Treatment adherence and level of control in moderate persistent asthma in children and adolescents treated with fluticasone and salmeterol

University of Groningen

Treatment adherence and level of control in moderate persistent asthma in children and

adolescents treated with fluticasone and salmeterol

Jentzsch, Nulma S.; Silva, Gabriela C. G.; Mendes, Guilherme M. S.; Brand, Paul L. P.;

Camargos, Paulo

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Jornal de pediatria

DOI:

10.1016/j.jped.2017.10.008

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Jentzsch, N. S., Silva, G. C. G., Mendes, G. M. S., Brand, P. L. P., & Camargos, P. (2019). Treatment

adherence and level of control in moderate persistent asthma in children and adolescents treated with

fluticasone and salmeterol. Jornal de pediatria, 95(1), 69-75. https://doi.org/10.1016/j.jped.2017.10.008

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www.jped.com.br

ORIGINAL

ARTICLE

Treatment

adherence

and

level

of

control

in

moderate

persistent

asthma

in

children

and

adolescents

treated

with

fluticasone

and

salmeterol

夽,夽夽

Nulma

S.

Jentzsch

_,

_Gabriela

_C.G.

_Silva

_,

_Guilherme

_M.S.

_Mendes

_,

Paul

L.P.

Brand

_,

_Paulo

_Camargos

a_{FaculdadedeCiênciasMédicasdeMinasGerais,HospitalUniversitárioCiênciasMédicas,BeloHorizonte,MG,Brazil} b_{IsalaHospital,PrincessAmaliaChildren’sCentre,Zwolle,TheNetherlands}

c_{UniversityMedicalCentreandUniversityofGroningen,UMCGPostgraduateSchoolofMedicine,Groningen,TheNetherlands} d_{UniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,UnidadedePneumologiaPediátrica,BeloHorizonte,MG,} Brazil

Received3April2017;accepted18October2017

Availableonline20December2017

KEYWORDS Asthma; Fluticasone; Salmeterol; Inhaled corticosteroids Abstract

Objective: Thereisascarcityofstudiesthatassessedtheassociationbetweenadherenceto combination therapyandasthmacontrolinpediatric patients.Theauthors investigatedthe associationbetweenadherencetofluticasonepropionate/salmeterolxinafoate combination-meteredaerosolandthelevelofasthmacontrolinchildren.

Methods: Thiswasaprospectiveobservationalstudyof84patientsaged5---16yearswith mod-eratepersistentasthma,whoremaineduncontrolleddespitetheuseof1000␮g/dayofinhaled nonextrafine-hydrofluoric alkane-beclomethasonedipropionatein thethreemonths prior to study enrollment. Participants were prescribed two daily doses of FP (125_{␮g)/salmeterol} xinafoate(25␮g)combinationbymeteredaerosol/spacerforsixmonths.Adherencerateswere assessedusingthedevice’sdosecounterafterthe2nd,4th,and6thmonthsoffollowup.Asthma controlwasassessedusingasimplifiedGlobalInitiativeforAsthma2014Reportclassification.

夽 _{Pleasecitethisarticleas:JentzschNS,SilvaGC,MendesGM,BrandPL,CamargosP.Treatmentadherenceandlevelofcontrolinmoderate}

persistentasthmainchildrenandadolescentstreatedwithfluticasoneandsalmeterol.JPediatr(RioJ).2019;95:69---75.

夽夽_{ThemedicationsandspacerswereprovidedfreeofchargethroughtheBrazilianUnifiedHealthSystem(SUS)ofBeloHorizonteCity}

Hall.

∗_{Correspondingauthor.}

E-mails:nulma.jentzsch@cienciasmedicasmg.edu.br,nulmasj@gmail.com(N.S.Jentzsch).

https://doi.org/10.1016/j.jped.2017.10.008

0021-7557/©2017SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

70 JentzschNSetal. Results: Meanadherenceratesafterthesecond,fourth,andsixthmonthswere87.8%,74.9%, and62.1%respectively,forcontrolledasthma,and71.7%,56.0%,and47.6%respectively,for uncontrolledasthma(allp-values≤0.03).Theproportionofchildrenachievingasthmacontrol increasedto42.9%,67.9%and89.3%afterthe2nd,4thand6thmonthsoffollow-up,respectively (p≤0.001).

