Asthma-chronic obstructive pulmonary disease overlap syndrome - Literature review and contributions towards a Portuguese consensus

www.revportpneumol.org

SPECIAL

ARTICLE

Asthma-chronic

obstructive

pulmonary

disease

overlap

syndrome

---

Literature

review

and

contributions

towards

a

Portuguese

consensus

D.

Araújo

_,

_E.

_Padrão

_,

_M.

_{Morais-Almeida}

_,

_J.

_Cardoso

_,

_F.

_Pavão

_,

R.B.

Leite

_,

_A.C.

_Caldas

_,

_A.

_Marques

a_{InstituteofHealthSciences,UniversidadeCatólicaPortuguesa,Portugal} b_{PulmonologyDepartment,CentroHospitalardeSãoJoão,Porto,Portugal} c_{CoordinatorofAllergyCenterofCUFHospitals,Lisbon,Portugal}

d_{PulmonologyDepartment,CentroHospitalardeLisboaCentral,Lisboa,Portugal} e_{NovaMedicalSchool,Lisbon,Portugal}

f_{InstituteofHealthSciences,UniversidadeCatólicaPortuguesa,Portugal} g_{FacultyofHealth,MedicineandLifeSciences,MaastrichtUniversity,Portugal} h_{FacultyofMedicine,UniversityofPorto,Portugal}

Received25October2016;accepted5November2016

KEYWORDS Asthma; Chronicobstructive pulmonarydisease; Overlapsyndrome; Portugueseconsensus Abstract

Introduction:Phenotypic overlapbetweenthetwomainchronicairwaypulmonarydiseases, asthmaandchronicobstructivepulmonarydisease(COPD),hasbeenthesubjectofdebatefor decades,andrecentlythenomenclatureofasthma-COPDoverlapsyndrome(ACOS)wasadopted forthiscondition.Thedefinitionofthisentityintheliteratureis,however,veryheterogeneous, itisthereforeimportanttodefinehowitappliestoPortugal.

Methods:A literaturereviewofACOSwasmade inafirstphaseresultinginthedrawingup of adocument thatwas later submitted for discussionamong a panel ofchronic lung dis-easesexperts,resultinginreflexionsaboutdiagnosis,treatmentandclinicalguidanceforACOS patients.

Abbreviations: ACOS,asthma-COPDoverlapsyndrome;BD,bronchodilation;CARAT,controlofallergicrhinitisandasthmatest;COPD, chronicobstructive pulmonarydisease; FENO,fractionalexhalednitricoxide;FEV1,forcedexpiratoryvolumein1s; FVC,forcedvital capacity;GINA,GlobalInitiativeforAsthma;GOLD,GlobalInitiativeforChronicObstructiveLungDisease;ICS,inhaledcorticosteroid;IgE, immunoglobulinE;IL,interleukin;LABA,longactingbetaagonist;LAMA,longactingmuscarinicantagonist;LLN,lowerlimitofnormal; mMRCscale,modifiedMedicalResearchCouncilscale;PEF,peakexpiratoryflow;RCT,randomizedcontrolledtrial;6MWT,6-minwalking test.

∗_{Correspondingauthor.}

E-mailaddress:eva.padrao@gmail.com(E.Padrão).

1 _{Thefirsttwoauthorslisted(DavidAraújoandEvaPadrão)shouldbeconsideredCo-FirstAuthor(equalcontributionsandcredittothe}

work).

