱ&ȱDohmeȱBV,ȱ NederlandsȱAstmaȱFonds,ȱNederlandsȱBijwerkingenȱFonds,ȱNovartisȱPharmaȱBV,ȱ NycomedȱBV,ȱRijksuniversiteitȱGroningen,ȱStichtingȱAstmabestrijding,ȱUniversityȱ ofȱAberdeenȱandȱwww.memailorder.com.ȱ ȱ ©ȱJulietȱM.ȱFoster,ȱ2007ȱ Allȱ rightsȱ reserved.ȱ Noȱ partȱ ofȱ thisȱ publicationȱ mayȱ beȱ reproduced,ȱ storedȱ inȱ aȱ retrievalȱ systemȱ orȱ transmitted,ȱ inȱ anyȱ formȱ orȱ byȱ anyȱ meansȱ Ȭelectronic,ȱ mechanical,ȱ photocopying,ȱ recordingȱ orȱ otherwiseȬȱ withoutȱ theȱ priorȱ writtenȱ permissionȱofȱtheȱauthor.ȱ ȱ ISBN:ȱ978Ȭ90Ȭ367Ȭ3241Ȭ3ȱ

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ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ForȱMaryȱElizabethȱFosterȱ

ȱȱȱ “Iȱfindȱtheȱmedicineȱworseȱthanȱtheȱmalady”ȱ ȱ JohnȱFletcherȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ Pillsȱ ȱ Someȱhaveȱsideȱeffectsȱ Someȱdonȇtȱ Someȱwillȱhelpȱyouȱ Someȱwonȇt,ȱ ȱ Someȱwillȱdamageȱkidneysȱ Someȱyourȱheartȱ Someȱwillȱmakeȱyouȱsickȱ Someȱwillȱgiveȱyouȱaȱnewȱstart.ȱ ȱ Pillsȱthatȱmakeȱyouȱsickȱ Andȱpillsȱthatȱmakeȱyouȱwellȱ Weȱhaveȱtoȱhaveȱthemȱ Orȱweȱfeelȱlikeȱhell!ȱ ȱ DonnaȱNimmoȱ ȱ

Contentsȱ ȱ Prefaceȱ ȱ ȱ Partȱ1ȱ Introductionȱ ȱ Chapterȱ1ȱ Theȱmechanismsȱofȱpositiveȱandȱnegativeȱeffectsȱandȱ functionȱofȱinhaledȱcorticosteroidsȱ ȱ Chapterȱ2ȱ SideȱeffectȱmeasurementȱbyȱselfȬreportȱquestionnaireȱ ȱ Chapterȱ3ȱ Theȱaimsȱofȱthisȱthesisȱ ȱ ȱ ȱ Partȱ2ȱ Reviewsȱofȱexistingȱworkȱ ȱ Chapterȱ4ȱ TheȱuseȱofȱquestionnairesȱforȱmeasuringȱpatientȬreportedȱ sideȱeffectsȱofȱdrugs:ȱitsȱimportanceȱandȱmethodologicalȱ challengesȱ

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Acceptedȱforȱpublication.ȱ

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Partȱ3ȱ ȱ

Letterȱtoȱtheȱeditors:ȱPatientȬreportingȱofȱsideȱeffectsȱmayȱ ȱ95ȱ provideȱanȱimportantȱsourceȱofȱinformationȱinȱclinicalȱ practiceȱ ȱEur.ȱJ.ȱClin.ȱPharmacol. 2007;ȱ63:979Ȭ980.ȱ ȱ Originalȱresearchȱ ȱ Chapterȱ5ȱ HigherȱpatientȬperceivedȱsideȱeffectsȱrelatedȱtoȱhigherȱ 103ȱ dailyȱdosesȱofȱinhaledȱcorticosteroidsȱinȱtheȱcommunity:ȱ AȱcrossȬsectionalȱanalysisȱ Chapterȱ4aȱ

Respir.ȱMed.ȱ2006;ȱ100:1318Ȭ1336.ȱ

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Chapterȱ6ȱ

AȱselfȬratingȱscaleȱforȱpatientȬperceivedȱsideȱeffectsȱofȱ inhaledȱcorticosteroidsȱ

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Respir.ȱRes.ȱ2006;ȱ7:131.ȱ

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Chapterȱ7ȱ

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Chapterȱ8ȱ

Cumulativeȱexposureȱtoȱinhaledȱcorticosteroidsȱisȱassociatedȱ 151ȱ withȱincreasedȱriskȱofȱpatientȬreportedȱsideȱeffectsȱ Submittedȱforȱpublication.ȱ

Personalityȱisȱimportantȱinȱtheȱreportingȱofȱsideȱeffectsȱ ofȱinhaledȱcorticosteroidsȱinȱasthmaȱpatientsȱȱ

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Partȱ4ȱ ȱ ȱ ȱ ȱ Partȱ5ȱ

ȱ Generalȱdiscussionȱandȱsummaryȱ Chapterȱ9ȱ Discussionȱandȱrecommendationsȱforȱfutureȱresearchȱ Chapterȱ10ȱ SummaryȱofȱthesisȱinȱEnglishȱ Chapterȱ11ȱ Nederlandseȱsamenvattingȱȱ ȱ Appendicesȱ TheȱInhaledȱCorticosteroidȱQuestionnaireȱ(ICQ)ȱ Dankwoordȱ(Acknowledgements) Listȱofȱpublications Aboutȱtheȱauthor

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Prefaceȱ ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Dependingȱ onȱ yourȱ ownȱ areaȱ ofȱ expertiseȱ orȱ interest,ȱ thereȱ mayȱ beȱ aȱ seriesȱ ofȱ questionsȱ thatȱ immediatelyȱ springȱ toȱ mindȱ whenȱ readingȱ theȱ titleȱ ofȱ thisȱ thesis:ȱ Whatȱareȱinhaledȱcorticosteroidsȱandȱhowȱdoȱtheyȱtreatȱdisease?ȱWhatȱisȱitȱinȱtheȱ mechanismȱ ofȱ actionȱ ofȱ inhaledȱ corticosteroidsȱ thatȱ resultsȱ inȱ sideȱ effectȱ occurrence?ȱ Isȱ thereȱ reallyȱ aȱ needȱ forȱ aȱ selfȬreportȱ questionnaireȱ whichȱ measuresȱ patients’ȱ perceptionsȱ ofȱ sideȱ effects?ȱ Theseȱ andȱ manyȱ otherȱ questionsȱ willȱ beȱ answeredȱ inȱ theȱ introductionȱ sectionȱ ofȱ thisȱ bookȱ inȱ orderȱ toȱ explainȱ theȱ backgroundȱtoȱthisȱthesisȱandȱhowȱitȱcameȱtoȱfruition.ȱȱ ȱ Thisȱ thesisȱ isȱ aboutȱ inhaledȱ corticosteroids.ȱ However,ȱ theȱ primaryȱ subjectȱ ofȱ thisȱ workȱ concernsȱ theȱ measurementȱ ofȱ patients’ȱ experiencesȱ ofȱ drugȬinducedȱ symptoms.ȱThatȱis,ȱitȱisȱnotȱaboutȱaȱseriesȱofȱobjectiveȱtestsȱwhichȱcanȱeitherȱproveȱ orȱ disproveȱ theȱ incidenceȱ orȱ prevalenceȱ ofȱ theȱ rangeȱ ofȱ potentialȱ inhaledȱ corticosteroidȬinducedȱsymptoms.ȱRather,ȱthisȱthesisȱasksȱwhetherȱweȱcanȱmeasureȱ patients’ȱ perceptionsȱ ofȱ drugȬrelatedȱ symptomsȱ byȱ questionnaire,ȱ andȱ whetherȱ patientȱ factors,ȱ suchȱ asȱ personalityȱ orȱ pastȱ orȱ currentȱ drugȱ exposure,ȱ influenceȱ thoseȱperceptions.ȱTheȱquestionsȱareȱaskedȱinȱtheȱcontextȱofȱinhaledȱcorticosteroidȱ treatmentȱ forȱ patientsȱ withȱ asthmaȱ orȱ chronicȱ obstructiveȱ pulmonaryȱ diseaseȱ (COPD).ȱButȱrespiratoryȱmedicineȱisȱonlyȱoneȱofȱmanyȱclinicalȱspecialitiesȱinȱwhichȱ aȱ toolȱ assessingȱ patientȬreportedȱ sideȱ effectȱ perceptionsȱ couldȱ beȱ ofȱ use.ȱ Withinȱ manyȱofȱtheȱchaptersȱtheȱrationaleȱfor,ȱandȱvalueȱof,ȱmeasurementȱofȱpatients’ȱsideȱ effectȱperceptionsȱwillȱbeȱdiscussed.ȱInȱtheȱcurrentȱclimateȱofȱincreasingȱinterestȱinȱ patientȬreportedȱqualityȱofȱlifeȱ(orȱhealthȱstatus)ȱinstrumentsȱforȱtheȱassessmentȱofȱ theȱefficacyȱofȱdrugsȱorȱotherȱinterventionsȱinȱclinicalȱresearch,ȱtheȱissueȱofȱpatientȬ reportedȱ sideȱ effectsȱ willȱ undoubtedlyȱ gainȱ increasingȱ attentionȱ inȱ theȱ comingȱ years.ȱTheȱtitleȱfromȱanȱarticleȱpublishedȱinȱ2000ȱjustȱbeforeȱthisȱresearchȱbeganȱ– “theȱpatient’sȱappraisalȱofȱsideȬeffects:ȱtheȱblindȱspotȱinȱqualityȱofȱlifeȱassessments”ȱ –1ȱraisesȱanȱimportantȱneglectedȱissueȱinȱassessmentȱofȱqualityȱofȱlife,ȱwhichȱmayȱ beȱcentralȱtoȱtheȱfutureȱimpactȱofȱthisȱthesis.ȱ ȱ ȱ ȱ ȱ ȱ ȱȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ

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Prefaceȱ ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Referencesȱ ȱ ȱ 1.ȱȱ DeȱGeestȱS,ȱMoonsȱP.ȱTheȱpatientȇsȱappraisalȱofȱsideȬeffects:ȱtheȱblindȱspotȱinȱqualityȬ ofȬlifeȱassessmentsȱinȱtransplantȱrecipients.ȱNephrolȱDialȱTransplantȱ2000;15:457Ȭ9.ȱ

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Partȱ1ȱ Introductionȱ ȱ Thisȱ introductionȱ includesȱ threeȱ chapters.ȱ Inȱ theȱ firstȱ chapter,ȱ theȱ functionȱ andȱ deliveryȱ ofȱ inhaledȱ corticosteroids,ȱ asȱ wellȱ asȱ anȱ explanationȱ ofȱ theȱ mechanisms,ȱ andȱtheȱdesiredȱ(therapeutic)ȱandȱunwantedȱ(sideȱeffects)ȱeffectsȱofȱtheȱmedicationȱ isȱprovided.ȱTheȱsecondȱchapterȱbeginsȱbyȱdelineatingȱtheȱpotentiallyȱproblematicȱ sequelaeȱofȱinhaledȱcorticosteroidȬrelatedȱsideȱeffects.ȱTheȱchapterȱthenȱgoesȱonȱtoȱ introduceȱ theȱ conceptȱ ofȱ patientȬreportedȱ questionnairesȱ forȱ sideȱ effectȱ measurementȱ andȱ brieflyȱ describesȱ theȱ (psychometric)ȱ methodsȱ usedȱ forȱ theȱ developmentȱ ofȱ suchȱ instruments.ȱ Inȱ theȱ thirdȱ andȱ finalȱ chapterȱ ofȱ thisȱ introduction,ȱtheȱaimsȱofȱtheȱthesisȱareȱintroduced.ȱ

Chapterȱ1ȱȱ

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Theȱmechanismsȱofȱpositiveȱandȱnegativeȱeffectsȱ ȱandȱfunctionȱofȱinhaledȱcorticosteroidsȱȱȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ

J.M.ȱFosterȱ

Chapterȱ1.ȱTheȱmechanismsȱofȱpositiveȱandȱnegativeȱeffectsȱandȱfunctionȱofȱinhaledȱcorticosteroidsȱ

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Diseasesȱtreatedȱwithȱinhaledȱcorticosteroidsȱ Inhaledȱ corticosteroidsȱ areȱ usedȱ toȱ treatȱ bothȱ asthmaȱ andȱ chronicȱ obstructiveȱ pulmonaryȱ diseaseȱ (COPD).ȱ Anȱ estimatedȱ 300ȱ millionȱ peopleȱ (aroundȱ 5%ȱ ofȱ theȱ worldȱ population)ȱ haveȱ asthmaȱ andȱ increasingȱ worldwideȱ urbanisationȱ overȱ theȱ nextȱ 20ȱ yearsȱ mayȱ resultȱ inȱ aȱ oneȬthirdȱ increaseȱ inȱ thisȱ number.1ȱ Asthmaȱ isȱ responsibleȱ forȱ significantȱ morbidityȱ andȱ mortalityȱ Ȭȱ itȱ accountsȱ forȱ aroundȱ 1ȱ inȱ everyȱ250ȱdeathsȱworldwideȱȬȱandȱresultsȱinȱsubstantialȱhealthȱcareȱcostsȱasȱwellȱasȱ patientȬburdenȱ andȱ indirectȱ costsȱ dueȱ toȱ lostȱ workȱ orȱ schoolȱ days.1ȱ COPDȱ isȱ alsoȱ responsibleȱforȱsignificantȱmortalityȱwithȱaroundȱ3ȱmillionȱpeopleȱkilledȱeachȱyearȱ dueȱtoȱtheȱdisease.2ȱTheȱcurrentȱprevalenceȱofȱCOPDȱisȱthoughtȱtoȱbeȱaroundȱ9Ȭ10%ȱ inȱadultsȱagedȱ40ȱorȱoverȱandȱthisȱisȱpredictedȱtoȱincreaseȱinȱtheȱnextȱdecadeȱalongȱ withȱmortality.3ȱFourteenȱtoȱsixteenȱmillionȱpeopleȱinȱtheȱUSAȱaloneȱareȱestimatedȱ toȱhaveȱCOPD.2ȱ ȱ Theȱ twoȱ diseasesȱ haveȱ similaritiesȱ asȱ wellȱ asȱ importantȱ differences.ȱ Bothȱ areȱ inflammatoryȱ conditionsȱ characterisedȱ byȱ excessiveȱ mucusȱ productionȱ andȱ bronchoconstrictionȱwhichȱcauseȱairflowȱlimitationȱandȱchangeȱinȱtheȱstructureȱofȱ theȱsmallȱairwaysȱinȱtheȱlung.ȱHowever,ȱthereȱareȱdifferentȱtypesȱofȱcellȱinvolvedȱinȱ eachȱdisease.ȱInȱasthma,ȱinflammationȱisȱdrivenȱprimarilyȱbyȱeosinophilsȱwhereasȱ inȱ COPDȱ neutrophilsȱ areȱ involved.ȱ Thisȱ distinctionȱ betweenȱ theȱ diseasesȱ isȱ importantȱwithȱrespectȱtoȱinhaledȱcorticosteroidȱtreatment,ȱbecauseȱalthoughȱthereȱ isȱ muchȱ evidenceȱ toȱ suggestȱ thatȱ theȱ eosinophilicȱ inflammationȱ inȱ asthmaȱ canȱ beȱ effectivelyȱ treatedȱ withȱ inhaledȱ corticosteroids,ȱ thereȱ isȱ littleȱ evidenceȱ thatȱ thisȱ treatmentȱ isȱ effectiveȱ inȱ treatingȱ theȱ neutrophilicȱ inflammationȱ associatedȱ withȱ COPD.4ȱ Corticosteroidsȱ areȱ theȱ mostȱ potentȱ antiȬinflammatoryȱ agentsȱ currentlyȱ availableȱforȱtheȱtreatmentȱofȱasthma,ȱthusȱinhaledȱcorticosteroidsȱhaveȱbecome,ȱinȱ theȱ 30ȱ yearsȱ sinceȱ theirȱ launch,ȱ theȱ firstȬlineȱ preventativeȱ treatmentȱ forȱ childrenȱ andȱ adultsȱ withȱ asthma.5ȱ Inȱ asthma,ȱ inhaledȱ corticosteroidsȱ areȱ associatedȱ withȱ aȱ reductionȱ inȱ airwayȱ inflammation,ȱ hyperresponsiveness,ȱ symptomȱ severity,ȱ frequencyȱ ofȱ exacerbations,ȱ frequencyȱ ofȱ hospitalisationȱ andȱ death;ȱ anȱ improveȬ mentȱ inȱ lungȱ functionȱ andȱ anȱ increaseȱ inȱ symptomȬfreeȱ days.6ȱ Withȱ respectȱ toȱ COPD,ȱ thereȱ continuesȱ toȱ beȱ someȱ controversyȱ regardingȱ theȱ efficacyȱ ofȱ inhaledȱ corticosteroidsȱ forȱ treatingȱ theȱ disease.7ȱ Recentȱ dataȱ suggestȱ that,ȱ inȱ someȱ COPDȱ patients,ȱinhaledȱcorticosteroidsȱmayȱdecreaseȱfrequencyȱofȱexacerbations,8;9ȱhealthȱ statusȱ decline10ȱ andȱ mortality,11ȱ althoughȱ theseȱ dataȱ mustȱ beȱ replicatedȱ toȱ defineȱ responsiveȱsubȬgroupsȱandȱtoȱfullyȱunderstandȱtheȱmechanismȱofȱsuchȱoutcomes.12ȱ Inȱtheȱrecentȱ(2006)ȱGlobalȱinitiativeȱforȱchronicȱObstructiveȱLungȱDiseaseȱ(GOLD)ȱ guidelineȱupdate,ȱinhaledȱcorticosteroidȱtreatmentȱisȱrecommendedȱforȱsevereȱandȱ veryȱ severeȱ patientsȱ withȱ repeatedȱ exacerbations,ȱ althoughȱ theȱ guidelinesȱ warnȱ thatȱ theȱ doseȬresponseȱ andȱ theȱ longȬtermȱ safetyȱ areȱ stillȱ notȱ known.13ȱ Cliniciansȱ mustȱ thereforeȱ considerȱ theȱ relativeȱ risksȱ andȱ harmsȱ ofȱ inhaledȱ corticosteroidȱ treatmentȱ inȱCOPDȱ patientsȱ whoȱ haveȱseveralȱ characteristicsȱ whichȱ mayȱincreaseȱ theirȱ riskȱ forȱ sideȱ effectsȱ (inȱ comparisonȱ toȱ theȱ oftenȱ youngerȱ asthmaȱpatients),ȱsuchȱasȱhistoricalȱuseȱofȱlargeȱamountsȱofȱtobaccoȱandȱadvancedȱ age.14ȱȱ

