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Educational Review Manua

in Pulmonary Disease2nd Edition 2009

Editors-in-Chief:

Dennis E. Doherty, MD

Professor of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine

Chief of Medical Services, Lexington Veterans Affairs Medical Center

Past Chief, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentu

Barry Make, MD

Professor of Medicine, Division of Pulmonary Sciences and Critical Care

University of Colorado School of Medicine

Co-Director, COPD Program

Director, Pulmonary Rehabilitation and Respiratory Care

National Jewish Medical and Research Center, Denver, CO

CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

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CHAPTER3: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) 55

Contents

1. Introduction

2. RiskFactors for COPD

3. Pathology ofCOPD

4. ClinicalAspects ofCOPD

5. Management of COPD

6. Acute Exacerbation of COPD

7. Suggested Readings

8. Questions

Chapter 3:

ChronicObstructive

PulmonaryDisease(COPD)Dennis E. Doherty, MD, FCCP

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1. Introduction

Definition

Traditionally, COPD hasbeen defined asa disease

state characterized by chronicairflowlimitationdue

to chronicbronchitis and/or emphysema. Our incom-

pleteunderstandingof this complex diseaseprocess is

reflectedinourattempt todefine thedisease itself.

Chronic bronchitis is clinicallydefined as thepres-

ence ofa chronic productive coughfora minimumof

threemonths a year fortwoconsecutiveyears. This

process leadstoa narrowingof theairway caliber and

subsequent increased airwaysresistance.Emphy-

sema,on theotherhand,isdefinedpathologicallyas

anenlargement of airspacesdistal to theterminal

bronchiolescoexistent withdestructionof theairway

walls in theabsenceofobvious fibrosis. This process

leads toa decrease inexpiratoryairflowdue toa lossof elastic recoiland a decrease in thetethering of the

airways.

Past definitions ofCOPD have been pessimisticand

have stated that thedisease process is irreversiblewith

little therapy to offer. Thisnihilistic approachper-

sisted forquitesome time.Amoreoptimisticdefini-

tion ofCOPD wasfirst published in theGlobalInitia-

tiveforChronicObstructiveLungDisease (GOLD)

guidelines developed as the resultof a collaborative

effort of theU.S.NationalHeart,Lung,and Blood

Institute(NHLBI)and theWorldHealth Organization(WHO).GOLDdefines COPD asa diseasestatechar-

acterizedby airflow limitation that isnotfully

reversible.Theairflowlimitation isusually progres-

sive and isassociated with anabnormal inflammatory

responseof the lungs to inhalednoxious particlesor

gases.Thisdefinition implies that COPD canbea par-

tially reversible processandtherefore not totally irre-

versible. Thisoptimismisalso evident in themost

recentversion ofATS/ERS COPD Guidelines. In

addition, it isnowrealized that COPD oftenaffects

other systemicdiseaseprocesseswhichareoftencon-

sidered tobeco-morbidities ofCOPD. Both theaboveguidelines state that COPD isnotjust a disease

of the lung, but rathera systemicprocess. IfCOPDis

optimally controlled, it is possible to alsopositively

affectmanyof itsassociated comorbidities (anxiety,

depression, cardiovascular andcerebrovasculardis-

ease).

Epidemiology and Economic Burden of

COPD

Alackof uniformity indefining thedisease in con-

junctionwithvariances within databases analyzedand

thecostassociated withcomprehensive datacollec-

tion inCOPD limitstheconsistencyofepidemiologi-

cal informationpublished on COPD.Thefollowing

statistics aresummarized fromseveral recent reports.

The totalburden of COPD isgrossly underestimated

sincethedisease remains undiagnoseduntil it is fairly

advancedandclinically obvious(NHANESIII),and

COPD isoftenmis-diagnosed(eg, asasthma, CHF).

The worldwideprevalence ofCOPD in1990 wasesti-

matedto be9.34/1,000 in men and 7.33/1,000 in

women.TwoUnitedStatessurveys have shown that

COPDisunder-diagnosed. NHANES III,publishedin2000, statedthatapproximately16 million people

hadbeendiagnosedat that time with COPD,yetmore

than 30million Americanswere actuallyaffectedby

thedisease.In 2002,a CDCMMWR publication

advancedourunderstanding of theepidemiologyof

COPD.This reportstates that approximately 10mil-

lion Americansreportedhaving COPD,yetover24

millionwereestimated epidemiologically to havethe

disease,and 70%of thosewith thediagnosisofCOPD

were less than 65yearsofage. ANIH-NHLBIreport

in2004 estimated that 11.2million Americans were

diagnosedwith COPD (9.1 million with chronicobstructivebronchitis and3.1millionwithemphy-

sema),and a reportusing SocialSecurity statistics

from theAgency forHealthcareResearchand Quality

statedthat COPD wassecondonly toheartdisease as

a cause of disability.

COPDisthe fourthleading cause ofdeath inthe

United States,exceededonlyby cancers,heart

attacks,andstrokes.AspertheCDC MMWR report,

for the first timein2000, morewomen diedofCOPD

thanmen.Of the top five causesofmortality inthe

U.S.,only the death rate from COPD continuesto rise,havingincreasedby163% from 1965-1998(GOLD

report), and when statistics areused from the 2002

MMWR report, death rate hadincreased by 183%

from 1965 to 2000.Annually, COPD bears the

responsibility forover125,000deaths,550,000hospi-

talizations, 16million health care officevisits, 50 mil-

lion days of disability, 14milliondays of restricted

activity, andover $37billion spent indirect and indi-

rect health carecosts in theUnited States.

56 EDUCATIONALREVIEW MANUAL IN PULMONARY DISEASE

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2.RiskFactors for COPD

HostFactors

Genes

Anumber of epidemiologicalstudiessuggest that

manygenetic factorscontribute to thedevelopmentof

COPD.Geneticallysusceptible individualsoften

develop COPD only aftera sufficientexposureto

environmental factors such as tobaccosmokeorother

environmental/occupationalexposures (including

biomassfuels).Currently, alpha-1antitrypsin (AAT)

deficiency is themostunderstood geneticabnormality

associated withCOPD.Studiesclearlyshowthat

homozygous deficiency of AAT isassociated withan

increasedrisk fordevelopmentof COPD.Othermuta-

tionsof genes such asGST-M1, VDBPandCFTR

have been implicated as risk factors inmore than one

population.Further advancesin ourunderstanding ofthepathogenesis ofCOPD liein more in-depth inves-

tigations ata molecular level,whichin turn will lead

to identificationof othergenetic risk factorswhose

influencemayvaryin specificat-riskpopulations.

AAT isa serumproteinproduced in theliverand

coded for bya singlegeneonchromosome14. Its

deficiency leads to thefailureof inactivationofneu-

trophil elastase, destructionof lungconnective tissue,

andsubsequent developmentof emphysema. The

serumphenotype is determined by twoindependent

alleles.Pi MMdenotes thenormal M allele phenotypewith AAT levels of 150-350 mg/dL. Almostall

patientswhohavesevere AAT deficiency are

homozygous forthe Z allele(Pi ZZ). Rarely, other

phenotypes such asPi SZ,Pi null-nulland Pinull-Z

areassociatedwith very lowlevels ofserumAAT.

Most patientswith Pi ZZareof NorthernEuropean

descent.AAT deficiency is rare inAsiansandAfrican

Americans. Additional mutations which leadto the

secretion of dysfunctionalAAT havealsobeen

describedand maycontributeto thedevelopmentof

COPD.

Airway Hyperresponsiveness

Asthma andairway hyperresponsiveness,especially

whenuntreated or under-treated forprolonged periods

of time(eg,decades)maycause pathophysiological

changessimilar to COPD.These pathologic changes

mayoccurin theabsenceof a history ofsignificant

inhalation of tobacco smokeandhave been identified

as risk factors fordevelopmentofCOPD.This is the

so-calledairwayremodelingof asthma thatmay

lead to a fixed component of airflow obstructionin

patientswhohavehadasthmafor many yearsand

whoperhaps didnot useanti-inflammatory agents, or

inwhom these agents, ifused regularly, didnotade-

quatelycontrol themechanismsresponsible for theprogressive remodeling of airways.

LungGrowth

Anumber of factors such as intrauterine events, birth

weight andchildhood exposurescontribute to lung

growthandachievementof maximal lung function. It

hasbeen proposed that persons whodonotattain nor-

mal lung functionwith ageas assessedbyspirome-

tryare at increasedrisk fordevelopingCOPD later

in life.