http://dx.doi.org/10.1016/j.rppnen.2016.11.005

2173-5115/©2016SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Results:TherewasaconsensusamongtheexpertsthatthediagnosisofACOSshouldbe consid-eredintheconcomitantpresenceof:clinicalmanifestationscharacteristicofbothasthmaand COPD,persistent airwayobstruction(post-bronchodilator FEV1/FVC<0.7), positive response tobronchodilatortest(increaseinFEV1of_≥200mLand_≥12%frombaseline)andcurrentor pasthistoryofsmokingorbiomassexposure.Inreachingdiagnosis,thepresenceofperipheral eosinophilia(>300eosinophils/_␮Lor>5%ofleukocytes)andprevioushistoryofatopyshouldalso beconsidered.Therecommendedfirstlinepharmacologicaltreatmentinthesepatientsisthe ICS/LABAassociation;ifsymptomaticcontrolisnotachievedorincaseofclinicalseverity,triple therapywithICS/LABA/LAMAmaybeused.Aneffectivecontroloftheexposuretoriskfactors, vaccination,respiratoryrehabilitationandtreatmentofcomorbiditiesisalsoimportant. Conclusions:ThecreationofinitialguidelinesonACOS,whichcanbeappliedinthePortuguese context,hasanimportantroleinthegenerationofabroadnationwideconsensus.Thiswill give,inthenearfuture,afarbetterclinical,functionalandepidemiologicalcharacterization ofACOSpatients,withtheultimategoalofachievingbettertherapeuticguidance.

©2016SociedadePortuguesadePneumologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

AsthmaandCOPDarechroniclungdiseaseswhicharehighly prevalent and have significant socio-economic impact.1,2 Datafromarecentnationwidestudyindicatethatthe cur-rent asthma prevalence in the Portuguese population is 6.8%.3_{Thenationalprevalence forCOPDwasestimatedin} 9.0%and5.3%in2previousstudies---inselectedagegroups (≥40yearsoldinone studyandbetween 35and69 years oldin the other); there is also anotherstudy carriedout inthe Lisbon areathat showed aprevalence of 14.2% (in patientsof40yearsoldormore).4,5_{BothasthmaandCOPD} affectthe airways andarecharacterized by thepresence ofbronchial obstruction.1,2 _{Even thoughthesepathologies} areheterogeneous, they usually present quite character-isticclinicalsymptoms,functional changesandunderlying physiopathology,whichenablesastraightforwarddiagnosis in a majority of patients.1,2,6 _{However, there is a} grow-ingconsensusthattypicalasthmaandCOPDcharacteristics can both exist simultaneously in one patient, especially in thosewho are older and have a history of smoking.6---8 DatafromtheINAsmastudyclearlyshowthat,inPortugal, asthmaticpatientssmokeinthesameproportionasthe non-asthmaticandthat thepassive exposureis evenhigherin thefirstgroup.9 _{In reality,therearepatients withsevere} asthma,thathasevolvedoveralongperiodandfrequently withsmokinghabits, that eventuallydevelop fixedairway obstruction,apatternusuallyseeninCOPD.10,11_Ontheother hand,apositivebronchodilatortest,asseeninmanyasthma patients,canbefoundin asignificantproportionofCOPD patients,althoughnotofsamemagnitude.12,13_Inthis con-text,theconceptofACOS(asthma-COPDoverlapsyndrome) hasbeenusedtodescribethissetofpatientsthatpresent concomitantasthmaandCOPDcharacteristics.Itis impor-tanttohighlightthatinthisgroupofpatients,althoughthey showa broad clinical heterogeneity,thereare essentially twotypesofpatients:theasthmaticpatientthatdevelops ACOSandthe COPDpatientthat presentsclinical charac-teristics of ACOS. It is, thus, important tobe awarethat inthesecasesthereisaninitialdistinctphysiologicalbase

thatculminatesinanoverlapofsymptoms,whichcanhave implicationsfordiagnosisandtherapy.

Thewaythesepatientsarecharacterizedbytheseveral entities analysing this issue is very heterogeneous, which makesitdifficulttoapplytheconceptofACOStothe clini-calsituationinPortugal.Inthiscontext,thereisaneedfor afirststeptowardsclarificationofconceptsappliedtothe nationalcontext,inordertodevelop,inthenearfuture,a broaderACOSmedicalconsensus.Thispaperisanindexed literaturerevisiononthesubject,complementedbyaseries of criticalreflexions regardingdiagnostic criteria, patient identification, therapeutic approaches and guidelines for futureclinicalinvestigation.

