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A teaching hospital of Harvard Medical School

ChronicObstructivePulmonaryDiseaseGoingBeyondtheWheeze

RichardM.Schwartzstein,MD

Chief,DivisionofPulmonary,CriticalCareandSleepMedicine

EllenandMelvinGordonProfessorofMedicine

HarvardMedicalSchool

Director,ShapiroInstituteforEducationandResearch

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A teaching hospital ofHarvard Medical School

Disclosures

• Ihavenorelationshipswithcommercialentities.• IreceivesupportfromtheNIHformyresearchondyspnea.

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GoalsandObjectives• Todescriberecentinsightsintotheepidemiologyand

pathologyofCOPD• ToincorporateknowledgeaboutCOPDphenotypesinto

decision-makingabouttreatmentoptions• Todelineatethekeyelementsofthephysiologyofairflow

obstructioninemphysemaandtheimplicationsoftheseprinciplesforclinicalpractice

• TodetailtheessentialelementsintheevaluationofpatientswithCOPDandtohighlightcommonpitfallsintheassessmentofthesepatients

• TooutlinetherapeuticadvancesinthetreatmentofCOPD

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COPD– Definitionincludes:• Chronicairflowobstruction• Rangeofpathologicchangesinthelung(abnormalinflammatoryresponsetonoxiousparticlesorgases)

• Extra-pulmonaryeffects• Theobstructionisprogressive• Mayhaveelementsofairwaysreactivity,i.e.,theobstructionmaybepartiallyreversible

• “Preventableandtreatable.”

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DiagnosisofCOPD– GOLDUpdate

AJRCCM2017;195:557-582 COP

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COPD- Definition“…aclinicalsyndromecharacterized bychronicrespiratorysymptoms, structural abnormalities(airwaysdisease,emphysema, orboth),lung-function impairment (primarilyairflowlimitationthatispoorlyreversible)oranycombinationofthese.”

CelliB,WedzichaJA.NewEnglJMed2019;381:1257-1266.

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COPD–oldphenotypes• Chronicbronchitis:productivecoughfor3months ineachof2consecutive years

• Emphysema: abnormalpermanentenlargementoftheairspacesdistaltotheterminalbronchioles, accompaniedbydestructionoftheirwalls,andwithoutevidenceoffibrosis

• Other:bronchiectasis, airwayreactivity

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COPDPhenotypesareGrowing• Hersh etal.,COPD2007;4:33191patientsearlyonset,severeCOPD(FEV1<40%pred):emphysemapredominant,lowFEV1,lessbronchospasm

• Friedlanderetal.,COPD2007;4:355“Frequentexacerbater,”pulmonarycachectic,rapiddecliner,airwayshyperresponsive,impairedexercisetolerance

• Jankowich andRounds,Chest2012;141:222 (review)Combinedpulmonaryfibrosisandemphysemasyndrome;spiro maybenormal,butCTwithextensiveemphysema

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FrequentExacerbator

2138 pts-ECLIPSE study (Eval of COPD Longitudinally to Identify Predictive Surrogate End points). Exacerbation freq in 3 yrs. Multivariate analysis. New Engl J Med 363:1128, 2010

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COPDEPIDEMIOLOGY:StillGrowingNewEnglJMed2019;381:1257-1266

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GOLDClassificationGlobalInitiativeforChronicObstructiveLung Disease

AmJRespCritCareMed176;532-555,2007

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ShouldPeoplebeScreened forCOPDwithSpiro?• Linetal.,AnnIntMed2008;148:535

– USPreventativeServicesTaskForce– Metaanalysis- couldyoupreventCOPDexacerbations?Reducemorbidityandmortality?Enhancesmokingcessation?

– Screen833ptstoprevent1COPDexacerbation– NodatatosuggestdecreaseM&M– Nodatatosupportenhancedsmokingcessation

• Note:FEV1/FVCratiodeclineswithnormalaging• Controversyabout“smalllungs”ingrowthanddevelopment

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LungSizeatBirth:DiagnosisofCOPDNewEnglJMed2019:381;1248-1256

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RateofHospitalizationforCOPD(comparedtoCAD)PersistsDespite

DecreaseinSmoking

Likely related to aging population.AJRCCM 2017;195:287-291.