ExternalFactors

Tobacco Smoke

Cigarettesmoking is themajor risk factorfordevelop-

mentof COPD and inmost industrialized countries is

responsible for85%-90% of cases. It isoftenstated

thatonlyone ofevery five heavy smokers (one pack

perday)developclinically significant COPD, sug-

gesting thatgeneticpredisposition and/or exposure to

additional environmental factorsmayplayan impor-


Table 1

Risk Factors for COPD

Host Factors

Genes: -1 Antitrypsindeficiency,

+/- metalloproteinase deficiencies

Airway hyperresponsiveness

Impaired lung growth

External Factors

Tobacco smoke

Occupational dusts and chemicalsOutdoor and indoor pollution (biomass fuels)

Infections

Socioeconomic status

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tant role(s) in the developmentof disease.The state-

ment that only 20%of heavysmokersdevelopCOPD

is likelyanunderestimate.Moremild andmoderate

COPD isnowbeing diagnosed insmokers andformer

smokers dueto spirometry testing beingordered ear-

lier inthose at risk for COPD, and asthe recognition

andacknowledgement of theearlier signsandsymp-

toms ofCOPD arenow beingappreciatedby the

patientandhealthcare providers. Althoughcigar and

pipe smokers have a lower risk compared tocigarette

smokers, theirmorbidity andmortality from COPD is

higherthan that of nonsmokers.Thosewhoutilize

smokeless tobaccoalsohaveassociativecomor-

bidities (eg, head andneckcancers).There isnow

clear evidencethatpassive exposureto cigarette

smoke(sidestreamor second-handsmoke) canlead to

thedevelopmentof COPD.Smoking duringpreg-nancyhas beenshown toadverselyaffect the lung

growthof thefetusand thereforeincreasetherisk for

COPD. Therefore,moreemphasisneeds tobeplaced

on smoking cessation duringpregnancy inorder to

allowforfull developmentof theairwaysof thefetus.

Nonsmokers withouta history of significant respira-

tory illnesses lose approximately25 to30ccofFEV1

per yearafter the age of18-25 years; thisdecline in

lungfunctionaccelerateswithaging, ie, theabsolute

FEV1 lossincreases withage.Smokerssusceptible to

developmentof COPD can lose anywhere from

60-150ccormoreofFEV1

peryear and develop vary-

ingdegreesof airflow obstruction.Smokingcessation

does notresultin long-term recoveryof lost lung

function,asassessedbythemeasurementof FEV1,

but itcan slowthe rateofdecline tonear thatofan

individual whoisnota smoker(Figure1).TheLung

HealthI study reportedthat therewasa slightincrease

inFEV1 withinthe first year aftercessation of tobacco

smoking, andin lateryearsthedecline in lung func-

tion reverted to a rate similar to that observed innon-

smokers.

Occupational Dustsand ChemicalsIntenseor sustainedexposureto occupationaldusts

andchemicals can causeCOPD independent of

cigarette smoking.Continuous exposure to particulate

matter,airway irritantsandorganicdustscanlead to

airway hyperresponsivenessandCOPD;thisriskis

increased in thepresenceof cigarette smoking.


Figure1

The rateofchangeofFEV1 with ageandeffectof tobacco exposure

Modified by Doherty DE andBuch KP from Fletcher C, Peto R. Thenatural history of chronic airflow obstruction.BrMed J.

1977;Jun25;1(6077):1645-8.

Age (y)

Disability

Death

Symptoms

Never smoked or not

susceptible to smoke

Stopped smoking at 45

(mild COPD)

Stopped smoking at 65

(severe COPD)

100

75

50

25

0

FEV1

(%o

fvalueatage25y)

25 50 75

Smoked regularly

and susceptible

to effects of smoke

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OutdoorandIndoor Pollution(BiomassFuels)

Although outdoor pollutionhasbeen implicated in the

developmentofCOPD, itsrole isunclear and itscon-

tribution is small compared to cigarette smoking.

Indoorpollutionin the form ofbiomass fuel (eg,

wood,coal, animal waste) used forcookingandheat-

inginpoorlyventilatedhomeshasbeen implicatedas

a risk factor forCOPD, especially indeveloping coun-

tries where thiscooking technique is usedroutinely.

Infections

Severe andrecurrent childhood infections areassoci-

ated with a long-term reduction in lung functionand

in some cases, subsequent developmentof COPD.

Lowbirthweight, besidesbeingan independent risk

factorin thedevelopment ofCOPD, isassociated with

recurrent viral infectionsduring childhood.

SocioeconomicStatus

There is an inverse relationshipbetweensocioeco-

nomicstatusandrisk fordeveloping COPD. It is

unclear if this isa reflection of factors suchas

increased exposure to indoor andoutdoorpollution,

poornutrition, smoking,or other factorsassociated

withovercrowded living environments.


3. Pathology of COPD

LargeAirways

Cigarette smoking leads to mucousgland enlargement

andgoblet cellhyperplasia in the largerairways.This

is clinically manifestedbychronic coughandmucus

productionthe definition of chronicbronchitis.Spu-

tum production isoften 20to30mL/dayand can

exceed 100mL/day. Goblet cells increasein number

andappearin theperipheral airways.Thereis squa-

mous metaplasiaof theepithelial cellswith loss of

cilia,which predisposes to carcinogenesis,disruption

of mucociliaryclearance, anda reductionin theserous

aciniof thesubmucosalglands, which leads todepres-

sionof local defenses(decreased lactoferrin,antipro-

teasesand lysozyme).These factors contribute toan

increased riskforbacterial infections, chronic inflam-

mation andairway remodeling.

SmallAirways (less than 2 mm)

Thecross-sectionalarea ofsmall airways ismuch

largerthan that of thecentral airways;normally, small

airwayscontributevery littleto total airwayresis-

tance.However, inCOPD, small airwaysare themain

sites of increased airway resistance becauseof airway

narrowing, lossof alveolarattachmentsand increased

tortuosity. There isgoblet cellmetaplasia,smooth

muscle hypertrophy, excess mucus, edema and

inflammatorycellularinfiltrate in thesmall airways.

Subepithelialfibrosis andcollagendeposition con-

tribute to airway narrowing.

Alveoli

Emphysema isa structuraldeformityof thelung

affecting thegas-exchanging airspaces (respiratory

bronchioles,alveolarducts andalveoli). There is oblit-

erationof airspacewalls, coalescenceof small distinct

airspacesinto much largerones andpermanent

enlargement of thegas-exchanging units of the lungs.

Emphysema isoftenclassifiedinto twodistinctsub-

types: 1.)Centroacinaremphysema, characterized by

enlargement of airspacesfound in association with

respiratory bronchioles;2.)Panacinar emphysema,characterized by abnormally enlarged spaces dis-

tributedevenlywithinandacross acinarunits. The for-

mersupposedly distinguishesemphysema associated

with cigarette smoking from thelatter, which is associ-

atedwithAAT deficiency. However, in reality, smok-

ing-relatedemphysema isusuallymixed. Somerecent

studies havesuggestedthat theloss ofalveolarwall

integrity issecondarytoa dysregulation of theapop-

totic process.

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Evenin young asymptomaticsmokers,BAL(bron-

choalveolar lavage)studieshavefound an increased

number of alveolarmacrophages and presenceofneu-

trophils.As thediseaseadvances, T lymphocytes

(mainly CD8+)andneutrophils are seen in theepithe-

lium andT lymphocytes and macrophagesareseen in

thesubepithelium of theairway. Preliminarystudies

have begun tosubtype CD8+ lymphocytesbasedon

thephenotypicexpression of variousmediators

(CD81, CD82).

Pathophysiology

Airflowobstruction, definedbya reduction in the

FEV1/FVC ratio (

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theexpiratory phase, wheezingandcoarse crackles.

Heart soundsaredistantandtheremay beevidence of

corpulmonale. Cyanosissuggests thepresenceof

hypoxia,andasterixis suggestshypercapnia.It is

important to realize thatthese physicalsigns manifest

late inCOPDand are not useful inthe early detection

of thedisease.However, symptomatology of cough

andsputumproductionanda reducedFEV1 areuseful

to detect COPD early. In fact,it hasbeen proposedby

theNationalLungHealth Education Program

(NLHEP) andother membersof theUnited States

COPD Coalition that determination of the FEV1 and

its ratio tothe FVC (or FEV6) byofficespirometry is

vitalandshouldbeperformed inprimarycare and

specialistsoffices on those individualsat risk for

COPD(case finding or selected early detection).