Conclusion: Adherenceratesbetween87.8%inthe2ndmonthand62.1%inthe6thmonthwere strongdeterminantsofasthmacontrol.

©2017SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/

4.0/). PALAVRAS-CHAVE Asma; Fluticasona; Salmeterol; Corticosteroide inalatório

Adesãoaotratamentoeníveldecontroledaasmapersistentemoderadaemcrianc¸as eadolescentestratadoscomfluticasonaesalmeterol

Resumo

Objetivo: Sãoescassososestudosqueavaliaramarelac¸ãoentreataxadeadesãoàcombinac¸ão deproprionatodefluticasona/xinafoatodesalmeteroleoníveldecontroledaasmanainfância. Opresenteestudotevecomoobjetivoavaliaressarelac¸ão.

Métodos: Estudoprospectivoobservacionalcom84participantes,de5a16anos,todoselescom asmapersistentemoderadaquepermaneceramnãocontroladosapesardousode1.000_␮g/dia dedipropionatodebeclometasonaempartículasnãoextrafinasnostrêsmesesque anteced-eramaadmissãonoestudo.Osparticipantesreceberamprescric¸ãode125_␮gdepropionatode fluticasonae25␮gxinafoatodesalmeterolatravésdeinaladorpressurizado,duasvezesaodia, eforamavaliadosapóso2◦,4◦e6◦mesesdetratamento.Ataxadeadesãofoiobtidapormeio docontadoranalógicodedosesincorporadoaoinalador.Aclassificac¸ãodoníveldecontroleda asmafoibaseadanumasimplificac¸ãodasrecomendac¸õesdaGlobalInitiativeforAsthma. Resultados: Astaxasdeadesãoaos2,4e6mesesparaaasmacontroladaforam87,8%,74,9% e62,1%eparaaasmanãocontroladade71,7%,56,0%e47,6%(p≤0,03),respectivamente. Aproporc¸ãodepacientescomasmacontroladaelevou-separa42,9%,67,9%e89,3%nastrês avaliac¸õessubsequentes(p≤0,001).

Conclusões: Taxasdeadesãoentre87,8%no2◦mêsede62,1%no6◦.mêsforamdeterminantes paraoníveldecontroledaasma.

©2017SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Este ´eumartigo OpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.

0/).

Introduction

Thefirst-linetreatmentofasthmaistheuseofinhaled cor-ticosteroids(IC),butdiseasecontrolisnotalwaysattained withtheuseofthesedrugsalone.1

Adherencetoagiventherapeuticregimenistheprocess bywhichthepatientstrictlyfollowsaregimenofcareand, regardinginhaledmedications,themostaccurateand reli-ablemethodsofevaluatingadherencearetheelectronicand analogdose-countingmonitors.Botharemorereliablethan thereports by patients or family members, clinical judg-ment, drug dispensing by the pharmacy, and weighing of dose-countinginhalers.2,3_{Assessingadherencethroughthe}

analogcounter in thepressurizedinhaler issimilartothe electronic method, thus allowing the obtaining of a reli-ableadherencerate.4 _{Inturn,both have thedrawbackof}

intentionalemptyingofthepressurizedinhaler.5

Asthma treatmentadherence rates aregenerallylower thanprescribed,andstudieshaveshownthatalow adher-ence rate is one of the most common causes of lack of clinicalandfunctionaldiseasecontrol.6_Inthecaseof

chil-dren,whenparentshaveanegativeperceptionofasthma,

theymayquestiontheneedforICuseatthesametimeas theyareconcernedabouttheadverseeffectsofmedication. Moreover, when they donot have the necessary informa-tiontounderstandthedisease,theadherenceratemaybe evenlower.7_{Adherenceratesgreaterthan 60%are}

associ-atedwithabetterlevelofasthmacontrol.8_{However,great}

variability can befound in studies carriedout in the last twodecades.Bender,forinstance,reportedratesof19---58% in tenstudies that assessedadherence throughelectronic dose-counting,9_{whereasotherresearchersreporteda}

vari-ationof30%to70%.Ratesoflessthan50%areinsufficientto controlthediseaseand,consequently,areassociatedwith a greaterfrequency ofdisease exacerbations, hospitaliza-tions,andtheneedforemergencycare.10