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COPDMortality• “Chroniclowerrespiratorydisease”nowthethirdleadingcauseofdeathintheUS.

• Numberofwomendying>men(studiessuggestwomenmaybemoresusceptibletocigs:Silvermanetal.AJRCCM2000;162:2152)

• Onlydiseaseintop10à mortality increasing.• Evensmokers<1ppdhaveé mortalitycomparedtonon-smokers Inoue-Choietal.JAMAIntMed2017

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COPD- CausesofDeathpulm>cardiovasc>cancer NEJM356;851854,2007

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COPD- RiskFactors• Cigarettes- activeandpassivesmoking(30-50%ofcurrent/formersmokershaveairflowobstruction)

• Airwaysreactivity:“DutchHypothesis”– commonlinksbetweenCOPDandasthma

• Geneticsusceptibility– alpha1anti- trypsindeficiency– Othergenesmayexplainvariabilityinriskwithsmoking

• Bacterial,viralinfections;cigsmokereducesimmuneresponse– interferon,IL-1(Chest143:196,2013)

• Airpollutionandoccupationalexposures

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SmokingasRisk:duration>intensity

Smokingdurationgreaterriskforemphysemathancigarettesperday

Thorax 2018;73:414-421

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DutchHypothesis• Firstproposedin1961• Threeprinciples

– VariousformsofCOPDhaveoverlappingfeatures– Oneformofobstructivelungdisease(asthma)mayevolveintoanother(COPD)

– Developmentofobstructivelungdiseaseresultofcombinationof:1)inflammationandairwayreactivity2)geneticpredisposition3)environmentalfactors

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Asthma-COPDOverlapSyndrome(ACOS)

Chest 2019;155:168-177Estimated present in 15-45% of people with obstructive lung disease

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Emphysema(lungsmorecompliant)inNonsmokingAsthmaPatients

Chest 2018;153;6118-629

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GeneticRiskFactors• Alpha1anti-trypsin• 30-50%oflungfunctionmaybedeterminedbygenetics;susceptibilitytoCOPDlikelypolygenic.Familystudies:SiblingsofCOPDpatientsincreasedrisk

AmJRespirCritCareMed164:1419, 2001• Genesactivatedbysmokingmayleadtodisease(Chest133:1344, 2008)OR maybeprotective(protectivegenesinpromoterregionMMP12associatedwithhigherFEV1,reducedriskofCOPD-NewEnglJMed361:2599,2009)

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GeneticsandDiseaseInsights• COPDGeneStudy

– Analysisof2500peopleofAfricanandEuropeanancestry;multivariatelogisticregressionmodeling

– African-Americansmorelikelytohaveearlyonsetdisease

AmJRespirCritCareMed2011;184:414-420• GeneticsandCOPDphenotypes

– 12,031subjects– Fivelociidentifiedwithemphysemarelatedphenotypes,onewithairway,twowithgastrapping

AmJRespirCritCareMed2015;192:559-569

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Smoking® Inflammation• Inflammation- increasedneutrophilsinmucosa;increasedCD-8cellsinsubepithelium.

MaestrelliP.AmJRespirCritCareMed2001

• LVHmorecommoninCOPDpts(evenwithnormalO2levels)withouthxofhypertensionc/wcontrols

Andersonetal.Chest143:91,2013

• Datafeedscontroversyaboutsteroidsandanti-oxidants

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PresenceofIL-17AinLungTissueandSeverityofDiseaseAmJRespirCritCareMed2016:193:1092-1100

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Mepolizumab– AntibodytoInterleukin5• Phase3trial;

randomized,placebo,doubleblinded

• 462patients;eosinophilicphenotype(eos150-300/ml);highdoseICS

• Reducedcumulativeexacerbationsover52weekswhenaddedtosteroids

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MuscleDysfunctioninCOPDSystemiccatabolicstate?