TheNLHEPsuggests that anycurrent or formersmoker40years ofage orolder, oranindividualof

any age withone ormoreof the signs/symptomsof

COPD(chroniccough, excess mucus production,

dyspnea onmild exertion outof proportion to the

activity performed fortheirage, or wheeze) should

have their lungs tested at least once viaspirometry to

determinethepresence orabsence of airflow obstruc-

tion.Spirometry was recentlynameda HEDISmea-

surement forthediseasestateof COPD.

Laboratory Tests

Currently, laboratory tests areverynonspecific andnothelpful in theearly detectionofCOPD. In more

end-stage disease,chronichypoxia maylead topoly-

cythemia. Chronic respiratoryacidosis leads to ele-

vated serumbicarbonate levels.Arterialblood gas

analysisshows hypoxemia andhypercapnia.These,

again, are indicationsof severe disease.In selected

COPDpatientsspecifically, those whoare lessthan

50 yearsofageand nonsmokersmeasurementsof

serumAAT levels andquantitativeimmunoglobulin

levels (to ruleout selective immunodeficiencies that

mayleadto bronchiectasis)are indicated.AAT levels

maybe usefulinpatientsofanyage, particularly forearlier identification of thedeficiency andforcounsel-

ingfamily members.

RadiographicFindings

Chestx-raysusually appear normal inearlyandmod-

eratedisease andthusarenot usefulfor screeningfor

COPD. Insevere disease, therecan bea flatteningof

thediaphragm, evidenceof hyperinflation (increased

retrosternalspace andincreased lungheight),pres-

ence of bullae, a small tubular cardiac silhouette, and

pruning ofpulmonary arteries. The role ofCXRear-

lier in thecourse of COPD ismore foridentificationof

co-morbidities (pneumonia, pneumothorax, nodules).

High-resolutionCTscan of thechestismuch more

sensitiveand specific comparedtochestx-raysin

diagnosisofemphysema,butdoes notcorrelatewell

withphysiologic impairment. It isnot recommended

forroutineusein thediagnosis/detectionof COPD.

PulmonaryFunction Tests

Spirometry shows evidenceof airflow obstruction

veryearly inthe timecourseofCOPD. The disease is

manifestedbya reductionin theFEV1/FVC ratio to

less than70%. TheNational Lung HealthEducation

Program (NLHEP) and NHANESIIIsuggest usingFEV6 (forced expiratory volumein sixseconds) asa

surrogate measurementforFVCin theofficesetting

anddiagnosing airflowobstruction whenboththe

FEV1 and the FEV1/FEV6 ratioarebelowthelower

limitofnormal.Thesesuggestionshavebeen ade-

quatelycorroborated. Onceairflowobstruction is

diagnosed, thedegree ofobstruction can begraded

from mild to very severebasedon thepercentageof

predicted FEV1 asdefinedbyATS(Table2)orby


Table 2

AmericanThoracicSociety (ATS)Criteria for

AssessingSeverity of AirflowObstruction

Severity Postbronchodilator FEV1

(as % of predicted when

FEV1/FVC is 80

Moderate 50

Severe 30

Very severe

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GOLD(Table3) Guidelines.TheGOLDGuidelines

initially (2001)introduced twonewstagesto help

detect COPD earlier. Stage0,whichwaseliminated

from thestaging process byGOLD inthe11-07

update,wasdefined asnormal pulmonary function

(FEV1/FVC ration> 70%) with thepresence ofearly

symptomsofCOPD,such asmild sputumproduction

with cough. Itwasfelt that this stage identifiedindi-

viduals at risk forprogressing to moresevereCOPD

before physiologic impairment is evident.Subsequent

studies havesincesuggested that a very smallpercent

ofStage 0 COPDprogressestoStage 1 orbeyond,

thus Stage0 wasdropped from themost recentrevi-

sionyet it is still recommended that these patients

shouldbeobservedforpotentialprogressionofdis-

ease. Stage I remains, and isdefinedbya normal

FEV1 (> 80%of predicted) with a reductionin the

FEV1/FVC ratio< 70%. Stage I identifiesindividuals

with very earlyCOPD.

Lung volumemeasurements in COPD can show the

presenceof hyperinflation (increased total lungcapac-

ity) andair trapping(increased residualvolume). This

processcanoccurat rest (statichyperinflation)or with

activity(dynamichyperinflation). Hyperinflation can

bepresent even in patientswith moderatedisease

(more apparentwithvigorousactivity) andoccurs

more frequently at rest and with exercise in those with

a moreadvanced COPD-emphysema component in

severe andvery severedisease. In thepresenceof

severe airflow limitation, thelung volumes may be

underestimated if measuredby gasdilutiontech-

62 EDUCATIONALREVIEW MANUAL IN PULMONARYDISEASE

Table 3

Treatment of COPD by Severity(GOLD Guidelines)

I. Mild II. Moderate III. Severe IV. Very Severe

Characteristics

FEV1 /FVC

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niquesdueto the presenceofareasof hyperinflation

that donotreadily communicateviaopenairways (eg,

bullae);bodyplethysmographyshould be usedin

these instances to accuratelymeasure the true

intrathoracicvolume. DLCO isoftenreduced inmore

advanceddisease.

Cardiopulmonaryexercisetestingis not routinely

indicated in thediagnosis ormanagementof patients

withCOPD. However, whenperformed in patients

withadvanceddisease, it characteristically shows

ventilatory limitation during exercise. VO2 max is

reducedwitha normal or indeterminate anaerobic

threshold; heartrate reserve may behigh andO2 pulse

isnormal orhigh.Ventilatory reserve is reduced or

absent,deadspace fractionis increased (increased

VE/VCO2 atAT)andVD/VTiselevatedat rest withless than normal reduction with exercise. Theremay

behypercapnia,hypoxia, oran increase in the

P(A-a)O2 gradient.

ExtrapulmonaryManifestationsof COPD

Life expectancy forpatientswith COPD has increased

with improved medicalcare.Like any other chronic

illness, systemiccomplications of thediseasebecome

more manifestaspatients live longer. In caring for

these patients, it is important to realize that COPD is

indeed a systemicdisease thataffects multipleorgan

systems besides therespiratorysystem.Themajorityof theseabnormalities inotherorgansystems aresec-

ondaryto theeffectsof chronichypoxemia,while

some abnormalities aredue toside effectsof therapy.

Often, COPDpatientswhohaveexerciselimitation

anddyspnea can tend tobe less active,depressed,

and/oranxiouswith regard to their respiratory condi-

tion. In postmenopausal women, this inactivity can

enhancetheir alreadyincreased riskof osteoporosis

due to COPD.Theinflammatorymediators produced

in the lungsof COPD patients, especially if they are

watersoluble,candiffuseoutof thelung andpoten-

tially enhancethe inflammationpresent in thecardio-,cerebral-, and/or peripheral-vasculature.The2005

ATS/ERS COPDGuidelines specificallystate that

COPDismorethanjust a disease of the lungit is

alsoa systemicprocess.Themechanism(s) underly-

ingmanyof theextrapulmonary manifestations of

COPD arepoorlyunderstood and arecurrently being

activelyinvestigated.

Cardiovascular

Extrinsicto the respiratorysystem, thecardiovascular

systemis themostcommonorgan systeminvolvedin

patientswith COPD. Inpatientswith advanced

COPD,chronichypoxemia leads to pulmonary hyper-

tensionandeventually to corpulmonale (presenting

with signsand symptomsof overt right-sidedheart

failure).

Patientswith COPD arealso exposed toa majorrisk

factor fordevelopmentof coronaryartery disease

(CAD),ie, tobaccosmoke. Onemust bewary about

thepresence ofconcomitantCAD and left-sided fail-

urethat then leads to thedevelopmentof right-sided

heart failure.Exercise limitationduetoCOPD may

preempt these patientsfrompresenting withtheclas-

sical symptomsof anginapectorisuntil thecoronarydisease is so severe that angina occurswith minimal

exertionor at rest.Sometimes it isdifficult todistin-

guish symptomsof acutecardiac ischemia from those

ofanacuteexacerbation ofCOPD.There is strong

epidemiologic evidencethatlinks COPDandcardio-

vascularmorbidity andmortality. COPDpatients

have a two- to threefoldincrease in the risk ofcardio-

vascularevents, including death, evenafter adjust-

ments for traditionalcardiovascular riskfactors.In

patientswithmild-to-moderateCOPD,forevery 10%

decrease inFEV1, cardiovascular mortality increases

byabout 28%and nonfatalcoronaryevent increasesbyabout 20%.

