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DOI 10.1378/chest.07-2061 2008;133;1451-1462 Chest

Bartolome R. Celli

Update on the Management of COPD

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Update on the Management of COPD*

Bartolome R. Celli, MD, FCCP

COPD is highly prevalent and will continue to be an increasing cause of morbidity and mortalityworldwide. COPD is now viewed under a new paradigm as preventable and treatable. Inaddition, it has become accepted that COPD is not solely a pulmonary disease but also one withimportant measurable systemic consequences. Patients with COPD have to be comprehensivelyevaluated to determine the extent of disease so that therapy can be adequately individualized. Wenow know that smoking cessation, oxygen for hypoxemic patients, lung reduction surgery forselected patients with emphysema, and noninvasive ventilation during severe exacerbations havean impact on mortality. The completion of well-planned pharmacologic trials have shown theimportance of decreasing resting and dynamic hyperinflation on patient-centered outcomes andthe possible impact on mortality and rate of decline of lung function. In addition, therapy withpulmonary rehabilitation and lung transplantation improve patient-centered outcomes such ashealth-related quality of life, dyspnea, and exercise capacity. Rational use of single or multipletherapeutic modalities in combination have an impact on exacerbations and hospitalizations. Thismonograph presents an integrated approach to patients with COPD and updates their manage-ment incorporating the recent advances in the field. The future for patients with COPD is brightas primary and secondary prevention of smoking becomes more effective and air qualityimproves. In addition, current research will unravel the pathogenesis, clinical, and phenotypicmanifestations of COPD, thus providing exciting therapeutic targets. Ultimately, the advent ofnewer and more effective therapies will lead to a decline in the contribution of this disease topoor world health. (CHEST 2008; 133:1451–1462)

Key words: BODE index; COPD; management; pharmacotherapy; therapy

Abbreviations: BODE � body mass index, airflow obstruction, dyspnea, exercise capacity; ICS � inhaled corticoste-roids; LABA � long-acting �-agonist; LVRS � lung volume reduction surgery; MDI � metered-dose inhaler;NIPPV � noninvasive positive pressure ventilation; TORCH � Towards a Revolution in COPD Health

COPD is defined as a preventable and treatabledisease state characterized by airflow limitation

that is not fully reversible. Airflow limitation isusually progressive and associated with an abnormalinflammatory response of the lungs to noxious par-ticles or gases, primarily caused by cigarette smok-ing. Although COPD affects the lungs, it also pro-

duces significant systemic consequences.1,2 Thisdefinition changes the paradigm that characterizedolder definitions3,4 in two important aspects. First, itpresents a positive attitude toward the disease; andsecond, it highlights a salient feature of COPD: itsfrequent expression of systemic manifestations. Thismonograph summarizes the recent advances in themanagement of this disease, provides the evidencethat patients with COPD respond to treatment, andshows that treatment is effective in multiple out-comes of importance to patients.

COPD Is Highly Prevalent,Underdiagnosed, Undertreated, and

Underperceived

COPD affects millions of individuals, limits thefunctional capacity of many, and has become an

*From Pulmonary and Critical Care, Caritas St. Elizabeth’sMedical Center, Boston. MA.The author has no conflict of interest to disclose.Manuscript received August 14, 2007; revision accepted Novem-ber 19, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Bartolome R. Celli, MD, FCCP, Chief,Pulmonary and Critical Care Medicine, Caritas St. Elizabeth’sMedical Center, 736 Cambridge St, Boston, MA 02135-2997;e-mail: [email protected]: 10.1378/chest.07-2061

CHEST Recent Advances in Chest Medicine

www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 1451



important cause of death worldwide. Although pre-ventable, COPD has a long subclinical phase. Thepreviously accepted thought that COPD develops inonly 15% of smokers is an underestimation of theactual number that is now known to be much larger.Once dyspnea develops, it occurs at ever lower levelsof exercise. With disease progression, gas exchangebecomes compromised and patients may have respi-ratory failure.1–4 In the end, death can occur eitherfrom respiratory failure or from frequently associ-ated comorbidities such as heart disease and lungcancer.5–7 The estimated prevalence of COPD variesfrom 7 to 19% in several well-conducted studies8–13

around the world. It is a disease that is increasing inwomen, and if we assume the lowest prevalence, thetotal number of cases of COPD in the world approx-imates 280 million persons. Unfortunately, COPDremains largely underdiagnosed.14,15 Finally, due tomany possible reasons, patients underperceive themagnitude of their problem and accept the limita-tions associated with disease progression as naturalfor a person who has smoked.16