Am J Respir Crit Care Med 2015;191:616COP

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MuscleDysfunctioninCOPDAm J Resp Crit Care Med2018;198;175-186

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COPDPhysiology

• Lossofelasticrecoil• Airwaysobstruction- the‘equalpressurepoint’

• Hyperinflation• AutoPEEPCOPYRIG

LungParenchymasupportsAirwaysSchwartzsteinRM,ParkerMJ,RespiratoryPhysiology2005

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Hyperinflation

• Shorteningofmusclesleadstoamechanicaldisadvantageintheattempttogeneratenegativeintra-pleuralpressure

• Contributestothedevelopmentofventilatorymusclefatigue

• Maystimulatechestwallreceptorscontributingtodyspnea

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Auto-PEEP

• Persistenceofpositivepressureintheairwaysattheendofexhalation

• Associatedwithhyperinflation• Resultsinanadditionalburdenduringinspiration- a‘thresholdinspiratoryload’COPYRIG

AutoPEEP• AutoPEEPaccompaniesexpiratoryflowlimitation

• Heterogeneouslungunitswithvariabletimeconstants(TC=RXC)

• Contributestoworkofbreathing,dyspnea

Marini,AJRCCM2011;184:756

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Dyspnea:Morethanyouthought…• Basicphysiologyofdyspnea iscomplex- manyfactorscontributetorespiratorydiscomfort

• Thequalitiesofrespiratorydiscomfort vary;mayprovideinsightintotheetiologyofthedyspnea

• Levelofdyspneamore closelycorrelatedwith5-yearsurvival thanFEV1(Chest121:1434, 2002)

• Dailyphysicalactivity isindependentpredictorformortalityandhospitalizationduetoexacerbation (Chest142:338, 2012;andThorax67:117,2012)

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DescriptorsofDyspnea• Mybreathdoesnotgoinall

theway• Mybreathingrequireseffort• IfeelthatIamsmothering• I feelahungerformoreair• Mybreathingisheavy• Icannottakeadeepbreath• Ifeeloutofbreath• Mychestfeelstight• Mybreathingrequiresmore

• IfeelthatIamsuffocating• Ifeelthatmybreathstops• Iamgaspingforbreath• Mychestisconstricted• Mybreathingisrapid• Mybreathingisshallow• IfeelthatIambreathingmore• Icannotgetenoughair• Mybreathdoesnotgooutall

theway

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PhysiologyofDyspnea• ‘Tightness, constriction’ - bronchospasm• ‘Urgetobreathe,airhunger’- increasedrespiratorydrive:e.g.,CO2,severeasthma, CHF

• ‘Effortofworkofbreathing’ - increasedmechanical impedance

• ‘Unsatisfied inspiratory effort’ - hyperinflation• ‘Heavybreathing, breathingmore’-deconditioning

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PulmonaryFunctionTests• Spirometry - maybemoreconsistent inCOPDthanarepeakflows

• Lungvolumes- airtrapping, hyperinflation;bewareofimpactofbullousdiseaseonheliumdilutionmeasurements oflungvolumes

• Diffusingcapacity- predictiveofdesaturation• Flowvolume loop- mayhelpdistinguish“pure”emphysemaandasthma

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PFT’sinCOPD

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Flow-volumeCurveinCOPD

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Oximetry• Assessoxygenationatrest• Desaturationonexercise(correlatewithlowdiffusingcapacityPFT’s)

• Considernocturnaloximetryifevidenceofrightheartfailureorpolycythemia

• Increasingdataonroleofpulmonaryhypertensionasfactorindecreasedexercisecapacity

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It’sNeverTooLateToStopSmokingSchwartzsteinRM

Smokers lose one decade of life expectancy; stop by age 40, reduces risk by 90%NEJM 368:4, 2013

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SmokingCessation:Multi-prongedApproach• Behavioral(telephoneandgroupcounseling)andpharmacotherapyinterventionscombinedbestresults

• PatnodeCDetal.AnnIntMed,2015-- ReviewofreviewsforUSPreventiveServicesTaskForce– Behavioralinterventions(phone,counseling,etc.)pluspharmacotherapy1.76oddsratioofsuccesscomparedtousualcare

