Understanding COPD: A Vision on Phenotypes, Comorbidities and Treatment Approach

www.revportpneumol.org

SPECIAL

ARTICLE

Understanding

COPD:

A

vision

on

phenotypes,

comorbidities

and

treatment

approach

E.

Fragoso

_,

_S.

_André

_,

_J.P.

_Boleo-Tomé

_,

_V.

_Areias

_,

_J.

_Munhá

_,

_J.

_Cardoso

_,

_on

behalf

of

GI

DPOC-Grupo

de

Interesse

na

Doenc

¸a

Pulmonar

Obstrutiva

Crónica

a_{PulmonologyDepartment,HospitaldeSantaMaria,CentroHospitalarLisboaNorte,EPE(CHLN),Lisbon,Portugal} b_{PulmonologyDepartment,HospitalEgasMoniz,CentroHospitalardeLisboaOcidental,EPE(CHLO),Lisbon,Portugal} c_{PulmonologyDepartment,HospitalProf.DoutorFernandodaFonseca,EPE,Amadora,Portugal}

d_{PulmonologyDepartment,HospitaldeFaro,CentroHospitalardoAlgarve,EPE,Faro,Portugal} e_{DepartmentofBiomedicalSciencesandMedicine,AlgarveUniversity,Portugal}

f_{PulmonologyDepartment,CentroHospitalardoBarlaventoAlgarvio,EPE,Portimão,Portugal}

g_{PulmonologyDepartment,HospitaldeSantaMarta,CentroHospitalardeLisboaCentral,EPE(CHLC),Lisbon,Portugal} h_{NovaMedicalSchool,NovaUniversity,Lisbon,Portugal}

Received17September2015;accepted2December2015

Availableonline27January2016

KEYWORDS COPD; Phenotypes; Riskfactors; Modifiablerisk factors; Symptoms; Severity; Comorbidities; Exacerbations

Abstract ChronicObstructivePulmonaryDisease(COPD)phenotypeshavebecomeincreasingly recognizedasimportantforgroupingpatientswithsimilarpresentationand/orbehavior,within the heterogeneity ofthe disease. The primary aimof identifyingphenotypes is to provide patientswiththebesthealthcarepossible,tailoringthetherapeuticapproachtoeachpatient. However,theidentificationofspecificphenotypeshasbeenhinderedbyseveralfactorssuch aswhichspecificattributesarerelevant,whichdiscriminantfeaturesshouldbeusedfor assign-ingpatientstospecificphenotypes,andhowrelevantaretheytothetherapeuticapproach, prognostic and clinical outcome. Moreover, the definition ofphenotype is still not consen-sual. Comorbidities, risk factors, modifiable risk factorsand disease severity, although not phenotypes,haveimpactacrossallCOPDphenotypes.

Althoughtherearesomeidentifiedphenotypesthatarefairlyconsensual,manyothershave beenproposed,butcurrentlylackvalidation.The on-goingdebateaboutwhichinstruments andtestsshouldbeusedintheidentificationanddefinitionofphenotypeshascontributedto thisuncertainty.

In thispaper,theauthors reviewpresentknowledgeregardingCOPDphenotyping,discuss theroleofphenotypesandcomorbiditiesontheseverityofCOPD,proposenewphenotypes

∗_{Correspondingauthor.}

E-mailaddresses:[email protected](E.Fragoso),[email protected](S.André),[email protected](J.P.Boleo-Tomé), [email protected](V.Areias),[email protected](J.Munhá),[email protected](J.Cardoso).

http://dx.doi.org/10.1016/j.rppnen.2015.12.001

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

andsuggestaphenotype-basedpharmacologicaltherapeuticapproach.Theauthorsconclude thatapatient-tailoredtreatmentapproach,whichtakesintoaccounteachpatient’sspecific attributesandspecificities,shouldbepursued.

© 2016 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a com-plex,multicomponent,heterogeneousdisease.Theclassical COPDclassificationhasbeenbasedonForcedExpiratory Vol-umeinthefirstsecond (FEV1), butthisaloneis nolonger accepted as a single parameter to define severity or to guidetreatment.1_{TheupdatedGlobalInitiativeforChronic}

ObstructiveLungDisease(GOLD)recommendationspropose treatment approachbased on twoadditional parameters, symptomsandexacerbations,whichmaystillbeinsufficient toreflecttheheterogeneityofCOPD.Thereisarealneedto identifyspecificattributesinordertogroupthe heteroge-neousCOPDpopulationintodifferentphenotypes,andguide a patient oriented therapeutic approach. Several pheno-typeshavealreadybeenproposed,2---21_{buttheunderstanding}

ofwhichattributesdefinewhichgroupsofpatientsremains achallenge.

