Considerations in the Management of Chronic Obstructive ... · PDF fileManagement of Chronic...

SUPPLEMENT TO

Considerations in the Management of Chronic Obstructive Pulmonary Disease

•Impact of Symptoms on Activities of Daily Living and Quality of Life

•Is It a Systemic Disorder?

•Bronchodilators and Reversibility of Airflow Obstruction

•Treatment Options: Current Recommendations and Recent Findings

MATTHEW L. MINTZ, MD

NICOLA A. HANANIA, MD, MS

DONALD P. TASHKIN, MD

BARBARA P. YAWN, MD, MSc, FAAFP

Funding for this supplement was provided by AstraZeneca LP.

PEER-REVIEWED CONSULTATIONS IN PRIMARY CAREDECEMBER 2011VOL.51 NO.12

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Chronic obstructive pulmonar y disease (COPD) is a progressive disease with dev-astating consequences, surpassing stroke as the third leading cause of death in 2008.1 COPD is estimated to af fect 24 million

adults in the United States, imparting substantial burden to the patient and to society.2 Historically, there has been a nihilistic approach to COPD management, but the cur-rent Global Initiative for Chronic Obstructive Lung Dis-ease (GOLD) guidelines define COPD as a “preventable and treatable disease.”3

The present understanding of COPD has extended well beyond the perception of COPD patients as “pink puffers” or “blue bloaters.” Although disease pathophys-iology still is not understood completely, COPD is char-acterized by airflow obstruction that is not fully revers-ible, with disease development and progression associ-ated with chronic inflammation and structural changes in the airways.3 Progress has been made and research is ongoing to better characterize the disease and improve our current understanding of the factors that contribute to individual differences and variability in COPD. In that regard, research efforts are focused on identifying spe-cific COPD phenotypes that would allow for optimizing treatment and moving beyond a “one drug treats all” ap-proach to COPD management. Despite our current un-derstanding of COPD, misunderstandings persist in cer-tain areas. For example, the concept of bronchodilator reversibility in COPD is poorly understood and often confused with disease reversibility. Contrary to evidence from clinical studies, it is commonly thought that pa-tients with COPD do not exhibit a significant bronchodi-lator response, which may contribute to confusion in dif-ferentiating between asthma and COPD and hinder ap-propriate disease management.

Despite the lack of major advances recently in novel COPD treatments, many effective pharmacologic and non-pharmacologic treatments are available that can im-prove COPD symptoms and pulmonary function, reduce exacerbations, and improve quality of life. However, con-sidering the prominent systemic inflammatory compo-

nent of COPD, novel pharmacologic agents that reduce systemic inflammation are needed. Novel treatments that have the ability to modify disease progression also are needed. Patients with COPD commonly suffer from comorbidities, including arthritis, hypertension, diabetes mellitus, cardiac disorders, lipid disorders, psychiatric conditions, gastrointestinal diseases, cancer, and osteo-porosis. Thus, to optimize treatment, COPD manage-ment programs should consider the “whole patient” and treat coexisting morbidities that often complicate COPD management.

Primary care physicians are the primary point of contact for many patients with COPD. Therefore, they play a critical role in disease prevention and should en-courage smoking cessation in all of their patients who smoke. With the exception of smoking cessation, cur-rently available treatments do not reduce the decline in lung function seen in COPD patients. Thus, timely COPD diagnosis is critical for initiating appropriate treat-ment as early as possible to minimize the effects of the disease on the patient’s quality of life and daily function-ing. In this collection of articles, information surround-ing the impact of COPD on the patient is reviewed, in particular with respect to effects on daily activities of liv-ing and quality of life. We also discuss the comorbidities commonly experienced by patients with COPD that could contribute to disease severity and complicate dis-ease management, the misconceptions and evidence sur-rounding bronchodilator reversibility and airflow ob-struction in COPD, and current and emerging treatment options in COPD. ■

REFERENCES:1. Miniño AM, Xu JQ, Kochanek KD. Deaths: preliminary data for 2008. Natl Vital Stat Rep. 2010;59:1-52.2. National Heart, Lung, and Blood Institute. Morbidity & Mortality: 2009 Chart Book on Cardiovascular, Lung, and Blood Disease. http://www.nhlbi.nih.gov/resources/docs/2009_ChartBook_508.pdf. Accessed September 23, 2011.3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2010. http://www.goldcopd.org. Accessed September 23, 2011.