Methods

AliteraturereviewwascarriedoutviathePubMeddatabase bysearchingforMeSHTerms(‘‘asthma’’,‘‘chronic obstruc-tivelungdisease’’,‘‘overlapsyndrome’’).Articlesbetween 2006 and2016 were selectedasrelevant ifthey had epi-demiological data, diagnostic criteria, clinical symptoms andimpactandtherapeuticapproaches.Inasecondphase, aworkingmeetingwasheldwithmedicalexpertsfromthe chronic lung diseases field (Pulmonology, Immunoallergol-ogy, FamilyMedicine) where the several topicspresented in this paper were discussed and proposals for recom-mendations on ACOS adapted to the Portuguese context drawnup.

Clinical

characterization

and

impact

The differentiation in terms of respiratory symptoms betweenasthmaandCOPDis,inmanycases,quitedifficult, because thereare several areas where they can overlap, makingthedistinctionmorecomplicated.Forexample,the presence of chronic productive cough is more associated withCOPDbutcanalsobepresentinanasthmaticpatient, whichleadstoaworseprognosisintermsofpulmonary func-tiondecline.14_{Ontheotherhand,itisalsocommontohave}

thepresenceofasthmaticsymptoms(occasionaldyspnoea, sibilance) in COPD patients.15 _{In terms of bronchodilator} response,thereversibilityseen,althoughtypicalinasthma, isnotexclusivetoit,asitisalsoobservedinupto50%of COPDpatients.16 _{Furthermore,thebronchial} hyperrespon-siveness,whichispresentinalmostallasthmapatients,can alsobeseeninasignificantpercentageofCOPDcases.17

Thisclinicaldiversityleadstotheoverlapbetweenthese two obstructive respiratory diseases. It is possible, how-ever,toisolatecharacteristicsthatenabletherecognition ofanewentity(ACOS)whichaggregatesfeaturesfromboth (asthmaandCOPD).

Several studies have analyzed the clinical differences betweenACOS,COPDandasthma,showingahigher preva-lence of respiratory symptoms in patients with ACOS compared to the other two alone.18,19 _{In the ACOS} group,studiesshowamoresignificantexertionaldyspnoea (assessedbythemMRCscore),20_{ahigherpercentageof} sibi-lance when comparedwith COPDpatients,21 _{less physical} capacity,moreexacerbationsandlowerqualityoflife.22 _In thepopulation-based study (EPI-SCAN21_{) theauthors} com-paredtheprevalenceofsymptomsbetweenCOPD,asthma andACOSpatients,observingahigherpercentageof dysp-noeaintheACOSgroup,moresibilanceintheACOSgroup whencomparedtotheCOPDgroup,andanequalpercentage ofproductivecoughin COPDandACOS.Two otherstudies (GEIRDandPLATINO18,22_{)revealed, however,a higher} per-centageofproductivecough inACOSpatients,evenwhen comparedtoisolatedcasesofCOPD.

Ontheotherhand,theexercisecapacityshownbyACOS patients was prospectively analyzed by Fu et al. in a 4-year follow-up study which concludedthat the functional decreaseintermsof6-minwalktest(6MWT)waslowerin thesepatientscomparedtotheCOPDgroup.23

Thereisnoconsensusontheresultsconcerninglung func-tion,althoughmanystudiesshowlowervaluesofFEV1,FVC andFEV1/FVCinpatientswithACOScomparedtoCOPDand asthma.18,24 _{Other studiesrevealthatthereareno} signifi-cantdifferencesbetweenthesegroupsinthisarea.23,25,26

InrelationtoradiologicaldifferencesbetweenACOSand COPD,thereseemstobeaslightlylessemphysema expres-sioninthefirstgroupaswellasapredilectionfortheupper lunglobes.27