COPD, a Multicomponent Disease

The airflow obstruction of COPD, as expressed byFEV1, is by definition only partially reversible.1,2 Ina paradoxical way, this defining physiology has beenused as the outcome to determine the effectivenessof interventions. It is no surprise that the lack oflarge response in FEV1 to different therapies17–26

has resulted in an undeserved nihilism. There isincreasing evidence that independent of the degreeof airflow obstruction, lung volumes are important inthe genesis of the symptoms and limitations ofpatients with more advanced disease. A series ofstudies27–31 have demonstrated that dyspnea per-ceived during exercise, including walking, moreclosely relates to the development of dynamic hyper-inflation than to changes in FEV1. Further, theimprovement in exercise brought about by severaltherapies including bronchodilators, oxygen, lungvolume reduction surgery (LVRS), and even rehabil-itation is more closely related to delaying dynamichyperinflations than by improving the degree ofairflow obstruction.27–30,32 Casanova et al33 showedthat hyperinflation, expressed as the inspiratory ca-pacity/total lung capacity ratio, predicted survivalbetter than FEV1. The importance of lung volume asdeterminant of outcomes provides us not only withnew insights into pathogenesis, but also opens thedoor for new imaginative ways to alter lung volumesand perhaps impact on disease progression.

It is now accepted that COPD may be associatedwith important systemic expressions in patients with

more advanced disease.1,5,34 Perhaps as a conse-quence of a persistent systemic inflammatory state ordue to other yet unproven mechanisms such as imbal-anced oxidative stress or abnormal immunologic re-sponse, the fact is that many patients with COPD mayhave decreased fat-free mass, impaired systemic mus-cle function, anemia, osteoporosis, depression, pulmo-nary hypertension, and cor pulmonale, all of which areimportant determinants of outcome. Indeed, dyspneameasured with simple tools such as the modifiedMedical Research Council scale,35 the body mass in-dex,36,37 and the timed 6-min walk distance38,39 are allbetter predictors of mortality than FEV1. The incorpo-ration of these variables into the multidimensionalBODE (body mass index, airflow obstruction, dyspnea,exercise capacity) index predicts survival even better.5The BODE index, also responsive to exacerbations,40

and more importantly acts as a surrogate marker offuture outcome after interventions,41 may better helpclinicians determine the comprehensive severity ofdisease.

Based on the multidimensional nature of thedisease and the availability of multiple effectivetherapies, the proposed approach shown in Figure 1may help clinicians evaluate patients comprehen-sively and choose therapies other than the currentapproach using primarily the percentage of pre-dicted FEV1 from reference values.

COPD, a Treatable Disease

Current evidence suggests that smoking cessation,6long-term oxygen therapy in hypoxemic patients,42,43

noninvasive mechanical ventilation in some patientswith acute-on-chronic respiratory failure,44–46 andLVRS for patients with upper-lobe emphysema andpoor exercise capacity47 improve survival. The TORCH(Towards a Revolution in COPD Health) study48 of� 6,000 patients showed that the combination of sal-meterol and fluticasone not only improved lung func-tion and health status, but that the relative risk of dyingover the 3 years decreased by 17.5% over the 3 years ofthe study. Other therapies such as pulmonary rehabil-itation and lung transplantation improve symptoms andthe quality of life once the diagnosis has been estab-lished.1,2,49,50 The overall goals of treatment of COPDare to prevent further deterioration in lung function,improve symptoms and quality of life, treat complica-tions, and prolong a meaningful life.1,3

Therapy Is Effective for the RespiratoryManifestations of COPD

Once COPD is diagnosed, the patient should beencouraged to actively participate in disease manage-

1452 Recent Advances in Chest Medicine



ment. This concept of “collaborative management”may improve self-reliance and esteem. All patientsshould be encouraged to lead a healthy lifestyle andexercise regularly. Preventive care is extremely im-portant at this time, and all patients should receiveimmunizations including pneumococcal vaccine andyearly influenza vaccinations.1,3 This comprehensiveapproach is summarized as a proposal in Figure 1. Itdirects action according to the multidimensionalevaluation of the patient.