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Partȱ1.ȱIntroductionȱ ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Howȱinhaledȱcorticosteroidsȱworkȱinȱtheȱbodyȱtoȱtreatȱdiseaseȱȱ Inhalerȱdevicesȱȱ Oralȱ corticosteroidsȱ haveȱ beenȱ usedȱ toȱ treatȱ respiratoryȱ diseaseȱ sinceȱ theȱ 1950’s.ȱ Howeverȱ oralȱ corticosteroidsȱ areȱ associatedȱ withȱ commonlyȱ occurringȱ andȱ problematicȱ sideȱ effects.15;16ȱ Withȱ theȱ aimȱ ofȱ reducingȱ sideȱ effectȱ burden,ȱ theȱ firstȱ corticosteroidȱpreparationsȱdeliveredȱviaȱanȱinhalerȱdeviceȱwereȱintroducedȱinȱtheȱ earlyȱ1970’s.17ȱInhalerȱdevicesȱareȱimportantȱinȱrespiratoryȱdiseaseȱbecauseȱtheyȱnotȱ onlyȱ allowȱ medicationȱ toȱ beȱ deliveredȱ directlyȱ toȱ theȱ ‘diseased’ȱ lungȱ whereȱ itȱ isȱ needed,ȱbutȱtheyȱalsoȱdrasticallyȱreduceȱtheȱpotentialȱsystemicȱimpactȱofȱtheȱdrugȱ inȱcomparisonȱtoȱsystemicȱdelivery.18ȱȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ Figureȱ1.ȱExamplesȱofȱinhalerȱdevicesȱ ȱ Twoȱ mainȱ groupsȱ ofȱ inhalerȱ devicesȱ exist:ȱ theȱ pressȬandȬbreatheȱ pressurisedȱ meteredȱ doseȱ inhalersȱ (MDI)ȱ andȱ theȱ breathȬactuatedȱ dryȱ powderȱ inhalersȱ (DPI)ȱ (figureȱ 1).ȱ Inȱ theȱ MDI,ȱ theȱ corticosteroidȱ medicationȱ isȱ dissolvedȱ orȱ suspendedȱ underȱpressureȱinȱaȱpropellantȱ(previouslyȱchloroȬfluorocarbons:ȱ(CFCs),ȱbut,ȱmoreȱ recently,ȱ theȱ environmentallyȱ friendlyȱ hydrofluoroalkanesȱ (HFAs)).19ȱ Aȱ valveȱ systemȱ allowsȱ theȱ patientȱ toȱ releaseȱ aȱ meteredȱ doseȱ ofȱ corticosteroidȱ fromȱ theȱ deviceȱratherȱlikeȱaȱsprayȬcan.ȱInȱcontrastȱtheȱDPIȱrequiresȱtheȱpatientȱtoȱprimeȱtheȱ inhalerȱreadyȱforȱ‘automaticȱdosing’ȱonȱinspiration,ȱwithȱorȱwithoutȱsomeȱtypeȱofȱ powerȱassistance.20ȱPatientsȱmustȱthereforeȱlearnȱdeviceȬspecificȱtechniquesȱforȱtheȱ correctȱ useȱ ofȱ theȱ differentȱ inhalers.ȱ Confusion ȱ mayȱ preventȱ adequate inhaler technique,ȱ resultingȱ inȱ poorȱ depositionȱ ofȱ inhaledȱ corticosteroidȱ intoȱ theȱ lung.21ȱ Suboptimalȱ inhalerȱ techniqueȱ isȱ notȱ onlyȱ associatedȱ withȱ reducedȱ drugȱ efficacy,ȱ butȱ alsoȱ withȱ increasedȱ riskȱ forȱ adverseȱ effectsȱ (moreȱ onȱ thisȱ later).22ȱ ȱ Theȱ DPIȱ isȱ oftenȱ easierȱ toȱ useȱ thanȱ theȱ MDIȱ becauseȱ itȱ doesȱ notȱ requireȱ theȱ patientȱ toȱ coordinateȱactivatingȱtheȱinhalerȱwithȱinspiration,ȱwhichȱisȱessentialȱforȱoptimumȱ lungȱdepositionȱofȱinhaledȱcorticosteroid.ȱPoorȱinhalerȱtechniqueȱmayȱoccurȱinȱupȱ toȱtwoȬthirdsȱofȱpatientsȱwhoȱuseȱtheȱrelativelyȱcheaperȱMDI.23ȱForȱsomeȱpatients,ȱ coordinationȱ problemsȱ canȱ beȱ reducedȱ byȱ theȱ useȱ ofȱ aȱ largeȱ volumeȱ spacerȱ inȱ conjunctionȱ withȱ theirȱ MDI.24ȱ Theȱ spacerȱ allowsȱ patientsȱ toȱ expelȱ aȱ meteredȱ doseȱ fromȱ theirȱ inhalerȱ deviceȱ intoȱ aȱ separateȱ largerȱ chamberȱ beforeȱ inhalation.ȱ However,ȱspacersȱcanȱbeȱproblematicȱifȱelectrostaticȱchargesȱbuildȱupȱonȱtheȱwallsȱ ofȱtheȱchamber,ȱtherebyȱpreventingȱoptimalȱdepositionȱofȱinhaledȱcorticosteroidȱinȱ theȱlung.19ȱ ȱ 18ȱ

ȱ

Chapterȱ1.ȱTheȱmechanismsȱofȱpositiveȱandȱnegativeȱeffectsȱofȱinhaledȱcorticosteroidsȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Inhalerȱdevicesȱoftenȱincludeȱtwoȱactiveȱdrugs,ȱsuchȱasȱaȱlongȬactingȱΆ2Ȭagonistȱandȱ aȱ corticosteroidȱ (e.g.ȱ salmeterol/fluticasone,ȱ formoterol/budesonide),ȱ inȱ theȱ sameȱ device.ȱThisȱcombinationȱreducesȱtheȱneedȱforȱuseȱofȱmultipleȱinhalersȱwhichȱmayȱ contributeȱtoȱnonȬadherenceȱorȱconfusionȱinȱtheȱpatientȱwithȱrespectȱtoȱtheȱpurposeȱ (bronchodilationȱorȱantiȬinflammation)ȱofȱeachȱseparateȱinhaler.ȱ ȱ AntiȬinflammatoryȱmechanismsȱ Inhaledȱcorticosteroidsȱreduceȱtheȱunderlyingȱairwayȱinflammationȱexperiencedȱbyȱ patientsȱ withȱ asthma25ȱ andȱ COPD.26ȱ Itȱ isȱ nowȱ knownȱ thatȱ inhaledȱ corticosteroidsȱ beginȱtoȱexertȱtheirȱantiȬinflammatoryȱeffectsȱafterȱonlyȱaȱfewȱhours.27;28ȱCommonlyȱ prescribedȱinhaledȱcorticosteroidsȱinȱEuropeȱincludeȱbeclomethasoneȱdipropionateȱ (BDP),ȱ budesonide,ȱ andȱ fluticasoneȱ propionate,ȱ withȱ aȱ newȱ steroidȱ (ciclesonide)ȱ moreȱrecentlyȱlaunched.ȱNonȬsteroidȱpreparationsȱwhichȱalsoȱreduceȱinflammatoryȱ responseȱ inȱ asthmaȱ areȱ available,ȱ suchȱ asȱ leukotrieneȱ receptorȱ antagonists,ȱ butȱ theseȱ areȱ predominantlyȱ usedȱ asȱ addȬonȱ medicationsȱ inȱ additionȱ toȱ inhaledȱ corticosteroids.6ȱȱ ȱ Theȱmechanismȱofȱactionȱofȱglucocorticoidsȱ Itȱwasȱnotȱuntilȱmoreȱthanȱ30ȱyearsȱafterȱcorticosteroidsȱwereȱfirstȱlaunchedȱthatȱtheȱ receptorȱ forȱ theȱ corticosteroidȱ moleculesȱ wasȱ characterised,ȱ inȱ 1985.29ȱ Theȱ mechanismȱofȱactionȱofȱtheseȱdrugsȱisȱstillȱbeingȱresearchedȱandȱunderstood.30ȱItȱisȱ nowȱ knownȱ thatȱ inhaledȱ corticosteroidsȱ suppressȱ multipleȱ inflammatoryȱ genesȱ thatȱ areȱ activatedȱ inȱ theȱ airwaysȱ ofȱ patientsȱ withȱ respiratoryȱ disease.ȱ Theȱ glucocorticoidȱtriggersȱtheȱactionȱofȱglucocorticoidȱreceptorsȱwhichȱbindȱdirectlyȱtoȱ specificȱsequencesȱinȱgeneȱpromoters,ȱtherebyȱregulatingȱtheȱlevelsȱofȱtranscriptionȱ fromȱtargetȱgenes.ȱInȱsomeȱgenes,ȱsuchȱasȱprolactinȱandȱosteocalcin,ȱexpressionȱisȱ decreasedȱ whenȱ theȱ activatedȱ glucocorticoidȱ receptorȱ isȱ boundȱ toȱ theirȱ promoter.ȱ However,ȱ theȱ activatedȱ glucocorticoidȱ receptorȱ canȱ alsoȱ interactȱ directlyȱ withȱ proteins,ȱ suchȱ asȱ nuclearȱ factorȬΎBȱ andȱ activatingȱ proteinȬ1,ȱ therebyȱ decreasingȱ theirȱ abilityȱ toȱ stimulateȱ transcriptionȱ withoutȱ directlyȱ contactingȱ theȱ promoterȱ DNA.31;32ȱ Soȱ corticosteroidsȱ canȱ mediateȱ geneȱ expressionȱ byȱ bindingȱ directlyȱ toȱ promotersȱ toȱ transactivateȱ orȱ downregulateȱ expression,ȱ orȱ throughȱ indirectȱ transrepressionȱ ofȱ transcriptionȱ factorȱ activity.33ȱ Throughȱ reducedȱ productionȱ ofȱ proinflammatoryȱ andȱ immunostimulatoryȱ genesȱ andȱ theirȱ productsȱ (includingȱ mostȱ cytokinesȱ andȱ chemokines,ȱ aȱ fewȱ proteases,ȱ neuropeptidesȱ andȱ theirȱ receptors),ȱairwayȱinflammationȱandȱmucusȱproductionȱisȱdecreased.34ȱ ȱ Thisȱ said,ȱ theȱ efficacyȱ ofȱ inhaledȱ corticosteroidsȱ differsȱ strikinglyȱ whenȱ treatingȱ asthmaȱ orȱ COPD.ȱ Althoughȱ theȱ eosinophilȬdrivenȱ inflammationȱ inȱ asthmaȱ isȱ broadlyȱreducedȱbyȱinhaledȱcorticosteroidȱtreatment,35ȱinȱcontrast,ȱtheȱneutrophilicȱ inflammationȱ inȱ COPDȱ isȱ mostlyȱ unresponsiveȱ toȱ inhaledȱ corticosteroids.36ȱ Howeverȱ forȱ someȱ COPDȱ phenotypes,ȱ suchȱ asȱ thoseȱ withȱ evidenceȱ ofȱ allergicȱ orȱ inflammatoryȱ responseȱ orȱ aȱ historyȱ ofȱ frequentȱ exacerbations,ȱ treatmentȱ withȱ inhaledȱ corticosteroidȱ hasȱ beenȱ shownȱ toȱ beȱ useful.37ȱ Theȱ relativeȱ efficacyȱ ofȱ differentȱinhaledȱsteroidȱtreatmentsȱinȱasthmaȱisȱalsoȱpartlyȱdependentȱonȱpatientȱ characteristicsȱ suchȱ asȱ inhalerȱ technique,ȱ adherenceȱ toȱ treatmentȱ regimensȱ prescribed,ȱ andȱ individualȱ differencesȱ inȱ responseȱ toȱ corticosteroidsȱ (withȱ theȱ 19ȱ

Partȱ1.ȱIntroductionȱ ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

extremesȱ beingȱ steroidȱ resistanceȱ orȱ hypersensitivity).38;39ȱ Theȱ particleȱ sizeȱ ofȱ theȱ inhaledȱcorticosteroidȱcouldȱtheoreticallyȱimproveȱefficacyȱthroughȱimprovedȱlungȱ deposition.40ȱ Severalȱ ofȱ theseȱ factorsȱ mayȱ alsoȱ beȱ importantȱ withȱ respectȱ toȱ sideȱ effectȱoccurrence,ȱbecauseȱmanyȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱareȱmediatedȱ throughȱtheȱsameȱreceptorȱbindingȱsiteȱasȱthatȱofȱtheȱtherapeuticȱeffects.41ȱȱ ȱ InhaledȱcorticosteroidȬinducedȱsideȱeffectsȱ Aȱdefinitionȱofȱ“sideȱeffect”ȱ Althoughȱ theȱ termȱ “sideȱ effect”ȱ isȱ usedȱ throughoutȱ thisȱ thesis,ȱ aȱ numberȱ ofȱ differentȱtermsȱexistȱincludingȱ“adverseȱevent”,ȱ“adverseȱdrugȱreaction”ȱ“adverseȱ effect”ȱ andȱ “toxicȱ effect”,ȱ whichȱ althoughȱ havingȱ subtlyȱ differentȱ meanings,ȱ allȱ referȱ toȱ theȱ unwantedȱ effectsȱ ofȱ drugȱ treatments.42ȱ Inȱ thisȱ thesisȱ weȱ concentrateȱ specificallyȱ onȱ theȱ negative,ȱ unwantedȱ effectsȱ ofȱ inhaledȱ corticosteroidsȱ thatȱ areȱ oftenȱ clinicallyȱ mildȱ (i.e.ȱ nonȬlifeȱ threatening),ȱ occurȱ commonlyȱ andȱ areȱ recognisableȱ (andȱ thereforeȱ perceivable)ȱ byȱ patients.ȱ Althoughȱ theȱ sideȱ effectsȱ describedȱinȱthisȱthesisȱareȱpredominantlyȱ“mild”,ȱatȱleastȱinȱaȱclinicalȱsense,ȱsuchȱ sideȱeffectsȱareȱlikelyȱtoȱhaveȱaȱdetrimentalȱimpactȱonȱtheȱlivesȱofȱpatients.ȱȱ ȱ “Local”ȱsideȱeffectsȱ Oropharyngealȱcandidiasisȱȱ Oropharyngealȱ candidiasisȱ isȱ aȱ fungalȱ infectionȱ ofȱ theȱ mouthȱ and/orȱ throat.ȱ Theȱ exactȱpathogenesisȱofȱinhaledȱcorticosteroidȬinducedȱoropharyngealȱcandidiasisȱisȱ notȱ fullyȱ understood,ȱ butȱ itȱ isȱ thoughtȱ toȱ beȱ causedȱ eitherȱ byȱ aȱ generalisedȱ immunosuppressiveȱeffectȱofȱsteroidȱtreatmentȱorȱdueȱtoȱstimulatedȱfungalȱgrowthȱ asȱaȱresultȱofȱincreasedȱglucoseȱlevelsȱinȱsaliva.43ȱTheȱprevalenceȱofȱoropharyngealȱ candidiasisȱ isȱ thoughtȱ toȱ beȱ betweenȱ 10ȱ andȱ 30%ȱ inȱ patientsȱ currentlyȱ usingȱ inhaledȱ corticosteroids,44;45ȱ andȱ itȱ isȱ relatedȱ toȱ inhaledȱ corticosteroidȱ doseȱ andȱ dosingȱfrequency.46ȱAȱreviewȱofȱclinicalȱtrialsȱdataȱshowedȱthatȱbetweenȱ4ȱandȱ16%ȱ ofȱ patientsȱ canȱ experienceȱ oropharyngealȱ candidiasisȱ inȱ theȱ firstȱ 6ȱ monthsȱ ofȱ inhaledȱcorticosteroidȱuse.43ȱȱ ȱ Pharyngitisȱandȱtasteȱproblemsȱ Throatȱ sorenessȱ (pharyngitis)ȱ andȱ alteredȱ sensationȱ ofȱ tasteȱ andȱ areȱ bothȱ sideȱ effectsȱ ofȱ inhaledȱ corticosteroids.ȱ Pharyngitisȱ isȱ aȱ commonȱ sideȱ effect,ȱ withȱ anȱ incidenceȱ ofȱ betweenȱ 4ȱ andȱ 25%ȱ inȱ inhaledȱ corticosteroidȱ users.47ȱ Dataȱ onȱ theȱ prevalenceȱofȱinhaledȱcorticosteroidȬinducedȱtasteȱdisturbanceȱisȱhardȱtoȱcomeȱby.ȱ Pharyngitisȱ andȱ alteredȱ tasteȱ sensationȱ mayȱ occurȱ secondaryȱ toȱ oropharyngealȱ candidiasis48ȱ orȱ dueȱ toȱ aȱ directȱ effectȱ ofȱ inhaledȱ corticosteroids.ȱ Thereȱ isȱ alsoȱ anȱ ‘unpleasantȱ taste’ȱ associatedȱ withȱ theȱ inhalationȱ ofȱ corticosteroidsȱ whichȱ isȱ wellȬ known,ȱ butȱ rarelyȱ studiedȱ specifically,ȱ andȱ appearsȱ toȱ beȱ infrequentlyȱ spontaneouslyȱreportedȱasȱaȱsideȱeffectȱbyȱpatientsȱinȱclinicalȱtrials.49ȱȱ ȱ Coughȱandȱoropharyngealȱirritationȱ Upȱ toȱ 34%ȱ ofȱ adultȱ patientsȱ receivingȱ inhaledȱ corticosteroidsȱ experienceȱ coughȱ afterȱ inhalation.50ȱ Thisȱ sideȱ effectȱ mayȱ occurȱ dueȱ toȱ aȱ directȱ irritantȱ effectȱ ofȱ theȱ inhaledȱcorticosteroid47ȱorȱdueȱtoȱirritationȱcausedȱbyȱnonȬactiveȱingredientsȱinȱtheȱ inhaler51;52ȱ (implicatedȱ ingredientsȱ haveȱ includedȱ chlorofluorocarbons,ȱ sorbitanȱ trioleate,ȱ oleicȱ acidȱ andȱ soyaȱ lecithin).53ȱ Itȱ mayȱ beȱ exacerbatedȱ byȱ spacerȱ use.52ȱ 20ȱ