Itisrecognizedthatfuturestudiesshouldfocuson estab-lishingsimple algorithms based on the most discriminant featuresforassigningpatientstospecificphenotypes.Such algorithms have tobe tested in validationcohorts before theycanbeusedinclinicalpractice.4_{Hanetal.proposea}

schematoidentifycandidatephenotypesandvalidatethem oncetheirrelevancetoclinicaloutcomesisestablished.6

COPD patients frequently have several

comorbidities6,14,15,18,22,23 _{that should be actively sought}

for andduly addressed therapeutically.Some associations between comorbidities and phenotypeshave been identi-fied,andalthoughtheyarerelevanttotheoverallseverity andrisk,theirrealimpactonCOPDisnotclearlyestablished. Inthispaper,theauthorsreviewpresentknowledgeand acceptedcriteriafor thesecrucialaspectsofthedisease, proposedefinitionsforphenotypingCOPD,discusstheroleof phenotypesandcomorbiditiesontheseverityofCOPD,and suggestatherapeuticapproachforconsensualphenotypes.

Phenotypes,

risk

factors

and

severity

Phenotypes

WiththerecognitionthatFEV1isnotsufficientto

character-izeandclassifyCOPDpatients,theconceptofphenotypes re-emerged,andthetraditionalconceptof‘‘bluebloaters’’ and‘‘pink puffers’’,abandonedin the past, isnow being replacedbyavarietyofdifferentphenotypes.24 _The

phen-otypingprocess emergesasa consequence of the clinical need to group patients with similar presentation and/or behavior,withintheheterogeneityofthedisease,inorder toprovide themwiththebesthealth carepossible, tailo-ringthetherapeutic approachtoeach patientinterms of

symptoms control, disease progression, health status and qualityoflife.

Hanetal.6_{proposedthefollowingphenotypedefinition:}

‘‘asingleorcombinationofdiseaseattributesthatdescribe differencesbetweenindividualswithCOPDastheyrelateto clinicallymeaningful outcomes(symptoms,exacerbations, responsetotherapy,rateofdiseaseprogression,ordeath)’’. Itfollowsfromthisdefinitionthatpatientsmaybeclassified intodistinct prognosticand therapeuticsubgroups. Mirav-itllesetal.25_{simplifythisdefinitionbysayingthat‘‘theterm}

COPDphenotypeisreservedforthedifferentclinicaltypes that have therapeutic impactand areidentified in COPD patients’’.Salzman proposesthatan outcomecanalsobe included,24_{andsomeauthorssuggestthat,dependingonthe}

context, someCOPD features,e.g., dyspneaor exacerba-tions,couldbeconsideredbothoutcomesandphenotypes.26

Weproposethataphenotypeisanattributeorasetof attributesthatcanbeclinicallycharacterized,issomewhat stableovertime,anddefinearelevantgroupofindividuals, bothintermsoftherapeuticandprognosticimplications.

Riskfactors

The latest GOLD guidelines contemplate the cross-combination of two distinct dimensions: a symptom dimension,assessedbytheModifiedMedicalResearch Coun-cil Dyspnea Scale (mMRC) or the COPD Assessment Test (CAT),andariskdimension,assessedbyFEV1andfrequency

of exacerbations. Patients are classified as A, B, C, or D dependingonthecombinationofthesethreeparameters.25

However,differentpatientsexistwithintheriskdimension, giventhatariskassessmentbasedonthedegreeofairflow obstructionisdifferentfromariskassessmentbasedonthe occurrenceofexacerbations.Moreover,exacerbationshave differenttypes,severityandpresentations,andarenot pre-dictiveofthesamerisk.Also,patientsmayhavesymptoms and risk that are independent of the respiratory disease, namelythepresenceofsignificantcomorbidities.

Thus,risk and symptoms shouldbe considered vectors or dimensions of COPD, which can be present in several phenotypes.

Some factors can be present in several phenotypes andmodify thedevelopmentandclinical course ofCOPD. In this view, comorbidities would be modifying factors since they both change over time and can exist across allphenotypes,27 _{andsowouldinflammation}28 _andgenetic

polymorphisms,11,29_{sincetheymodifytheexpressionof}

rec-ognized phenotypes. However,noprecise definitionexists formodifyingfactorsinCOPD.

In COPD, the most consensual modifiable risk factor (or behavior) is smoking. Other modifiable behaviors that impact COPD are Body Mass Index (BMI)30 _{and physical}

activity.31 _{Environmentalexposure suchasexposure toair}

pollutioncanbemodifiablebutcanhardlybeconsidereda behavior. Furthermore,it canbe arguedthat professional exposureisconsideredamodifiableriskfactor,asforsome patientsitcontributestoworseningofthediseaseanditcan beinterrupted.

Severity

Historically,assessment ofCOPDseveritywasbasedsolely on FEV1. Currently, and although spirometry is required

to establish a diagnosis of COPD, it is considered insuf-ficient to describe COPD severity.1,15,32 _{A comprehensive}

assessment of COPD including symptom assessment using validatedquestionnairessuchasmMRC,theClinicalCOPD Questionnaire (CCQ)33 _{and CAT,}34 _{degree of airflow}

limi-tation, riskof exacerbations, existenceof comorbidities,1

overallimpactofCOPDinapatient’sQualityofLife(QoL), and exercise tolerance35 _{and levels of physical activity,}

is nowrecommended.The latter isparticularly important because the amount of physical activity a patient takes and their functional status predict exacerbations, hospi-talizations,and mortality.31 _{Indeed, theUPLIFT study has}

shown that although FEV1 did not differ between

treat-ment groups (long-acting muscarinicantagonist [LAMA] vs placebo),healthstatus,timetofirstexacerbationandtime to exacerbationresulting in hospital admission were bet-ter in the LAMA group,36 _{strongly suggesting that FEV}