Dr Mintz is associate professor of medicine, George Washington University School of Medicine, Washington, DC.

Considerations in the Management of Chronic Obstructive Pulmonary DiseaseMATTHEW L. MINTZ, MDGeorge Washington University

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Introduction

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The opinions expressed herein are those of the author and do not necessarily represent those of CONSULTANT, Scientific Connexions, or AstraZeneca LP. Any procedures or other courses of diagnosis or treatment discussed or suggested by authors should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s prescribing information, and comparison with the recommendations of other authorities.

ABSTRACT: The burden of chronic ob-structive pulmonary disease (COPD) to patients and society is substantial. As the disease progresses, activities of daily living—from the most basic of tasks to more involved activities—are limited, and quality of life is diminished. Dyspnea, the most burdensome symp-tom of COPD, worsens over time, re-ducing exercise tolerance, which further limits daily activities and reduces health status. Due to the progressive nature of COPD, patients may be unaware of the extent of their disability or unable to recognize worsening of symptoms. Therefore, it is important for primary care physicians to evaluate patients for respiratory symptoms and ability to perform activities of daily living and to educate their patients on the disease and associated risk factors. As the first point of contact for most patients with COPD, primary care physicians play a critical role in diagnosing COPD as early as possible and initiating ap-propriate therapy, thereby alleviating the detrimental clinical consequences of COPD and its symptoms.

Chronic obstructive pulmonary dis-ease (COPD) has replaced cerebro-vascular diseases as the third-lead-ing cause of death in the United States.1 An estimated 12 million adults have a physician diagnosis of COPD, and 12 million more are esti-mated to have undiagnosed COPD.2 The clinical and economic burden of the disease is substantial.3 In 2006 alone, there were 672,000 hospital-

izations due to COPD in the United States.4 In developed countries, exac-erbations of COPD represent the greatest burden on the health care system.3 The National Heart, Lung, and Blood Institute projected the total cost of COPD to be $49.9 billion in the United States in 2010.2,4

The pathophysiology of COPD is not completely understood, but it is characterized by airflow obstruc-tion that is not fully reversible, chronic inflammation, and structural changes in the airways.3 In patients who develop COPD, cigarette smoke or other noxious particles cause an exaggerated inflammatory response that is associated with a specific pat-tern of increase in inflammatory cell types in different parts of the lung.3 The pathogenesis of COPD is fur-ther worsened by an increase in oxi-dative stress and proteinase activity, which leads to the breakdown of connective tissue such as elastin.3 In the lungs of patients with COPD, the air ways lose their elasticity and many of the walls between the alveo-li are destroyed, leading to tissue de-struction and gas exchange abnor-malities characteristic of emphyse-ma.3,5 The airway walls also become thicker and inflamed, and mucus hy-persecretion occurs in some patients (Figure 1), clogging the bronchioles and leading to a chronic productive cough characteristic of chronic bron-chitis.3,5 These pathological changes are coupled with a gradual worsen-ing of COPD symptoms and disease

MATTHEW L. MINTZ, MDGeorge Washington University

Chronic Obstructive Pulmonary Disease:Impact of Symptoms on Activities of Daily Living and Quality of Life

Dr Mintz is asso-ciate professor of medicine, George Washington University School of Medicine, Washington, DC.

DECEMBER 2011 (SUPPLEMENT) CONSULTANT S1www.Consultant360.com

DisclosuresMatthew L. Mintz, MDConsultant/Advisor: AstraZeneca, GlaxoSmithKline, Sepracor, TevaSpeaker: AstraZeneca, GlaxoSmithKline

www.Consultant360.comS2 CONSULTANT DECEMBER 2011 (SUPPLEMENT)

severity with increasing impact on patients’ daily lives.3

CHARACTERISTIC FEATURES OF COPD AND DISEASE PROGRESSION

The burden of COPD on an in-dividual is dependent on the degree of airflow limitation and the severity of symptoms, including dyspnea, sputum production, wheezing, and chest tightness.3 Acute exacerbation, which is generally defined as an in-

crease in COPD symptoms (eg, dys-pnea, cough, and/or sputum) that is beyond the normal day-to-day varia-tion,3 results in greater disease bur-den for the patient3 and may contrib-ute to more rapid progression of COPD.6-9