– Nicotinereplacement,buproprionandvareniclinealleffective(vareniclinemosteffective)

• Quitesmokingà reducedriskofdementia(Choietal.AnnClinandTranslationalNeuro2018)

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ElectronicCigarettesNEJM2016;375:1372-1381

• Batteryoperated,nicotinedeliverydevices;producevaporwithnicotineandpropyleneglycolorglycerol

• 18%quitsmokingwithe-Cigsinrandomizedtrialc/w10%incontrol(standardnicotinereplacement;lowersuccessratethanmoststudies)(NEJM2019;380:629)

• 1/3ofusershaveneversmokedcigarettes;vapormaycontainformaldehydeandothercarcinogensà recentmini-epidemicofacutelungreactionsanddeaths(NEJMSeptember6,2019- epub)

• Nicotinemaybe“gatewaydrug;”associatedwithotherdrugabuse(NEJM2014;371:932);particularproblemforadolescentssusceptibletoaddiction(AnnIntMed2015;163:59-60)

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E-CigarettesandSmokingCessation• Supplementaryuseofe-cigsforpatientsbeingdischargedfromhospitalwithgoalofsmokingcessationà lessabstinencefromsmokingat6months(Rigottietal.,AnnIntMed2018)

• PopulationstudyinEurope;cross-sectionallogisticalregressionofassociationofe-cigsandbeingformersmokerà e-cigsassociatedwithloweroddsofbeingaformersmoker(Kuliketal.,AmJPrevMed2018;54:603-609)

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BronchodilatorsinCOPDInspirationorExpiration?

• Taubeetal.AJRCCM162:216,2000

– Betaagonists:∆FIV1(inspiratoryflow!)bestpredictorofdecreaseddyspnea;∆ICalsobetterthanFEV1.

• O’Donnelletal.EurRespirJ.18:914,2002

– Postsalbutamol,83%ofpatientsimprovedlungvolumemeasurements,i.e.,lesshyperinflation,inabsenceof∆FEV1

• Cellietal.Chest124:1743,2003

— TiotropiumincreasedICmorethanFEV1

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GoalsofTherapyinCOPD?• FEV1– severity• ChangeinFEV1–progression

• Exacerbations–activity

• Qualityoflife,symptoms– Impactonpatient

• Future:biomarkers;diseaseactivity Am J Resp Crit Care Med 2016;194:541-549

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GoalsofTherapyinCOPDEvolving

Am J Resp Crit Care Med 2016;194:541-549COPYRIG

LABA+LAMAvs.LABA+ICSNEJM2016;374:2222-2234

• Indacterol+GlycopyrroniumvsSalmeterol+Fluticasone

• 11%reductioninannualrateofCOPDexacerbationwithoutsteroids

• Absoluteratereduction:4.03to3.59

Time to First Exacerbation

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WithdrawalofInhaledSteroidsDecreasesPFTsNEJM2014;371:1285

• 2485pts,hxofCOPDexacerbation;tio+salmeterol+ICS

• RandomlyassignedtostopICSover12weeks

• NodiffinexacerbationsbutgreaterdeclineinFEV1withstopinICS

AJRCCM2017;195:1189

• ↑bloodeos→↑riskexacerbationpoststoppingICS

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De-escalationofTripleTherapyandIncreasedExacerbations:Assoc.WithEosOverall,smalldecreaseinFEV1withnodiff.inexacerbations.HigherexacerbationriskandfallFEV1inpts.with> 300bloodeos/microliter

Am J Resp Crit Care Med 2018;198;329-339

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GOLDSummaryonBronchodilators

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Corticosteroids• Approximately1/3ofpatientswillrespondtosteroidswithimprovedlungfunction

• Cannotpredictwhichpatientswillrespondbasedonpreandpostbronchodilatorchallengewithbetaagonist

• SmallchangesinFEV1maymakebigchangesindyspnea

• Increasingevidenceonroleofbloodeosinophilsasmarkerforresponsiveness

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PneumoniaandMortalityinCOPD• LimitsofstudiesofpneumoniainCOPDandICS