Inturn,itisknownthataclinicalresponsetotheisolated use of IC is observed only after the first weeks of treat-ment,whereastheassociationwithprolonged-actionbeta-2 agonistcouldbringfasterclinicalbenefits,duetoits bron-chodilatoraction.Studieshaveshownthatthisassociation mayhelp theattainmentof controlin patientswith mod-erate andseverepersistent asthmathroughitssynergistic effect.11,12

AliteraturesearchinthePubmed/MedLine,Lilacs, Sci-elo,Ebsco,andCochraneCollaborationdatabasesincluding thepast 15 yearsidentifiedfew studies thatassessed the adherence rate to the fluticasone propionate-salmeterol xinafoateassociationandthelevelofasthmacontrolin chil-dren in developing countries.12 _{The present study aimed}

to evaluate the association between asthma treatment adherenceandcontrolratesthroughthistherapeutic com-bination.

Methods

Studysiteanddesign

Thiswasaprospectiveobservationalstudywithasix-month follow-up, for which patients with moderate persistent asthma were recruitedand werefollowed at a secondary pediatricreferralservicelinkedtotheMunicipalHealth Sec-retariatofthecityofBeloHorizonte,stateofMinasGerais, Brazil.Thenumberofchildrentreatedatthatserviceduring theperiodcoveredbythestudywas127.All84childrenwho mettheinclusioncriteriawereconsecutivelyadmittedand completedthefollow-upperiodpredefinedintheresearch protocol.Datacollectionlastedoneyearandthreemonths.

Inclusionandexclusioncriteria

Children and adolescents aged 5---16 years of age, with moderate persistent asthma without clinical control at admission despite adequate adherence (verified through medication dispensing at the pharmacy) to the prescrip-tionof 1000␮g/day ofbeclomethasone dipropionate with hydrofluoroalkanepropellant (hydrofluoric alkane) in non-extrafineparticles. The diagnosis ofasthma wasbasedon the clinical criteria proposed by the Global Initiative for Asthma (GINA).13 _{The parents or guardians, all of whom}

wereliterate,signedtheinformedconsentformto autho-rizetheparticipationoftheir childreninthe study;those olderthan12yearsalsosignedthetermofassent.Children andadolescentswhowerepassivesmokersandthosewith comorbiditieswereexcluded.

Asthmacontrollevel

As the main objective of asthma treatment is toachieve full diseasecontrol,only twocategorieswereadopted on thetwo-, four-,and six-monthfollow-upvisits: controlled asthma anduncontrolledasthma, thelatter encompassing partiallyandtotallyuncontrolleddiseasepresentations,in accordancewiththeGINAclassification.13 _{Thus,controlled}

asthmawasdefinedbythefollowingcriteria:(1)absenceof daytimesymptoms,maintenanceofnormalphysical activi-ties,absenceofnocturnalsymptoms,absenceofnocturnal arousalwithsymptoms,noneedtouserescuemedication, andnoexacerbationinthefourweeksprecedingthe two-,four-,andsix-monthevaluations.Thepresenceofoneof theabovecriteriawasconsideredasuncontrolledasthma. Spirometry, albeit notpart of theGINA control criteria,13

leads toa more reliable asthma monitoring andwas per-formed in thosepatients capable of undergoingthe test.

AKoko® spirometer(PDS Instrumentation,Colorado,USA), PulmonaryFunctionTests(PFT)version4.12usedwasand thereliabilityandreproducibilitycriteriarecommendedby the American Thoracic Society and European Respiratory Society were used,14 _{whereas the reference values used}