Chapterȱ1.ȱTheȱmechanismsȱofȱpositiveȱandȱnegativeȱeffectsȱofȱinhaledȱcorticosteroidsȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Oropharyngealȱ irritationȱ canȱ occurȱ inȱ aroundȱ 40%ȱ ofȱ patientsȱ usingȱ inhaledȱ corticosteroids.50;54ȱAtȱpresentȱthereȱareȱstillȱrelativelyȱfewȱdataȱonȱtheȱincidenceȱofȱ inhaledȱcorticosteroidȬinducedȱirritationȱinȱtheȱmouthȱorȱpharynxȱseparately.ȱȱ ȱ Thirstȱ Aȱ feelingȱ ofȱ thirstȱ afterȱ inhalationȱ ofȱ inhaledȱ corticosteroidsȱ mayȱ occur,ȱ dueȱ toȱ irritationȱofȱtheȱthroatȱorȱsecondaryȱtoȱoralȱcandidiasis.22ȱInȱaȱsurveyȱofȱpaediatricȱ patients,ȱ22%ȱreportedȱthisȱsideȱeffect.52ȱ ȱ Dysphoniaȱ Dysphoniaȱ(voiceȱproblemsȱsuchȱasȱhoarsenessȱorȱchangesȱinȱphonationȱquality)ȱisȱ reportedȱ inȱupȱ toȱ 58%ȱofȱpatientsȱusingȱ inhaledȱ corticosteroids55ȱandȱisȱ relatedȱ toȱ inhaledȱ corticosteroidȱ dose.50;56ȱ Dysphoniaȱ canȱ occurȱ independentlyȱ ofȱ oralȱ candidiasisȱ orȱ pharyngitis.57ȱ Dysphoniaȱ mayȱ beȱ causedȱ byȱ inhaledȱ corticosteroidȬ inducedȱ bowingȱ ofȱ theȱ vocalȱ folds,ȱ orȱ mucosalȱ changesȱ whichȱ preventȱ closureȱ ofȱ theȱglottisȱandȱhenceȱinterfereȱwithȱsupraglotticȱhyperfunctionȱ(theȱvocalȱmusclesȱ areȱtenseȱratherȱthanȱrelaxedȱduringȱphonation).55ȱHoweverȱtheȱaetiologyȱisȱstillȱnotȱ fullyȱunderstood.ȱ ȱ Systemicȱsideȱeffectsȱ Dermalȱeffects:ȱskinȱbruisingȱandȱthinningȱ Bruisingȱ occursȱ inȱ aroundȱ 47Ȭ71%ȱ ofȱ patientsȱ treatedȱ withȱ inhaledȱ corticosteroidsȱ (12Ȭ32%ȱofȱcontrols).58Ȭ61ȱInȱpatientsȱwhoȱreceivedȱhighȱdoseȱ(1200ȱΐgȱdaily)ȱinhaledȱ corticosteroidsȱinȱaȱrandomisedȱclinicalȱtrialȱforȱupȱtoȱ4.5ȱyears,ȱbruisingȱoccurredȱ inȱ 11.2%ȱ ofȱ patientsȱ (3.5%ȱ ofȱ controls).62ȱ Prevalenceȱ andȱ incidenceȱ appearsȱ toȱ dependȱonȱaȱrangeȱofȱfactors.ȱForȱexample,ȱinhaledȱcorticosteroidȬinducedȱbruisingȱ isȱ thoughtȱ toȱ beȱ moreȱ commonȱ inȱ patientsȱ usingȱ higherȱ dosesȱ ofȱ inhaledȱ corticosteroids60ȱ andȱ olderȱ menȱ mayȱ beȱ atȱ aȱ greaterȱ riskȱ ofȱ developingȱ itȱ thanȱ women.62ȱ Inhaledȱ corticosteroidȬinducedȱ bruisingȱ isȱ thoughtȱ toȱ occurȱ moreȱ commonlyȱ inȱ patientsȱ treatedȱ forȱ longerȱ periodsȱ ofȱ timeȱ (e.g.ȱ 55ȱ versusȱ 43ȱ months).60ȱHowever,ȱlittleȱisȱgenerallyȱreportedȱaboutȱtheȱtemporalȱappearanceȱofȱ inhaledȱcorticosteroidȬinducedȱsideȱeffects.ȱEasyȱbruisingȱhasȱbeenȱassociatedȱwithȱ suppressedȱ hypothalmicȬpituitaryȬadrenalȱ functionȱ throughȱ detectionȱ ofȱ reducedȱ urinaryȱ cortisolȱ inȱ patientsȱ withȱ bruising,ȱ suggestingȱ thatȱ bothȱ areȱ mediatedȱ throughȱsystemicȱabsorptionȱofȱinhaledȱcorticosteroid.59ȱ ȱ Skinȱ thicknessȱ canȱ alsoȱ beȱ reducedȱ asȱ resultȱ ofȱ inhaledȱ corticosteroidȱ use.ȱ Inȱ anȱ observationalȱ studyȱ comparingȱ 51ȱ patientsȱ usingȱinhaledȱ corticosteroidsȱ dailyȱ forȱ atȱleastȱ6ȱmonthsȱwithȱ17ȱcontrols,ȱtheȱskinȱthicknessȱofȱpatientsȱtakingȱhighȱdoseȱ inhaledȱcorticosteroidsȱ(1000Ȭ2250ΐg)ȱwasȱsignificantlyȱreducedȱbyȱ15,ȱ17ȱandȱ19%ȱ atȱ theȱ hand,ȱ armȱ andȱ buttockȱ respectively.61ȱ Thisȱ smallȱ studyȱ mayȱ haveȱ beenȱ underȬpoweredȱ toȱ detectȱ differencesȱ inȱ patientsȱ takingȱ lowerȱ dosesȱ (800ΐgȱ perȱ dayȱ inȱ aȱ doseȬdependentȱ mannerȱ (inȱ adults).98ȱ Corticosteroidsȱ causeȱ adrenalȱ suppressionȱ byȱ reducingȱ adrenocorticotropinȱ production,ȱ whichȱ leadsȱ toȱ reducedȱcortisolȱsecretionȱbyȱtheȱadrenalȱgland.99ȱBoneȱmineralȱdensityȱisȱthoughtȱ toȱ beȱ reducedȱ inȱ patientsȱ whoȱ receiveȱ highȱ inhaledȱ corticosteroidȱ dosesȱ forȱ longȱ periodsȱ ofȱ time.86ȱ Corticosteroidsȱ canȱ decreaseȱ calciumȱ absorption,ȱ increaseȱ 23ȱ

Partȱ1.ȱIntroductionȱ ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

calciumȱlossȱbyȱdirectȱkidneyȱeffects,ȱinhibitȱosteoblastsȱandȱinhibitȱboneȱformationȱ directly.99ȱInhaledȱcorticosteroidsȱmayȱdecreaseȱlinearȱgrowthȱinȱchildren,ȱbutȱthereȱ isȱ noȱ evidenceȱ thatȱ finalȱ adultȱ heightȱ isȱ affected.100ȱ Corticosteroidsȱ canȱ reduceȱ growthȱ byȱ directȱ andȱ indirectȱ inhibitionȱ ofȱ growthȱ hormoneȱ secretion,ȱ byȱ interferingȱ withȱ theȱ bioactivityȱ ofȱ insulinȬlikeȱ growthȱ factorȬ1ȱ viaȱ alterationȱ ofȱ proteinȱ binding,ȱ orȱ byȱ directlyȱ inhibitingȱ synthesisȱ ofȱ newȱ connectiveȱ tissue,ȱ althoughȱtheȱageȱofȱtheȱchildȱisȱimportantȱforȱdeterminingȱtheȱfactorsȱinvolvedȱ(e.g.ȱ pubertyȱversusȱinfancy).101ȱ ȱ Mechanismsȱbyȱwhichȱinhaledȱcorticosteroidsȱcauseȱsideȱeffectsȱȱ Thereȱ areȱ twoȱ mainȱ mechanismsȱ byȱ whichȱ inhaledȱ corticosteroidsȱ canȱ causeȱ sideȱ effects.102ȱ Theȱ firstȱ isȱ byȱ precipitationȱ ofȱ corticosteroidȱ atȱ theȱ siteȱ ofȱ drugȱ administrationȱ (i.e.ȱ inȱ theȱ oralȬpharyngealȱ space),ȱ whichȱ canȱ leadȱ toȱ localȱ sideȱ effectsȱsuchȱasȱvoiceȱcomplaintsȱorȱoralȱcandidiasis.ȱTheȱsecondȱisȱbyȱabsorptionȱofȱ glucocorticoidȱ intoȱ theȱ systemicȱ circulation,ȱ whichȱ mayȱ leadȱ toȱ systemicȱ sideȱ effectsȱsuchȱasȱskinȱbruisingȱandȱglaucomaȱ(seeȱFigureȱ2).ȱȱ ȱ ȱ ȱ Absorption from lung ȱȱ Fraction of steroid into systemic ȱ deposited in lung circulation ȱ Systemic Lungs circulation ȱ Fraction of steroid deposited in mouth ȱ and oropharynx Local ȱ side effects ȱ Swallowed fraction ȱ Orally bio-available ȱ fraction ȱ Absorption from gut ȱ ȱ Systemic ȱ side effects Liver ȱ First pass ȱ GI tract inactivation ȱ ȱ Figureȱ2.ȱRouteȱofȱactionȱofȱinhaledȱcorticosteroidsȱleadingȱtoȱsideȱeffects.ȱAdaptedȱ fromȱDerendorfȱetȱal.102ȱ ȱ Thereȱ areȱ twoȱ routesȱ byȱ whichȱ inhaledȱ corticosteroidsȱ canȱ becomeȱ systemicallyȱ absorbed.ȱTheȱfirstȱisȱtheȱfractionȱofȱcorticosteroidȱthatȱisȱswallowedȱwhichȱentersȱ theȱgastrointestinalȱtractȱwhereȱitȱisȱavailableȱforȱsystemicȱabsorption.ȱTheȱmajorityȱ ofȱ thisȱ orallyȱ absorbedȱ portionȱ isȱ metabolisedȱ duringȱ theȱ firstȱ passȱ throughȱ theȱ liver.ȱ Theȱ remainingȱ orallyȱ ‘bioȬavailable’ȱ fractionȱ isȱ veryȱ lowȱ (0.5).ȱ ȱ Reliabilityȱofȱ domains:ȱNR.ȱ

ȱ

Constructionȱofȱ domainsȱwithinȱ questionnaireȱ andȱdomainȱ reliabilityȱtestingȱ

Totalȱ (summed)ȱ score:ȱ least=0;ȱ most=72.ȱ

ȱ

Scoringȱ

ȱ

Itemȱgeneration:ȱ Literatureȱreview,ȱ outcomesȱofȱ3ȱ previousȱresearchȱ projectsȱbyȱtheȱ authorsȱinȱ700ȱ patients.ȱ ȱ Faceȱandȱcontentȱ validity:ȱ Pilotȱinterviewsȱwithȱ 20ȱpatientsȱleadingȱtoȱ theȱadditionȱofȱ questionsȱ(numberȱ notȱreported).ȱ Criterionȱvalidity:ȱInȱ96ȱ patientsȱwithȱepilepsy,ȱ treatedȱwithȱantiȬepilepticȱ drugsȱforȱ>4ȱmonths,ȱ ABNASȱscoresȱcorrelatedȱ statisticallyȱsignificantlyȱ withȱ4ȱofȱ5ȱ neuropsychologicalȱ (objective)ȱtests.ȱ ȱ Constructȱvalidity:ȱInȱaȱ doubleȬblindȱplaceboȬ controlledȱstudyȱofȱ30ȱ normalȱvolunteersȱ randomisedȱtoȱeitherȱ placebo,ȱ10ȱorȱ20ȱmgȱofȱ temazepam,ȱABNASȱscoresȱ wereȱsignificantlyȱlowerȱinȱ placeboȱthanȱtreatedȱ groupsȱatȱ2ȱhoursȱpostȱ medicationȱ(noȱbaselineȱ measureȱtaken).ȱTheȱ originalȱ33ȱitemsȱwereȱ reducedȱtoȱ24ȱbasedȱonȱthisȱ study.ȱȱ ȱ ABNASȱscoresȱwereȱ significantlyȱhigherȱinȱ200ȱ antiȬepilepticȱtreatedȱ patientsȱthanȱuntreatedȱ nonȬepilepticȱcontrolȱ patientsȱforȱallȱ6ȱdomainsȱ andȱtotalȱscore.ȱ

Itemȱgeneration,ȱfaceȱ Criterionȱorȱconstructȱ andȱcontentȱvalidityȱ validityȱ proceduresȱ

Validityȱ

Scaleȱinternalȱ consistency:ȱ΅ȱ ǃ0.95.ȱ ȱ Itemȱtotalȱ correlations:ȱ NR.ȱ ȱ Scaling:ȱ Itemȱfloorȱ effects:ȱ(7ȱtoȱ 69%ȱofȱ patientsȱscoredȱ 0);ȱ Itemȱceilingȱ effects:ȱ(0ȱtoȱ 4%ȱofȱpatientsȱ scoredȱ3).ȱ

Internalȱ consistencyȱ

ȱ

Reliabilityȱ

NRȱ

ReprodȬȱ ucibilityȱȱ (TestȬ retest)ȱ

ȱ

NRȱ

Abilityȱtoȱ detectȱ changeȱ overȱtimeȱ

ResponȬȱ sivenessȱ

Appendixȱ2.ȱPsychometricȱpropertiesȱofȱaȱrangeȱofȱexistingȱpatientȬreportedȱsideȱeffectȱquestionnairesȱ

NRȱ

Minimalȱ clinicallyȱ importantȱ differenceȱ

ȱ

ȱ

Excellentȱitemȱ generationȱandȱ validityȱtesting.ȱȱ Itemȱreductionȱ wasȱbasedȱonȱaȱ smallȱgroupȱofȱ healthyȱ volunteersȱusingȱ medicationȱforȱ2ȱ hoursȱmakingȱtheȱ scaleȱlessȱsuitableȱ forȱtheȱ measurementȱofȱ mediumȱtoȱlongȬ termȱsideȱeffects.ȱ ȱ Theȱ4Ȭpointȱscaleȱ mayȱbeȱlessȱ reliableȱthanȱaȱ scaleȱofȱ5ȱtoȱ7ȱ points.56ȱ ȱ ABNASȱhasȱbeenȱ usedȱinȱanȱRCTȱtoȱ compareȱdifferentȱ drugsȱpreȱandȱ postȱtreatment. ȱ

ȱ

Generalȱ Comments*ȱ

ȱ

Chapterȱ4.ȱȱAppendicesȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱ

ȱ

17ȱ

ȱ

ASCȬSR:ȱ Approachesȱtoȱ schizophreniaȱ communicationȬ selfȬreportȱ(ASCȬ SR)ȱchecklist.ȱȱ ȱ Antipsychoticȱ drugȱsideȱeffectsȱ checklistȱforȱuseȱ inȱclinicalȱ practice.ȱ