– Riskofbias– Lackofsystematicascertainmentofpneumonia;dependenceonadverseriskreporting

– Retrospective,observationalstudydesigns

• Noevidenceofincreasedmortality• Possible“double-effect”– anadverseeffectplusanunexplainedmitigatingeffect;ICSmayimprovemortality

AmJRespirCritCareMed2015;191:141-148

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InhaledSteroidsandPneumonia• CochraneDatabaseSystematicReview2014

– Randomizedcontrolledstudies;atleast12weeksduration

– BudesonideorFluticasonevs.placebowith/withoutLABA

– ICSincreasednon-fatalseriousadversepneumoniaevents,i.e.,requirehospitaladmission

– Nodifferenceinoverallmortalityrates

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ICSAssociatedwithLowerRiskofHospitalizationinOlderPtswithCOPD

Retrospective longitudinal population cohort age > 66 with COPD in Canada.Exposure = new receipt of ICS.Y-axis = proportion free of hospitalization.AnnalsATS 2019;16:1252-1262

No ICSCOPYRIG

InhaledSteroidsandRiskofTBandFlu

• Systematicreview;randomized,controlledtrials– 25forTB(showningraph),26forinfluenza

• HigherriskforTB(butfewevents);nodifferenceforflu

Chest 2014;145:1286

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ProphylacticAntibioticsandCOPDExacerbations

• CochraneReview2013• SevenRCTs;studiesinvolvedmacrolideseithercontinuousorintermittent;duration3to36months

• Results:numberofpatientsexperiencingexacerbationsreducedfrom69to54%;statisticallybutnotclinicallysignificant↑QOL

• Nomajorproblemswithresistantorganisms

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Azithromycinfor3monthsforHospitalizedCOPDExacerbations

• Randomized,double-blinded,placebocontrolled• PatientshospitalizedforCOPDexacerbation;randomizedwithin48hourstoazithromycinvsplacebofor3months(addedtostandardtreatmentwithsteroidsandin-hospitalantibiotics).

• Followedfor6months;treatmentfailure(increaseinmedsorhospitalization)was49%intreatmentgroup;60%inplacebo

Vermeersch K,etal.AmJRespir Crit CareMed- October2019- epub

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COPDReadmissions– onlyhalfduetoRespiratoryillness

• 26millionadmits• 3.5%COPD• 20.2%readmitin30days;onlyhalfduetorespillness

• Dualmedicare–medicaidhigherrisk

Chest 2015;147:1219

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KeyPointsonAnti-Inflammatories

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OxygenTherapy- IndicationsChest 138:179, 2010

Note: use of O2 for sats 89-93 with mild exercise desat–no mortality benefitNEJM 2016;375:1617.

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OxygenandMortality• COT– continuousoxygentherapy(24hrs/day)

• MRC– MedicalResearchCouncil(15hrs/day)

• NOT– nocturnaloxygentrial

Chest138:179,2010

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Roflumilast– Phosphodiesterate4Inhibitor• Anti-inflammatoryagent• 2placebo-controlled,multi-

centertrials;note:inhaledsteroidsstopped

• 3091pts,overage40,FEV1<50%predicted

• Roflumilast500mcg/day• Exacerbationsreduced1.37

to1.14(p<0.003)• FEV1increased48ml

• Calverleyetal.Lancet2009;374:686

Roflumilast reduced frequency of exacerbations in severe COPD patients with freq exacerbator phenotype. Wedzicha et al.Chest 143:1302, 2013; Martinez et al. AJRCCM 2016;194:559-567

Eos > 150 predictor of effect as wellAJRCC 2018;1268

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COPDandPrognosisThe“BODE”Index

• MultidimensionalgradingsystemthatincorporatesrespiratoryandsystemicexpressionsofCOPDüBody-massindex(B)üAirflowobstruction(O)üDyspnea(D)üExercisecapacity(E)

• HigherBODEscore® greaterriskofhospitalizationanddeathCellietal.NEnglJMed350:1105,2004Ongetal.Chest128:3810,2005