Tachyarrhythmias,suchasmultifocal atrial tachycar-

dia, knownasMAT (often responsive to treatment

with a calciumchannelblocker), are common and

may bedue tounderlyinghypoxia ora sideeffectof

treatment withtheophyllineor beta-agonists (ie,

hypokalemia).

Nutritional/GastrointestinalAbnormalities

Weight losshas longbeenacceptedtobea partof the

terminalprogression of COPD. Nutritional depletionmay bea manifestation ofadvancedCOPD, butat the

sametimeit contributes to respiratory andperipheral

muscle weaknessandto decreased exercisecapacity

independentof impairedlungfunction. Depletion of

fat-freemasshasbeenreportedinuptoa third ofclini-

cally stable patientswithmoderate-to-severe COPD.

Weight lossandunderweight status areassociated

with decreaseddiffusingcapacityand aremore fre-

quent inpatientswith emphysema than those with


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chronicbronchitis.There is increased restingenergy

expenditureandactivity-relatedenergy expenditure

aswell as reduceddietary intake, allof whichcon-

tribute toweightloss andmuscle wasting inpatients

with COPD.Body weightbelowideal (ortheBody

Mass IndexBMI) is a marker forincreased mortality

in COPD.

COPD patientsmay bemore prone todevelop gas-

troesophagealrefluxdiseaseor peptic ulcer disease

eitherindependently orasa complication of therapy

withsystemicsteroids. Severe hyperinflation may

also impair gastric emptying, leading toa sense of

early satiety and/ora feeling of bloating.

Musculoskeletal

Osteoporosis iscommonand may bedueto theeffectsof inactivity, prolonged therapywithsystemicgluco-

corticoids,or cigarette smoking.Radionuclidebone

scan is requiredforearlydetectionof loss of bone

massin patientson prolonged systemicglucocorticoid

therapy.

Peripheral muscle dysfunction,a common systemic

complicationof moderate-to-severe COPD,is charac-

terizedby muscle atrophy, weakness, and lowoxida-

tivecapacity. It hasbeenassociated withexercise

intolerance,poorqualityof life, andreducedsurvival

independentof the impairment in lungfunction.

Chronic inactivity anddeconditioning,systemic

inflammation, nutritional imbalance,useof systemic

corticosteroids,hypoxemia,andelectrolytedistur-

bancesarethe main factors believedtobe responsible

forskeletalmuscle dysfunctioninCOPD.Unlikethe

irreversiblenature of lungimpairment,peripheral

muscledysfunction is potentially reversible with

exercisetraining, nutritional intervention, oxygen and

anabolicdrugs.

NeuropsychiatricMemorydeficitsdueto theeffectsof chronic hypox-

emiaarecommonin end-stage disease.Anxietyasso-

ciatedwiththe fearofdyspnea isalsocommon, asare

alteredmoodstates, including clinicaldepression aris-

ingfrominability to accomplishroutineactivities and

relativesocial isolation. Sleep disturbancesother than

sleepapneaarecommon inpatientswith COPD and

aredue tonocturnal dyspnea aswell as side effectsof

therapy(corticosteroids,beta-agonists, theophylline).

Theoverlapsyndromerefers to concomitantobstruc-

tive sleepapnea-hypopneasyndromein a patient with

respiratorydiseasesuchasCOPD. Atheroscleroticcerebrovasculardisease is alsoprevalent in thispopu-

lation,mostoften secondary to tobaccosmoking.

Neoplasm

Smokerswithspirometricevidence of airflow

obstruction are at increasedrisk fordevelopmentof

lung cancer compared to smokers without airflowlim-

itation.Indeed, there is a high comorbidity of COPD

andlung cancer dueto thecommonality of themajor

risk factor in both diseaseprocesses tobacco smoke

inhalation.Also, tobaccousehasbeen implicatedas

an important risk factorina numberofmalignanciesof theaerodigestive tractaswell ascancersof thegen-

itourinary tract. Onemust bewary of undiagnosed

malignancy in COPDpatientswithunexplained

weight loss(Table4).


Table 4

Extrapulmonary Malignancies

Associated with Tobacco Use

Risk Compared to

Site Nonsmokers

Oral 9-fold increase

Throat 9-fold increase

Esophageal 75%increase

Bladder 7-fold increase

Kidney 5-fold increase

Pancreatic 2-fold increase

Gastric 1.5-fold increase

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Prognosisof COPD

FEV1 is thesingle best variabletoclassifyseverityof

COPD. However, in itself it does notaccuratelypre-

dictdyspnea,exercisetolerance, other symptomsof

COPD,or mortality, reflecting thesystemicnature of

COPD. Anumberof variables were studied in a

cohortof COPD patientswith varying severityof dis-

easeand itwas found that4 of these variables were

stronglyassociated with1-year mortality. BODE

index(0 to10 points) includes these4 variables: BMI

(B), FEV1 asa percentage of thepredictedvalueasan

indication ofairflowobstruction(O), score on the

modifiedMedicalResearchCouncil [MMRC] dysp-

nea scale (D),and the distancewalkedin6 minutes as

an indicator of exercisecapacity (E). HigherBODE

scores correlated withthestratification of severityof

COPD basedonGOLD spirometriccriteria,and wereassociatedwith greater risk fordeath.BODE indexis

betterthan theFEV1 aloneatpredicting therisk of

death from anycauseandfrom respiratory causes

among COPDpatients.

5.ManagementofCOPD

SmokingCessation

This is thesingle most effective intervention that

improvesoverallhealth, reduces theriskof develop-

mentof manydiseases, including COPD (eg, cardio-

vascularandcerebrovascular disease), andcansignifi-

cantly affect theprogressionof COPD. Ithasbeen

shownthat even briefcounseling by thephysician to

urgea smoker toquit canbeeffective.TheAgency for

Healthcare Policy andResearchrecommendsa five-

stepprogramfor interventionthe fiveAs (Table

5).Threetypesof counseling havebeen clearly shown


Table 5

Strategies to Help thePatient Willing to

Quit Smoking: The Five As

1. Ask

Systematically identify all tobacco users at every visit.

Implement an office-wide systemthat ensures that for

EVERYpatient at EVERY clinicvisit tobacco usesta-

tusis queried anddocumented.

2. Advise

Stronglyurgeall tobacco users toquit ina clear,

strong and personalized manner.

3. Assess

Determinewillingness to make a quitting attempt.Ask

every tobacco user if heorshe iswilling tomakea

quitattempt at this time(eg,within the next30days).

4. Assist

Aidthepatient in quitting.Help thepatient with a quit

plan; provide practicalcounseling; provide intra-

treatmentsocialsupport; help thepatient obtain

extra-treatment social support; recommenduse of

approvedpharmacotherapy except in special cir-

cumstances; provide supplementarymaterials.

5. Arrange

Schedule follow-upcontact inpersonorviatele-

phone or letter.

Adapted from Fiore MC,Bailey WC,CohenSJ. Smoking

Cessation: Informationfor Specialists. Rockville, Md:US

Department of Health and Human Services, Public Health

Service,Agency forHealth Care Policy andResearch and

Centers for DiseaseControl and Prevention; 1996. AHCPR

Publication No. 96-1.

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to be effective:practical counseling; social support as

partof treatment; andsocial support arrangedoutside

of treatment (ie,peerrecruitment).

Pharmacotherapymaybe needed to assist smokers

whoareunable toquit with counseling andsocial sup-

portalone.Pharmacological tools available to fight

nicotineaddiction aremoreextensiveandmoreeffec-

tivethaneverbefore.Treatmentswiththeantidepres-

santbupropion or nicotinereplacementtherapy in any

form have beenshown tobeeffective in initiating and

maintainingabstinence fromtobacco.Acombination

of bupropion andnicotinereplacementtherapyhas

been showntobemore effective than eitherdrug

alone. At12 months of treatment with thenicotine

patchalone, theabstinence rate is16.4%;with bupro-

pion alone,it is30.3%.After12 months of treatmentwith a combinationofa nicotinepatchandbupropion,

theabstinencerate is35.5%.A newclassof therapeu-

ticagents for smokingcessation, theendocannabi-

noids,hasrecentlybeen investigatedand thefirst

agentwasapprovedbytheFDAin 2006.These

agents, whichbind to thealpha-4 beta-2 nicotinic

receptorsin thebrain (present in theventral tegmental

area)arepartial agonists (lead toa low levelof

dopaminesecretionin thebrain), yetare very potent

competitiveantagonists (preventexogenous nicotine

frombindingto these samereceptors)thusprevent-

ingthe surgeofdopaminerelease in thebrain that nor-mallyoccurs in response tosmoking tobacco.