Dyspnea is the most common reason patients with COPD seek medical care.3,10 It occurs as a result of lung hyperinflation, which reduc-es inspiratory capacity and increases functional residual capacity, making

it more difficult for patients to move air in and out of the lungs, particu-larly during exercise.3,11 Hyperinfla-tion, which occurs as a result of air trapping during expiration, can de-velop early in COPD.3 Early in the disease, patients generally experi-ence dyspnea only during unusual exertion.3 As COPD and airflow limi-tation progress, patients experience dyspnea with minimal effort; eventu-ally, it is present during everyday activities or even during rest.3

The gradual progressive and chronic nature of the symptoms of COPD may lead to a diminished abil-ity of patients to recognize the effects of COPD on their daily functioning. In a recent survey (“Confronting COPD in America”) of 573 patients with COPD, many of those with sub-stantial functional impairment, deter-mined by scores from the validated Medical Research Council (MRC) dyspnea scale,12 did not recognize their condition as severe.13 In fact, 36% of patients with the most severe grade of dyspnea (score of 5) de-scribed their condition as “mild” or “moderate.”13 Similarly, in a telephone survey of 3265 patients with COPD in North America and Europe, 60% and 36% of patients with the second most severe (score of 4) and the most se-vere (score of 5) grade of dyspnea, respectively, based on the MRC dys-pnea scale reported their condition as “mild” or “moderate.”14 This dimin-ished ability of patients to recognize the severity of their condition may lead to a delay in seeking treatment and a greater impact of the disease.

IMPACT OF COPD SYMPTOMS ON ACTIVITIES OF DAILY LIVING AND QUALITY OF LIFE

The importance of recognizing and treating worsening of COPD symptoms is underscored by the negative impact of these symptoms on patients’ basic activities of daily


Figure 1 – Cross section of normal lungs (A) and lungs with COPD (B).Reprinted with permission from: National Heart, Lung, and Blood Institute. Diseases and Conditions Index: COPD.5 Revised June 2010. http://www.nhlbi.nih.gov/health/dci/Diseases/Copd/Copd_WhatIs.html.

COPD, chronic obstructive pulmonary disease.


living and quality of life. Most pa-tients included in the “Confronting COPD in America” survey reported that COPD limits what they can do “some or a lot” in normal physical exer tion (70%), lifestyle (58%), household chores (56%), social ac-tivities (53%), and sleeping (50%).13 Although more than half of the pa-tients surveyed were retired, 51% of patients also reported that COPD limits their ability to work, with 34% reporting that COPD keeps them from working and 17% stating that COPD limits the amount or kind of work they can perform.13

In a telephone survey of patients with COPD in North America and Europe, 36% of respondents reported that their COPD kept them from working, limited their ability to work, or caused them working time loss in the past year.14 In addition, functional limitations in sports and recreation, social activities, household chores, sex life, and family activities due to COPD were reported by a similar or greater percentage of middle-aged patients (aged < 65 years) compared with older patients (aged ≥ 65 years).14 However, limitations in nor-mal physical exertion were reported by significantly fewer middle-aged patients compared with older pa-tients (56% versus 62%, P < .05).14

Evidence suggests that patients particularly are af fected by their COPD symptoms during the morn-ing hours. Findings from a quantita-tive Internet interview of 803 pa-tients with COPD showed that morning was most commonly re-ported (37%) as the time of day when COPD symptoms were worse than usual.15 When limiting respondents to those with severe COPD, this per-centage was even higher (46%).15 In particular, patients’ morning activi-ties that were most af fected by COPD included walking up and down stairs, putting on shoes and socks, making the bed, showering

and bathing, drying the body with a towel, and dressing.15

Similar findings were observed in a study of 2441 patients with COPD.16 Patients reported that all of their COPD symptoms (breathlessness, phlegm, coughing, wheezing, and chest tightness) were most trouble-some upon waking up in the morn-ing.16 The morning activities most af-fected by COPD symptoms were washing, dressing, drying, and getting out of bed, while the daily activities most affected were going up and down stairs, doing heavy household chores, going shopping, and doing sports or hobbies (Figure 2).16 In addition, 13% of the patients reported that they needed assistance to perform their daily activities, and a majority of those patients believed that they were a bur-den to others for this reason.16