There is a higher degree of consensus between the studies over exacerbations, with a higher rate in ACOS patients.18,19,21_{Thereisalsoahigherpercentageofsevere} exacerbations and a higher rate of hospitalizations. In a studyperformedbyBrzostekandKokotasignificantrateof recentexacerbations(69%inthelastyear)wasobserved.28 In termsof comorbidities,studies pointtowardsahigh prevalence in ACOS, especiallycardiovascular ones.Some authorshavereferredtoahigherincidenceinACOSpatients comparedto COPDand asthma but that is notapplicable tothewhole literature.20,24,28 _{Miravittles etal.have used} the Charlson Comorbidity Index as a mortality prognos-tic indicator,showing a significantly highervalue in ACOS patients.21

Chronicobstructivepulmonarydiseases,duetoits preva-lenceandhealth-resourceconsumptionneeds,haveahigher economicburdenassociatedwiththem.Withinthese,COPD has clearly more burdensome than asthma.29 _{However, a} costcomparativeanalysisbetweenACOSandCOPD,clearly

showsahighervaluefortheformer,mainlybecauseofthe higherrateofhospitaladmission.30

The ACOS-associatedmortalityratewasaddressed ina recentanalysisofamulticentricItalianstudy(SARAstudy),31 showingno significant differences compared toCOPD but muchhigherthanasthma.

Diagnostic

criteria/biomarkers

Clinicalcriteria

The identification of patients with ACOS in daily clinical practiceisbased,inafirstphase,ontherecognitionof cer-tainclinicalfeaturesofbothasthmaandCOPDbeingpresent simultaneouslyinthesamepatient,aspreviouslystated.6,7 Proposed recommendation: simultaneous presence of clinicalfeaturesofasthmaandCOPDshouldbeconsidered asacriterionforthediagnosisofACOS.

Spirometriccriteria

The presence of persistent airflow limitation, defined as post-bronchodilator FEV1/FVC<0.7, is one of the criteria proposedbyseveralauthorsforthediagnosisofACOS.18,32,33 Thefixedcut-off valueof thisratio,although anessential criterionforthediagnosisofCOPD,doesnothelp,however, thedifferentiationbetweenasthmaandCOPD.2,6

A positive responseto the bronchodilatortest, usually associatedwithasthmadiagnosis,canalsobefoundin cer-tainpatientswithCOPD.1,16,34_{Inthese,thisresponsetends} topresentalowermagnitude,maybeinconsistentovertime and does not necessarily reflect the presence of overlap syndrome.16,34,35 _{However, sincetherearecertain} individ-uals who only manifest the first symptoms of asthma in adulthood, the presence of a positive response to bron-chodilatortestisalsofrequentlyassumedtobeanagreed criteriontobeconsideredforthediagnosisofACOS, espe-ciallyifit isaverypositiveresponse(increaseof15%and 400mLinFEV1).36,37

Proposedrecommendation:therewasconsensusamong expertsthatthepresenceofpersistentairwayobstruction (definedaspost-bronchodilator FEV1/FVC<0.7)associated withevidenceofapositiveresponseinbronchodilatortest (definedasanincreaseinthevalueofFEV1of≥200mLand ≥12%frombaseline) at leastin onefunctional evaluation shouldbeacriterionforthediagnosisofACOS.

Systemicandairwayinflammation

Airway inflammation is a common feature of asthma and COPD; in many asthma phenotypes it is predomi-nantlyeosinophilic, while inCOPD thereis apredominant neutrophilia.38 _{However,inasthmaticsmokersorinsevere} orlate-onsetasthma,aneutrophilicinflammationhasbeen demonstrated,whichis similartoCOPD.38,39 _{Onthe other} hand, peripheral or sputum eosinophilia, as well as the elevation of the fractional exhaled nitric oxide (FENO) andimmunoglobulinE(IgE),althoughgenerallymoreoften observed in asthmatic patients, have also been demon-strated in certain patients with COPD.1,40---43 _{In addition,}