PharmacologicTherapy forCOPD

Therecent GOLDandATS/ERS COPDguidelines

suggest tailoring therapyto the individual patient

based ontheseverity of disease (Table3) and symp-

toms(ATS/ERS).Noneof thecurrently available

medicationsforCOPD have been shownto alterthe

long-term decline in lungfunction, althougha 4-year

study toexamine theeffectsof thelong-actinganti-

cholinergic tiotropiumon thisparameter hasrecently

been completed with results duein late 2008.

Bronchodilators (Table6)

Maximizingbronchodilation in COPDis the founda-

tionandthecornerstoneof pharmacologic therapy.

The current Guidelines emphasize that it is crucial to

maximize thisso-calledfirst-line pharmacologic

therapyforsymptomaticmanagement of COPD.

Currentlyavailablebronchodilators (anticholinergics,

beta2-agonists, andmethylxanthines)decreaseairway

resistance andhyperinflation, decreaseshortnessof

breath, andimproveexercisecapacity. Beta2-ago-

nists cause bronchodilationby relaxingtheairway

smoothmuscle viabeta2-adrenergic-mediated activa-

tion of adenylatecyclase andsubsequent increasesin

intracellular cyclicadenosinemonophosphate

(cAMP). Inhaledbeta2-agonists arepreferred over

oral tablets as theyhavea morerapid onset ofactionin

the lungandfewer systemicsideeffects. Short-acting

beta2-agonistsrequire frequentdosing(every3 to4

hours) andareassociated withtachyphylaxis (toler-

ance). With twice daily dosing, long-acting inhaled

beta2-agonists(salmeterol, formoterol, arformoterol)

versusplacebo have been shown tosignificantly

increasebronchodilation, in somecases preventor

decreaseacute exacerbations andhospitalizations,and

improvehealth status,often without inducingtachy-phylaxisover the periodof time studied.

Anticholinergics, alsousedas first-linemaintenance

bronchodilatortherapy forCOPD, inadditionto their

excellent ability to bronchodilate,havealsobeen

shownto reducemucus hypersecretion, reduce the

sensationof dyspnea,preventanddecreaseacute

exacerbations of COPD(AECOPD)andhospitaliza-

tion duetoAECOPD, andbluntnocturnaloxygen

desaturation. Ipratropiumbromideis a short-acting

anticholinergicbronchodilator. It hasa longer dura-

tion of action (4 to6 hours)comparedtoshort-actingbeta2-agonists(3 to4 hours), a relatively benignside-

effectprofile, andis notassociatedwith tachyphy-

laxis. Treatmentwitha combinationof theanticholin-

ergic ipratropiumwith theshort-acting beta2-agonist

albuterol, or withthe long-actingbeta2-agonists for-

moterol or salmeterol,has beenshown toproduce

greater andmoresustained improvementin FEV1 and

symptomscompared to treatment with anyof these

agentsalone.

Tiotropiumisa quaternary ammoniumderivative of

ipratropium. It bindsto themuscarinicM1,M2 andM3 receptors butdissociates from M1andM3100

timesmore slowlythan ipratropium. Ithasanonsetof

actionover 30-60 min,butitsdurationofactionis for

over 24 hoursallowingforonce a daydosing.

Tiotropiumhas beenshown tobemore selective,

more potent, andhavea longerduration ofaction

comparedto ipratropium.Tiotropiumhasbeenshown

to havesignificant effectson lungfunction, dyspnea,

quality of life and exercise toleranceand endurance. It

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is alsoeffective in preventing COPDexacerbations

andrelated hospitalizationswhen compared to useof

ipratropiumor placebo in severalstudies.

Methylxanthineshave fallenoutof favor in recent

yearsdueto theirhavinga higherpotentialfor toxicity

andweaker bronchodilationcompared to theagents

listedabove(which arealso safer, at a minimum

equally effective andeasy touse). Theophylline is the

most commonlyused medicationin this class; incer-

tainpatientsit leads to bronchodilation,enhanced

right ventricularfunction, increased exerciseperfor-

mance, relief of dyspnea,improvement in mucocil-

iaryclearance andimproveddiaphragmatic function.

Serumlevelsneed tobemonitored inorder toavoid

toxicity;a levelof 8-10 mcg/mLis therapeuticin


Table 6

Pharmacology of FDAApproved, CurrentlyAvailable,andCommonlyUsed

Bronchodilators for MaintenanceTherapy(MDI-CFCor HFA, DPIFormulations)

Medication Dose/Puff Oral Onset of Peak Effect Duration

(mcg) (mg) Action (min) (min) (hr)

2-Agonists

Albuterol 108 (HFA) 4 5-15 30-90 3-4

Metaproterenol 650 (CFC) 5-15 10-60 1-3

Terbutaline 200 (CFC) 5 5-30 60-120 3-6

Pirbuterol 200 (Autoinh) 5-10 30-60 3-5

Salmeterol 50 (DPI) 30-60 60-180 10-14

Formoterol 12 (DPI) 5 30 10-14

Anticholinergics

Ipratropium (HFA) 17 5-30 60-120 4-8

Tiotropium (DPI) 18 30-60 90-120 >24

Combined Agents

Albuterol/Ipratropium (CFC) 90/18 5-15 60-120 6-8

Salmeterol/Fluticasone (DPI) 250/50 30-60 60-180 10-14

Methylxanthines

Theophylline (CR) 400-600 15-60 60-120 Variable

CFC = chlorofluorocarbon; HFA = hydrofluorocarbon; DPI = dry powder inhaler.

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Systemic steroids (intravenous solumedrol or oral

prednisone) should be utilized for the treatment of an

acute exacerbation of COPD. The efficacy of a short

course of these agents for the treatment of acute exac-

erbations of COPD has been well established. How-

ever, the use of a 10-14 day trial of oral prednisone for

maintenance treatment of COPD or as a positive pre-

dictive value in determining which COPD patients

will respond to chronic administration of ICS has

recently been challenged, and is not recommended by

current Guidelines. Response to therapy is defined by

the GOLD guidelines as a significant increase in FEV1(12% and 200 cc above baseline) or a decrease in the

frequency of exacerbations, but only after bronchodi-

lation has been maximized using the combination of

the bronchodilator agents reviewed above. It is further

recommended that the utility and side effect profile ofICS be reevaluated at some point after their initiation

(ie, 3-6 months). Equally convincing is the evidence

showing no long-term benefit of systemic steroids in

COPD. In fact, prolonged use of steroids can be detri-

mental to function in some patients with advanced

COPD as it may cause osteoporosis and steroid

myopathy.

Miscellaneous

Vaccines. Influenza vaccine is recommended annually

in the fall to reduce serious morbidity and mortality

from Influenza A in COPD patients who have no his-tory of severe anaphylaxis to egg protein. This vaccine

has been shown to be 30%-80% effective in prevent-

ing illness, complications, and death in high-risk pop-

ulations. Influenza vaccine can be administered con-

currently with pneumococcal vaccine if administered

at different sites.

A polyvalent pneumococcal vaccine is recommended

in COPD. However, evidence for the efficacy of the

pneumococcal vaccine is inconclusive (some studies

show a 65%-85% efficacy amongst high-risk popula-

tions).

Mucolytics have not been shown to be of benefit in the

management of COPD. Inhaled N-acetylcysteine may

in fact increase sputum volume and cause bron-

chospasm.

Antioxidantsare not routinely recommended for use

in treatment of COPD. Oral N-acetylcysteine was

shown in some preliminary studies to reduce the fre-

COPD for its beneficial effects other than bronchodi-

lation. Because of its narrow therapeutic index and

potential interaction with a number of drugs including

antibiotics that may be used to treat acute exacerba-

tions, theophylline is generally reserved for the patient

who has suboptimal response after maximizing the

doses of the other classes of bronchodilatorsanti-

cholinergics and beta2-agonists.

Corticosteroids

In contrast to their use in asthma treatment, inhaled

corticosteroids (ICS) by themselves have shown no

effect on long-term disease progression nor on the

accelerated loss of FEV1 in COPD. ICS may reduce

the number and severity of acute exacerbations in

patients with severe or very severe (but not mild or

moderate) COPD as defined by both the ATS/ERSand GOLD.

Guidelines

These guidelines recommend a trial of inhaled corti-

costeroids in severe COPD patientsa postbron-

chodilator FEV1 less than 50% of predictedwho

continue to remain symptomatic despite already hav-

ing maximized bronchodilation (which by definition

is the concurrent use of an inhaled anticholinergic and

a beta2-agonist) and who have frequent exacerbations.