Dyspnea also showed a strong association with poorer health status in a recent meta-analysis of 66 stud-ies in patients with COPD.17 In that analysis, other COPD symptoms, in-cluding sputum production, chronic

cough, wheezing, and fatigue, also were associated with poorer health status.17 These findings are particu-larly important, as health status has been recognized as a major factor af-fecting patients’ quality of life.18

Taken together, these data sug-gest that COPD has a substantial neg-ative impact on patients’ daily func-tioning, from the most minor of daily tasks to more involved activities, and that it results in substantial decre-ments to patients’ health status. These effects in turn lead to poorer quality of life in patients with COPD.18

EFFECT OF COPD SYMPTOMS ON EXERCISE TOLERANCE

Exertional dyspnea occurs in pa-tients with COPD as a result of dy-namic hyperinflation, which involves an increase in air trapping in the lungs during exercise.3 This phenom-enon contributes substantially to ex-ercise intolerance in patients with COPD.3,11 Patients with COPD often experience a downward spiral of re-duced ability to exercise and physical

Figure 2 – Morning and daily activities most affected by symptoms of chronic obstructive pulmonary disease.16


deconditioning and fatigue, leading to further reduction in exercise toler-ance and increasing disability.18,19

Findings from a study in elderly patients with COPD (n = 50) and healthy elderly subjects (n = 25) showed that patients with COPD are considerably less active than their healthy counterparts.20 They spent a smaller percentage of time during the day walking or standing and a greater percentage of time in the sit-ting or lying position compared with healthy subjects (Figure 3).20 In ad-dition, patients with COPD experi-enced significantly (P < .0001) re-duced movement intensity (1.8 m/s2) during walking compared with healthy subjects (2.4 m/s2).20 In that study, activity level (walking and standing time) was positively corre-lated with exercise capacity (based on 6-minute walking distance) in pa-tients with COPD.20

Diminished exercise capacity is a strong indicator of health status impairment3,21 and poorer progno-sis.3 In addition, in a study in 452 pa-tients with COPD, increased disabil-ity as measured by the Valued Life Activities scale was associated with onset of depression, assessed using the Geriatric Depression Scale Short

Form.22 Taken together, these find-ings highlight the substantial limita-tions to exercise capacity experi-enced by patients with COPD and the detrimental clinical consequenc-es of such disability.22

EFFECT OF COPD SEVERITY ON EXERCISE TOLERANCE AND DAILY ACTIVITIES

Exercise tolerance and ability to perform daily activities generally worsen as COPD progresses.3,12,19,23 As COPD severity increases, patients lose muscle bulk and experience di-minished exercise endurance.19 This decrement is most noticeable in pa-tients at Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II (moderate: forced expirato-ry volume in 1 second [FEV1] % pre-dicted 50% to < 80%), III (severe: FEV1 % predicted 30% to < 50%), and IV (very severe: FEV1 % predicted < 30% or < 50% plus chronic respiratory failure).3 Findings from a study of 100 patients with COPD showed that as patients’ disability (measured using the MRC scale) increases, there is a progressive and significant (P ≤ .003) decline in exercise toler-ance (based on shuttle walking dis-tance) and diminished ability to per-

form daily activities (assessed using the Nottingham Extended Activities of Daily Living scale).12

The effect of COPD disease se-verity on daily activities and health status was assessed in 2 cross-sec-tional studies of 1596 patients with moderate COPD and 2012 patients with severe or very severe COPD.23 Patients’ ability to perform activities of daily living (assessed using the London Chest Activity of Daily Liv-ing), including self-care, household chores, physical activity, and leisure activity, was significantly (P < .0001) diminished in patients with severe or very severe COPD compared with patients with moderate COPD.23 Ap-proximately two-thirds of patients with severe or very severe COPD versus one-third of patients with moderate COPD reported that their disease af fected them “much” in their daily lives.23 In addition, pa-tients with severe or very severe COPD had significantly (P ≤ .0001) worse health status, based on the EuroQol-5D visual analogue scale, than patients with moderate COPD.23 These findings show that the effects of COPD on patients’ ability to per-form daily activities and health sta-tus worsen with increasing severity of the disease and highlight the need for initiating appropriate COPD ther-apy as early as possible in the dis-ease process to minimize the nega-tive impact on patients’ daily lives.