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a higher peripheral and sputum eosinophilia have been found in patients with COPD and partial reversibility of airflowlimitation44_{;itwasfurtherobservedthatthe} pres-ence of eosinophilia in the sputum of COPD patients hasbeen associated witha better response to treatment withinhaled corticosteroids.16 _{It is further notedthat, in} asthma,thepresenceofsputumeosinophiliaisafactorthat can be determinant for the development of fixed airway obstruction.45 _{Thus,theapplicabilityof thesemarkershas} beensubjectofstudytosupportthediagnosisofACOS.43,46 The identification of other systemic inflammation biomarkersthataidthediagnosisandhelptowardsabetter classificationof patients withobstructive airway diseases hasbeeninvestigated.Althoughseveralmarkershavebeen suggested,suchasinterleukin-6(IL-6),periostin,C-reactive protein,among others, none of these has been, todate, includedasdiagnosticcriteria, giventhelack ofevidence tosupporttheirapplicability,sincetheirrolehasnotbeen yetcompletelydetermined.47---49

Proposed recommendation: peripheral eosinophilia (defined by the presence of >300eosinophils/␮L or >5% of the leukocytes) and elevation of IgE are aspects fre-quentlyfoundinthisgroupofpatients,andshouldbetaken intoaccountwhenconsideringthediagnosis,althoughthey cannotbeusedasmaindiagnosticcriteria.Sincethe deter-mination of sputum eosinophilia is a method that is not widelyavailableinPortugalandthedeterminationofFENO hasfallenintodisuse,we didnotconsiderrecommending theirinclusionasdiagnosticcriteriawhichcouldbeusedin clinicalpractice.Thereisnoscientificevidenceenoughto supportitsuse.Thereisnotenough scientificevidenceto supporttheuseofotherpotentialserumbiomarkersinthis context.

Exposure(tobaccoandbiomasscombustion)

Smokinghasbeenestablishedasariskfactorforthe devel-opmentofCOPDanditacceleratestherateoflungfunction declineinbothasthmaandCOPD.1,2,50_{Additionally, itmay} beatthebottomoffixedairwayobstructiondevelopmentin asthmatics.1,51_{Inasimilarway,exposuretobiomass} combus-tion is also associated with airway obstruction.2,52 _Thus, (currentorpast)smokinghabits,aswellasahistoryof expo-suretobiomass,aregenerallyincluded ascriteriaforthe diagnosisofACOS.

Proposedrecommendation:thepresenceofcurrentor past history of smoking or biomass combustion exposure shouldbeconsideredasacriterionforthediagnosisofACOS, asthis exposure is associated with the development and severityofasthmaandCOPD.

Historyofasthmaoratopybefore40yearsold

Thediagnosis of asthmais mostcommonly made in child-hood,butsometimesitcanonlybediagnosedinadulthood.1 Additionally, asthma, by itself, is a risk factor for COPD development.53 _{Ontheotherhand,atopyisassumedtobe} ariskfactorcommonlyassociatedwithasthma,butcanalso befoundinasignificantpercentageofpatientswithCOPD andmay be a risk factor for developmentof COPD.1,54---56 Thus, in most publications, for patients diagnosed with

COPD,thesecriteriahavebeentakenintoconsiderationfor diagnosisofACOS.

Proposedrecommendation:thepresenceofaprevious history of atopyis an aspect often found in this group of patients,soitshouldbetakenintoaccountwhenconsidering thediagnosis,althoughitcannotbeassumedasadiagnostic criterion. Itwasnot considered importantto establishan agelimitthatshouldbetakenintoaccountorappliedasa criterion.

Bronchialhyperresponsiveness

Ithasbeenshownthatthepresenceofbronchial hyperre-sponsiveness,eventhoughitmaybefoundasymptomatically in thegeneralpopulation, isassociated withan increased risk of asthma and COPD, and might in both cases be a marker of more severe, more symptomatic disease and a greaterdeclineinlungfunction.57,58_{Infact,bronchial} hyper-responsiveness,presentin virtuallyallasthmaticpatients, mayalsobefoundin60---90%ofpatientswithCOPD,andin theseitmaybeassociatedwithmoresymptomsandgreater severityofobstruction.17,59

Proposed recommendation: since the presence of bronchial hyperresponsiveness is expected in asthmatic patients and bearing in mind that it can be detected in a veryhigh proportion of COPDpatients, the presence of thisaspect,whichhasalowspecificity,wasnotconsidered relevantforthediagnosis.