1

perseis notsufficient todeterminedisease severity.The TORCHstudy showed that FEV1 declined faster in current

smokers,patients withalowerbody massindex,patients withmoderatedisease,andpatientswhoexacerbatedmore frequently,37 _{also suggesting that comorbidities might be}

majordeterminantsofdiseaseseverity.18

COPD severityisdifferent fromCOPDactivity.Severity hasbeen proposedasa conceptthatshouldberelatedto lossoforganfunctionthateventuallyimpactsonfunctional impairmentandprognosis,whereasCOPDactivityrelatesto theactivationlevel ofthecellularmechanismsunderlying diseaseprogression.26

We propose that disease severityshould bedefinedby mortalityrisk,dailyimpactofthediseaseandlossoforgan function.

Identifying

phenotypes

in

COPD

Detailed questionnaire data and pulmonary function tests have been proposed todifferentiate between COPD phenotypes.12 _{Multidimensional indexes built to}

strat-ify risk/severity are not useful in identifying different phenotypes. Nevertheless, functional measurements of severity that correlate with mortality in COPD, such as FEV1,theratioofinspiratorycapacitytototallungcapacity

(IC/TLC), the diffusing capacity of the lung for carbon monoxide (DLCO), 6-min walking distance, and maximum O2 consumption or maximum watts on exercise testing,

may help in identifying phenotypes. Although it is not diagnostic, bronchodilator responsiveness can be useful in the distinction between asthma and COPD, and in the definition of the mixed asthma-COPD (ACOS) phenotype. However,pulmonaryfunctiontestsdonotidentifysubsets thatrespondtoparticulartherapies.24

Imaging techniques, such as Computed Tomogra-phy (CT),6,12,38---42 _{high-resolution computed tomography}

(HRCT)16,43 _{and magnetic resonance imaging (MRI)}39 _have

been suggested to be of clinical use in discriminating betweensome COPD phenotypes,and maybe novel tools thatwillallowforamoreaccuratediagnosisandhelpguide clinical management.39,40 _{The usefulness of these}

tech-niquesis stilldebatable, sinceit is recognizedthat there arefactorsnoteasilyassessedbycurrenttechniques.41

We propose that a combination of questionnaires, objective parameters such as pulmonary function tests, includingIC/TLC, 6-minwalkingdistance, exercisetesting and thoracic CT, should be able to discriminate between phenotypes.

Mostclinicallyrelevantphenotypes

The most consensual or most clinically relevant pheno-types are the non-exacerbator phenotype,14 _{the ACOS}

phenotype,8,12,14,15,17 _{the exacerbator with}

emphy-sema phenotype,8,12,14,16 _{the exacerbator with chronic}

bronchitis,8,12,14,16,18 _{and the frequent exacerbator.}2,6,7,23

However, even these most consensual phenotypes may not be easy to manage, since considerable overlap has been described between COPD phenotypes with chronic bronchitis,emphysema or asthma, which has therapeutic consequences.12_{ACOPD-bronchiectasisclinicalphenotype}20

hasalsobeen suggested.TheSpanishguidelinesrecognize theneed toidentify bronchiectasis and chronic bronchial infectionin patientswiththeexacerbatorphenotypewith chronic bronchitis, but do not support them as clinical phenotypeswiththeirownclinicalrelevance forthe time being.14

We agree with the less symptomatic non-exacerbator, the exacerbator with emphysema, the exacerbator with chronicbronchitis, andACOSphenotypes asbeing fourof themostclinicallyrelevantphenotypes,propose the addi-tionofthesymptomaticnon-exacerbatorwithemphysema asaclinicallyrelevantphenotype,andfurtherproposethat theCOPD-bronchiectasisshouldbeconsideredanimportant clinicalphenotypewithitsownclinicalrelevance---Fig.1.

Otherpotentialphenotypes

Several other COPD phenotypes have been

proposed,3---5,10,11,13,21 _{but it remains unclear if these}

are actually specific phenotypes. The proposed fast decliner phenotype19 _{can only be identified over time}

and not a priori and thus it is difficult to include as a clinical phenotype. The combined pulmonary fibrosis and emphysema syndrome9 _{is another potential, albeit not}

consensual,phenotype, in which imagingis pivotal. Since many aspects of COPD clinical phenotypes are related to inflammation,28 _{it has been proposed that the presence}

of systemic inflammation may represent a unique COPD phenotype,6_{andpatientswithsubstantialsystemic}

inflam-mation and relevant comorbidities might form specific phenotypes that lead tomodified treatment strategies.18

However, this is not consensual.27 _{Therefore, systemic}

inflammationandcomorbiditieswouldbemodifyingfactors andnotphenotypes.Currentsmokerscouldalsorepresent