Smoking Cessation and Decreased Exposureto Biomass Fuel Combustion Fumes

As smoking is the major cause of COPD, smokingcessation is the most important component of ther-apy for patients who still smoke.1,3 Because second-hand smoking is known to damage lung function,limitation of exposure to involuntary smoke, partic-ularly in children, should be encouraged. The factorsthat cause patients to smoke include the addictivepotential of nicotine; conditional responses to stimulisurrounding smoking; psychosocial problems such asdepression, poor education, and low income; andforceful advertising campaigns. As the causes thatdrive the patient to smoke are multifactorial, smok-

ing cessation programs should also involve multipleinterventions. The clinician should always participatein the treatment of smoking addiction because aphysician’s advice and intervention and use of theappropriate medications including nicotine patch,gum or inhalers, bupropion, and verenicline helpdetermine successful results.51–54 The significantburden of COPD in patients exposed to the fumes ofbiomass fuel consumption in certain areas of theworld should improve by changing to more efficientand less polluting sources of energy.

Pharmacologic Therapy of AirflowObstruction

Many patients with COPD require pharmacologictherapy. This should be organized according to theseverity of symptoms (dyspnea and functional capacity),the degree of lung dysfunction, and the tolerance tospecific drugs.1,3 A step-wise approach similar in con-cept to that developed for systemic hypertension maybe helpful because medications alleviate symptoms,improve exercise tolerance and quality of life, and maydecrease mortality. Tables 1 and 2 provide a summaryof the evidence supporting the effect of individual andcombined pharmacologic agents on outcomes of im-portance to patients with COPD.

All patients(Spirometry)Healthy lifestyle

Immunizations Smoking cessation

At riskEducate patient

Follow over time

ModerateTreat obstructionEducate patient

Monitor response

Very SevereTreat obstruction.Educate patient

Monitor responseAssess and treat hypoxemia

Rehabilitation

Evaluate for Lung volume reduction

orLung transplant

If smoking

FEV1/FVC<0.7FEV1 >80 % predicted

BODE index(BMI,FEV1%, MMRC, 6MWD)

FEV1 < 80 %predicted

BODE = 3-4 BODE = 5-6

ConsiderRehabilitation

BODE = 7-10

SevereTreat obstructionEducate patient

Monitor responseAssess gas exchange

BODE = 0-2

MildTreat obstructionEducate patient

Monitor response

Figure 1. Schematic algorithm to approach patients with COPD. The evaluation of the multipledomains using simple validated tools can better help stage the global severity of the disease.BMI � body mass index; FEV1% � percentage of predicted FEV1; MMRC � modified MedicalResearch Council scale; 6MWD � 6-min walk distance.




Bronchodilators

Several important concepts guide the use of bron-chodilators. In some patients, the changes in FEV1may be small and the symptomatic benefit may bedue to other mechanisms such as a decrease in lunghyperinflation.55,56 Some older COPD patients can-not effectively activate metered-dose inhalers (MDIs),and we should work with the patient to achievemastery of the MDI. If this is not possible, use of aspacer or nebulizer to facilitate inhalation of the med-ication will help achieve the desired results. The adventof once-daily or twice-daily nebulized bronchodilatorssuch as formoterol offers an interesting alternative tothe MDI in those patients unable to activate themeffectively. Mucosal deposition in the mouth can resultin local side effects (ie, thrush with inhaled steroids) orgeneral absorption and its consequences (ie, tremorafter �-agonists). Finally, the inhaled route is preferredover the oral administration,1,3 and long-acting bron-chodilators are more effective than short-acting bron-chodilators.1,2

Currently Available Bronchodilators

�-Agonists: These drugs increase cyclic adenosinemonophosphate within many cells and promote airwaysmooth-muscle relaxation. Other nonbronchodilator ef-fects have been observed, but their significance isuncertain. In patients with mild intermittent symp-toms, it is reasonable to initiate drug therapy with an

MDI of a short-acting �-agonist as needed for relief ofsymptoms.1,2 In patients with persistent symptoms, it isindicated to use long-acting �-agonists (LABAs)1,2,57–60

at a dose of one or two puffs bid. LABAs preventnocturnal bronchospasm, increase exercise endurance,and improve quality of life. The safety profile ofsalmeterol in the TORCH trial48 is reassuring to clini-cians who frequently prescribe selective LABAs to theirpatients with COPD. The advent of longer-actingagents and preparations that can be provided vianebulizer will increase our choices and perhaps helpincrease compliance.