wereobtainedfromPolgarandPromadhat.15 Therapeuticregimen

All participants received the medications free of charge: salbutamolfortreatmentofexacerbations,100ug/jet Neb-ulizer(Aerolin® --- GlaxoSmithKleine,Brazil)andthe combi-nationof125␮/fluticasonepropionateand25␮/salmeterol xinafoatejetnebulizer (Seretide® --- GlaxoSmithKleine,SP, Brazil),the latter with a dose counter, prescribed in two daily doses (morning and evening). The number of doses consumedinthetwopreviousmonthscorrespondedtothat recordedbythecounterduringeachofthethreebimonthly evaluations performed during follow-up. A large-volume valve spacer (Flumax® --- Inside Materiais Avanc¸ados, SP, Brazil)wasalsosupplied.Allchildrenusedthesametypeof spacer,theonlyoneprovidedfreeofcharge,regardlessof age.Thisconservativemeasurewastakenduetothelackof resourcesbytheparticipatingfamilies,whichoftenlacked goodunderstandingandeducationallevel,despitethefact thatparents wereliterate; this aimedtoensure the ade-quatequalityoftheinhalationtechnique,acrucialcondition forthe evaluationof bothadherence andlevel ofdisease control.Regardingtheguidelinesfortheinhalationroutein eachconsultation,thefollowingparameterswereobserved: spacerhygiene,agitationofthepressurizedinhalerbefore use,andnumberofinspirationsaftereachnebulization.

Adherencerates

Theadherenceratewasexpressedbycalculatingthe per-centageofthenumberofuseddosesdividedbythenumber ofprescribeddoses×100,considering the dayof medica-tiondispensation (theinhalercontains 120doses)andthe numberofremainingdosesverifiedonthedateofthethree controlvisits (two, four,and six monthsafteradmission). The service where themedication wasdispensed wasthe samewherethestudywascarriedout.Theexpected ade-quateadherencewas100%.

Statisticalanalysis

The dependent variable was the asthma control level, i.e.,adequatecontrolorlack ofcontrol.The independent variablesweretimeoffollow-up, adherencerate,gender, maternal age and level of schooling, and mean monthly familyincome.When assessingthepatients’profileatthe firstconsultation, absolute and relative frequencies were usedforthecategoricalvariables,whereasthemeansand standard deviations were usedfor the quantitative varia-bles.

The chi-squared test was used to compare the group of patients who had controlledand uncontrolled asthma. Non-parametric tests were used to compare the rate of adherence among participants who had controlled

72 JentzschNSetal.

Table1 Characteristicsofthepatientsineachgroupatthefirstconsultation(2monthsoftreatment).

Characteristics Uncontrolled Controlled p-Valuea

n=58 n=26

Child’sgender Female 29 60.4% 18 56.0% 0.341

Male 19 39.6% 18 44.0%

Child’sage(year) 5---6 27 56.2% 19 54.8% 0.752

Olderthan6 21 43.8% 17 45.2% Maternalage (years) Upto30 24 50.0% 21 53.6% 0.449 Olderthan30 24 50.0% 15 46.4% Maternallevelof schooling(years) Upto8 36 75.0% 25 72.6% 0.572 Morethan9 12 25.0% 11 27.4% Familyincome >2MW 15 31.2% 12 32.1% 0.840 2MW 33 68.8% 24 67.9%

MWs,Brazilianminimumwages.

a_{Chi-squaredtest.}

asthma andthose withuncontrolled asthma, stratifiedby consultation(Mann---Whitneytest),andtocomparetherate ofadherencebetweenconsultations,stratifiedbycontrolled anduncontrolledasthma(Kruskal---Wallistest;theNemenyi testwasusedformultiplecomparisons).

Marginallogistic regressionwasusedtoverifywhether theindependentvariableshadaninfluenceonasthma con-troland,forthispurpose,thebackwardmethodwasused, whichistheprocedureofconsecutivelyremovingthe varia-bleswithgreaterp-value;thisprocedureisrepeateduntil only significant variables remain in the model. A conven-tionalsignificance level of 5% wasusedfor thebackward method.

Thegeneralizedestimatingequations(GEEs)methodwas used to evaluate the individual correlation of adherence measurementswiththeasthmacontrollevel.16

Themeanrateofdrugadherencewascomparedwiththe asthmacontrollevelandexpressedinbox-plotchartsinthe second,fourth,andsixthmonths.Themeans(and respec-tivestandarddeviation),medians,minimumandmaximum variations, and first and third quartiles of the adherence rates of therespective monthswere alsocalculated. The boxplotisadequatetorepresentthenon-parametrictests, sinceit providesclinically importantinformation, such as themediansandquartilesofeachgroup/time.Thesoftware usedintheanalysiswasR® version3.0.3(RFoundationfor StatisticalComputing,Vienna,Austria).

Ethicalaspects

The study protocol, aswell as the terms of consent and assent,were approvedby the ResearchEthics Committee of Faculdade de CiênciasMédicas deMinas Gerais, under number0117.0.418.000-11.