Chronic respiratory symptoms in patients with risk factors for COPD

FEV 1/FVC post-BD <70% → COPD

History of exacerbations

≥2/year

(or≥1 hospitalization) (no hospitalizations)<2/year

Wheezing as a dominant feature Symptom variabilty

Significnt response to bronchodilation Sputum or peripheral eosinophilia

Past history of bronchial asthma

Overlap asthma-COPD (mixed phenotype)

Scarce symptoms

Severe lung overinflation (IC/TLC<25%)

End-stage lung disease: Chronic respiratory failure Heavily symptomatic (marked exercise intolerance) Optional: Thoracic CT showing thickened bronchial walls, large/ small-airways mucoid impaction Cough and phlegm most of the days for 3 consecutive months during 2 years Thoracic CT: Emphysema-predominant pattern Thoracic CT: Significant bronchiectasis

Relatively preserved lung function

Other features

Non exacerbator Exacerbator

Exacerbator with

emphysema Less symptomatic

Comorbidities Symptomatic (usually emphysematous) COPD-bronchiectasis Exacerbator with chronic bronchitis Phenotype?

Clinical features, complete pulmonary function test (PFT) , thoracic CT scan, additional assessments (sputum cytology, complete blodd count)

Figure1 Proposedmostclinicallyrelevantphenotypes.

a different phenotype, but since they must be identified across all phenotypes and intensive smoking cessation strategiesmustbeadopted intheseindividuals,27 _smoking

would bea modifiable risk factor, or behavior, and not a phenotype.COPDseverityisnotaphenotypicfeaturesince itcanbeaconsequenceofaspecificclinicalphenotype.26

Undoubtedly,theissueofwhichclinicalphenotypesactually existwarrantsfurtherdiscussion.

Finally,itmustbeemphasizedthatcomorbidities, respi-ratoryfailureandend-stagediseasehaveimpactacrossall COPDphenotypes.

Risk

factors

---

significant

comorbidities

The presence of significant comorbidities is perhaps one of the most important modifying risk factors for sever-ity in COPD. They contribute to the overall severity in individual patients,18,44 _{have a major impact on quality}

of life,23 _{increase the risk of certain causes of mortality}

and of all-cause mortality3,15,23 _{and are major causes of}

hospitalization,14,23_{especiallycardiovasculardisease(CVD)}

and cancer.3,15,45 _{They should always be considered as a}

very important feature in all patients, regardless of the stageorgrade.

Althoughtheprevalenceofdifferentcomorbiditiesvaries withtheGOLDstage,46_{availableevidencedoesnotsupport}

arelationshipbetweencomorbiditiesandGOLDgroups. Dys-pnea,health status,exacerbationsandcomorbiditiessuch as chronic heart failure anddepression are markedly dif-ferentamongsubjects withthesame GOLDclassification, underscoring the need for a multidimensionalassessment ofCOPDpatients.3_{Metabolicandcardiovascular}

comorbidi-ties appear relatively unrelated to the degree of airflow limitation.4

Comorbidities can be associated with any clinical phenotype27 _{andshouldbeconsideredinacomprehensive}

therapeutic approach. A few recent studies have investi-gatedassociationsbetweencomorbiditiesandspecificCOPD phenotypes,47---50 _{oridentifiednovel phenotypesassociated}

withcomorbidities,3---5,21_{butresultsarestillscarceto}

estab-lishassociationsordrawdefiniteconclusions.Theexistence of COPDis associated withhigher risk for other diseases, suchascardiovasculardiseaseandlungcancer,butwhether thisassociation is due tocommonrisk factorsor common disease pathways (e.g.,smoking), susceptibilitygenes, or impairedclearanceofcarcinogensisnotclear.18,23_Giventhe

factthatmorethan50%ofCOPDpatientshavefourormore comorbidities,51_{itiscurrentlydifficulttoascertainwhether}

COPDisadiseasedistinctfromitscomorbiditiesorwhether thesearepartofthespectrumofCOPDmanifestations.

Comorbidities in COPDshouldbemanaged inthe same wayasforallotherpatientswithoutCOPD.1_Infact,there

is growingevidencethat someof thetreatmentsusedfor comorbidities,suchasbetablockers,mayhaveabeneficial effect on the course of COPD. The Spanish guidelines provide an outline of the most common comorbidities of COPD,withitsdiagnosis andtreatment.14 _{Finally,whether}

treatmentofco-morbidconditionsaltersthenaturalhistory of COPD or whether treatment effectiveness of COPD is altered by the presence of a concomitant comorbidity awaitsfurtherstudy.6,52

Cardiovasculardisease

The most frequent comorbidities associated with COPD are those related to the cardiovascular system.1,15,53,54

TheLungHealthStudyreportedthatcardiovascularcauses accounted for 42% of first hospitalizations and 44% of second hospitalizations of patients with relatively mild COPD,whereas respiratorycauses accounted for only14% of hospitalizations.15 _{Hypertension seems to be the most}

prevalent cardiovascular comorbidity1,53 _{across all GOLD}

stages.46 _{COPD patients are at greater risk of}

cardiovas-cularmortality,55 _{withatrialfibrillation/flutter,congestive}

heartfailureandcoronaryarterydiseasehavingacombined prevalence of 58.9% and being strongly associated with increasedriskofdeath.53_{Moreover,heartfailureprevalence}

is muchhigheramongpatients experiencing an exacerba-tion,andistheleadingcauseofhospitalizationanddeath inCOPD patients.54 _{Also,aworseningofheart failureis a}

challengeinthedifferentialdiagnosisofanexacerbation.1

The presence of heart failure may bea confounding fac-toraswell,whentryingtoidentifyapatient’sphenotype. With respect torecurrent interstitial lung edema, it may be responsible for wheezing and dyspnea in the setting of chronic obstructivelung disease, thus misidentifying a patientashavingACOS.