Anticholinergics: These drugs act by blockingmuscarinic receptors that are known to be effectivein COPD. The appropriate dosage of the short-acting ipratropium bromide is two to four puffs tid orq6h, but some patients require and tolerate largerdoses.1,3 The therapeutic effect is a consequence of adecrease in exercise-induced dynamic hyperinfla-tion.28 The long-acting tiotropium is very effective ininducing prolonged bronchodilation18,21 and de-creasing hyperinflation55 in patients with COPD. Inaddition, it improves dyspnea, decreases exacerba-tions,61 and improves health-related quality of lifewhen compared to placebo and even to ipratropriumbromide.62,63 The results of the large UnderstandingPotential Long Term Impacts on Function WithTiotropium trial64 evaluating the potential role oftiotropium as a disease-modifying agent will deter-

Table 2—Effect of Some Combined Pharmacologic Agents on Important Outcomes of Patients With COPD*

Agents FEV1

LungVolume Dyspnea

Quality ofLife

AdverseEvents

ExerciseEndurance

Disease Modifierby FEV1 Mortality

Salmeterol plus theophylline Yes (B) NA Yes (B) Yes (B) NA NA NA NAFormoterol plus tiotropium Yes (A) NA Yes (B) Yes (B) NA NA NA NASalmeterol plus fluticasone Yes (A) Yes (B) Yes (A) Yes (A) Yes (A) Yes (B) Yes SomeFormoterol plus budesonide Yes (A) NA Yes (A) Yes (A) Yes (A) NA NA NATiotropium plus salmeterol plus

fluticasoneYes (A) NA Yes (B) Yes (A) Yes (A) NA NA NA

*See Table 1 for expansion of abbreviations and definition of terms. Modified from Celli and MacNee.1

Table 1—Effect of Individual Pharmacologic Agents on Important Outcomes of Patients With COPD*

Agents FEV1

LungVolume Dyspnea

Quality ofLife

AdverseEvents

ExerciseEndurance

Disease Modifierby FEV1 Mortality

Albuterol Yes (A) Yes (B) Yes (B) NA NA Yes (B) NA NAIpratropium bromide Yes (A) Yes (B) Yes (B) No (B) Yes (B) Yes (B) No NALABAs Yes (A) Yes (A) Yes (A) Yes (A) Yes (A) Yes (B) No NATiotropium Yes (A) Yes (A) Yes (A) Yes (A) Yes (A) Yes (A) NA NAICS Yes (A) NA Yes (B) Yes (A) Yes (A) NA No NoTheophylline Some (A) Yes (B) Yes (A) Yes (B) NA Yes (B) NA NA

*Yes supports an improvement in outcome, Some supports an improvement in outcome, and No supports no improvement in outcome. Level ofevidence: A � more than one randomized trial; B � limited randomized trials. NA � not available. Modified from Celli and MacNee.1




mine its place in the overall armamentarium oftreatments for patients with COPD. Currently,tiotropium represents a first-line agent for patientswith persistent symptoms.

Phosphodiesterase Inhibitors: Theophylline is anonspecific phosphodiesterase inhibitor that in-creases intracellular cyclic adenosine monophos-phate within airway smooth muscle. Bronchodilatoreffects are best seen at high doses, where there isalso a higher risk of toxicity. The potential for toxicityof theophylline has led to a decline in its popularity.Theophylline is of particular value for less-compliantor less-capable patients who cannot use aerosoltherapy optimally. The previously recommendedtherapeutic serum levels of 15 to 20 mg/dL are tooclose to the toxic range and are frequently associatedwith side effects. Therefore, a lower target range of8 to 13 mg/dL is safer and still therapeutic.1,3 Thecombination of two or more bronchodilators (the-ophylline, albuterol, and ipratropium) has some ra-tionale because they seem to have additive effectsand can result in maximum benefit in stableCOPD.2,65 A possible action of theophylline on theexpression of genes central to inflammation inCOPD66 deserves further investigation.