Results

Eighty-fourpatientswererecruitedforthestudy withthe followingadmissioncharacteristics:themeanage was7.4 years,54.8%ofthemwereagedbetween5and7years,with apredominanceoffemales(56.0%).Themeanmaternalage was32.5 years,ofwhom46.4%wereolder than30 years,

andmostmothers (72.6%)reportedat leasteightyearsof elementary school education. The mean monthly family incomewasR$700.00in67.9%ofthefamilies.

As expected, 47 of the 84 patients (56.0%) underwent spirometry,ofwhom38werechildrenolderthan6yearsand ninewere aged5 years.The meaninitialandfinal forced expiratory flow in the firstsecond (FEV1)were 76.3% and

80.3%ofthepredictedvalues,respectively.

Table1showstheresultsoftheevaluationofthesecond monthoftreatment;nostatisticaldifferencewasobserved betweenthetwogroups.

Table 2 shows the distribution of the asthma control levelaccordingtotheadherencerateverifiedinthethree bimonthlyconsultations.Itwasobservedthatinthegroup whereasthmawasnotcontrolled,themeanadherencerates inthesecond,fourth,andsixthmonthswere71.7%,56.0%, and47.6%,whereasthegroupwithcontrolledasthma pre-sentedsignificantlyhigherrates,87.8%,74.9%,and62.1%, respectively,andthisdifferencewasstatisticallysignificant (p-value=0.002).

Table3 shows the results of the multivariate analysis, demonstratingtheinfluenceoftimeoftreatment, partici-pant’sgenderandage,maternalageandlevelofschooling, andmonthlyfamilyincomeonthelevelofasthmacontrol.

Adherencerate,gender,andmaternallevelofschooling weresignificantlyassociatedwithcontrolledasthma. Boys were2.84 times(95% CI:1.02---7.87) morelikelytoattain asthmacontrolthangirls,andeachadditionalyearof mater-nal schoolingincreasedthelikelihoodof achievingasthma controlby1.19times(95%CI:0.99---1.42).

Fig.1 shows the comparison of the adherence rate in thesecond,fourth,andsixthmonthsoftreatmentandthe levelofasthmacontrol.Onceagain,higheradherencerates were associated witha better level of disease control. A consistentdose---responsegradientwasobservedfor adher-encerateandasthmacontrollevelatthethreemomentsof theclinical---functionalevaluation.

Discussion

In this observational study carried out exclusively in the pediatric population, it was observed that adher-ence greater than 60% led to better controlof moderate

Table2 Comparisonofadherenceratesbetweengroupsstratifiedbytimeoftreatment.

Adherencerate n(%) Mean(SD) Min 1stQ Median 3rdQ Max. p-Valuea

2months Uncontrolled 48(57.1%) 71.7(13.2) 42.9 62.8 70.6 80.0 98.4 0.000 Controlled 36(42.9%) 87.8(8.8) 64.5 80.5 89.6 95.2 98.4 4months Uncontrolled 27(32.1%) 56.0(8.7) 40.8 50.0 58.8 60.3 75.9 0.000 Controlled 57(67.9%) 74.9(11) 53.1 65.9 75.0 83.3 100 6months Uncontrolled 9(10.7%) 47.6(11.1) 33.9 37.3 49.2 52.6 67.4 0.002 Controlled 75(89.3%) 62.1(13.5) 42.0 53.1 59.4 66.7 100

SD,standarddeviation;Q,quartile;Min.,minimum;Max.,maximum.

a _{Mann---Whitneytest.}

Table3 Factorsassociatedwiththelevelofasthmacontrol.

Source Backwardmarginallogisticregression

p-Value OR 95%CI Consultationat2months --- 1 ---Consultationat4months 0.000 31.16 [11.3;85.93] Consultationat6months 0.000 794.9 [120.4;5245.8] Adherencerate 0.000 1.15 [1.11;1.20] Femalegender --- 1 ---Malegender 0.045 2.84 [1.02;7.87]

Maternalschooling(years) 0.067 1.19 [0.99;1.42]

OR,oddsratio;95%CI,95%confidenceinterval.