Itshouldbenotedthatdifferentcardiovasculardiseases haveadifferentclinicalimpactonCOPD,andtheGOLD2015 guidelinespropose that fourseparate entities withinCVD shouldbeconsidered:ischemicheartdisease,heartfailure, atrialfibrillationandhypertension.1

Although the precise mechanisms by which COPD may be a risk factor for CVD are not fully understood, evi-dencehassuggestedthatairflowlimitationandparticularly hyperinflation affect cardiac function and gas exchange, and that inflammatory mediators in circulation may initi-ateorworsencomorbiditiessuchasischemicheartdisease

andheartfailure.1,15_{Hyperinflationdirectlyaffectscardiac}

dimensions, diastolicfilling,systolicejection fractionand cardiacmass,thusbeingacrucialcomponentforsomeofthe mostrelevantclinicalaspectsofCOPD,dyspneaand exer-ciselimitation.56,57 _{Ontheother hand,tworecentreports}

didnotfinddifferencesinlow-gradesystemicinflammation betweenfiveidentifiedcomorbidityclusters,oneofwhich wascardiovascular,51_{norconfirmedthatamore}

inflamma-toryCOPDmaybeacoronaryheartdiseaseriskfactor.55_One

possibleexplanationisthatinflammationisindirectly asso-ciatedwithcardiovascularrisk,influencingotherfactorsor comorbiditiesthatinturnincreasethecardiovascularrisk.

Cardiovascularcomorbiditiesshouldbetreatedaccording tousualguidelines,andbeta-blockersshouldnotbe with-heldfromthesepatients,althoughselectivebeta1-blockers

arepreferred.1 _{In fact, recent studies reported a}

reduc-tionof theriskfor exacerbationsrelatedtobeta-blockers use. The use of statins to reduce exacerbations is more controversial, and recent studies have reported different results.58---61

WeagreethatCOPDpatientsshouldbeactivelytreated for cardiovascular comorbidities, toreduce CV exacerba-tionsandmortalityandthatcardioselective beta-blockers shouldbeusedifrecommendedfortheexisting cardiovas-cularcomorbidity.

Lungcancer

Agrowing body of evidence supports COPD asa risk fac-torforlungcancer.62_{However,theincidenceoflungcancer}

amongdifferentstagesofCOPDhasshowndifferentresults, withsome studies finding increased incidence withCOPD severity45 _{and others reporting the opposite.}63 _{A possible}

justificationforthesecontradictoryresultscouldberelated to the two proposed underlying mechanisms associating COPDtolungcancer:ifapatienthasgeneticorepigenetic riskfactorscommontobothdiseases,thenlungcancercould bemoreprevalentatlesssevereCOPDstages,andpatients inthemoreseverestageswouldnothavethepredisposing riskfactors;if,ontheotherhand,chronicinflammationis theculprit,then the worsethe COPDseverity, thehigher theprobabilityofdevelopinglungcancer.However,thetrue reasonforthesedifferentresultsawaitsfurtherstudies.

Earlylungcancerdiagnosisisofparamountimportance, andarecentstudysuggeststhatcurrentandformer smok-erswithCOPDmaybenefitfromlowerpack-yearthreshold forlungscreeningeligibility.64_{Apotentiallyinteresting}

com-plementarytestwouldbetomonitorcirculatingtumorcells, whichhavebeenshowntobedetectedinpatientswithCOPD withoutclinicallydetectablelungcancer.65

LungcancerinCOPDpatientsshouldbetreatedaccording tolungcancerguidelines1_.

Wepropose thatCOPD patientsshouldbescreened for lung cancer regardless of their smoking history, for early diagnosis.

Nutritionalanomalies,anxiety/depressionand metabolicpathologies

Nutritionalanomalies, metabolicdisturbancesand psycho-logical disorders arethree comorbidity clustersidentified

in COPD.51 _{The link between COPD and these and other}

frequentcomorbiditiesmaybesystemicinflammation due to spillover,66 _{but this hypothesis remains to be fully}

proven.52,67_{Depressionand/oranxietyarecommoninCOPD}

and should be actively sought for, due to their associa-tionwithincreasedriskofexacerbationsandpoorerhealth status.1 _{LowerBMIis associated withahigher prevalence}

ofacuteexacerbations46 _{andis anindependentriskfactor}

formortalityandpoorprognosis.1_{PatientswithCOPD}

fre-quentlyhave oneor severalcomponentsof themetabolic syndromeand/ortype2diabetes,andseveralmechanisms have been proposed to explain the link between COPD andmetabolicdisturbances.However,theyarestillpoorly understood.68 _{Osteoporosis isalso avery frequent}

comor-bidityinCOPD,oftennotdiagnosedespeciallyinmen,and associatedwithpoorhealthstatusandprognosis.