ȱ

Constructionȱofȱ domainsȱwithinȱ questionnaireȱandȱ domainȱreliabilityȱ testingȱ

Checklistȱwithȱoneȱ NRȱ responseȱoption:ȱ ȈIȱhaveȱhadȱthisȱ experienceȱrecentlyȈȱ (aȱfurtherȱresponseȱ optionȱindicatesȱ patientsȇȱwishȱtoȱ discussȱsideȱeffectsȱ withȱaȱhealthcareȱ professional).ȱȱ ȱ Stemȱquestionȱ (explicit):ȱȈPatientsȱ onȱmedication…ȱ sometimesȱ experienceȱsideȱ effects.ȱPleaseȱ…ȱ checkȱ(tick)ȱboxesȱ thatȱapplyȱtoȱyou)Ȉ.ȱ ȱ Recallȱperiod:ȱ ȈrecentlyȈ.ȱ

ȱ

Responseȱoptionsȱ (scaling),ȱstemȱ questionȱandȱȱ recallȱperiodȱ

Noȱscoringȱ system:ȱ Frequenciesȱ (incidence/ȱ prevalence)ȱȱ forȱeachȱitemȱ only.ȱ

ȱ

Scoringȱ

ȱ

Itemȱgeneration:ȱ NR Itemsȱselectedȱonȱtheȱ basisȱofȱprevalenceȱ publishedȱinȱ antipsychoticȱsideȱ effectȱliterature,ȱandȱ theȱcollectiveȱ experiencesȱofȱtheȱ research/clinicalȱ groupȱmembers,ȱtoȱ identifyȱmoreȱ commonȱorȱclinicallyȱ importantȱsideȱ effects.ȱ ȱ Faceȱandȱcontentȱ validity:ȱNR.ȱ ȱ

Itemȱgeneration,ȱȱ Criterionȱorȱconstructȱȱ faceȱandȱcontentȱ validityȱ validityȱproceduresȱ

Validityȱ

NR

Internalȱ consistencyȱ

Reliabilityȱ

ResponȬ sivenessȱ

ȱ

NR

NR

NR

ReprodȬȱ Abilityȱtoȱ Minimalȱ ucibilityȱȱ detectȱchangeȱ clinicallyȱ (TestȬretest)ȱ overȱtimeȱ importantȱ differenceȱ

ȱ

Noȱformalȱcontentȱ validity,ȱpatientȱ acceptability,ȱorȱ psychometricȱ testingȱhasȱbeenȱ reportedȱforȱthisȱ simpleȱchecklist.ȱ Reportingȱofȱtheseȱ testsȱisȱ recommendedȱinȱ orderȱtoȱ demonstrateȱtheȱ reliabilityȱandȱ validityȱofȱtheȱ scale.ȱ ȱ

ȱ

Generalȱ Comments*ȱ

ȱ

NRȱ=ȱnotȱreported;ȱ*ȱResponsivenessȱtestingȱandȱascertainmentȱofȱaȱminimalȱclinicallyȱimportantȱdifferenceȱisȱrecommendedȱforȱallȱscalesȱwhichȱareȱtoȱbeȱusedȱasȱanȱoutcomeȱmeasureȱinȱclinicalȱtrialsȱorȱinȱsimilarȱlongitudinalȱstudies.ȱ

No.ȱȱ itemsȱ

Nameȱandȱ purposeȱȱ ofȱscaleȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ Chapterȱ4.ȱAppendicesȱ

75ȱ

ȱ

ȱ

76 ȱ

ȱ

ȱ

Noȱscoringȱ system:ȱ Frequenciesȱ (incidenceȱ/ȱ prevalence)ȱ forȱeachȱȱ itemȱonly.ȱ

ȱ

Constructionȱofȱ Scoringȱ domainsȱwithinȱ questionnaireȱȱ andȱdomainȱ reliabilityȱtestingȱ

Simpleȱchecklistȱ NRȱ withȱoneȱresponseȱ option:ȱȱ ȈIȱamȱexperiencingȱ thisȱsymptom”:ȱȱ (aȱfurtherȱresponseȱ optionȱindicatesȱ patientsȇȱwishȱtoȱ discussȱsideȱeffectsȱ withȱaȱhealthcareȱ professional).ȱȱ ȱ Stemȱquestionȱ (explicit):ȱ ȈHormoneȱ treatmentsȱ sometimesȱcauseȱ sideȱeffects.ȱPleaseȱ goȱthroughȱthisȱlistȱ andȱtickȱ(dž)ȱboxesȱ thatȱapplyȱtoȱyou…Ȉ.ȱ ȱ Recallȱperiod:ȱ currentȱstatusȱ ȈIȱamȱ experiencing...Ȉ.ȱ

ȱ

Responseȱoptionsȱ (scaling),ȱstemȱ questionȱandȱȱ recallȱperiodȱ

ȱ

Itemȱgeneration:ȱȱ NR Sideȱeffectȱlistȱwasȱ constructedȱthroughȱ discussionȱwithȱ15ȱ membersȱofȱaȱ workingȱgroup.ȱȱ ȱ Faceȱandȱcontentȱ validity:ȱȱ Theȱchecklistȱwasȱ translatedȱ(methodsȱ notȱreported)ȱandȱ pilotedȱinȱ148ȱ patientsȱ(7ȱcentresȱ acrossȱ4ȱEuropeanȱ countries)ȱforȱ contentȱvalidityȱandȱ comprehension.ȱ ȱ Aȱ14thȱitemȱ (ȈvaginalȱdrynessȈ)ȱ notȱinȱoriginalȱpilotȱ studyȱhasȱbeenȱ addedȱtoȱaȱrecentȱ versionȱofȱtheȱ checklist.28ȱ

Itemȱgeneration,ȱ Criterionȱorȱconstructȱ faceȱandȱcontentȱ validityȱ validityȱproceduresȱ

Validityȱ

ȱ

NR

NR

Internalȱconsistencyȱ ReprodȬȱ ucibilityȱȱ (TestȬretest)ȱ

Reliabilityȱ

ȱ

NR NR

Abilityȱtoȱdetectȱ Minimalȱ changeȱoverȱtimeȱ clinicallyȱ importantȱ differenceȱ

ResponȬȱ sivenessȱ

ȱ

Noȱformalȱ psychometricȱtestingȱ hasȱbeenȱreportedȱforȱ thisȱscale.ȱReportingȱ ofȱtheseȱtestsȱareȱ recommendedȱinȱ orderȱtoȱdemonstrateȱ theȱreliabilityȱandȱ validityȱofȱtheȱscale.ȱ ȱ TheȱCȬPETȱhasȱbeenȱ usedȱinȱcrossȬsectionalȱ researchȱtoȱcompareȱ differentȱtreatmentȱ regimens,ȱandȱtoȱ exploreȱassociationsȱ betweenȱcancerȬ relatedȱfatigueȱandȱ sideȱeffectsȱofȱ hormonalȱcancerȱ treatment.ȱ

ȱ

GeneralȱComments*ȱ

ȱ

CȬPET:ȱClinicalȱ 13ȱ Checklistȱforȱ Patientsȱwithȱ Endocrineȱ Therapy.ȱȱ ȱ Toolȱtoȱmeasureȱ occurrenceȱofȱ sideȱeffectsȱ associatedȱwithȱ hormonalȱ treatmentȱofȱ breastȱcancer.ȱ

No.ȱȱ itemsȱ

Nameȱandȱ purposeȱȱ ofȱscaleȱ

Chapterȱ4.ȱȱAppendicesȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱ

24ȱ

ȱ

CȬSAS:ȱ Chemotherapyȱ Symptomȱ Assessmentȱ Scale.ȱ ȱ Instrumentȱtoȱ documentȱsideȱ effectsȱofȱ chemotherapy.ȱ

ȱ

Meanȱscoreȱ forȱeachȱȱ item.ȱ ȱ Noȱtotalȱȱ Score.ȱ

ȱ

Constructionȱofȱ Scoringȱ domainsȱwithinȱ questionnaireȱȱ andȱdomainȱ reliabilityȱtestingȱ

Responseȱoptions:ȱȱ NRȱ 2ȱscales:ȱȱ ȱ Severityȱscaleȱ 4Ȭpointȱscale:ȱ “notȱexperiencedȱ theȱsideȱeffectȱatȱ all”ȱ “extremelyȱbad”.ȱ ȱȱ Botherȱscaleȱ 4Ȭpointȱscale:ȱ “notȱatȱallȱ important”ȱ “veryȱimportant”.ȱ ȱ Stemȱquestionȱ (explicit):ȱȈTheȱ questionnaire...ȱ containsȱa...listȱofȱ sideȬeffects...ȱ[andȱ asks]ȱwhetherȱyouȱ have...experiencedȱ aȱparticularȱ problem...Ȉ.ȱ ȱ Recallȱperiod:ȱInȱ theȱweeksȱ followingȱ chemotherapyȱ (specificȱtimeȬ periodȱnotȱ specified).ȱ

ȱ

Responseȱoptionsȱ (scaling),ȱstemȱ questionȱandȱȱ recallȱperiodȱ

ȱ

Itemȱgeneration:ȱȱ 31ȱpatientsȱȱ receivingȱchemoȬ therapyȱreportedȱ initialȱsideȱȱ effectsȱ(64ȱitems).ȱȱ ȱ Faceȱandȱcontentȱ validity:ȱȱ Aȱliteratureȱreviewȱ andȱfocusȱgroupsȱȱ (48ȱpatients)ȱconȬ firmedȱitemsȱinȱȱ theȱCȬSAS.ȱȱTwoȱ separateȱpilotȱ studiesȱinȱpatientsȱ receivingȱchemoȬ therapyȱ(n=132/ȱ n=72)ȱrevealedȱ13ȱ newȱitemsȱandȱ excludedȱ33ȱitemsȱ (endorsedȱbyȱ800ΐgȱICS).ȱ Medianȱgroupȱscoreȱinȱbold,ȱinterquartileȱrangeȱinȱnormalȱfont.ȱ

118ȱ

Chapterȱ5.ȱHigherȱpatientȬperceivedȱsideȱeffectsȱrelatedȱtoȱhigherȱdailyȱdosesȱofȱinhaledȱcorticosteroidsȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ ȱ Referencesȱ ȱ 1.ȱȱ NAEPP.ȱ Nationalȱ Institutesȱ ofȱ Health,ȱ Nationalȱ Asthmaȱ Educationȱ &ȱ Preventionȱ Program.ȱ Expertȱ panelȱ report:ȱ Guidelinesȱ forȱ theȱ diagnosisȱ andȱ managementȱ ofȱ asthma—anȱ updateȱ onȱ selectedȱ Topics.ȱ (NIHȱ Publicationȱ No.ȱ 02Ȭ5075).ȱ 2002.ȱ Bethesda,ȱMD,ȱGovernmentȱPrintingȱOffice.ȱȱ ȱ 2.ȱȱ HananiaȱNA,ȱChapmanȱKR,ȱKestenȱS.ȱAdverseȱeffectsȱofȱinhaledȱcorticosteroids.ȱAmȱJȱ Medȱ1995;98:196Ȭ208.ȱ ȱ 3.ȱȱ Wasserfallenȱ JB,ȱ Baraniukȱ JN.ȱ Clinicalȱ useȱ ofȱ inhaledȱ corticosteroidsȱ inȱ asthma.ȱ Jȱ AllergyȱClinȱImmunolȱ1996;97:177Ȭ82.ȱ ȱ 4.ȱȱ Toogoodȱ JH.ȱ Sideȱ effectsȱ ofȱ inhaledȱ corticosteroids.ȱ Jȱ Allergyȱ Clinȱ Immunolȱ 1998;102:705Ȭ13.ȱ ȱ 5.ȱȱ Williamsonȱ IJ,ȱMatusiewiczȱSP,ȱ Brownȱ PH,ȱGreeningȱ AP,ȱ Cromptonȱ GK.ȱ Frequencyȱ ofȱ voiceȱ problemsȱ andȱ coughȱ inȱ patientsȱ usingȱ pressurizedȱ aerosolȱ inhaledȱ steroidȱ preparations.ȱEurȱRespirȱJȱ1995;8:590Ȭ2.ȱ ȱ 6.ȱȱ ShimȱC,ȱWilliamsȱMH,ȱJr.ȱCoughȱandȱwheezingȱfromȱbeclomethasoneȱaerosol.ȱChestȱ 1987;91:207Ȭ9.ȱ ȱ 7.ȱȱ CapewellȱS,ȱReynoldsȱS,ȱShuttleworthȱD,ȱEdwardsȱC,ȱFinlayȱAY.ȱPurpuraȱandȱdermalȱ thinningȱassociatedȱwithȱhighȱdoseȱinhaledȱcorticosteroids.ȱBMJȱ1990;300:1548Ȭ51.ȱ ȱ 8.ȱȱ Makȱ VH,ȱ Melchorȱ R,ȱ Spiroȱ SG.ȱ Easyȱ bruisingȱ asȱ aȱ sideȬeffectȱ ofȱ inhaledȱ corticosteroids.ȱEurȱRespirȱJȱ1992;5:1068Ȭ74.ȱ ȱ 9.ȱȱ Cummingȱ RG,ȱ Mitchellȱ P,ȱ Leederȱ SR.ȱ Useȱ ofȱ inhaledȱ corticosteroidsȱ andȱ theȱ riskȱ ofȱ cataracts.ȱNȱEnglȱJȱMedȱ1997;337:8Ȭ14.ȱ ȱ 10.ȱȱ Jickȱ SS,ȱ VasilakisȬScaramozzaȱ C,ȱ Maierȱ WC.ȱ Theȱ riskȱ ofȱ cataractȱ amongȱ usersȱ ofȱ inhaledȱsteroids.ȱEpidemiologyȱ2001;12:229Ȭ34.ȱ ȱ 11.ȱȱ Mitchellȱ P,ȱ Cummingȱ RG,ȱ Mackeyȱ DA.ȱ Inhaledȱ corticosteroids,ȱ familyȱ history,ȱ andȱ riskȱofȱglaucoma.ȱOphthalmologyȱ1999;106:2301Ȭ6.ȱ ȱ 12.ȱȱ Connettȱ G,ȱ Lennyȱ W.ȱ Inhaledȱ budesonideȱ andȱ behaviouralȱ disturbances.ȱ Lancetȱ 1991;338:634Ȭ5.ȱ ȱ 13.ȱȱ Corriganȱ OP.ȱ Aȱ riskyȱ business:ȱ theȱ detectionȱ ofȱ adverseȱ drugȱ reactionsȱ inȱ clinicalȱ trialsȱandȱpostȬmarketingȱexercises.ȱSocȱSciMedȱ2002;55:497Ȭ507.ȱ ȱ 14.ȱȱ AlvarezȬRequejoȱ A,ȱ Carvajalȱ A,ȱ Begaudȱ B,ȱ Morideȱ Y,ȱ Vegaȱ T,ȱ Ariasȱ LH.ȱ UnderȬ reportingȱ ofȱ adverseȱ drugȱ reactions.ȱ Estimateȱ basedȱ onȱ aȱ spontaneousȱ reportingȱ schemeȱandȱaȱsentinelȱsystem.ȱEurȱJȱClinȱPharmacolȱ1998;54:483Ȭ8.ȱ ȱ 15.ȱȱ StormsȱWW,ȱTheenȱC.ȱClinicalȱadverseȱeffectsȱofȱinhaledȱcorticosteroids:ȱresultsȱofȱaȱ questionnaireȱsurveyȱofȱasthmaȱspecialists.ȱAnnȱAllergyȱAsthmaȱImmunolȱ1998;80:391Ȭ 4.ȱ ȱ 16.ȱȱ BouletȱLP.ȱPerceptionȱofȱtheȱroleȱandȱpotentialȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱ amongȱasthmaticȱpatients.ȱChestȱ1998;113:587Ȭ92.ȱ