Definition

Several study groups have published highly diverse pro-posals for definitions and diagnostic criteria for ACOS, most of these recommendations originating from expert opinion consensus.47,60---62 _{The description proposedby the} joint project of GOLD and GINA characterizes ACOS as the presence of persistent airflow limitation with several characteristics usuallyassociatedwithasthma andseveral characteristics usuallyassociated withCOPD.6 _This defini-tionisvague andthediagnosisis basedonthe balanceof attributestaken fromachecklist withtypicalasthma and COPDaspects.

Infact,ACOSisstillpoorlycharacterized,bothinterms ofgeneralriskfactorsandpathophysiology,andintermsof clinicalsymptoms,treatmentresponseandprognosis.This is largelydue tothe factthat patients whomeetcriteria compatible with a possible diagnosis of ACOS are usually excludedfromclinicaltrialstargetingCOPDorasthma.

Table1summarizesthemain definitionsanddiagnostic

criteriaproposedbyseveralauthors.

Therefore,althoughthereisnoagreed,establishedand validated definitionfor ACOS, this entityis widely recog-nized in clinical practice as an individualized phenotype demarcated fromthe spectrumofchronic obstructive air-ways disease.67 _{In addition,the identification/recognition} ofthisphenotypeofchronicobstructiverespiratorydisease may influence the prognostic and therapeutic approach. Thus,itisreallynecessarytoestablishaconsensus,basedon areviewoftheavailableliteratureandprofessional expe-rience, to standardize the diagnosis of ACOS and outline

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AR

TICLE IN PRESS

X X

Simultaneously diagnosisofasthma andCOPD

X X

COPDanddiagnosisor symptomsofasthma beforeage40

X X X(M)

COPDwithprevious diagnosisofasthma

X(M) X(M) X X(M) X(M)

Bronchodilationtest

Verypositiveresponse (>400mLand>15% FEV1)inCOPD

patients

X(M) X(M) X(M) X(M)

Verypositiveresponse (>400mLFEV1) X(M) Positiveresponse (>200mLand>12% FEV1)inCOPD patients X(m)R X(m) X X(m)R X(m)2R X(m)2R Positiveresponse (≥15%FEV1or≥12% and200mLFEV1) X Eosinophilia Peripheral,inCOPD patients X(m) X(m) Insputum,inCOPD patients X(M) X(M) X(M) Other

↑TotalIgEorprevious historyofatopy +COPD X(m) X(m) X X(m) X X(m) X(m) ↑FENO+COPD X(M) X(M) Bronchial hyperre-sponsiveness+DPOC X(M) X EvolutionofPEF typicalof asthma/PEF variability+COPD X(m) X Age≥40years X

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anapproachstrategyfor thisgroupof patients,for whom randomizedcontrolledclinicaltrials(RCTs)arestillmissing. Proposed recommendation: the diagnosis of ACOS shouldbeconsideredintheconcomitantpresenceof: 1) simultaneous clinical manifestations characteristic of

bothasthmaandCOPD

2) persistent airway obstruction, defined as post-bronchodilatorFEV1/FVC<0.7,evaluatedinaperiodof clinicalstability

3) positive responsein bronchodilatortest,definedby an increaseinthevalueofFEV1of≥200mLand≥12%from baseline

4) currentorpasthistoryofsmokingorexposuretobiomass combustion

As aspects that are usually present in this group of patients and that can be taken intoaccount in the diag-nostic consideration, we highlight peripheral eosinophilia (>300eosinophils/␮Lor>5%ofleukocytes)andprevious his-toryofatopy.Inannex1,arepresentationoftheproposed algorithmispresented.