ICS are therefore not recommended for routine use inCOPD, except in specific situations (Table 3). Several

uncontrolled, large, retrospective, observational stud-

ies have shown that ICS reduce hospitalizations and

mortality in severe COPD. The question of a clinically

relevant ICS effect in COPD was partially answered

by a recently completed placebo-controlled trial with

mortality as the primary endpoint. While mortality

was not significantly affected by three years of main-

tenance therapy of long-acting beta2-agonist alone,

high-dose inhaled corticosteroid alone, or their com-

bination, there was a trend for benefit with the combi-

nation in some patients with severe COPD.

Inhaled glucocorticosteroid combined with a long-

acting beta2-agonist can lead to a greater increase in

FEV1 versus the effect observed in response to either

agent alone. Short-term treatment with a combined

inhaled glucocorticosteroid and a long-acting beta2-

agonist in some studies has been found to achieve a

greater control of lung function and symptoms than

combined anticholinergic and short-acting beta2-ago-

nist.

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quency of exacerbations, but subsequent studies have

not confirmed their efficacy in the long-term manage-

ment of COPD patients with or without recurrent

exacerbations.

Antibiotics (ie, continuous rotating antibiotics) have

no role in the routine management of COPD. How-

ever, the intermittent use of short-course antibiotics

are effective when treating acute infectious exacerba-

tions that are usually due toHaemophilus influenzae ,

Streptococcus pneumoniae andMoraxella

catarrhalis, and other bacterial infections.

Antitussives are generally contraindicated and should

be used with caution. There are no evidence based

studies supporting the use of mucolytics in COPD and

it is debated if efficacious mucolytics are even avail-able currently.

Alpha -1 Antitrypsin augmentation therapy is still

controversial and because of its limited availability

and cost, should be reserved for certain AAT deficient

patients (Pi ZZ or Pi null-Z) with emphysema.

There is no evidence to support use of respiratory

stimulants, narcotics, nedocromil or leukotriene mod-

ifiers in the routine management of patients with

COPD.

Nonpharmacologic Therapy for COPD

Oxygen Therapy

To date, this is the only therapy for COPD besides sus-

tained smoking cessation that has shown a positive

impact on mortality. Two landmark trials, the British

Medical Research Council (MRC) Trial and Noctur-

nal Oxygen Therapy Trial (NOTT) have established

the efficacy of supplemental oxygen in COPD

patients. The benefits of oxygen therapy are realized

only if it is used for at least 15-18 hours each day.

There is a reduction in mortality when oxygen is used

continuously compared to only nocturnally. Oxygentherapy should be prescribed when the PaO2 is

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vention should be combined with an exercise program

to stimulate an anabolic response and an increase in

fat-free mass rather than fat storage. Results of early

trials with anabolic steroids are encouraging, but more

studies are needed before their use can be recom-

mended in the routine management. Studies in the

pulmonary and cardiology literature have not sup-

ported the use of the antioxidant vitamins A or C in the

treatment of COPD, and some studies even suggest a

detrimental effect.

Mechanical Ventilation in COPD

Temporary use of mechanical ventilation is often

required to support a patient with moderate-to-severe

COPD during acute ventilatory failure. Ventilatory

support via nasal or full facemask should be attempted

at an early stage in patients hospitalized for COPD.Noninvasive ventilation may prevent intubation and

related complications. It should be considered when,

in the judgment of the physician, the premorbid func-

tional status of the COPD patient can be regained after

resolution of the acute event. Beyond its short-term

benefit, the effect of mechanical ventilation on the nat-

ural history of COPD is unclear. In patients who fail to

wean from mechanical ventilation within three weeks,

transfer to a respiratory special care unit for prolonged

weaning should be considered. Outcome for such

patients is generally poor; on average only half of

these patients are liberated from mechanical ventila-tion. Mechanical ventilation per se does not alter mor-

tality or outcome. This is more likely determined by

the premorbid functional status, comorbidities, sever-

ity of underlying COPD, and severity of the acute

medical event.

Surgical Treatments

Bullectomy may be effective in reducing dyspnea and

improving lung function in carefully selected patients.

Lung volume reduction surgery (LVRS). Several

early studies evaluating the efficacy and safety ofLVRS were encouraging, but large randomized con-

trolled trials were lacking, and LVRS was considered

an unproven palliative surgical procedure that could

not be routinely recommended. Based upon the rec-

ommendations of a NIH-NHLBI working panel of

investigators, a larger multicenter randomized clinical

trial was designed that was funded by the Center for

Medicare and Medicaid Services (CMS). The results

of the National Emphysema Treatment Trial NETT

are reported elsewhere, and further data analysis con-

tinues to yield important findings from this study.

Briefly, eligible patients with COPD were enrolled

into a formal pulmonary rehabilitation program and

therapies were maximized. At the end of rehab,

patients were randomized to LVRS with standard

medical care or to standard medical care alone. The

study identified those who benefited most from the

surgerythose with a low exercise capacity at the end

of rehabilitation who had upper lobe predominant

emphysema (at a cost of approximately >$190,000

per patient quality year salvaged). The study also

importantly revealed what COPD patient population

should not be offered surgery those with diffuse

emphysema and a FEV1 or a DLCO

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Evaluation

Clinical

Upon examination, patients may be tachycardic,

tachypneic, febrile and in varying degrees of respira-

tory distress, depending on the severity of exacerba-

tions. Patients with ventilatory failure and hypercarbia

may be somnolent and confused. Respiratory exami-

nation reveals use of accessory muscles, hyperinfla-

tion of lungs, diminished air movement, and wheez-

ing. There may be also be signs of cor pulmonale.

Laboratory

Arterial blood gases are helpful in assessing the

degree of hypoxemia as well as hypercarbia. Elevated

serum bicarbonate levels are helpful in diagnosing

chronic respiratory acidosis, as electrolyte imbalancescontributing to the episode may be identified. Leuko-

cytosis is often present, especially with infections.

Examination of the sputum gram stain may help iden-

tify the responsible pathogen in complicated cases or

with frequent recurrences.

Radiography

Chest x-rays help in identifying comorbidities of

COPD, eg, the presence of pneumonia and, more

importantly, help to exclude pneumothorax and pul-

monary edema. A spiral CT scan of the chest and leg

studies should be considered if there is clinical suspi-cion for a pulmonary embolism.

EKG

EKG tracings help to exclude acute myocardial

infarction. It may often reveal presence of atrial tach-

yarrhythmia, such as multifocal atrial tachycardia.

Pulmonary Function Testing

This is not useful in diagnosis of acute exacerbations.

FEV1 correlates poorly with arterial blood gases and

does not predict need for hospitalization. However, it

may be useful as a marker for the severity of the exac-erbation and the need for systemic steroids if patients

can tolerate and properly perform spirometry.

Management

The administration of inhaled (MDI or nebulized)

bronchodilators, usually a combination of short-act-

ing beta2-agonists and a short-acting anticholinergic,

is equivalent or superior to the use of oral or parenteral

methylxanthines in the treatment of an acute exacer-

6. Acute Exacerbation of COPD

Intermittent episodes of worsening symptoms and

lung function characteristically punctuate the natural

history of COPD and contribute to the morbidity, mor-

tality and decreased quality of life associated with

COPD.

Definition

Acute exacerbations of COPD (AECOPD) have been

variably defined, but the most widely accepted defini-

tion is based on clinical criteria. Acute exacerbation of

COPD is defined as an acute or subacute onset of one

or more of the following: worsening dyspnea,

increase in sputum volume, and the presence of spu-

tum purulence. Definitions to stratify the severity of

AECOPD (mild, moderate, severe) have also been

utilized, but have not been yet validated: eg, moder-

ate-to-severe AECOPD is often defined as an increasein dyspnea, purulenent sputum, and the use of an

antibiotic +/- a short course of systemic corticos-

teroids (po or IV).

Differential Diagnosis

A number of other conditions can mimic an acute

exacerbation of COPD; several of these may also

worsen the severity of a COPD exacerbation. Pneu-

monia, congestive heart failure, myocardial ischemia,

pneumothorax, pulmonary embolism, upper respira-

tory tract infection, and conditions such as sepsis or

severe metabolic acidosis, which increase ventilatorydemand, should be considered in the differential of

COPD exacerbation.