The specific phosphodiesterase E4 inhibitors cilo-milast and roflumilast may have an antiinflammatoryand bronchodilator effect but less GI irritation, andthis could prove extremely useful if these theoreticalbenefits are clinically confirmed. Data from the first6-month studies67,68 show modest bronchodilationeffects and some benefits on quality of life.

Nonsteroidal Antiinflammatory Therapy: In con-trast to their value in asthma, nonsteroidal antiin-flammatory drugs have not been documented tohave a significant role in the treatment of patientswith stable COPD.1,2 Cromolyn and nedocromilcould possibly be helpful if the patient has associatedrespiratory tract allergy. One study69 using monoclo-nal antibody against interleukin-8 and anotherstudy70 using an antibody against tumor necrosisfactor-� failed to detect any response. However,patients were selected according to the degree ofairflow obstruction and not based on the presence orincreased level of the specific targeted molecules.Groups of leukotriene inhibitors that have provenuseful in asthma have not been adequately tested inCOPD, so that final conclusions about their potentialuse cannot be drawn at this time.

Corticosteroids: Glucocorticoids act at multiplepoints within the inflammatory cascade, althoughtheir effects in COPD appear more modest com-

pared with bronchial asthma. In outpatients, exacer-bations necessitate a course of systemic corticoste-roids as will be discussed later in this monograph, butit is important to wean patients quickly because theolder COPD population is susceptible to complica-tions such as skin damage, cataract development,diabetes, osteoporosis, and secondary infection.These risks do not accompany standard doses ofinhaled corticosteroid (ICS) aerosols, which maycause thrush but pose a negligible risk for otheroutcomes such as development of cataracts andosteoporosis. Several large multicenter trials23,24,71–73

evaluated the role of ICS in preventing or slowingthe progressive course of symptomatic COPD; theresults of these earlier studies showed minimal if anybenefits in the rate of decline of lung function.However, in the one study23 in which it was evalu-ated, inhaled fluticasone decreased the rate of loss ofhealth-related quality of life and frequency of exac-erbations. Recent retrospective analyses74,75 of largedatabases suggesting a possible effect of ICS onimproving survival were not confirmed in theTORCH trial,48 in which the combination of ICS andLABAs was superior to ICS alone with regard to alloutcomes evaluated, including survival. This coupledwith the more frequent development of pneumonia(described as an adverse event but not preciselydiagnosed with chest radiography, sputum cultures,or laboratory confirmation) in the patients receivingICS suggests that in patients with COPD, ICSshould not be prescribed alone but rather in combi-nation with an LABA.48

Combination Therapy: Most studies that haveexplored the value of combination therapy haveshown significant improvements over single agentsalone, and it may be time to think of combinationtherapy as first-line therapy. Initially, the inhaledcombination of ipratroprium and albuterol provedeffective in the management of COPD.26 Morerecently, the combination of tiotropium once dailyand formoterol twice daily was better than eitheragent alone. In that study,62 the administration ofonce-daily tiotropium and once-daily formoterol wasvery effective, suggesting that once-daily dosing ofcombinations may offer a viable option to the morecomplex twice-daily therapy. In another trial,22 thecombination of theophylline and salmeterol was signif-icantly more effective than either agent alone in lungfunction and health status. The TORCH study48

showed the benefits of the salmeterol/fluticasone com-bination on survival, FEV1, exacerbation rate, andquality of life compared with placebo and either of thesingle components, confirming earlier studies76–78 eval-uating the combination of �-agonists and corticoste-roids. A recent trial79 comprising � 400 patients with