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ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ ȱ 17.ȱȱ Chambersȱ CV,ȱ Marksonȱ L,ȱ Diamondȱ JJ,ȱ Laschȱ L,ȱ Bergerȱ M.ȱ Healthȱ beliefsȱ andȱ complianceȱ withȱ inhaledȱ corticosteroidsȱ byȱ asthmaticȱ patientsȱ inȱ primaryȱ careȱ practices.ȱRespirȱMedȱ1999;93:88Ȭ94.ȱ ȱ 18.ȱȱ Cochraneȱ GM.ȱ Complianceȱ andȱ outcomesȱ inȱ patientsȱ withȱ asthma.ȱ Drugsȱ 1996;52ȱ Supplȱ6:12Ȭ9.ȱ ȱ 19.ȱȱ vanȱ Grunsvenȱ PM.ȱ Theȱ magnitudeȱ ofȱ fearȱ ofȱ adverseȱ effectsȱ asȱ aȱ reasonȱ forȱ nonparticipationȱinȱdrugȱtreatment:ȱaȱshortȱreview.ȱJȱAsthmaȱ2001;38:113Ȭ9.ȱ ȱ 20.ȱȱ Spectorȱ S.ȱ Noncomplianceȱ withȱ asthmaȱ therapyȬareȱ thereȱ solutions?ȱ Jȱ Asthmaȱ 2000;37:381Ȭ8.ȱ ȱ 21.ȱȱ FleuranceauȬMorelȱ P.ȱ Howȱ doȱ pharmaceuticalȱ companiesȱ handleȱ consumerȱ adverseȱ drugȱ reactionȱ reports?ȱ Anȱ overviewȱ basedȱ onȱ aȱ surveyȱ ofȱ Frenchȱ drugȱ safetyȱ managersȱandȱofficers.ȱPharmacoepidemiolȱDrugȱSafȱ2002;11:37Ȭ44.ȱ ȱ 22.ȱȱ Geijerȱ RMM,ȱ Vanȱ Hensbergenȱ W,ȱ Bottemaȱ BJAM,ȱ vanȱ Schayckȱ CP,ȱ Sachsȱ APE,ȱ Smeeleȱ IJMȱ etȱ al.ȱ NHGȬstandaardȱ Astmaȱ bijȱ volwassenen:ȱ behandeling.ȱ Huisartsȱ enȱ Wetenschapȱ2001;44:153.ȱ ȱ 23.ȱȱ OȇByrneȱPM,ȱHargreaveȱFE.ȱRoleȱofȱInhaledȱCorticosteroids.ȱInȱFitzGeraldȱJM,ȱErnstȱ PP,ȱ Bouletȱ LP,ȱ OȇByrneȱ PM,ȱ eds.ȱ Evidenceȱ basedȱ asthmaȱ management.,ȱ ppȱ 245Ȭ61.ȱ Hamilton,ȱOntario:ȱDecker,ȱ2001.ȱ ȱ 24.ȱȱ McDerraȱ EJ,ȱ Pollardȱ MA,ȱ Curzonȱ ME.ȱ Theȱ dentalȱ statusȱ ofȱ asthmaticȱ Britishȱ schoolȱ children.ȱPediatrȱDentȱ1998;20:281Ȭ7.ȱ ȱ 25.ȱȱ ShulmanȱJD,ȱTaylorȱSE,ȱNunnȱME.ȱTheȱassociationȱbetweenȱasthmaȱandȱdentalȱcariesȱ inȱ childrenȱ andȱ adolescents:ȱ Aȱ populationȬbasedȱ caseȬcontrolȱ study.ȱ Cariesȱ Resȱ 2001;35:240Ȭ6.ȱ ȱ 26.ȱȱ Kargulȱ B,ȱ Tanbogaȱ I,ȱ Ergeneliȱ S,ȱ Karakocȱ F,ȱ Dagliȱ E.ȱ Inhalerȱ medicamentȱ effectsȱ onȱ salivaȱandȱplaqueȱpHȱinȱasthmaticȱchildren.ȱJȱClinȱPediatrȱDentȱ1998;22:137Ȭ40.ȱ ȱ 27.ȱȱ Selroosȱ O,ȱ Halmeȱ M.ȱ Effectȱ ofȱ aȱ volumaticȱ spacerȱ andȱ mouthȱ rinsingȱ onȱ systemicȱ absorptionȱ ofȱ inhaledȱ corticosteroidsȱ fromȱ aȱ meteredȱ doseȱ inhalerȱ andȱ dryȱ powderȱ inhaler.ȱThoraxȱ1991;46:891Ȭ4.ȱ ȱ 28.ȱȱ vanȱ derȱ Molenȱ T,ȱ MeyboomȬdeȱ Jongȱ B,ȱ Mulderȱ HH,ȱ Postmaȱ DS.ȱ Startingȱ withȱ aȱ higherȱdoseȱofȱinhaledȱcorticosteroidsȱinȱprimaryȱcareȱasthmaȱtreatment.ȱAmȱJȱRespirȱ CritȱCareȱMedȱ1998;158:121Ȭ5.ȱ ȱ 29.ȱȱ Committeeȱ onȱ Safetyȱ ofȱ Medicines/Medicinesȱ Controlȱ Agency.ȱ Currentȱ problemsȱ inȱ pharmacovigilance:ȱfocusȱonȱinhaledȱcorticosteroids.ȱ24(2).ȱ1998.ȱȱ ȱ 30.ȱȱ Hawkinsȱ G,ȱ McMahonȱ AD,ȱ Twaddleȱ S,ȱ Woodȱ SF,ȱ Fordȱ I,ȱ Thomsonȱ NC.ȱ Steppingȱ downȱ inhaledȱ corticosteroidsȱ inȱ asthma:ȱ randomisedȱ controlledȱ trial.ȱ BMJȱ 2003;326:1115.ȱ ȱ

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Chapterȱ6ȱȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱ ȱ ȱ ȱ ȱ ȱ ȱ

AȱselfȬratingȱscaleȱforȱpatientȬperceivedȱȱ sideȱeffectsȱofȱinhaledȱcorticosteroidsȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ

ȱ ȱ ȱ ȱ

J.M.ȱFosterȱ E.ȱvanȱSonderenȱ A.J.ȱLeeȱ R.ȱSandermanȱ A.ȱDijkstraȱ D.S.ȱPostmaȱ T.ȱvanȱderȱMolenȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ

RespiratoryȱResearchȱ2006;ȱ7:131.ȱ ȱ

Chapterȱ6.ȱAȱselfȬratingȱscaleȱforȱpatientȬperceivedȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Abstractȱ Backgroundȱ PatientȬreportedȱsideȱeffectȱquestionnairesȱofferȱaȱsimpleȱmethodȱforȱtheȱsystematicȱ measurementȱ ofȱ drugȬrelatedȱ sideȱ effects.ȱ Inȱ orderȱ toȱ measureȱ patients’ȱ inhaledȱ corticosteroidsȱ (ICS)ȱ relatedȱ sideȱ effectȱ perceptionsȱ theȱ 14Ȭdayȱ retrospectiveȱ Inhaledȱ Corticosteroidȱ Questionnaireȱ (ICQ)ȱ wasȱ developed.ȱ Inȱ thisȱ researchȱ weȱ aimȱ toȱ assessȱ theȱ constructȱ validityȱ andȱ reliabilityȱ ofȱ theȱ ICQȱ andȱ testȱ itsȱ responsivenessȱtoȱdoseȱchangesȱinȱadultȱasthmaȱpatients.ȱ Methodsȱ InȱaȱcrossȬsectionalȱstudy,ȱcurrentȱinhalerȱusersȱwithȱasthmaȱcompletedȱtheȱICQȱ(27ȱ withȱnonȱICSȱinhaler;ȱ61ȱBDPȱequivalentȱdailyȱICSȱlowȱdoseȱǂ400Pg;ȱ62ȱmidȱdoseȱ 401Ȭ800Pg;ȱ andȱ 105ȱ withȱ highȱ doseȱ >800Pg).ȱ Weȱ generatedȱ 3ȱ constructȱ validityȱ hypotheses:ȱ 1)ȱ aȱ hierarchicalȱ doseȬresponseȱ patternȱ forȱ scoringȱ ofȱ theȱ individualȱ itemsȱonȱtheȱICQ,ȱandȱstatisticallyȱsignificantȱdifferencesȱinȱtheȱscoresȱofȱeachȱofȱtheȱ 15ȱICQȱdomainsȱbyȱICSȱdoseȱgroup;ȱ2)ȱanȱassociationȱbetweenȱICSȱdoseȱandȱICQȱ scoringȱ afterȱ adjustingȱ forȱ appropriateȱ confoundersȱ inȱ multipleȱ regression;ȱ 3)ȱ greaterȱconvergenceȱbetweenȱlocalȱsideȱeffectȱdomainsȱthanȱbetweenȱsystemicȱandȱ localȱ domainsȱ ofȱ theȱ scale.ȱ TestȬretestȱ reliabilityȱ wasȱ assessedȱ onȱ aȱ randomlyȱ selectedȱ subgroupȱ ofȱ patientsȱ (n=73)ȱ whoȱ alsoȱ completedȱ theȱ ICQȱ aȱ secondȱ timeȱ afterȱ7ȱdays.ȱInȱaȱseparateȱlongitudinalȱstudy,ȱ61ȱpatientsȱwithȱasthmaȱcompletedȱ theȱICQȱatȱbaselineȱandȱafterȱchangingȱtheirȱdailyȱICSȱdose,ȱatȱ2ȱandȱ6ȱmonths,ȱinȱ orderȱtoȱtestȱtheȱICQ’sȱresponsiveness.ȱ ȱȱ Resultsȱ Allȱ threeȱ constructȱ validityȱ hypothesesȱ wereȱ wellȱ supported:ȱ 1)ȱ aȱ statisticallyȱ significantȱ differenceȱ existedȱ inȱ scoresȱ forȱ 14ȱ domains,ȱ theȱ highȱ ICSȱ doseȱ groupȱ scoringȱ highest;ȱ 2)ȱ ICSȱ doseȱ independentlyȱ predictedȱ ICQȱ scoringȱ afterȱ adjustingȱ forȱ confounders;ȱ 3)ȱ greaterȱ convergenceȱ existedȱ betweenȱ localȱ ICQȱ domainsȱ thanȱ betweenȱlocalȱandȱsystemicȱdomains.ȱTheȱICQȱhadȱgoodȱreproducibility:ȱtestȬretestȱ intraclassȱ correlationȱ coefficientsȱ wereȱ ǃ0.69ȱ forȱ allȱ butȱ theȱ ‘Facialȱ Oedema’ȱ domain.ȱ Inȱ theȱ longitudinalȱ study,ȱ ICQȱ scoresȱ forȱ ‘Voiceȱ Problems’ȱ changedȱ significantlyȱ atȱ 2ȱ andȱ 6ȱ monthsȱ fromȱ baselineȱ andȱ otherȱ ICQȱ domainsȱ displayedȱ trendsȱinȱscoringȱchangeȱaccordantȱwithȱdoseȱmodulationȱatȱ6ȱmonths.ȱ ȱȱ Conclusionsȱ Theȱ ICQȱ hasȱ goodȱ doseȬrelatedȱ discriminativeȱ properties,ȱ isȱ valid,ȱ reliable,ȱ andȱ showsȱpotentialȱresponsivenessȱtoȱICSȱdoseȱchange.ȱ ȱ

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ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Backgroundȱȱ Drugȱsideȱeffectsȱareȱofȱconsiderableȱconcernȱtoȱpatients.1;2ȱInhaledȱcorticosteroidsȱ (ICS),ȱ whichȱ areȱ effectiveȱ andȱ widelyȱ recommendedȱ forȱ controllingȱ airwayȱ inflammationȱ inȱ asthma,ȱ areȱ alsoȱ knownȱ toȱ causeȱ manyȱ localȱ andȱ systemicȱ sideȱ effects.3Ȭ6ȱAȱcrucialȱchasmȱmayȱexistȱbetweenȱdoctorsȱandȱpatientsȱwithȱrespectȱtoȱ theirȱapproachȱtoȱdrugȱsideȱeffects.ȱOnȱtheȱoneȱhand,ȱdoctorsȱmayȱavoidȱdiscussingȱ patients’ȱ aversionsȱ toȱ prescribedȱ medicines,7ȱ andȱ onȱ theȱ otherȱ handȱ patientsȱ independentlyȱmodifyȱtheirȱtreatmentȱregimesȱdueȱtoȱconcernsȱaboutȱpotentialȱorȱ perceivedȱsideȱeffectsȱwithoutȱinformingȱtheirȱdoctor.1;8ȱItȱisȱperhapsȱunsurprisingȱ then,ȱ thatȱ drugȱ sideȱ effectsȱ areȱ associatedȱ withȱ nonȬcomplianceȱ toȱ prescribedȱ medicationȱregimesȱinȱasthma,9Ȭ12ȱandȱtoȱpoorȱasthmaȱoutcomes.13;14ȱȱ ȱ PatientȬcenteredȱ selfȬreportȱ questionnairesȱ needȱ toȱ beȱ properlyȱ developed,ȱ validatedȱ andȱ widelyȱ usedȱ toȱ permitȱ theȱ measurementȱ ofȱ patientȬperceivedȱ sideȱ effectsȱ inȱ theȱ contextȱ ofȱ realȬlifeȱ practice,ȱ clinicalȱ trialsȱ andȱ otherȱ research.ȱ Theseȱ instrumentsȱ mayȱ alsoȱ provideȱ aȱ systematicȱ methodȱ forȱ theȱ explorationȱ ofȱ associationsȱ betweenȱ sideȱ effectȱ perceptionsȱ andȱ medicationȱ takingȱ behaviorȱ orȱ otherȱimportantȱhealthȬrelatedȱoutcomes.ȱFewȱdrugȱsideȱeffectȱquestionnairesȱexist,ȱ probablyȱdueȱtoȱtheȱlackȱofȱaȱclearlyȱdefinedȱmethodologyȱforȱtheȱdevelopmentȱofȱ suchȱcomplexȱinstruments.ȱThoseȱthatȱareȱfrequentlyȱcitedȱareȱpredominantlyȱusedȱ forȱ theȱ measurementȱ ofȱ psychoactiveȱ drugȱ sideȱ effectsȱ (Udvalgȱ forȱ Klinischeȱ Undersøgelserȱ (UKU),15;16ȱ Liverpoolȱ Universityȱ Neurolepticȱ Sideȱ Effectȱ Ratingȱ Scale)17ȱandȱmanyȱstillȱrequireȱfurtherȱvalidationȱwork.ȱ ȱ WeȱdevelopedȱtheȱInhaledȱCorticosteroidȱQuestionnaireȱ(ICQ)ȱusingȱaȱcombinationȱ ofȱ wellȬestablishedȱ methodsȱ fromȱ theȱ fieldsȱ ofȱ healthȱ statusȱ andȱ psychologicalȱ assessmentȱ scaleȱ development.18Ȭ20ȱ Inȱ ourȱ previousȱ workȱ weȱ usedȱ qualitativeȱ methodsȱtoȱgenerateȱtheȱ57ȱsideȱeffectȱitemsȱincludedȱinȱtheȱ15ȱdomainsȱofȱtheȱICQȱ (Tableȱ 2),ȱ andȱ inȱ subsequentȱ crossȬsectionalȱ testingȱ weȱ demonstratedȱ theȱ faceȱ validityȱ ofȱ theȱ scaleȱ inȱ 395ȱ inhalerȱ users.3ȱ Theȱ ICQȱ coversȱ aȱ rangeȱ ofȱ patientȬ perceivedȱ sideȱ effectsȱ includingȱ voice,ȱ throat,ȱ skinȱ andȱ moodȱ problems.ȱ Theȱ questionnaireȱ thenȱ underwentȱ linguisticȱ validationȱ forȱ translationȱ intoȱ 19ȱ languagesȱ (carriedȱ outȱ byȱ Mapiȱ France),ȱ withȱ internationalȱ harmonizationȱ andȱ cognitiveȱ debriefingȱ resultingȱ inȱ someȱ minorȱ changesȱ toȱ theȱ wordingȱ ofȱ theȱ originalȱ Englishȱ versionȱ (currentȱ questionnaireȱ onȱ ourȱ website).21ȱ Theȱ aimsȱ ofȱtheȱ twoȱ studiesȱ presentedȱ inȱ thisȱ currentȱ paperȱ areȱ fourȬfold.ȱ Inȱ theȱ firstȱ studyȱ weȱ empiricallyȱ constructȱ theȱ domainsȱ ofȱ theȱ ICQ,ȱ andȱ testȱ theȱ constructȱ validityȱ andȱ reliabilityȱofȱtheȱfullȱICQȱandȱrespectiveȱdomains.ȱInȱtheȱsecondȱstudyȱweȱexamineȱ theȱresponsivenessȱofȱtheȱquestionnaireȱtoȱchangeȱinȱICSȱdose.ȱȱ ȱ Methodsȱ Studyȱ1ȱ–ȱDomainȱconstruction,ȱconstructȱvalidityȱandȱreliabilityȱofȱtheȱICQȱȱ Ethicalȱapprovalȱwasȱnotȱrequiredȱforȱthisȱstudyȱwhichȱrequiredȱonlyȱquestionnaireȱ completion.ȱ