Etiology

Respiratory infections are associated with up to 80%

of all COPD exacerbations. Viruses account for up to

50% of these infections; bacteria and/or other factors

account for the remainder. Of the bacterial causes, the

most common offenders areHaemophilus influenzae ,

Streptococcus pneumoniae andMoraxella

catarrhalis. Other agents include:Haemophilus

parainfluenzae, Staphylococcus aureus, Pseu-domonas aeruginosa, and Chlamydia pneumoniae.

Mycoplasma pneumoniae is much less common.

Patients with more severe COPD are more likely to

harbor Gram-negative enteric organisms than those

with mild disease. Noninfectious causes of COPD

exacerbations include environmental changes, pollu-

tion, allergies, and noncompliance with prescribed

therapy.

CHAPTER 3: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) 71

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7. Suggested Readings

Agency for Healthcare Research and Quality, US

Dept of Health and Human Services; 2002; AHRQ

publication 02-M016. Available at:

http://www.ahrq.gov/news/focus/focdisab.pdf.

Accessed December 16, 2005.

The Alpha-1 Antitrypsin Deficiency Registry Study

Group. Survival and FEV1 decline in individuals with

severe deficiency of-1 antitrypsin.Am J Respir Crit

Care Med. 1998;158:49-59.

American College of Chest Physicians and American

Association for Cardiovascular and Pulmonary Reha-

bilitation: Pulmonary Rehabilitation. Joint ACCP and

AACVPR evidence-based guidelines. Chest.

1997;112:1363-1396.

American Medical Association. Guidelines for the

Diagnosis and Treatment of Nicotine Dependence:

How to Help Patients Stop.

American Thoracic Society. Standardization of

spirometry: 1994 update.Am J Respir Crit Care Med.

1995;152:1107-1136. Buist AS, Vollmer WM. Smok-

ing and other risk factors. In: Murray JF, Nadel JA,

eds. Textbook of Respiratory Medicine. 2nd ed.

Philadelphia, Pa: WB Saunders; 1994: 1259-1287.

American Thoracic Society. Standards for the diagno-sis and care of patients with chronic obstructive pul-

monary disease.Am J Respir Crit Care Med.

1995;152:S77-S121.

American Thoracic Society/European Respiratory

Society Task Force. Standards for the Diagnosis and

Management of Patients with COPD [Internet]. Ver-

sion 1.2. New York: American Thoracic Society;

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American Thoracic Society Statement: Pulmonaryrehabilitation1999.Am J Respir Crit Care Med.

1999;159:1666-1682.

Calverley PMA, Anderson JA, Celli B, Ferguson GT,

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bation of COPD. The combination of beta2-agonists

and an anticholinergic affords only a marginal, if any,

beneficial effect versus either nebulizer alone, accord-

ing to the currently published literature; however, this

is the usual therapy chosen for an exacerbation. Addi-

tional trials to investigate this question are underway.

Systemic steroids (intravenous solumedrol or oral

prednisone) are clearly indicated in patients who

require hospitalization for their exacerbation, and oral

steroids are often used in the outpatient setting along

with maximizing bronchodilation. Systemic steroids

have been shown to shorten recovery time and restore

lung function more quickly. No added benefit is

achieved with continued use of steroids beyond 7-14

days post-hospitalization. This effect has not been

definitively demonstrated with use of inhaled corti-costeroids.

Antibiotics, depending on the suspected etiologic

agent and prevalent resistance patterns, are indicated

in the treatment of an acute exacerbation of COPD;

they are more beneficial in patients with severe exac-

erbations, as defined by the presence of two or more of

the cardinal signs of increased dyspnea, increased

cough/sputum, and increased sputum purulence.

Antibiotics have been consistently shown to lead to an

improvement in peak expiratory flow rate over time

when compared to serial peak flow measurements inpatients who do not receive antibiotics.

Noninvasive positive pressure ventilation (NPPV) in

carefully selected patients with a high likelihood for

acute respiratory failure has been shown to provide a

significant difference in the need for intubation and to

decrease the length of hospital stay. Mechanical venti-

lation may be needed for patients who are not candi-

dates for NPPV or who fail to respond to NPPV.

Outcome

The mortality for patients with a COPD exacerbationwho require hospitalization is 6%-14%, and for those

who need ICU admission it can be as high as 24%.

Approximately 50% of patients with a history of

hypercarbic respiratory failure during an exacerbation

of COPD are readmitted within six months of dis-

charge for respiratory failure. Each episode of acute

exacerbation can take a significant toll on the func-

tional status and quality of life of the COPD patient.

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tion of chronic obstructive pulmonary disease: a

prospective randomized controlled trial.Lancet.

1999;354:456-460.

Decramer M, Celli B, Tashkin D, et al. Clinical Trial

Design Considerations in Assessing Long-Term

Functional Impacts of Tiotropium in COPD: The

Uplift Trial. COPD:Journal of Chronic Obstructive

Pulmonary Disease. 2004;1(2):303-312.

Doherty DE, Briggs DD. Chronic obstructive pul-

monary disease: epidemiology, pathogenesis, disease

course and prognosis. Clin Cornerstone.

2004;6(2):S5-16.

Doherty DE. The pathophysiology of airways dys-

function.Am J Med. 2004;117(12A): 11S-23S.

Doherty DE. Detecting and managing COPD in the

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8. Questions

1. A 65-year-old man with a previous history of

smoking was diagnosed with COPD 12 months

ago. He is referred to you for further management

of his COPD. His postbronchodilator FEV1 is 1.8

L (57% of predicted) and his FEV1

/FVC is

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2. A 37-year-old engineer seeks your opinion regard-

ing his risk for developing COPD. He has never

been exposed to tobacco smoke and has no respi-

ratory symptoms. He has several first-degree rela-

tives with alpha-1 antitrypsin deficiency.

You suggest:

A. Alpha-1 Antitrypsin phenotyping, but there is

little risk for COPD since he does not smoke

B. Alpha-1 Antitrypsin phenotyping; start treat-

ment with inhaled prolastin while awaiting

results of test

C. Consider lung transplantation

D. Start treatment with inhaled bronchodilators

and steroids

3.The only therapy listed that is known to prolong

survival in patients with COPD is:

A. Combination of inhaled albuterol and ipra-

tropium

B. Inhaled glucocorticoids

C. Pulmonary rehabilitation

D. Prophylactic antibiotics

E. Long-term oxygen therapy for hypoxic patients

4. A 71-year-old woman who has COPD and contin-

ued tobacco use is referred for management of her

lung disease. She complains of a daily cough pro-ducing white mucoid sputum and dyspnea on

exertion, which has been getting worse over the

past sixteen months. Her COPD medications were

an inhaled long-acting beta2-agonist (salmeterol)

and prn albuterol. In the past six months, she has

been treated in the emergency room at least four

times for COPD exacerbation and required sys-

temic steroids and antibiotics. Her FEV1 is 43% of

predicted and the FEV1/FVC ratio is 64%. Her

routine maintenance therapy should include:

A. Inhaled albuterol, ipratropium and theophylline

B. Smoking cessation, inhaled tiotropium,

albuterol as needed, inhaled steroids (in combi-

nation with a long-acting beta2-agonist) and

pulmonary rehabilitation

C. Inhaled ipratropium, albuterol, salmeterol,

prednisone and doxycycline

D. Pulmonary rehabilitation, inhaled tiotropium,

albuterol, salmeterol, prednisone and doxycy-

cline

E. Albuterol nebulizer, theophylline and pred-

nisone

5. A 71-year-old man with COPD is brought to the

emergency room by ambulance with a 3-day his-

tory of worsening dyspnea, wheezing, and cough

productive of mucoid sputum. He does not have

fever, chills, chest pain or hemoptysis. He is com-

pliant with his medications. Other than participat-

ing in grandparents day at his granddaughters

pre-school a week ago, he has had no change in his

daily routine.

His chest radiograph is clear. He responds well to

nebulized albuterol and 120 mg of intravenous

methylprednisolone. In addition to continuing his

baseline treatment, the optimal management of his

exacerbation should include:

A. Ipratropium inhaler 4 puffs every four hours

with inhaled albuterol every six hours as

needed

B. Prednisone 40 mg once a day for one week and

20 mg once a day for one week

C. Azithromycin 250 mg a day for 5 days

D. Addition of theophylline 300 mg bid

E. All of the above


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6. National Lung Health Education Program

(NLHEP) recommends the use of office spirome-

try to document the presence of airflow obstruc-

tion. In those patients at risk, based on its evidence

based publication in 2000:

A. Using FEV1/FVC ratio of

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4. A 67-year-old woman with COPD was started

on inhaled fluticasone in addition to inhaled

bronchodilators (tiotropium and salmeterol) by

her primary care physician two months prior to

her visit with you. Her respiratory symptoms

remain unchanged since her last visit. Spirome-

try shows that her FEV1 is 1200 cc (46% pre-

dicted). Her FEV1 three months prior was 800

cc (30% predicted).