Adherence r a te Controlled Uncontrolled Months of treatment 100 80 60 40 20 0 2 4 6 p=0.000 p=0.003 p=0.000 p=0.000

Figure1 Rateofadherencetothecombinationoffluticasone propionateandsalmeterolxinafoateandcorrespondinglevelof asthmacontrolinthethreeevaluationsperformedduringthe follow-upperiod.

persistent asthma.This is the mainclinical implicationof thepresentresults.

Studies on asthma treatment adherence in developing countriesthrough reliable methods suchasdose counters are rare, and those evaluating the rate of adherence to

combinationtherapy(i.e.,inhaledcorticosteroidand long-acting beta-agonist) and the level of asthma control are evenrarer.Thisisthesecondmessageofthepresentstudy, whichaimedtocontributetobettermanagementofasthma inchildren.

The factors that influenced asthma control were the decreaseintheadherencerateduringfollow-up,male gen-der,andmaternallevelofschooling.Studiesontheinfluence ofgenderarecontroversial,butthedecreaseinadherence rates duringthe course of treatment is well knownin all chronicdiseases,suchasasthma.16

The influence of maternal schooling observed in the present study is corroborated by a study carried out by Urrutia-Pereiraetal.,inan asthmapreventionprogramin RioGrandedoSul,where35.6%oftheparticipating moth-ers had an educational level of less than eight years of schooling.17

BenderreportsthattherehasbeenlittlechangeintheIC adherencerateinthelast25years;intenstudiesincluded in his review, the lack of asthma control was associated withadherenceratesrangingfrom19%to58%.Itwas con-cludedthatbetterunderstandingofthemanagementbythe caregiversanduseofthecorrectinhalationtechniquewere determinantforbetterdiseasecontrol.9

One limitation of the present study is that the dose countercoupledtotheinhalerdoesnotexcludedeliberate emptying of medication.18 _{However, Given et al.}

demon-stratedthereliabilityofthismethod.4_{Theadherencerate}

74 JentzschNSetal. such asdose counters, to differentiate between patients

adheringtothetherapeuticregimenandthosewhodonot, bothinclinicalpracticeandinresearch.19---21

Inclinicalpractice,ifanoptimallevelofasthmacontrol isnotachieved,thetreatmentadherencerate,amongother factors,shouldbeverifiedbeforeprescribingahigherdose ofIC,combinedornotwithanotherdrug.

In meta-analysisof ten studies that aimed tomeasure adherencetoICtreatment throughelectronic monitorsin pediatric patients,22 _{individuals whoexperienced}

exacer-bationshadamean rateof isolatedICadherence of14%, whereasinthosewithcontrolledasthma,themean adher-enceratewas68%,whichisveryclosetothatfoundinthe presentstudy,i.e.,sufficientforasthmacontrol.

Pedersenetal.followed-up19childrenaged6---15years withmoderateandsevereasthmawhousedbudesonidefor fourweeks. The use of half (i.e., 100mcg/day of budes-onide)of the prescribeddose --- assessed byweighing the inhalers--- wasenough tocontrolthesymptoms. Thevery shortperiodofstudyfollow-upisnoteworthy.23

Kloketal., in areview of 14studies onasthma treat-ment adherence using an electronic monitor in children, regardless of disease severity, found a time of follow-up from13weeksto18monthsandvariationinadherencetoIC treatmentof34---92%;intheresearchthatlastedsixmonths (similartothepresentstudy)anadherencerateof50%was observed.24

Thefinalmodelofthemultivariateanalysisshowedthat malegender,maternalschooling,anddurationoffollow-up wereassociatedwithadequateasthmacontrol.

The present study has further clinical implications in addition to those previously mentioned. The results sug-gestthatboththerateofadherencetoinhaledmedication and the level of asthma control should be systematically verifiedinanyclinicalevaluationoftheasthmaticpatient, whetherornotthoseevaluationswereprogrammed. More-over, they indicate that, to attain clinical and functional controlofmoderatepersistentasthmainchildrenand ado-lescentswhoareusingthetherapeuticregimenadoptedin thepresentstudy,therateofadherencecould,infact,be lowerthantheidealof100%,sinceaminimumof60% adher-encetothetherapeuticregimenadoptedwassufficientto achieveasthmacontrol.Theseadherencerateswerelower thanthosereportedintheliterature.1,24

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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