Metabolic and psychological comorbidities should be treated according to the usual guidelines, with special attentiontoBMIinpatientswithsevereCOPD,whichshould notfallbelow21kg/m2_.1

We agree that these comorbidities should be actively soughtfor,toallowearlytreatment.COPDpatientswill ben-efitfromamultidisciplinarytreatmentapproach,including nutritionalcounselingand psychologicor psychiatric ther-apy.

Assessing

severity

in

COPD

Thereis aneed for suitableinstruments toassessdisease severity,sothatmoreeffective therapeutic measurescan beapplied. Studies suggest that, although COPD patients withmoresevereairflowlimitationsuffermorerespiratory symptoms,worsequalityoflife andgreatercomorbidities thanthosewithmilderimpairment,lungfunctionalonedoes notadequatelyassesstheimpactofthedisease.35

Neverthe-less,FEV1hastobemeasuredsincespirometryisessential

forthediagnosisofCOPD,toevaluatethedegreeofairflow limitation,1 _{to monitor disease progression, and to guide}

therapy.69 _{Alow FEV}

1 is correlated withan increasedrisk

ofexacerbations1_{andpoorprognosis.}69

Asfortheassessmentofotherparameters,severaltools and other tests are currently available, such as ques-tionnaires. The most comprehensive reliable and valid disease-specific health-related quality of life or health status questionnaires1,34 _{are the St. George’s Respiratory}

Questionnaire (SGRQ)70 _{and the Chronic Respiratory}

Dis-easeQuestionnaire(CRQ).71_{However,theyarebothlengthy}

and have scoring algorithms that are too complexto use inroutineclinicalpractice.1,34 _CAT34 _{or CCQ}33 _areshorter,

practical,easy touse measuresthat canbe completedin two minutes, and are considered suitable for a compre-hensiveassessmentofsymptoms.1_{Botharevalidtoassess}

healthstatuscomparedtotheextensiveSGRQ,butpatients prefer the CCQ since it reflects their status better than CAT,asithasmoredetailsonbreathingproblems.72 _mMRC

assesses only the impact of dyspnea, but it is simple to useandrecommended.1_{Theinformationprovidedbythese}

questionnairesmaybetooscarcetoaccuratelyscoreCOPD severity,butallquestionnaireshavelimitationsandcannot extensivelyincludeallvariablesrelevant toassessdisease severity.Allthesescorescanbeusedbyeveryphysicianthat

dealswithCOPDpatients.Onereportadvisescautionwhen classifying patientsaccording totheGOLD groups,44 _since

theclassificationobtained bythemMRCwasnotidentical totheoneobtainedusingCAT.73

Multicomponentindexesincorporateseveraldimensions of COPD.Thethreemost commonlyusedmulticomponent indices are BODE (BMI, FEV1, dyspnea and 6-min walking

distance),30_{BODEx(BMI,FEV}

1,dyspneaandexacerbations)74

andADO (age,dyspnea andFEV1),75 andtheyareall

bet-terpredictors ofmortalityin COPDthanFEV1 alone.6The

BODEindexisconsideredtobethereferenceindex,thebest validatedandofwideruse.However,theneedtoperform the6-minutewalkingtestrendersitimpracticalinprimary care, andin thissetting it canbe replacedbythe BODEx index.74_{Bothindicesshowahighdegreeofcorrelationand}

a similarprognosticcapacityfor predicting mortality.76 _In

patientswithmoreseveredisease,theBODEindexshould always be used.14,76 _{BODE seemsto reflectCOPD severity}

betterthanothermultidimensionalgradingsystems,butnot itsclinical heterogeneity.77 _{The ADO indexseemstohave}

abettermedium-andlong-termpredictivereliabilitywhen comparedtootherindices,butafteradjustingforage,BODE andBODExhaveabetterprognosticreliability.14 _Moreover,

and although ADO seems adequate to predict survival in COPDpatients,75_{itneedsvalidationsacrossawiderangeof}

diseaseseverities.1_{TheBODEIndex,mBODE(BODEmodified}

ingradingofwalkeddistance),e-BODE(BODEplus exacer-bations),BODExandtheADOindexareallbetterpredictors ofmortalityinCOPDthanFEV1alone.

Otherindexessuch asthe COPDPrognostic index,that predicts mortality, hospitalization, and exacerbation fre-quency, and the SAFE and DOSE (Dyspnea, Obstruction, Smoking,Exacerbation)indexes,whichalsopredict exacer-bations, may be useful6 _{as well. It has been questioned}

whether prediction of mortality rates in patients using indexes such as BODE and ADO truly indicates patient-perceivedseverityandguidesappropriatetreatment,18 _but

thisisdebatablesinceotherauthorsarguethat,being mea-surementsofdiseaseseverity,theyareusefulinestablishing prognosisandguidingtherapy.78

All the above mentioned questionnaires and multi-component indexes can be completed during physician appointments and are therefore subject to recall bias. Another problem inherent to the use of questionnaires is thepotentialtogenerateamountsofdatathatarenot pos-sible toprocessand interpretin duetime,thus rendering the effortuseless. A balanceis needed between the use-fulnessoftheinformation,thetimeittakestocollectand process,anditstrueimpactontherapeuticchoices.