symptomatic COPD compared the effectiveness oftherapy using tiotropium in all patients combined withplacebo in group 1, with salmeterol in group 2, andwith the combination of salmeterol and fluticasone inthe third group. Although the primary outcome, theexacerbation rate, was similar among the groups, thenumber of hospitalizations, health-related quality oflife, and lung function was significantly better in thegroup receiving tiotropium plus salmeterol and flutica-sone compared with tiotropium plus placebo andtiotropium plus salmeterol. Based on these results, it isreasonable to propose the approach shown in Figure 2.Once symptoms become persistent, therapy shouldbegin with a long-acting antimuscarinic agent such astiotropium or LABAs twice daily. Once a patientreaches an FEV1 � 60% of predicted, and continues tobe symptomatic, the evidence from the TORCH trialsupports the addition of the combination of ICS andLABAs. Continuation of tiotropium is reasonable, givenits effectiveness and safety record. I believe that all ofthe trials support the concept that intense and aggres-sive therapy does modify the course of the disease,including rate of decline of FEV1, as was shown in theTORCH study.48 The results of the 4-year Understand-ing Potential Long Term Impacts on Function WithTiotropium trial,62 in which trough FEV1 is the primaryoutcome, should help clarify the disease-modificationeffect of the currently available medications.

Mucokinetic Agents: These drugs aim to decreasesputum viscosity and adhesiveness in order to facilitate

expectoration. The only controlled study80 in theUnited States suggesting a value for these drugs in thelong-term management of bronchitis was a multi-center evaluation of organic iodide. This study80

demonstrated symptomatic benefits. Oral acetyl-cysteine is favored in Europe for its antioxidanteffects. A large trial81 failed to document anysubstantial benefit, but patients were not selectedby the presence or absence of increased oxidativestress. Genetically engineered ribonuclease seemsto be useful in cystic fibrosis but is of no value inCOPD.1,2

Antibiotics: In patients with evidence of respira-tory tract infection, such as fever, leukocytosis, and achange in chest radiographic findings, antibioticshave proven effective.82–85 If recurrent infectionsoccur, particularly in winter, continuous or intermittentprolonged courses of antibiotics may be useful.86 Themajor bacteria to be considered are Streptococcuspneumoniae, Haemophilus influenzae, and Moraxellacatarrhalis, although patients with more severe airflowlimitation appear to have a higher prevalence of Gram-negative bacteria such as Pseudomonas aeruginosa. Theantibiotic choice will depend on local experience, sup-ported by sputum culture and sensitivities if the patientis moderately ill or needs to be admitted to hospital.1,2

�1-Antitrypsin: Although supplemental weekly ormonthly administration of this enzyme may be indi-cated in nonsmoking, younger patients with geneti-cally determined enzyme deficiency and emphy-sema, in practice such therapy is difficult to initiatebecause of its cost and need of long-term weekly ormonthly IV administration. �1-Antitrypsin is rela-tively safe.1,3,87,88 Although not entirely clear, thebest candidates for replacement therapy would bepatients with mild-to-moderate COPD for whomprogression of the disease can be stalled.

Vaccination: Ideally, infections of the respiratorytract should be prevented in patients with COPDby using effective vaccines. Thus, routine prophy-laxis with pneumococcal and influenza vaccines isrecommended.12,89,90

Lung Volume Reduction: Multiple operations havebeen tried in patients with COPD.91 For patientswith localized large bullae and relatively preservedlung function, bullectomy has proven useful. Inpatients with diffuse severe emphysema, lung trans-plantation results in normalization of pulmonaryfunction, and improvement in exercise capacity andquality of life, but its effect on survival remainscontroversial.92–95 Several issues must be considered

FEV1

Dyspnea, Functional limitation

Smoking cessation Exercise Vaccination

LAMA or LABA

Risk

Oxygen

LVR

MV

Theophylline

LAMA + LABA

LABA + ICS + LAMA

Pulmonary Rehabilitation

Figure 2. Schematic representation of the possible therapeuticoptions for patients at risk for COPD and those with establisheddisease. The progressive decrease in FEV1 is represented by thehorizontal decrease of the surface of the triangle. However, theincrease of the size of the opposing triangle reflects worsening ofdyspnea, exercise capacity, and development of systemic compro-mise. As COPD progresses (decreasing airflow and worsening ofsymptoms), the number of therapeutic options increases. No pre-defined thresholds of lung function or symptoms have been placedbecause the therapy is determined by the assessment of a particularpatient condition. LAMA � long-acting muscarinic agent; LVR � lungvolume reduction; MV � mechanical ventilation.