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ȱChapterȱ6.ȱAȱselfȬratingȱscaleȱforȱpatientȬperceivedȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Patientsȱ Contactableȱ patientsȱ fromȱ 3ȱ existingȱ Northȱ Netherlandsȱ asthmaȱ cohorts,ȱ withȱ aȱ physicianȱ diagnosisȱ ofȱ asthmaȱ andȱ hyperresponsiveȱ toȱ histamineȱ (30ȱ secondsȱ method;ȱPC20ȱ800ΐg).22ȱ Allȱ statedȱ ICSȱ dosesȱ areȱ BDPȱ equivalentȱ whereȱ 1ȱ ΐgȱ ofȱ beclomethasoneȱ dipropionate/budesonideȱ isȱ equivalentȱ toȱ 0.5ΐgȱ fluticasoneȱ propionateȱirrespectiveȱofȱdeliveryȱdeviceȱused.23;24ȱȱ ȱ Studyȱquestionnaireȱȱ Patientsȱ eachȱ completedȱ anȱ identicalȱ selfȬreportȱ questionnaireȱ atȱ home,ȱ whichȱ elicitedȱdataȱon:ȱ 1.ȱ Medicationȱ use:ȱ dailyȱ useȱ ofȱ inhaledȱ asthmaȱ medicationȱ (ICS,ȱ shortȬactingȱ Ά2Ȭ agonistȱ (SABA),ȱ longȬactingȱ Ά2Ȭagonistȱ (LABA));ȱ currentȱ useȱ ofȱ otherȱ steroidȱ medicationȱ(oralȱtablet,ȱnasal,ȱocular,ȱdermal,ȱeye,ȱearȱdropsȱorȱcreams);ȱprednisoneȱ coursesȱinȱpreviousȱthreeȱyears;ȱsteroidȱinjectionsȱinȱpreviousȱ6ȱmonths;ȱcurrentȱuseȱ ofȱadditionalȱprescribedȱmedications.ȱȱ 2.ȱInhalerȱbehavior:ȱspacerȱuse;ȱpostȬinhalationȱmouthȱrinsing.ȱ 3.ȱDateȱofȱstartingȱICS.ȱ 4.ȱPerceivedȱICSȱsideȱeffect:ȱInhaledȱCorticosteroidȱQuestionnaireȱ(ICQ).ȱ 5.ȱAsthmaȱseverityȱandȱhistory:ȱ6ȬitemȱAsthmaȱControlȱQuestionnaireȱ(ACQ)ȱ scoredȱ0Ȭ6ȱ(Forcedȱexpiratoryȱvolumeȱinȱoneȱsecond,ȱquestionȱomitted);25ȱnumberȱ ofȱemergencyȱGPȱappointmentsȱforȱasthmaȱinȱtheȱlastȱyear;ȱageȱasthmaȱdiagnosed.ȱ 6.ȱPersonality:ȱNeuroticismȱscaleȱofȱtheȱEysenckȱPersonalityȱQuestionnaireȱRevisedȱ Shortȱ Scaleȱ (EPQȬRSS)ȱ scoredȱ 0Ȭ12;26ȱ Negativeȱ affectȱ scaleȱ ofȱ theȱ Positiveȱ andȱ NegativeȱAffectȱScheduleȱ(PANAS)ȱscoredȱ10Ȭ50.27ȱ 7.ȱPatientȱdemographics:ȱage;ȱgender;ȱsmokingȱstatus;ȱeducationalȱlevel.ȱȱ Allȱreturnedȱquestionnairesȱwereȱcheckedȱforȱmissingȱresponsesȱorȱinconsistencies,ȱ andȱqueriesȱwereȱresolvedȱwithȱtheȱpatientȱbyȱtelephone.ȱȱ ȱ ICQȱdomainȱconstructionȱprocedureȱandȱanalysisȱ Weȱ choseȱ initialȱ factorsȱ withȱ anȱ eigenvalueȱ ofȱ greaterȱ thanȱ 1ȱ inȱ principleȱ componentȱ analysisȱ whichȱ wereȱ aboveȱ theȱ inflectionȱ pointȱ ofȱ theȱ Cattellȱ Screeȱ plot.28ȱ Subsequentlyȱ interȬitemȱ correlationsȱ ofȱ ǃ0.50ȱ wereȱ identifiedȱ toȱ clusterȱ remainingȱitems.ȱ ȱ ICQȱendorsementȱandȱscalingȱprocedureȱandȱanalysisȱ Theȱpercentageȱofȱpatientsȱendorsingȱ(scoringȱǃ1ȱonȱtheȱscale)ȱeachȱICQȱitemȱandȱ usingȱeachȱresponseȱoptionȱwasȱcalculated.ȱ

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ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Constructȱvalidityȱprocedureȱ Weȱ usedȱ crossȬsectionalȱ constructȱ validityȱ toȱ testȱ theȱ validityȱ ofȱ theȱ ICQ.ȱ Theȱ constructȱ validityȱ methodȱ isȱ appliedȱ whenȱ developingȱ aȱ testȱ ofȱ aȱ constructȱ (‘construct’ȱrefersȱtoȱtheȱmeasuredȱcharacteristicȱȬȱinȱthisȱcaseȱperceivedȱsideȱeffect)ȱ forȱ whichȱ noȱ otherȱ measureȱ exists.ȱ Constructȱ validityȱ canȱ beȱ undertakenȱ byȱ generatingȱ andȱ empiricallyȱ testingȱ aȱ numberȱ ofȱ hypotheses,ȱ basedȱ onȱ whatȱ isȱ alreadyȱ knownȱ aboutȱ theȱ construct.19ȱ Weȱ developedȱ theȱ followingȱ hypothesesȱ basedȱonȱtheirȱsupportingȱrationales:ȱ ȱ Rationaleȱ 1:ȱ Theȱ literatureȱ suggestsȱ thatȱ aȱ doseȬresponseȱ canȱ beȱ expectedȱ forȱ sideȱ effectsȱ relatedȱ toȱ theȱ useȱ ofȱ ICS,ȱ withȱ sideȱ effectsȱ mostȱ likelyȱ toȱ occurȱ inȱ higherȱ doses.6ȱ Hypothesisȱ 1:ȱ Thereȱ isȱ aȱ hierarchicalȱ doseȬresponseȱ patternȱ forȱ prevalenceȱ ofȱ theȱ individualȱitemsȱonȱtheȱICQȱandȱstatisticallyȱsignificantȱhierarchicalȱdifferencesȱinȱ scoresȱforȱeachȱofȱtheȱ15ȱdomainsȱȬȱwithȱtheȱhighȱICSȱdoseȱgroupȱscoringȱhighestȱonȱ theȱICQ.ȱ ȱ Rationaleȱ2:ȱAȱscaleȱmeasuringȱcurrentȱsideȱeffectsȱofȱICSȱshouldȱbeȱpredictedȱbyȱtheȱ currentȱdoseȱofȱICSȱused.ȱHowever,ȱdiseaseȱseverityȱmightȱalsoȱbeȱassociatedȱwithȱ greaterȱ ICQȱ scoring.ȱ Thus,ȱ inȱ orderȱ toȱ demonstrateȱ thatȱ ICQȱ scoresȱ areȱ predictedȱ byȱ ICSȱ dose,ȱ irrespectiveȱ ofȱ severity,ȱ theȱ ICQȱ scoresȱ ofȱ patientsȱ withȱ wellȬ controlledȱ(mild)ȱdiseaseȱmustȱstillȱbeȱindependentlyȱassociatedȱwithȱICSȱdose.ȱ Hypothesisȱ 2:ȱ ICSȱ doseȱ independentlyȱ predictsȱ ICQȱ scoringȱ afterȱ adjustingȱ forȱ confounders,ȱanȱassociationȱwhichȱremainsȱinȱpatientsȱwithȱhomogenousȱdisease.ȱ ȱ Rationaleȱ 3:ȱ Localȱ sideȱ effectsȱ areȱ causedȱ byȱ theȱ actionȱ ofȱ steroidȱ inȱ theȱ oralȬ pharyngealȱspace,ȱwhereasȱsystemicȱsideȱeffectsȱoccurȱdueȱtoȱsteroidȱabsorbedȱintoȱ theȱsystemicȱcirculation.ȱTheseȱdisparateȱmechanismsȱsuggestȱstrongerȱassociationsȱ amongȱ itemsȱ inȱ domainsȱ withȱ aȱ potentiallyȱ homogeneousȱ routeȱ ofȱ actionȱ thanȱ thoseȱwithȱaȱpotentiallyȱheterogeneousȱrouteȱofȱaction.ȱ Hypothesisȱ 3:ȱ Thereȱ isȱ greaterȱ convergenceȱ (thatȱ is,ȱ strongerȱ association)ȱ amongȱ itemsȱinȱICQȱdomainsȱcausedȱbyȱaȱpotentiallyȱhomogenousȱrouteȱofȱactionȱ(e.g.ȱtheȱ localȱsideȱeffectȱdomainsȱ‘Voice’ȱandȱ‘Oropharynxȱproblems’)ȱthanȱamongȱitemsȱinȱ domainsȱcausedȱbyȱheterogeneousȱroutesȱ(e.g.ȱ‘OropharynxȱProblems’ȱversusȱICQȱ sideȱ effectȱ domainsȱ thoughtȱ toȱ beȱ causedȱ systemicallyȱ e.g.ȱ ‘Moodȱ Problems’ȱ andȱ ‘Skin,ȱHairȱandȱNails’ȱdomains).ȱ ȱ Constructȱvalidityȱanalysesȱ Usingȱunivariateȱanalyses,ȱweȱexploredȱdifferencesȱinȱICQȱscoresȱbetweenȱtheȱfourȱ ICSȱ doseȱ groupsȱ (Hypothesisȱ 1).ȱ Weȱ alsoȱ exploredȱ differencesȱ inȱ otherȱ studyȱ variables,ȱ betweenȱ theȱ fourȱ ICSȱ doseȱ groups,ȱ inȱ orderȱ toȱ identifyȱ potentialȱ confoundingȱvariablesȱ(pȬvaluesȱǂ0.10),ȱalongsideȱthoseȱpredictedȱbyȱtheȱresearchȱ literature,ȱ forȱ subsequentȱ regressionȱ analysisȱ (Hypothesisȱ 2).ȱ NonȬnormallyȱ distributedȱ variablesȱ wereȱ analyzedȱ usingȱ appropriateȱ nonȬparametricȱ tests,ȱ andȱ forȱ uniformityȱ onlyȱ theȱ nonȬparametricȱ resultsȱ areȱ reportedȱ asȱ parametricȱ testȱ resultsȱwereȱsimilar.ȱPrevalenceȱ(scoresȱ>0)ȱofȱtheȱ57ȱitemsȱonȱtheȱICQȱwereȱplottedȱ ontoȱ graphsȱ toȱ showȱ theȱ doseȬresponseȱ patternȱ inȱ reporting.ȱ Medianȱ (IQR)ȱ scoreȱ 128ȱ ȱ

ȱChapterȱ6.ȱAȱselfȬratingȱscaleȱforȱpatientȬperceivedȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

andȱprevalenceȱ(scoresȱ>0)ȱwereȱalsoȱtabulatedȱforȱtheȱtotalȱscoreȱandȱeachȱdomainȱ ofȱtheȱICQ.ȱ ȱ Aȱ multiȬtraitȱ correlationȱ matrixȱ ofȱ theȱ domainsȱ ofȱ theȱ ICQȱ wasȱ calculatedȱ toȱ determineȱ theȱ associationȱ amongȱ itemsȱ inȱ domainsȱ predictedȱ toȱ beȱ causedȱ viaȱ systemicȱorȱlocalȱroutesȱofȱactionȱ(Hypothesisȱ3).ȱȱ ȱ Linearȱ regressionȱ analysisȱ wasȱ carriedȱ outȱ toȱ determineȱ theȱ extentȱ toȱ whichȱ theȱ totalȱICQȱscoreȱcouldȱbeȱexplainedȱbyȱdailyȱICSȱdoseȱafterȱadjustingȱforȱpotentialȱ confounders.ȱAllȱvariablesȱwereȱcheckedȱforȱnormalityȱpriorȱtoȱregressionȱanalysis.ȱ GivenȱthatȱICQȱscoresȱwereȱskewedȱwithȱmanyȱzeroȱvaluesȱweȱtookȱnaturalȱlogsȱofȱ theȱtotalȱICQȱscoreȱhavingȱinitiallyȱaddedȱ0.5ȱtoȱeachȱscore.ȱThisȱthenȱservedȱasȱtheȱ dependentȱvariableȱinȱaȱmultivariateȱmodel.ȱInȱtheȱregressionȱmodelȱindependentȱ variablesȱ wereȱ ICSȱ doseȱ group,ȱ ACQȱ scoreȱ andȱ variablesȱ forȱ whichȱ potentialȱ confoundingȱwasȱindicated.ȱICSȱdoseȱgroupȱandȱACQȱscoreȱwereȱfirstȱenteredȱintoȱ theȱ modelȱ followedȱ byȱ eachȱ singleȱ independentȱ confounderȱ inȱ orderȱ toȱ establishȱ whichȱ variablesȱ showedȱ independentȱ associationsȱ withȱ ICQȱ score.ȱ Finallyȱ aȱ stepwiseȱ procedureȱ wasȱ employedȱ (followingȱ entryȱ ofȱ ICSȱ doseȱ groupȱ andȱ ACQȱ score)ȱallowingȱsimultaneousȱentryȱofȱtheȱindependentȱconfounders.ȱThisȱanalysisȱ wasȱ subsequentlyȱ repeatedȱ inȱ thoseȱ patientsȱ withȱ wellȬcontrolledȱ asthmaȱ asȱ determinedȱbyȱtheȱACQȱquestionnaireȱ(totalȱACQȱscoreȱǂ0.75).25ȱȱ ȱ ReliabilityȱȬȱreproducibilityȱprocedureȱandȱanalysisȱ TestȬretestȱ reliabilityȱ assessesȱ theȱ stabilityȱ ofȱ aȱ scaleȱ forȱ producingȱ reproducibleȱ resultsȱ overȱ time.ȱ SeventyȬsixȱ randomlyȱ selectedȱ constructȱ validityȱ patients,ȱ whoȱ wereȱ currentlyȱ usingȱ anȱ ICSȱ inhaler,ȱ completedȱ aȱ secondȱ questionnaireȱ afterȱ 7ȱ days.ȱTheȱ7ȬdayȱquestionnaireȱincludedȱtheȱICQȱscale,ȱtheȱ6ȬitemȱACQ,ȱquestionsȱ onȱ medicationȱ changeȱ inȱ theȱ lastȱ 7ȱ days,ȱ ICQȱ completionȱ timeȱ (responseȱ options:ȱ lessȱthanȱ10ȱminutes,ȱ10Ȭ15ȱminutes;ȱ16Ȭ20ȱminutes;ȱmoreȱthanȱ20ȱminutes),ȱmissingȱ sideȱ effectsȱ notȱ includedȱ inȱ theȱ scaleȱ andȱ perceivedȱ difficultyȱ ofȱ theȱ ICQȱ scaleȱ (responseȱoptions:ȱveryȱdifficult;ȱdifficult;ȱnotȱdifficult;ȱeasy;ȱveryȱeasy).ȱExcludedȱ patientsȱ reportedȱ aȱ changeȱ inȱ theirȱ ICSȱ useȱ orȱ inȱ anyȱ otherȱ medicationȱ fromȱ baselineȱ measurement.ȱ Intraclassȱ correlationȱ coefficientsȱ (ICC)ȱ betweenȱ baselineȱ andȱfollowȬupȱICQȱscoresȱwereȱcalculatedȱtoȱassessȱreproducibility.ȱȱ ȱ ReliabilityȱȬȱinternalȱconsistencyȱprocedureȱandȱanalysisȱ Cronbach’sȱalphaȱcoefficientȱandȱitemȬtotalȱcorrelationsȱwereȱcalculatedȱtoȱtestȱtheȱ internalȱconsistencyȱofȱtheȱICQ.ȱȱ ȱ Studyȱ2ȱȬȱResponsivenessȱofȱtheȱICQȱtoȱchangesȱinȱICSȱuseȱ Ethicalȱ approvalȱ forȱ thisȱ studyȱ wasȱ obtainedȱ fromȱ Grampianȱ Researchȱ Ethicsȱ Committee.ȱDutchȱethicalȱapprovalȱwasȱsoughtȱbutȱnotȱrequired.ȱ ȱ Patientsȱ Generalȱ Practitionersȱ andȱ Pulmonologistsȱ inȱ Northȱ Netherlandsȱ andȱ Aberdeenȱ Scotland,ȱ invitedȱ byȱ letter,ȱ agreedȱ toȱ recruitȱ patientsȱ duringȱ anyȱ normalȱ consultationȱwhichȱresultedȱinȱstarting,ȱincreasingȱorȱdecreasingȱtheirȱpatientsȱICSȱ 129ȱ

Partȱ3.ȱOriginalȱresearchȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

doseȱ byȱ atȱ leastȱ 400ΐg.ȱ Patientsȱ wereȱ includedȱ inȱ twoȱ countriesȱ toȱ improveȱ recruitmentȱ numbersȱ andȱ provideȱ aȱ representativeȱ sampleȱ ofȱ inhalerȱ users.ȱ Physiciansȱinformedȱtheȱresearchersȱofȱtheȱpatients’ȱoldȱandȱnewȱICSȱprescriptions.ȱ Eligibleȱpatientsȱwereȱcurrentȱinhalerȱusersȱwithȱphysicianȱdiagnosedȱasthma,ȱwhoȱ gaveȱ informedȱ consent,ȱ wereȱ agedȱ ǃ16ȱ years,ȱ hadȱ notȱ usedȱ oralȱ steroidsȱ inȱ theȱ previousȱ3ȱmonths,ȱreceivedȱnoȱchangeȱinȱtheirȱICSȱprescriptionȱforȱ3ȱmonthsȱpriorȱ toȱ theȱ studyȱ andȱ receivedȱ noȱ furtherȱ changeȱ duringȱ theȱ 6ȱ monthsȱ ofȱ theȱ studyȱ (subsequentȱtoȱtheȱphysicianȬinstigatedȱdoseȱchangeȱatȱstudyȱentry).ȱȱ ȱ Responsivenessȱprocedureȱ ParticipantsȱcompletedȱaȱselfȬreportȱquestionnaireȱatȱbaselineȱandȱfollowȱupȱ(2ȱandȱ 6ȱmonthsȱafterȱICSȱchange),ȱwhichȱmeasured:ȱICQ;ȱ6ȬitemȱACQȱ(Forcedȱexpiratoryȱ volumeȱ inȱ oneȱ second,ȱ questionȱ omitted);ȱ Asthmaȱ Qualityȱ ofȱ Lifeȱ Questionnaireȱ (AQLQ(S));29ȱ dailyȱ ICSȱ useȱ andȱ patientȱ characteristics.ȱ Weȱ hypothesizedȱ thatȱ anyȱ changeȱinȱICSȱdoseȱ(higherȱorȱlower),ȱwouldȱbeȱassociatedȱwithȱaȱreciprocalȱchangeȱ inȱgroupȱsideȱeffectȱscores,ȱforȱtheȱtotalȱandȱdomainȱscoresȱofȱtheȱICQ.ȱ ȱ Responsivenessȱanalysisȱ Weȱ comparedȱ differencesȱ inȱ ICQ,ȱ ACQȱ andȱ AQLQ(S)ȱ scoresȱ atȱ 2ȱ andȱ 6ȱ monthsȱ fromȱbaselineȱusingȱtheȱWilcoxonȱtest.ȱTheȱICQȱscoresȱofȱpatientsȱwhoȱreceivedȱaȱ decreaseȱinȱdoseȱwereȱreversedȱtoȱanalyzeȱabsoluteȱchangeȱfromȱbaselineȱatȱ2ȱandȱ6ȱ monthsȱinȱtheȱwholeȱsampleȱsimultaneously.ȱWeȱproducedȱaȱboxȱplotȱofȱchangeȱinȱ totalȱ ICQȱ scoresȱ (theȱ differenceȱ (delta,ȱ NJ)ȱ betweenȱ ICQȱ medianȱ totalȱ scoreȱ atȱ baselineȱandȱfollowȬup)ȱbyȱICSȱdoseȱchangeȱgroupȱ(increasedȱICSȱversusȱdecreasedȱ ICS).ȱAllȱstatisticalȱanalysesȱinȱthisȱarticleȱwereȱperformedȱwithȱSPSSȱversionȱ11.0ȱ (SPSSȱInc.,ȱChicago,ȱIL,ȱU.S.A.).ȱȱ ȱ Resultsȱȱ Studyȱ1ȱ–ȱDomainȱconstruction,ȱconstructȱvalidityȱandȱreliabilityȱofȱtheȱICQȱȱ Patientsȱ Ofȱ 784ȱ patientsȱ invited,ȱ 90%ȱ respondedȱ (n=704).ȱ 318ȱ wereȱ notȱ eligibleȱ (noȱ inhalerȱ n=239;ȱ oralȱ orȱ injectedȱ steroidȱ n=44;ȱ ǃ20ȱ packȱ yearsȱ n=25;ȱ questionnaireȱ returnedȱ afterȱclosingȱdateȱn=8;ȱquestionnaireȱnotȱfilledȱinȱadequatelyȱn=2).ȱ131ȱdidȱnotȱwishȱ toȱ participate,ȱ leavingȱ 255ȱ eligibleȱ patientsȱ forȱ analysisȱ (seeȱ Tableȱ 1ȱ forȱ patientȱ characteristics).ȱTheȱ131ȱnonȬparticipantsȱwereȱofȱsimilarȱageȱ(medianȱ(IQR)ȱ38ȱ(26Ȭ 49))ȱ andȱ genderȱ (49%ȱ male)ȱ toȱ theȱ 255ȱ participantsȱ includedȱ inȱ theȱ studyȱ (ageȱ 42ȱ (33Ȭ50);ȱ44%ȱmale).ȱ ICQȱdomainȱconstructionȱ Eightȱ factorsȱ wereȱ identifiedȱ usingȱ eigenvaluesȱ andȱ theȱ Cattellȱ Screeȱ plot.ȱ Fourȱ itemsȱ wereȱ constructedȱ intoȱ 2ȱ additionalȱ domainsȱ usingȱ interȬitemȱ correlations,ȱ leavingȱtheȱremainingȱ5ȱitemsȱtoȱbeȱformedȱintoȱsingleȬitemȱdomains.ȱTheȱfinalȱ14Ȭ dayȱICQȱquestionnaireȱthereforeȱconsistsȱofȱ15ȱdomainsȱ(seeȱTableȱ2).ȱ ȱ ICQȱscoringȱ Theȱ ICQȱ wasȱ scoredȱ onȱ anȱ itemȱ levelȱ fromȱ 0ȱ (notȱ atȱ all)ȱ toȱ 6ȱ (aȱ veryȱ greatȱ deal)ȱ otherȱresponseȱoptionsȱbeing:ȱ1ȱ(aȱveryȱlittle),ȱ2ȱ(aȱlittle),ȱ3ȱ(aȱmoderateȱamount),ȱ4ȱ 130ȱ ȱ

ȱChapterȱ6.ȱAȱselfȬratingȱscaleȱforȱpatientȬperceivedȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

(quiteȱaȱlot),ȱ5ȱ(aȱgreatȱdeal).ȱInȱorderȱthatȱdomainȱscoresȱwithȱdifferingȱnumbersȱofȱ itemsȱcouldȱbeȱcompared,ȱtheȱ15ȱdomainȱscoresȱwereȱtransformedȱintoȱaȱscoreȱoutȱ ofȱ100ȱ((Rawȱdomainȱscoreȱ/ȱ(6ȱ*ȱno.ȱitemsȱinȱdomain))ȱ*100).ȱTheȱtotalȱscoreȱofȱtheȱ ICQȱ(0Ȭ100)ȱwasȱtheȱaverageȱofȱtheȱ15ȱdomainȱscoresȱ(sumȱtheȱscoresȱofȱ15ȱdomainsȱ /ȱ15).ȱTheȱhighestȱscoreȱrepresentsȱtheȱgreatestȱsideȱeffect.ȱ ȱ Endorsementȱandȱscalingȱȱ Endorsementȱfrequencyȱ(i.e.ȱtheȱpercentageȱofȱpatientsȱscoringȱǃ1)ȱforȱtheȱ57ȱitemsȱ inȱ theȱ ICQȱ scaleȱ rangedȱ fromȱ 13%ȱ toȱ 64%.ȱ Endorsementȱ frequencyȱ wasȱ lessȱ thanȱ theȱrecommendedȱ20%18ȱforȱ4ȱitemsȱonȱtheȱscale:ȱ‘oralȱthrush’ȱ(13%),ȱ‘lossȱofȱabilityȱ toȱtaste’ȱ(19%),ȱ‘aȱlossȱofȱappetite’ȱ(15%)ȱandȱ‘swollenȱfaceȱorȱfluidȱaroundȱtheȱface’ȱ (15%).ȱ Notwithstandingȱ this,ȱ weȱ leftȱ theȱ 4ȱ itemsȱ in,ȱ sinceȱ weȱ recommendȱ aȱ lessȱ stringentȱ approachȱ toȱ itemȱ endorsementȱ forȱ aȱ sideȱ effectȱ scaleȱ whereȱ evenȱ lowȱ percentagesȱ ofȱ reportingȱ onȱ theȱ groupȱ levelȱ mightȱ beȱ ofȱ significantȱ clinicalȱ importance.ȱWithȱrespectȱtoȱscalingȱ(thatȱis,ȱtheȱuseȱofȱeachȱofȱtheȱsevenȱresponseȱ optionsȱ onȱ theȱ ICQȱ Likertȱscaleȱ e.g.ȱ“notȱ atȱ all”ȱ toȱ“aȱ veryȱ greatȱ deal”),ȱ noȱ singleȱ responseȱoptionȱforȱtheȱICQȱscaleȱwasȱrespondedȱtoȱbyȱǃ95%ȱofȱparticipants.ȱȱ ȱ Constructȱvalidityȱ AȱnumberȱofȱvariablesȱshowedȱaȱlinearȱrelationshipȱwithȱICSȱdoseȱgroupȱ(Tableȱ1);ȱ whichȱmayȱhaveȱconfoundedȱscoringȱonȱtheȱICQ.ȱTheseȱvariablesȱwereȱage,ȱasthmaȱ control,ȱ emergencyȱ GPȱ appointmentsȱ forȱ asthmaȱ inȱ lastȱ year,ȱ educationalȱ level,ȱ numberȱofȱdailyȱpuffsȱofȱSABA,ȱdailyȱdoseȱofȱLABA,ȱcoursesȱofȱprednisoloneȱinȱtheȱ lastȱ3ȱyears,ȱnumberȱofȱconcomitantlyȱprescribedȱmedications,ȱnegativeȱaffectivityȱ scoreȱandȱuseȱofȱaȱspacerȱdevice.ȱVariablesȱwhichȱshowedȱnoȱlinearȱtrend,ȱbutȱwereȱ potentialȱ confoundersȱ indicatedȱ byȱ theȱ researchȱ literature,ȱ wereȱ gender,ȱ smokingȱ status,ȱuseȱofȱnasalȱsteroids,ȱneuroticismȱscoreȱandȱmouthȱrinsingȱafterȱinhalation.ȱ Ageȱ whenȱ asthmaȱ diagnosed,ȱ numberȱ ofȱ comorbidities,ȱ andȱ rhinitisȱ diagnosis,ȱ wereȱ alsoȱ assessedȱ (dataȱ notȱ shown)ȱ butȱ wereȱ notȱ significantlyȱ differentȱ betweenȱ groups.ȱȱ ȱ Hypothesisȱ 1.ȱ Aȱ doseȬresponseȱ wasȱ observedȱ forȱ allȱ 57ȱ itemsȱ onȱ theȱ ICQ,ȱ whenȱ comparingȱ highȱ versusȱ lowȱ doseȱ ICSȱ groupsȱ (Figuresȱ 1ȱ toȱ 2).ȱ Howeverȱ theȱ midȬ doseȱ groupȱ showedȱ aȱ lowerȱ prevalenceȱ thanȱ theȱ lowȬdoseȱ ICSȱ groupȱ inȱ theȱ ‘Unpleasantȱ Taste’ȱ domainȱ (itemsȱ 29,ȱ 30,ȱ 31,ȱ 38,ȱ 39),ȱ ‘Oropharynxȱ Problems’ȱ domainȱ (itemȱ 15)ȱ andȱ theȱ ‘Tasteȱ Disruption’ȱ domainȱ (itemsȱ 32,ȱ 33,ȱ 35).ȱ ICQȱ totalȱ andȱdomainȱscoresȱshowedȱhierarchicalȱdifferencesȱbetweenȱdoseȱgroupsȱ(withȱtheȱ highestȱscoringȱinȱtheȱhighȱdoseȱICSȱgroup)ȱthatȱwereȱstatisticallyȱsignificantȱforȱ14ȱ ofȱtheȱ15ȱdomainsȱ(Tableȱ3).ȱOnlyȱtheȱ‘VisionȱDeterioration’ȱdomainȱdidȱnotȱreachȱ statisticalȱsignificanceȱinȱthisȱsample,ȱalthoughȱthereȱwasȱaȱsuggestionȱofȱanȱeffectȱ (p=0.066).ȱȱ

131ȱ

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ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Tableȱ1.ȱPatientȱcharacteristicsȱandȱdemographicsȱbyȱICSȱdailyȱdoseȱgroupȱȱ ȱ Variableȱ ȱ ȱ ȱ

Totalȱȱ Sampleȱ ȱ n=255ȱ

Ageȱ(years)ȱȱ

42ȱ(33Ȭ50)ȱ 33ȱ(28Ȭ39)ȱ 40ȱ(32Ȭ51)ȱ 47ȱ(37Ȭ50)ȱ 42ȱ(33Ȭ50)ȱ 0.005ȱ

%ȱmaleȱ 44ȱ Smokingȱ ȱ %ȱcurrentȱorȱpastȱsmokersȱ 44ȱ Packȱyearsaȱ 0ȱ(0Ȭ3)ȱ Asthmaȱseverityȱ ȱ Asthmaȱcontrolȱquestionnaireȱ 0.8ȱȱ (ACQ)ȱscoreȱ(0Ȭ6)ȱ (0.3Ȭ1.5)ȱ No.ȱemergencyȱGPȱappointmentsȱ ȱ forȱasthmaȱinȱlastȱyearȱ %ȱnoneȱ/ȱ%ȱǃ1ȱȱȱ 80ȱ/ȱ20ȱ Educationalȱlevelȱachievedȱ ȱ %ȱPrimaryȱandȱlowerȱvocationalȱ 34ȱ %ȱSecondary/intermediateȱ ȱ vocationalȱ 38ȱ %ȱHigherȱvocational/universityȱ 28ȱ Useȱofȱasthmaȱmedicationȱ ȱ No.ȱofȱdailyȱpuffsȱSABAȱȱ ȱ %ȱnoneȱ/ȱ%ȱ1Ȭ2ȱ/ȱ%ȱǃ3ȱ 69ȱ/ȱ24ȱ/ȱ7ȱ Dailyȱequivalentȱdose†ȱofȱLABAcȱ ȱ %0ȱΐgȱ/ȱ%1Ȭ200ΐgȱ 39ȱ/ȱ61ȱ No.ȱofȱcoursesȱofȱprednisoloneȱinȱ ȱ lastȱ3ȱyearscȱ %ȱnoneȱ/ȱ%1Ȭ2ȱ/ȱ%ǃ3ȱ 57ȱ/ȱ27ȱ/ȱ16 %ȱcurrentlyȱusingȱnasalȱsteroidsȱȱ 25ȱ %ȱcurrentlyȱusingȱdermalȱorȱ ȱ ocularȱsteroidsȱ 6ȱ No.ȱofȱotherȱconcomitantlyȱ ȱ prescribedȱmedicationsȱȱ %ȱnoneȱ/ȱ%1Ȭ2ȱ/ȱ%ǃ3ȱ 37ȱ/ȱ42ȱ/ȱ21 Personalityȱ ȱ Negativeȱaffectivityȱscoreȱ(10Ȭ50)ȱ 17ȱ(14Ȭ22)ȱ Neuroticismȱscoreȱscoreȱ(0Ȭ12)dȱ 4ȱ(2Ȭ7)ȱ Inhalerȱbehaviorȱ ȱ %ȱrinsingȱmouthȱafterȱinhalationeȱ ȱ %ȱusingȱspacerȱdeviceȱȱ ȱ %ȱuseȱofȱICSȱ7ȱdaysȱperȱweekȱ(adherent)bȱ

Nonȱȱ ICSȱ Inhalerȱ n=27ȱ

Lowȱdoseȱ ICSȱ ǂ400ΐgȱ n=61ȱ

Midȱdoseȱ ICSȱ 401Ȭ800ΐg n=62ȱ

Highȱdoseȱ pȬvalueȱ ICSȱ ȱ >800ΐgȱ ȱ n=105ȱ ȱ

44ȱ ȱ 37ȱ 0ȱ(0Ȭ2)ȱ ȱ 1.2ȱȱ (0.5Ȭ1.7)ȱ ȱ

51ȱ ȱ 44ȱ 0ȱ(0Ȭ4)ȱ ȱ 0.5ȱȱ (0.2Ȭ1.3)ȱ ȱ

44ȱ ȱ 47ȱ 0ȱ(0Ȭ4)ȱ ȱ 0.7ȱȱ (0.3Ȭ1.2)ȱ ȱ

40ȱ ȱ 43ȱ 0ȱ(0Ȭ2)ȱ ȱ 0.8ȱȱ (0.3Ȭ1.7)ȱ ȱ

0.295*ȱ ȱ 0.775*ȱ 0.782ȱ ȱ ȱ 0.075ȱ ȱ

85ȱ/ȱ15ȱ ȱ 26ȱ ȱ 33ȱ 41ȱ ȱ ȱ 22ȱ/ȱ59ȱ/ȱ19 ȱ 89ȱ/ȱ11ȱ ȱ

87ȱ/ȱ13ȱ ȱ 31ȱ ȱ 33ȱ 36ȱ ȱ ȱ 79ȱ/ȱ20ȱ/ȱ1ȱ ȱ 53ȱ/ȱ47ȱ ȱ

84ȱ/ȱ16ȱ ȱ 34ȱ ȱ 47ȱ 19ȱ ȱ ȱ 84ȱ/ȱ10ȱ/ȱ6ȱ ȱ 33ȱ/ȱ67ȱ ȱ

73ȱ/ȱ27ȱ ȱ 37ȱ ȱ 37ȱ 26ȱ ȱ ȱ 68ȱ/ȱ25ȱ/ȱ7ȱ ȱ 20ȱ/ȱ80ȱ ȱ

0.034ȱ ȱ ȱ ȱ

74ȱ/ȱ19ȱ/ȱ7ȱ 7ȱ ȱ 7ȱ ȱ

64ȱ/ȱ27ȱ/ȱ9ȱ 28ȱ ȱ 10ȱ ȱ

58ȱ/ȱ27ȱ/ȱ15 31ȱ ȱ 2ȱ ȱ

49ȱ/ȱ29ȱ/ȱ22ȱ 0.002¶ȱ 25ȱ 0.296*ȱ ȱ ȱ 5ȱ 0.291*¶ȱ ȱ ȱ

52ȱ/ȱ30ȱ/ȱ18 ȱ 14ȱ(13Ȭ20)ȱ 4ȱ(1Ȭ7)ȱ ȱ ȱ ȱ ȱ

39ȱ/ȱ48ȱ/ȱ13 ȱ 15ȱ(13Ȭ21)ȱ 3ȱ(1Ȭ6)ȱ ȱ 75ȱ 2ȱ 82ȱ

34ȱ/ȱ48ȱ/ȱ18 ȱ 17ȱ(14Ȭ21)ȱ 4ȱ(2Ȭ6)ȱ ȱ 82ȱ 7ȱ 90ȱ

34ȱ/ȱ39ȱ/ȱ27ȱ 0.048ȱ ȱ ȱ 17ȱ(15Ȭ24)ȱ 0.09ȱ 4ȱ(1Ȭ7)ȱ 0.727*ȱ ȱ ȱ 77ȱ 0.928*ȱ 15ȱ 0.003ȱ 99ȱ ǂȱ0.001ȱ