There arecurrently noseverity scores adapted to the knownclinicalphenotypesthatcanbeusedtoguide treat-ment. It wouldcertainly be desirable tohave scores that better predict severity in different clinical phenotypes, anditcanbeexpected,giventheheterogeneityofCOPD, that multiple variableswillbe needed for differentCOPD subtypes.19_{We propose the combination of several}

instru-mentstoassessseverityinCOPD:

• FEV1isessential.

• mMRCshouldbeusedtoassesstheimpactofdyspneaon thepatient’sdailylife.

• BODEx can beused ina primary care setting butBODE mustbeusedformoreadvanceddisease,inarespiratory caresetting.

• BothCAT andCCQ arebetterin definingsymptoms,but CAThastheaddedadvantageofassessingdiseaseimpact. • ADOmayalsobeusedincombinationwiththeabove,but

notasastand-aloneindex.

CurrentchallengesregardingCOPDseverityand theroleofexacerbations

SeveralaspectsofCOPDseverityarecurrentlybeing chal-lenged,andthefirstis,perhaps,theroleofexacerbations intheclinicalevolutionofCOPD.

Anexacerbationcanbedefinedas:

• ‘‘an event that leads a care provider to prescribe antibiotics or corticosteroids (or both) or that leads to hospitalization(severeexacerbation)’’;7

• ‘‘aneventthatoftenoccurs,wherethereisarapidand sustainedworseningofsymptomsbeyondnormal day-to-dayvariations’’;32

• ‘‘an acute event characterized by a worsening of the patient’srespiratorysymptomsthatisbeyondnormal day-to-dayvariationsandleadstoachangeinmedication’’.1

Any oftheabove definitionspose challengesfor usein clinicalphenotypingandseverityevaluation.Howlongmust changesinsymptomsbesustainedbeforebeing character-ized as an exacerbation, is it two to three days or less? Moreover,andalthoughtheGOLDdefinitionstates:‘‘leads toachangeinmedication,’’thecriteriainvokedby health-careproviders tojudgewhen toaltermedicationremains unclear. Are these changes in medication quantitative or qualitativeorboth?Importantly,patient-recordedincreases in symptoms that appear tobe exacerbations outnumber thosethatcausethemtopresentformedicalattention.In addition,eventswithworseningsymptomsthatdonotlead patientstoseekadditionalcaremayalsoimpactprognosis.6

Whichclinicalorbiochemicalmarkerscanorshouldbeused to identify or grade severity of exacerbations? These are unfortunatelyunresolvedquestions.

Nevertheless,andregardlessofthedefinition,itis recog-nizedthatexacerbationscontributetotheoverallseverity in individual patients, are associated with an increased mortality,79 _{the risk of exacerbations increases asairflow}

limitationworsens,andhospitalizationforaCOPD exacer-bationisassociatedwithapoorerprognosisandincreased riskofdeath.1

Another important issue is that assessment of disease severity as envisaged in GOLD does not seem adequate. TheGOLDABCDclassificationresultsinveryheterogeneous populations,80 _{and does not reflectdisease progressionor}

mortalityrisk,81,82 _{assomestudies have shown thatGOLD}

B patients may be at a higher mortality risk than GOLD C patients.83 _{GOLD anticipates that lung function can be}

expected toworsen over time,1 _{but does not specifically}

state thatpatients mayswitchbetween GOLDcategories, althoughan analysisfromtheECLIPSEstudyreportedthat patientsmayindeedswitchbetweenanyGOLDcategories.82

Itdoesnotdefinedyspneaasafactorforworseprognosis,

includes subsets of patients defined by low lung function withpatientsdefinedbyfrequentexacerbations,anddoes not value the presence of respiratory failure, which has importantprognosticandtherapeuticimplications.

ThenoninclusionintheGOLDreportofrespiratory fail-ureasacriterionfor diseaseseverity1 _{canhaveimpactin}

clinical practice. Respiratory failure has been historically considered the hallmark of end-stage COPD, and thus, is intrinsically a severity criterion. On the other hand, is it a severity criterion only in the context of end-stage dis-ease, or should respiratory failure bea severity criterion independentofend-stagedisease?

Finally, a patient with COPD is considered to be well controlled who, during follow-up, shows minimal or no symptoms,has had noacute exacerbations sincethe last follow-upvisit, andnoimpairmentin QoLwhile receiving the current treatment.76 _{Therefore, in the same manner}

as severity assessment, disease control should be multi-component.Thereis aneedtointerveneinthesymptoms andbeyond the symptoms,namely usingpharmacological andnon-pharmacologicalapproachesthatreduce therisk, whichmeans,controlthesymptomsandcontrolthedisease beyondthesymptoms.

We acknowledge that GOLD is useful in terms of gen-eralrecommendationsandpublichealth,butdoesnottake intoaccounttheseveralphenotypes,andisnotsufficientto assessmortalityrisk.