Prevalence

Views onthe prevalence of ACOSvary greatly amongthe publishedstudies,reflectingthedifferentdiagnostic crite-ria applied in each, as well as the different populations analyzed.68---76

In asthmatic patients, prevalence of ACOS has been reportedasranging between 13and 30%.22,77---79 _However, whenbroadercriteriaareusedandsubpopulationsofolder patientsare analyzed,the prevalence recorded ishigher; forexample,inasubgroupofasthmaticpatientsolderthan 65years,aprevalenceof61%wasfound.22

Withinthegroupof patientswithCOPD,theestimated prevalenceofACOSisalsovariesgreatlyacrossstudies,with valuesrangingbetween9%and55%.18,65,77,80---82

Inthepopulation-basedstudyPLATINUM,theprevalence ofACOSwas2%,andtheprevalenceofasthmaandCOPDwas 2%and12%,respectively.18_{Inothersimilarstudies,a} preva-lenceof ACOSin thegeneral population ranging between 2and5%wasfound,withincreasingprevalenceassociated withanincreaseoftheagegroupbeinganalyzed.22,83

Due to lack of studies to date, ACOS prevalence data relatingtoPortugalarenotknown

Approach

Treatment

Similartotheotherchronicobstructivepulmonarydiseases, the therapeutic approach to ACOS patients always starts witharisk factor exposurecontrol, inwhich we highlight smoking, exposure to biomass, allergens exposure, anti-infectiousprevention,amongmanyothers.It isimportant tohaveaclinicalbasedapproach,balancedwiththe pres-enceofcomorbiditiesandfurtherassessment(lungfunction, eosinophilia,amongothers).

In terms of pharmacological therapy, the clinical evi-dence in ACOS is limited, because the majority of these

patientsaresystematicallyexcludedfrommostofthe clin-icalCOPDandasthmapharmacologicalclinicaltrials.Only threestudies(onewiththeuseofLAMA84_{andtheothertwo} with oral corticosteroids85,86_{) were performed specifically} in this group of patients. The majority of the consen-susdocumentspoints,however,towardsanimportantrole of bronchodilators with LABA, isolated or in combination withLAMA, alwaysassociated withICS.6,63,66,87 _{The use of} ICS/LABAasafirstlineoftherapy isrecommendedbythe majorityoftheconsensus.

TheuseofLABAaloneinasthmapatientshasbeen asso-ciated with poor disease control, increase of its severity and mortality, and therefore its use is contraindicated in asthma patients.88 _{Although thisfact has notbeen} estab-lished inACOS, themajorityof theguidelinesextrapolate thisconsiderationintothisgroup.

The use of ICS in ACOS patients has been revealed as beneficialwhencomparedtoitsuseinCOPD,resultinginan improvementinFEV1.89 TheICSdoseusedcanbeadjusted toeachpatient,dependingontheirsymptomsandsmoking habits.64,90,91

TripletherapywithICS/LABA/LAMAhasshownan exacer-bationreductioninCOPDpatients92_{butthisfacthasyetto} be proven in ACOS. However,most of the consensus doc-uments consistently point to the use of this approach in non-controlledpatientswithICS/LABA.

New therapies have begun to be studied in ACOS patients,suchastheuseofthemonoclonalantibody anti-IgE, omalizumab, which seems to show promising results in terms of symptomatic improvement and exacerbations reduction.93,94 _{Otherspecifictherapiesfocused onthe} rel-evant role of eosinophils (anti IL-5, anti IL-13 and anti IL-33drugs),treatmentsregardingtheneutrophilic expres-sion (macrolides, p38 mitogenactivated protein kinase inhibitors,antiIL-1andantiIL-17antibodies, phosphodie-sterase 4 inhibitors) could play a significant role on the prognosisofACOSpatients.95

Asreferredtoabove,theappropriatetreatment ofthe frequent comorbidities present in these patients is cru-cial, aswellasan effective vaccinationcoverage andthe implementationofapulmonaryrehabilitationprogramme, especiallyinpatientswithahigherCOPDburden,whichin moreadvancedstages,determinestheprognosisofpatients withACOScharacteristics.Moreover,itisnecessaryto ver-ifyinaconsistentandregularwaytheinhalationtechnique, reinforcing the importance of the inhaled therapy adher-ence.