when evaluating a candidate for lung transplantation,including pulmonary disability, projected survival with-out transplantation, comorbid conditions, and patientpreferences. General guidelines include that the pa-tient be � 65 years old without any other medicalcondition that could shorten predicted survival. Thepresence of a high BODE index helps facilitate theselection of candidates for transplant because they havea very poor prognosis if left untreated.96

The other surgical procedure that has receivedrecent attention is pneumoplasty, or LVRS.47,97–103 Itis an alternative for selected patients with severeinhomogeneous emphysema who remain symptom-atic after optimal comprehensive medical therapy.LVRS improves FEV1 by close to 10%, with largerimprovements in exercise tolerance, dyspnea, andhealth-related quality of life.47,101–103 The effect onsurvival is larger in patients with inhomogeneousupper-lobe disease and limited exercise performanceafter rehabilitation.47,104 The ideal candidate shouldhave an FEV1 between 20% and 35% of predicted, adiffusion capacity of the lung for carbon monoxideno lower than 20% of predicted, hyperinflation, andlimited comorbidities. Reports104–106 evaluatingtechniques capable of achieving lung volume reduc-tion without the surgical risk open exciting newavenues. Indeed, the bronchoscopic placement ofone-way valves107 or biological substances108–110 ca-pable of inducing closure of emphysematous areasmay add to an already exciting armamentarium totreat selected patients with advanced COPD.

Therapies That Are Effective for theNonrespiratory Manifestations of COPD

The most exciting changes in the way we concep-tualize COPD is the recognition of the extrapulmo-nary manifestations of COPD.5,111,112 Some of themost important advances in the therapy of COPDcenter on our capacity to impact on the diseasewithout having to necessarily alter lung function.Two of the proven forms of therapy for COPD fallwithin this category: pulmonary rehabilitation andoxygen therapy. If we add mechanical ventilationduring exacerbations, the field is wide open toexplore even more exciting therapies.

Pulmonary Rehabilitation

Pulmonary rehabilitation is an essential compo-nent of the comprehensive management of patientswith symptomatic COPD.1,2,113–120 Patients withmoderate-to-moderately severe disease are the bestcandidates for treatment, for whom the disabling

effects of end-stage respiratory failure can be pre-vented. The rehabilitation program should have re-sources available to teach and supervise respiratorytherapy techniques such as oxygen, use of inhalersand nebulizers, physical therapy (breathing tech-niques, chest physical therapy, postural drainage),exercise conditioning (upper and lower extremity),and activities of daily living (work simplification,energy conservation). Also desirable are servicesto evaluate and advise on nutritional needs, psycholog-ical, and vocational counseling. Exercise training is themost important component of a pulmonary rehabilita-tion program. Maltais et al121 documented that themuscle biopsy samples in trained patients, but notcontrol subjects, manifested significant increases in allenzymes responsible for oxidative muscle function.Pulmonary rehabilitation can change outcomes thatpredict survival.122 Indeed, in an observational study,Cote and Celli123 showed that rehabilitation improvedthe BODE score, and the 3-month change in theBODE index predicted survival. Reimbursement forpulmonary rehabilitation treatment remains a hurdle toits widespread application.

Supplemental Oxygen Therapy

The results of the Nocturnal Oxygen TherapyTrial42 and Medical Research Council study43

showed that supplemental oxygen improves survival inpatients with hypoxemic COPD. Other beneficial ef-fects of long-term oxygen include reductions in polycy-themia, pulmonary artery pressures, dyspnea, hypox-emia during sleep, and reduced nocturnal arrhythmias.Importantly, oxygen can also improve neuropsychiatrictesting124,125 and exercise tolerance.126–128 Oxygensupplementation to patients who desaturate duringexercise improves exercise performance. Currently,exercise-induced oxygen desaturation is an acceptedindication to provide supplemental oxygen therapy.1,2

The beneficial effects of oxygen without necessarilychanging the degree of airflow obstruction provideevidence that the disease can be modified withoutchanging the decline of the FEV1.