A. 1 and 3.

B. 1, 2, and 4.

C. 2 and 4.

D. None of the above

E. All of the above

10.The following statement regarding noninvasive

positive pressure ventilation (NPPV) in COPD is

correct:

A. There is good evidence that treatment with

NPPV provides a significant survival benefit

B. NPPV is clearly indicated in the treatment of a

patient with COPD and hypercapnic

encephalopathy who has previously indicated

that he would not want to be intubated

C. Patients who benefit the most from NPPV treat-

ment are those with significant hypercarbia

(PaCO2>50-55 mm Hg)

D. Patients treated with NPPV show sustained

improvement in functional status

E. Patients with severe stable COPD adapt to

NPPV more readily when compared to patients

with neuromuscular disease

Answers

1. D.

The long-acting anticholinergic (tiotropium) and/or

beta-agonist (formoterol or salmeterol) bronchodilator

have been shown to improve quality of life in patients

with COPD, despite their only sometimes leading to

modest improvements of FEV1. These long-acting

bronchodilators have also been shown to reduce dysp-

nea associated with activities of daily living in some

patients, and have been associated with reduced use of

supplemental or rescue albuterol. Current guidelines

suggest adding a long-acting bronchodilator as early as

moderate COPD, and to use a combination of long-act-

ing agents that work by different mechanisms (ie, an

anticholinergic plus 2-agonist) before adding an

inhaled corticosteroid in those patients who remainsymptomatic despite maximizing bronchodilation and

have frequent exacerbations.

Specifically, inhaled corticosteroids are not currently

recommended by guidelines for the routine mainte-

nance treatment of COPD. Inhaled corticosteroids in

COPD have not been shown to be of benefit in COPD,

except in specific patient groupsthose with severe

disease, defined by FEV1, who remain symptomatic

and have frequent exacerbations despite maximized

bronchodilations with one or more classes of bron-

chodilators (long-acting anticholinergic, long-actingbeta2-agonist, +/- a methylxanthine). Similarly, treat-

ment with systemic steroids has not shown benefit

except in acute exacerbations. Oxygen therapy is not

indicated in this patient since he is not hypoxic and

lung volume reduction surgery plays no role in the rou-

tine management of COPD.

Jones PW, Bosh TK, in association with an interna-

tional study group. Quality of life changes in COPD

patients treated with salmeterol.Am J Respir Crit Care

Med. 1997;155:1283-1289.

Mahler DA, Donohue JF, Barbee RA et al. Efficacy of

salmeterol xinafoate in the treatment of COPD. Chest.

1999;115:957-965.

2. A.

Alpha-1 antitrypsin deficiency follows a simple

Mendelian pattern of inheritance and is usually associ-

ated with the Z isoform of alpha-1 antitrypsin. Individ-

uals who are homozygous for the ZZ genotype have a


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severe deficiency of the enzyme and are at increased

risk for development of COPD. Exposure to tobacco

smoke accelerates the decline in lung function in these

individuals; the rate of decline in lung function is vari-

able in lifelong non-smokers. Other patterns of alpha-

1 antitrypsin deficiency such as MS and MZ geno-

types are associated with intermediate alpha-1 antit-

rypsin deficiency and it is controversial whether such

deficiency is a risk factor for COPD.

Testing for alpha-1 antitrypsin deficiency is indicated

in first-degree relatives of known cohorts for appro-

priate screening and counseling. In this asymptomatic

patient, only screening for alpha-1 antitrypsin defi-

ciency is currently indicated. Replacement therapy

with prolastin should be reserved for patients with

severe deficiency and established emphysema untilwe can predict who will progress to COPD.

Brantly ML, Paul LD, Miller BH, et al. Clinical fea-

tures and history of the destructive lung disease asso-

ciated with a-1 antitrypsin deficiency of adults with

pulmonary symptoms.Am Rev Respir Dis.

1988;138:327.

The Alpha-1 Antitrypsin Deficiency Registry Study

Group. Survival and FEV1 decline in individuals with

severe deficiency of alpha-1 antitrypsin.Am J Respir

Crit Care Med.1998;158:49-59.

3. E.

While sustained smoking cessation has been shown to

prolong survival in COPD, the only therapy listed in

the choices that has been shown to prolong survival in

COPD is the long-term administration of oxygen (15-

18 hours per day)indicated for hypoxemic COPD

patients with the goal of increasing the baseline PaO2to at least 60 mm Hg at sea level and rest, and/or pro-

duce SaO2 at least 90%. This is the only treatment that

has been shown to offer survival benefit in patients

with COPD. Other pharmacological and nonpharma-cological treatments improve symptoms and quality

of life but none have shown improvement in survival.

Doherty DE, Petty TL. Recommendations of the 6th

Long-Term Oxygen Therapy Consensus Conference.

Respiratory Care. 2006;51(5):519-525.

Nocturnal Oxygen Therapy Trial Group. Continuous

or nocturnal oxygen therapy in hypoxemic chronic

obstructive lung disease: a clinical trial.Ann Intern

Med. 1980;93:391-398.

Report of the Medical Research Council Working

Party. Long-term domiciliary oxygen therapy in

chronic hypoxic cor pulmonale complicating chronic

bronchitis and emphysema.Lancet. 1981;1:681-686.

4. B.

Smoking cessation is the single most effective inter-

vention that reduces the risk of development of COPD

and stops the progression of disease. Evaluation of

tobacco use status and smoking cessation should be a

part of every therapeutic plan for management of

patients with COPD.

In this patient with advanced COPD (GOLD StageIII), continued tobacco use and worsening pulmonary

status, smoking cessation must be emphasized along

with other treatment measures. Bronchodilation

should be maximized (long-acting anticholinergic

plus a long-acting B2-agonist). Due to the frequency

of exacerbations, maintenance inhaled corticosteroids

should be started initially, and re-evaluated after 3-6

months. If exacerbations are controlled, one could

consider the discontinuation of the ICS, realizing that

some reports have suggested that this may lead to the

recurrence of exacerbations. Systemic steroids and

antibiotics are indicated only to manage acute exacer-bations. Theophylline has a narrow therapeutic index,

especially in the elderly and smokers, and must be

used with caution.

Fletcher C, Peto R. The natural history of chronic

airflow obstruction.BMJ. 1977;1:1645-1648.

American Thoracic Society. Standards for the diagno-

sis and care of patients with chronic obstructive pul-

monary disease.Am J Respir Crit Care Med.

1995;152:S77-S121.

Fiore MC, Bailey WC, Cohen SJ. Smoking Cessation:

Information for Specialists. Rockville, Md: US


Health Service, Agency for Health Care Policy and

Research and Centers for Disease Control and Pre-

vention, 1996; AHCPR Publication No. 96-0694.


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8/14/2019 Pulmonary Ch3!9!24 09

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Pauwels RA, Buist AS, Calverley PM, et al. Global

strategy for the diagnosis, management and preven-

tion of chronic obstructive pulmonary disease.

NHLBI/WHO Global Initiative for Chronic Obstruc-

tive Lung Disease (GOLD) workshop summary.Am J

Respir Crit Care Med. 2001;163:1256-1276, updated

2005; www.goldcopd.com.

Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-

term treatment with inhaled budesonide in persons

with mild chronic obstructive pulmonary disease who

continue smoking. European Respiratory Society

study on chronic obstructive pulmonary disease. N

Engl J Med.1999;340:1948-1953.

10. C.

Results of trials with NPPV in COPD have beenconflicting. It may improve respiratory muscle func-

tion after short-term rest and increase total duration of

sleep. Patients who appear to benefit from NPPV are

those with significant hypercarbia

(PaCO2 >50-55 mm Hg). There are no studies that

have shown survival benefit or sustained improve-

ment in functional status in COPD patients. NPPV

should be used judiciously in carefully selected

patients; it is clearly contraindicated in those with

altered sensorium and inability to protect their air-

ways. Patients with COPD have a more difficult time

adapting to NPPV when compared to patients withneuromuscular disease.

International Consensus Conference in Intensive Care

Medicine: noninvasive positive pressure ventilation

in acute respiratory failure.Am J Respir Crit Care

Med. 2001;163:283-291


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