Proposedrecommendations:

- ICS/LABAasfirstline therapy.Inpatients whicharenot controlled or whose clinical severity justifies, a triple therapywithICS/LABA/LAMAshouldbeused.

- Non-pharmacologicaltherapysuchaspulmonary rehabili-tationshouldbedoneinACOSpatientswithuncontrolled symptomatology(frequentexacerbations).

- Comorbiditiestreatmentshouldbeoptimizedforabetter controlofthelungdisease.

- Riskfactorsexposurecontrol(smoking,biomass,allergens exposure)andvaccination coverage(influenzaand anti-pneumococcal).

Referralandfollow-up

The best way forward for these patients in terms of health care is still not completely established, however, the GINA and GOLD recommendation document reveals some guidancesuch as: ACOSpatients shouldbereferred to a specialist if they present persistent or uncontrolled symptomsand/orcommonexacerbations,ifthereisa diag-nostic uncertainty,atypical symptoms/signs,or important comorbidities.6

Proposedrecommendations:

- ThepatientwithACOSshouldbegivenaspecialized hos-pitalappointment if control of symptoms has not been achievedor ifthereis adiagnostic uncertainty.If clini-calstabilityisachievedinaconsistentway,thepatient’s follow-upcanbeperformedbythefamilydoctor. - Thefrequencyofthefollow-upofthesepatientsisgoing

todependontheirclinicalstabilityand/orseverity. How-ever, giventhecharacteristics shown bythese patients, amedicalobservationforsymptomscontrolon,atleast, atwiceayearbasisisrecommended,aswellasa spiro-metricevaluationwithabronchodilatortestatleastonce ayear. Tohelptheassessmentofsymptomscontrol,the mMRC dyspnoea scale and, especially, in patients with ahigherasthmaticcomponent,theCARATquestionnaire (althoughnotvalidatedinACOS)shouldbeused.

Conclusions

Thisdocumentsetsforwardtheheterogeneityofdiagnosis thatstillexistsinthisarea,whichunderlinesitsimportance asafirststageintheexaminationofthisfield.Itseemsclear thereis agroupofpatients whosharecharacteristics that crosstheCOPDandasthmaspectrum,itisthereforecrucial toachieveamoreaccurateidentificationofthesepatients, enabling a more effective therapeutic approach. In the futurethis characterization of ACOSpatients willprovide forthedevelopmentofnationalprevalencestudiesandthe evaluationoftheimpactofdifferentpharmacologicaland non-pharmacologicaltherapies,whichwillcomplementour knowledgeofthisentityandoptimizetreatmentstrategies. Thisdocumentconstitutesafirststeptowardswhatmight become a nationwidePortuguese consensusin relation to ACOS, which would strengthen the medical community’s visiononthissubject.

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethatnopatient dataappearinthisarticle.

Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

Acknowledgements

We would liketo thank the participation,as members of the Advisory Board, and contribution in the face-to-face meeting for discussion and revision of the theme to the physicians:MartaDrummond,MD,PhD,MafaldavanZeller, MD,Margarida Redondo, MD,Eurico Silva, MD, RuiCosta, MD,JaimeCorreiadeSousa, MD,PhD,Ana TodoBom,MD, PhD,TiagoAlfaro,MD,BugalhodeAlmeida,MD,PhD,Manuel BrancoFerreira,MD,PhD,SandraAndré,MDandFilipaTodo Bom,MD.

Itis recognizedthesupportin theformof Educational GrantfromMundipharmaPharmaceuticalsLtd.

Appendix

A.

Supplementary

material

Supplementary material associated with this article can be found in the online version available at doi:10.1016/

j.rppnen.2016.11.005.

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