Exacerbations

An exacerbation is an event in the natural courseof the COPD characterized by a change in thepatient’s baseline dyspnea, cough, and/or sputumbeyond day-to-day variability sufficient to warrant achange in management.1,3,129,130 Care must be taken torule out heart failure, myocardial infarction, arrhyth-mias, and pulmonary embolism, all of which maypresent with clinical signs and symptoms similar to




exacerbation of COPD. An algorithm describing arational approach to exacerbations is shown in Figure 3.

The pharmacologic therapy of exacerbations isinitiated with the same therapeutic agents availablefor the long-term management of COPD.1,3 Themost important agents include anticholinergic and�-agonists aerosols by nebulization. Several trials131–133

have proven the usefulness of systemic corticoste-roids. It is important to avoid prolonged (� 2 weeks)or high-dose therapy because older patients aresusceptible to severe complications such as psycho-sis, fluid retention, and a vascular necrosis of bones.Antibiotics have been helpful in purulent exacerba-tions of COPD.134 The antibiotics used in severeexacerbation have to be guided by knowledge of theprevalent pathogens in that area.1,2 Exacerbationsare to be prevented and treated aggressively becausethey have a prolonged and intense effect on health-related quality of life and can result in acceleratedloss of lung function.40,135–137 Besides pharmacologictherapy, some patients may need temporary admin-istration of supplemental oxygen.1,2

Ventilatory support should be considered if pa-tients have persistent hypoxemia and/or hypercapniawith low pH (� 7.35) despite maximal medical ther-apy.1 Several randomized trials40–43 have shown thatnoninvasive positive pressure ventilation (NIPPV) is

beneficial in selected patients with respiratory fail-ure, decreasing the need for invasive mechanicalventilation and its complications, and possibly im-proving survival. Certain conditions would makepatients less likely to respond to NIPPV. Theseconditions include respiratory arrest, medical insta-bility (shock, cardiac ischemia), inability to protectthe airway, excessive secretions, agitation or uncoop-erativeness, craniofacial trauma, or deformity. De-spite the usefulness of NIPPV in acute-on-chronicrespiratory failure, its use in patients with stableCOPD remains debatable and is not routinely rec-ommended.138,139

Conclusion

Over the years, our knowledge about COPD andthe capacity to treat it have increased significantly.We now know that COPD is not just a diseaseaffecting the lungs,140 but that it has importantsystemic consequences.141 Smoking cessation cam-paigns have resulted in a decrease in smoking prev-alence in the United States. Similar efforts in the restof the world should have the same impact. Thewidespread application of long-term oxygen therapyfor hypoxemic patients has resulted in increased

Exacerbation of COPD

Outpatient Inpatient

Mild Exacerbation. Mild COPD (FEV >50% pred) No comorbidity

Moderate-Severe Exacerbation Moderate-Severe COPD (FEV <50% pred)Severe dyspnea

Increase dose -Agonist

Add Anticholinergic

Consider Short Course Steroids

Consider Antibiotics if purulent sputum

Use O2 to achieve saturation 92-93%

Obtain ABG. Also, chest X-ray to exclude pneumonia, pneumothorax or heart failure

Inhaled bronchodilator ( -Agonist + Anticholinergic)Systemic Corticosteroids (IV initially followed by 2 weekor shorter oral taper)

Antibiotics (consider narrow spectrum)If sputum suggests bacterial infection

Consider NIPPV

Hypoxemia. PaCO2

<45 mmHgHypercapnia and pH< 7.35

β

β

1 1

s

. Comorbidity

Figure 3. Algorithm describing the approach to patients with COPD with exacerbations characterizedby increased dyspnea, cough, or change in the color or volume of sputum. pred � predicted;ABG � arterial blood gas; see Figure 1 legend for expansion of abbreviation.




survival. During this time, we have expanded ourpharmacologic armamentarium to effectively im-prove lung function and alter its rate of decline,exercise capacity, dyspnea, quality of life, and evensurvival. Several studies113–123 have documented thebenefits of pulmonary rehabilitation. Noninvasiveventilation has benefited patients with acute-on-chronic failure. The revival of surgery for emphy-sema or, in the immediate future, endobronchiallung volume reduction should provide an alternativeto lung transplantation for those patients with severeCOPD who are still symptomatic on maximal med-ical therapy. With all these options, a nihilistic attitudetoward the patient with COPD is not justified. Theevidence supports a positive and aggressive attitude.

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