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NutritionandCOPD• Bodyweighthasindependenteffectonsurvival• Thresholdvalueof25kg/m2 belowwhichmortalityriskincreased

• Possibleroleofsystemicinflammation;notmalnutritionperse.Increasedmarkersofcatabolism,e.g.,IL-6DebigareRetal.Chest124:83,2003

• Inunderweightpatient,unclearweightgainenhancessurvival

• VitDinptswithlowlevelsmayreduceexacerbationsLehoucketal.AnnIntMed156:105,2012

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Exercise

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PulmonaryRehabilitation• Importanceofdeconditioningasalimitingfactorinmany

patientswithCOPD;• Mechanismofeffectprobablyvarieswithpatient:

1)reconditioning;2)moreefficientuseofbreathingmuscles;3)strengtheningofbreathingmuscles;4)desensitizationtodyspnea

• Upto14%ofptswithCOPDstopexercisingduetolegdiscomfort(FEV144%pred.)Chest144:491,2013

• Patientsreporting“moderateorvigorousphysicalactivity”eachweek,significantreductioninreadmitrateafterexacerbationAnnAmThorSoc11:695;2014

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PulmonaryRehab• Riesetal.,AnnIntMed1995A)IncreasedtreadmillenduranceB)DecreaseddyspneaC)Decreasedmusclefatigue

-- Effectslastedfor12monthsoffollow-up

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MaintenanceRehabforTwoYears

Afterinitialrehabprogram,groupsrandomizedtorepeatvisitsq2weeksvs.controlworkingontheirown.Maintained6MWDbetterwithsupervision.BaselineFEV1<40%predicted.AJRCCM2017;195:622-629

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PulmonaryRehab- EfficacyCochraneDatabase; systematicreview2015;February 23

• 65RCT’sreviewed;3822participants• MeanFEV139%predicted• Statistically significant improvement inQOLoutcomes

• Significant increase in6MWTdistance

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COPDExacerbations

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VolumeReductionSurgery• Physiologicprinciples:A)reducethehyperinflationofthechest;B)allowmorenormalportionsofthelungtoexpandandreceivegreaterventilation/perfusion

• Appeartobefewercomplicationswiththoracoscopic vsmediansternotomyapproach

• Improvement inQOLmeasures, eg.,physicalandsocialfunctioning, vitality (Chest115:383, 1999)

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NETTStudySubgroupAnalysis

• PredominantlyUpperLobeEmphysemaand LowExerciseCapacity– Mortalitylowerinsurgeryvsmedicaltherapy(p=0.005)

• Non-upperLobeEmphysemaand HighExerciseCapacity– Mortalityhigherinsurgerythanmedicalgroup(p=0.02)

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EndobronchialValvesandCoilsHomogeneousemphysema;nocollateralvent;93patients;randomized

• SignificantbutmarginalabsolutechangeinFEV1

• Improvedqualityoflifeat3months

AmJRespir Crit CareMed194:1073,2016

Endocoilscompressemphysematouslung•315pts;bilateralcoils•↑6MWD(10mvslossof7.6m)•ImprovedQOLmeasures•Complications34.8%vs19.1%incontrolJAMA2016;315;2178

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LungTransplantation

• Singlelungtransplantationissuccessfuldespitetheverycompliantnatureofthelungleftbehind

• Longwaitfordonororgan• Survivalstill50%atfouryearsCOPYRIG

GOLDSummaryforAdvancedCOPD

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COPDSummary• COPDassociatedwithvaryingphenotypes;roleofinflammationleadstotherapeuticstrategies

• Elasticrecoilkeytophysiologyofemphysema• SmallchangesinFEV1andlungvolumesmayresultinbigchangesindyspnea;hyperinflationmajorconsequenceofobstruction

• FunctionallimitmaynotbefromCOPD;considerrehab• HypoxicpatientsneedsupplementalO2

• Increasinglylinktreatmenttophenotype,impactonpatient

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chronic obstructive pulmonary disease yright …...education is at the heart of patient care. a...

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