Phenotype-based

therapeutic

approach

Information regarding specific therapeutic approaches dependingonthephenotypeisgrowing.TheCanadian guide-lines propose treatment based on frequent or infrequent exacerbations15 _{and GOLD proposes treatment based on}

the risk and symptoms.1 _{The Spanish guideline proposes}

treatmentof COPDbased onfourclinical phenotypesand diseaseseverity.14 _{Bothphysiologic measures and}

patient-reported outcome questionnaires will help identify these patientphenotypesandallowforoptimalpharmacological treatmenttobeimplemented.31

We suggest a phenotype-based pharmacological ther-apeutic approach, considering the six most clinically relevantphenotypeswehaveproposed---Table1.The non-exacerbator and less symptomatic phenotype may start with a bronchodilator that, over time, will preferably bea long-acting medication. In the strongly symptomatic non-exacerbatorwithemphysematheaimshouldbe max-imumbronchodilation.The exacerbatorphenotypeshould be treated first with a long-acting bronchodilator or an associationofbronchodilators,tocontrolsymptoms.Ifnot controlled,atrialofinhaledcorticosteroid(ICS)association is recommended. The ACOS phenotypeshould be treated withLABA/ICSas firstoption. Whenever an ICS is recom-mended, the risk of increased bacterial load84 _{should be}

takenintoconsideration.SpecificICSdruganddoseshould also be appropriately chosen since there is no evidence thatahigherdoseproducesbetterresultsandtheavailable molecules are not equivalent.18,84 _{The chronic bronchitis}

phenotype, if not controlled with the proposed previous treatment, can be treated with a phosphodiesterase-4-inhibitor (PDE4i --- currently not available in Portugal),

Table1 Proposedphenotype-basedpharmacologicaltherapeuticapproach.

Phenotype Therapeuticapproach

Non-exacerbatororlesssymptomatic SABAorSAMA LABAorLAMA Non-exacerbator,symptomaticwithemphysema LABA+LAMA

LABA+LAMA+methylxanthines Exacerbatorwithemphysema LAMA+LABAa

LAMA+LABA+ICS

LAMA+LABA+ICS+methylxanthines

Exacerbatorwithchronicbronchitis LABA+ICS

LAMA+LABA+ICSand/orPDE4i

LAMA+PDE4i+cysteines

MixedAsthma-COPD(ACOS) LABA+ICS

LABA+ICS+LAMA

LABA+ICS+LAMA+methylxanthines

COPD-bronchiectasis LABA+ICS

LABA+cysteines+longtermmacrolide

COPD---ChronicObstructivePulmonaryDisease;ACOS---Asthma-COPDOverlapSyndrome;SABA---short-actingbetaagonist;SAMA--- short-actingmuscarinicantagonist;LABA---long-acting␤2-agonist;LAMA---long-actingmuscarinicantagonist;ICS---inhaledcorticosteroid; PDE4i--- phosphodiesterase-4-inhibitor.

a_{Alternativelyincaseofanaïvepatient,caninitiateLAMAorLABAmonotherapy,withashort-termfollow-up,andincaseof} non-control,shouldprogresstoLABA+LAMA.

mucoactivedrugs(acetylcysteine,erdosteine)and,if con-sideredineffective,alsowithlong-termoralantibiotics(e.g. azythromycin). In the COPD-bronchiectasis phenotype, a long-termoralantibioticshouldbeconsideredandinhaled antibioticscouldalsobeuseful inpatients withend-stage disease.

All phenotypes will benefit from non-pharmacological measuressuchassmokingcessation,influenzaand pneumo-coccalvaccination,minimumof150min/weekofmoderate tointense physical activity, and pulmonary rehabilitation programs.

The proposed phenotype-based pharmacological ther-apeutic approach should be interpreted as a general recommendation,assometreatment optionsarebasedon expertopinion.Werecommendpatienteducation,including correct inhalation technique, prompt recognition of exa-cerbations,andadoptionofhealthylifestyles.Westrongly recommendthattreatmentshouldbepatient-orientedand notCOPD-oriented.Apatient-tailoredtreatmentapproach, whichtakesintoaccounteach patient’sspecificattributes andspecificities,shouldbepursued.

Ethical

disclosures

Protection of human and animal subjects.The authors

declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethatnopatient dataappearinthisarticle.

Right to privacy and informed consent.The authors

declarethatnopatientdataappearinthisarticle.

Conflict

of

interest

The authors declare collaborating and receiving fees frompharmaceuticalcompaniesotherthanNovartiseither through participation in advisory board or consultancy meetings, congress symposia, clinical trial conduct or investigator-initiatedtrials.

Role

of

funding

source

Funding for thispaperwasprovided byNovartis Portugal. Fundingwasusedtoaccessallnecessaryscientific bibliog-raphyandcovermeetingexpenses.NovartisPortugalhadno roleinthecollection,analysisandinterpretationofdata,in thewritingofthepaperandinthedecisiontosubmitthe paperforpublication.

Acknowledgements

The authors wishtothankNovartis Portugalfor the fund-ingfor this paper,whichwasusedtoaccessallnecessary scientificbibliographyandcovermeetingexpenses.

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