0.070ȱ ȱ ȱ 0.049¶ȱ ȱ ǂȱ0.001ȱ ȱ

Allȱvariablesȱ%ȱorȱmedianȱ(IQR),ȱtestedȱwithȱChiȬsquareȱ(pȬvalueȱlinearȱtrend)ȱorȱKruskalȬWallisȱexceptȱ ¶ȱ FishersȱExactȱTestȱ(pȬ valueȱlinearȱtrend).ȱ *Variableȱenteredȱintoȱregressionȱdueȱtoȱpotentialȱconfoundingȱindicatedȱbyȱresearchȱliterature.ȱ Variableȱnotȱenteredȱintoȱregressionȱasȱ avariableȱ‘currentȱorȱpastȱsmokers’ȱenteredȱintoȱmodelȱ bvariableȱusedȱtoȱcalculateȱ Pgȱdailyȱ ICSȱdose.ȱ Missingȱdata:ȱcȱn=7ȱdn=2,ȱen=1.ȱ †Salmeterolȱequivalentȱdose:ȱ4ΐgȱsalmeterolȱ=ȱ1ΐgȱformoterolȱ(4%ȱofȱtotalȱsampleȱusedȱ>100ΐgȱdaily).ȱ

132ȱ ȱ

ȱChapterȱ6.ȱAȱselfȬratingȱscaleȱforȱpatientȬperceivedȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Tableȱ2.ȱTheȱ15ȱdomainsȱandȱ57ȱitemsȱofȱtheȱICQȱscale*ȱ ȱ VoiceȱProblemsȱȬȱ15ȱitems:ȱ x hoarsenessȱofȱtheȱvoiceȱ x aȱ‘rough’ȱvoiceȱ x aȱnoticeableȱchangeȱtoȱyourȱvoiceȱ x yourȱvoiceȱfeelingȱsimilarȱtoȱhowȱyourȱvoiceȱfeelsȱ whenȱrecoveringȱfromȱtheȱfluȱ x yourȱvoiceȱfeelingȱlikeȱitȱhadȱ‘goneȱtoȱtheȱbackȱofȱ yourȱthroat’ȱ x notȱbeingȱableȱtoȱsingȱ x lossȱofȱspeechȱvolumeȱsoȱthatȱyouȱcouldn’tȱtalkȱasȱ loudlyȱasȱnormalȱ x aȱfeelingȱofȱexhaustionȱwhenȱtalkingȱ x aȱpainfulȱthroatȱwhenȱtalkingȱ x aȱfeelingȱthatȱotherȱpeopleȱcouldn’tȱunderstandȱ yourȱspeechȱbecauseȱyouȱspeakȱtooȱsoftlyȱorȱnotȱ clearlyȱenoughȱ x aȱbreakingȱvoiceȱ x aȱ‘rough’ȱthroatȱ x aȱsoreȱthroatȱ x anȱunpleasantȱfeelingȱinȱyourȱthroatȱ x aȱdryȱthroatȱ

ȱ ȱ ȱ ȱ

ȱ UnpleasantȱTasteȱȬȱ7ȱitems:ȱ x aȱterribleȱtasteȱinȱyourȱmouthȱ x aȱ‘taste’ȱonȱtheȱteethȱ x aȱ‘badȱtaste’ȱorȱunfreshȱfeelingȱinȱyourȱmouthȱ x badȱbreathȱ x wantingȱtoȱrinseȱyourȱmouthȱ x wantingȱtoȱbrushȱyourȱteethȱ x wantingȱtoȱchewȱgumȱ ȱ Skin,ȱHairȱandȱNailsȱȬȱ7ȱitems:ȱ x dryȱskinȱ x dryȱskinȱonȱtheȱfaceȱ x bruisingȱeasilyȱ x bruisesȱthatȱareȱpainfulȱforȱaȱlongȱperiodȱ x thinnerȱskinȱorȱlessȱflexibilityȱinȱyourȱskinȱ x brittleȱnails,ȱorȱyourȱnailsȱbreakingȱeasilyȱ x hairȱlossȱ

ȱ ȱ

TasteȱDisruptionȱȬȱ3ȱitems:ȱ x aȱchangeȱinȱyourȱabilityȱtoȱtasteȱȱ x aȱlossȱofȱabilityȱtoȱtasteȱȱ x aȱlossȱofȱappetiteȱȱ

ȱ ȱ ȱ

PerspirationȱȬȱ2ȱitems:ȱ x sweatingȱȱȱ x sweatingȱduringȱtheȱnightȱȱ

ȱ ȱ ȱ ȱ ȱ ȱ

OropharyngealȱItchingȱȬȱ2ȱitems:ȱ x anȱitchyȱfeelingȱonȱtheȱroofȱofȱyourȱmouthȱ x anȱitchyȱfeelingȱinȱtheȱbackȱofȱyourȱthroatȱ ȱ ThirstȱȬȱ2ȱitems:ȱ x feelingȱthirstyȱ x wantingȱtoȱdrinkȱliquidȱ(becauseȱofȱaȱdryȱ mouth)ȱ ȱ TirednessȱȬȱ2ȱitems:ȱ x difficultyȱsleepingȱ x feelingȱtiredȱ ȱ OralȱCandidiasisȱȬȱ1ȱitem:ȱ x oralȱthrushȱ(fungalȱinfection:ȱsoreȱthroatȱ ȱȱȱȱȱȱȱȱȱcoveredȱwithȱpustules,ȱandȱdifficultyȱ ȱȱȱȱȱȱȱȱȱswallowing)ȱ

ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ

OropharynxȱProblemsȱȬȱ9ȱitems:ȱ x coughingȱ x coughingȱupȱphlegmȱ x coughingȱupȱthickȱmucusȱ x thickȱmucusȱcomingȱupȱ x thickȱmucusȱstickingȱatȱtheȱbackȱofȱyourȱthroatȱ x aȱneedȱtoȱclearȱyourȱthroatȱ x mucusȱinȱyourȱthroatȱ x aȱ‘clump’ȱinȱyourȱthroatȱ x aȱfeelingȱthatȱ‘aȱlayerȱofȱmucusȱstaysȱonȱtheȱback’ȱofȱ yourȱthroatȱ

MoodȱProblemsȱȬ 3ȱitems: x feelingȱ‘grumpy’ȱ x moodȱswingsȱ x feelingȱ‘easilyȱirritated’ȱ

ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ

FacialȱOedemaȱȬ 1ȱitem: x aȱswollenȱfaceȱorȱfluidȱaroundȱtheȱfaceȱ ȱ VisionȱDeteriorationȱȬȱ1ȱitem:ȱ x someȱkindȱofȱdeteriorationȱofȱyourȱvisionȱ ȱ DentalȱDeteriorationȱȬȱ1ȱitem:ȱ x anyȱformȱofȱdentalȱdeclineȱ(toothȱdecay,ȱ ȱȱȱȱȱȱȱȱȱstainingȱetc.)ȱ ȱ EyeȱdrynessȱȬȱ1ȱitem:ȱ x dryȱeyesȱ ȱ ȱ ȱ ȱ ȱ ȱ

*ICQȱstemȱquestion:ȱHowȱmuchȱhaveȱyouȱbeenȱaffectedȱbyȱtheȱfollowingȱsideȬeffectsȱrelatedȱtoȱtheȱuseȱofȱyourȱinhaler/sȱduringȱtheȱlastȱ14ȱdays?ȱ

ȱ

133ȱ

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ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱ ȱ

ȱ ȱ

Items in Voice Problems domain 70

% patients scoring >0 on the ICQ

ȱ

80

60

50

40

30

20

10

ȱ

0 4. [Your 5. [Your 6. Not being 7. [Loss of 8. A feeling 9. A painful 10. [Others 2. A 'rough' 3. A 1. can't throat when of voice noticeable voice similar voice 'gone able to sing speech Hoarseness understand talking volume] exhaustion to back of change to to of the voice your when talking throat'] your voice recovering speech] from flu]

ȱ 80

80

Items in Unpleasant Taste domain

23. An unpleasant feeling in your throat

24. A dry throat

Items in Oropharynx Problems domain

ȱ 70

ȱ 60

ȱ

50

40

ȱ

30

ȱ 20

% patients scoring >0 on the ICQ

70

% patients scoring >0 on the ICQ

21. A 'rough' 22. A sore 11. A breaking throat throat voice

60

50

40

30

20

ȱ

10

10

ȱ

0

28. A 29. A 30. A 'bad 31. Bad terrible 'taste' on taste' or breath taste in the teeth? unfresh your feeling in mouth your mouth

37. 38. 39. Wanting Wanting Wanting to rinse to brush to chew your your teeth gum mouth

ȱ ȱ

80

0

18. 19. A 20. [A 17. A 12. 13. 14. 15. Thick 16. CoughingCoughingCoughing mucus [Thick need to Mucus in 'clump' in layer of your your mucus clear up up thick coming mucus throat throat stays on your phlegm mucus up sticking back of at back throat throat] of throat]

Items in Skin, Hair and Nails domain

ȱ

% patients scoring >0 on the ICQ

70

ȱ 60

ȱ

50

ȱ

40

Non ICS inhaler Low dose ICS Mid dose ICS High dose ICS

30

ȱ

20

ȱ 10

ȱ

0

41. Dry skin

42. Dry skin on the face

43. 44. 45. 49. Brittle 50. Hair Bruising [Bruises [Thinner or nails, or loss easily painfulȱ for less your nails a long flexibility breaking period] in your easily skin] ȱ

SquareȱbracketsȱindicateȱtruncationȱofȱtextȱȬȱfullȱitemȱdescriptionȱinȱTableȱ2ȱ

Figureȱ 1.ȱ Prevalenceȱ ofȱ itemsȱ inȱ theȱ ‘Voiceȱ Problems’,ȱ ‘Unpleasantȱ Taste’ȱ ‘OropharynxȱProblems’ȱandȱ‘Skin,ȱHairȱandȱNails’ȱdomainsȱofȱtheȱICQȱ 134ȱ ȱ

ȱChapterȱ6.ȱAȱselfȬratingȱscaleȱforȱpatientȬperceivedȱsideȱeffectsȱofȱinhaledȱcorticosteroidsȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ 80

Items in Mood Problems domain

80

60

50

40

30

60

50

Non ICS inhaler 40

Mid dose ICS

0

0

46. Feeling 'grumpy'

47. Mood swings

80

Items in Perspiration domain

33. A loss of ability to taste

Items in Oropharyngeal Itching domain

35. A loss of appetite

80

Items in Thirst domain

70

60

50

40

30

60

50

40

30

20

20

10

10

0

0

52. Sweating

53. Sweating during the night

% patients scoring >0 on the ICQ

70

% patients scoring >0 on the ICQ

% patients scoring >0 on the ICQ

32. A change in your ability to taste

48. Feeling 'easily irritated'

70

60

50

40

30

20

10

0

25. An itchy feeling on the 26. An itchy feeling in the roof of your mouth back of your throat

Items in Tiredness domain

80

70

34. Feeling thirsty

36. Wanting to drink liquid (because of dry mouth)

Items in the five remaining 1-item domains

70

% patients scoring >0 on the ICQ

% patients scoring >0 on the ICQ

High dose ICS

10

10

80

Low dose ICS

30

20

20

80

Items in Taste Disruption domain

70

% patients scoring >0 on the ICQ

% patients scoring >0 on the ICQ

70

60

50

40

30

60

50

40

30

20

20

10 10

0

0

55. Difficulty sleeping

56. Feeling tired

27. [Oral thrush 40. A swollen face 51. Some kind of 54. Any form of dental decline (sore throat or fluid around the deterioration of (tooth decay, your vision face covered with tooth staining pustules..)] etc.)

57. Dry eyes

ȱ

SquareȱbracketsȱindicateȱtruncationȱofȱtextȱȬȱfullȱitemȱdescriptionȱinȱTableȱ2ȱ

Figureȱ 2.ȱ Prevalenceȱ ofȱ itemsȱ inȱ theȱ ‘Moodȱ Problems’,ȱ ‘Tasteȱ Disruption’,ȱ ‘Perspiration’,ȱ ‘Oropharyngealȱ Itching’,ȱ ‘Thirst’,ȱ ‘Tiredness’ȱ andȱ fiveȱ 1Ȭitemȱ domainsȱofȱtheȱICQȱ ȱ ȱ ȱ ȱ ȱ 135ȱ

Partȱ3.ȱOriginalȱresearchȱ

ȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱȱ

Tableȱ 3.ȱ Medianȱ scoreȱ andȱ prevalenceȱ byȱ ICSȱ doseȱ groupȱ forȱ ICQȱ totalȱ andȱ 15ȱ domainsȱȱ ȱ ICQȱDomainȱ

Nonȱȱ %ȱ>0ȱ Lowȱȱ ICSȱ doseȱ Inhalerȱ ICSȱ n=27ȱ n=61ȱ

%ȱ>0ȱ Midȱȱ doseȱȱ ICSȱ n=62ȱ

%ȱ>0ȱ Highȱȱ doseȱ ICSȱ n=105ȱ

%ȱ>0ȱ pȬvalue*ȱȱ

TotalȱScoreȱȱ VoiceȱProblemsȱ OropharynxȱProblemsȱ UnpleasantȱTasteȱ Skin,ȱHairȱandȱNailsȱ MoodȱProblemsȱ TasteȱDisruptionȱ Perspirationȱ OropharyngealȱItchingȱ Thirstȱ Tirednessȱ OralȱCandidiasisȱ FacialȱOedemaȱȱ VisionȱDeteriorationȱ DentalȱDeteriorationȱ EyeȱDrynessȱ

5ȱ(1Ȭ11)ȱ 2ȱ(0Ȭ8)ȱ 11ȱ(0Ȭ19)ȱ 7ȱ(0Ȭ24)ȱ 0ȱ(0Ȭ14)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ25)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ25)ȱ 0ȱ(0Ȭ13)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ17)ȱ

[92]ȱ [70]ȱ [75]ȱ [61]ȱ [57]ȱ [33]ȱ [23]ȱ [45]ȱ [27]ȱ [55]ȱ [51]ȱ [8]ȱ [7]ȱ [31]ȱ [15]ȱ [28]ȱ

[92]ȱ [63]ȱ [81]ȱ [68]ȱ [69]ȱ [46]ȱ [16]ȱ [46]ȱ [32]ȱ [58]ȱ [57]ȱ [8]ȱ [13]ȱ [33]ȱ [25]ȱ [31]ȱ

[97]ȱ [79]ȱ [86]ȱ [77]ȱ [81]ȱ [59]ȱ [39]ȱ [64]ȱ [41]ȱ [72]ȱ [74]ȱ [20]ȱ [22]ȱ [38]ȱ [40]ȱ [50]ȱ

[89]ȱ [56]ȱ [67]ȱ [67]ȱ [41]ȱ [11]ȱ [11]ȱ [30]ȱ [15]ȱ [48]ȱ [36]ȱ [7]ȱ [7]ȱ [19]ȱ [11]ȱ [26]ȱ

7ȱ(3Ȭ14)ȱ 3ȱ(0Ȭ13)ȱ 9ȱ(1Ȭ28)ȱ 5ȱ(0Ȭ20)ȱ 5ȱ(0Ȭ19)ȱ 0ȱ(0Ȭ19)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ33)ȱ 0ȱ(0Ȭ8)ȱ 8ȱ(0Ȭ25)ȱ 8ȱ(0Ȭ25)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ17)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ17)ȱ

10ȱ(3Ȭ21) 6ȱ(0Ȭ22)ȱ 18ȱ(3Ȭ41) 5ȱ(0Ȭ19)ȱ 14ȱ(0Ȭ24) 0ȱ(0Ȭ33)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ38)ȱ 0ȱ(0Ȭ8)ȱ 8ȱ(0Ȭ35)ȱ 8ȱ(0Ȭ33)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ17)ȱ 0ȱ(0Ȭ13)ȱ 0ȱ(0Ȭ17)ȱ

15ȱ(9Ȭ30) 13ȱ(3Ȭ34) 20ȱ(6Ȭ44) 10ȱ(2Ȭ29) 19ȱ(5Ȭ37) 11ȱ(0Ȭ39) 0ȱ(0Ȭ14)ȱ 17ȱ(0Ȭ42) 0ȱ(0Ȭ25)ȱ 25ȱ(0Ȭ50) 25ȱ(0Ȭ42) 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ0)ȱ 0ȱ(0Ȭ33)ȱ 0ȱ(0Ȭ33)ȱ 0ȱ(0Ȭ50)ȱ

*JonckheereȬTerpstraȱTest.ȱ ICQȱscoreȱmedianȱ(IQR).ȱ ICQȱdomainȱandȱtotalȱscores:ȱ0ȱtoȱ100.ȱ [%ȱpatientsȱscoringȱ>0ȱwithinȱICQȱtotalȱscoreȱandȱdomains].ȱ