ROLE OF PRIMARY CARE PHYSICIANS

As the primary point of contact for many patients with COPD,24 pri-mary care physicians play an impor-tant role in COPD prevention, early diagnosis, and appropriate manage-ment. Physicians should encourage smoking cessation in patients with or without a diagnosis of COPD, as smoking is a key factor in the devel-opment and progression of COPD.3 Educating patients about other inha-


Figure 3 – Daily time spent in activi-ties or body posi-tions in healthy subjects compared with patients with COPD.

Reprinted with permission from: Pitta F, Troosters T, Spruit MA, et al. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171:972-977.20

“Other” includes cycling or undetermined activity.



lational exposures that increase the risk of COPD, including dust and chemicals or air pollution, also is important.3

The GOLD guidelines recom-mend that a diagnosis of COPD, which is confirmed using spirometry (postbronchodilator FEV1/forced vital capacity [FVC] ratio of < 0.70), should be considered in patients with symptoms of COPD (eg, dys-pnea, chronic cough, or sputum pro-duction) and/or exposure to risk fac-tors for the disease.3 Recent COPD guidelines issued by the American College of Physicians, American Col-lege of Chest Physicians, American Thoracic Society, and European Re-spirator y Society recommend against using spirometry for COPD screening in patients who do not have respiratory symptoms.25 How-ever, if patients have symptoms of COPD but do not recognize them, they would fail to meet criteria for spirometry screening,25 which may lead to a delay in diagnosis. Given the substantial burden of the disease and the benefits of early interven-tion, early screening of COPD using alternative or less expensive tools may be beneficial.

The Lung Function Question-naire (LFQ) recently was developed as a tool to aid in COPD screening.26 The LFQ is a 5-item self-adminis-tered questionnaire, where a total score of ≤ 18 suggests an increased risk of air flow obstruction.26 In a study of 1575 patients aged ≥ 30 years who had a smoking history of 10 pack-years and were not taking asthma or COPD medications, an LFQ score of ≤ 18 identified a preva-lence of obstructive lung disease of approximately 18% in a primary care setting; these cases were confirmed by an FEV1/FVC ratio of < 0.70.26 If office spirometry testing is not avail-able, the LFQ is a simple and conve-nient way for primary care physi-cians to identify patients who may

have COPD and may need a referral for spirometry testing.26

Because patients may fail to rec-ognize the severity of their disease, it is important for primary care phy-sicians to evaluate respiratory symp-toms in their patients and explore the impact of dyspnea and other COPD symptoms on their patients’ daily activities and social activities, and work to optimize disease man-agement.3 Patient-physician commu-nication and patient education are critical to this goal because patients’ disease perceptions can affect out-comes,27,28 including quality of life.29 In addition, study findings showed

better treatment adherence in pa-tients with compassionate doctors who spend adequate time with them and in patients with greater under-standing of their disease and disease management options.30

The Table provides a list of questions that physicians can ask pa-tients to assess their ability to per-form activities of daily living and identify disease progression.18 Pa-tients at earlier stages of COPD who experience mild dyspnea on exertion should be able to perform all of the activities listed in the Table, along with additional “productive” activi-ties (employment, gardening, going

Table – Questions to assess patients’ activities of daily living18

Questions to evaluate basic activities of daily living

•Are you able to wash and bathe yourself?

•Are you able to climb stairs?

•Are you able to move (ie, transfer) from a bed to a chair on your own?

•Can you walk (and if so, how far)?

•When was the last time you walked that far?

•Are you able to feed yourself?

•Do you have difficulty using the toilet for either bladder or bowel functions?

•Are you able to groom yourself?

Questions to evaluate instrumental activities of daily living

•Are you able to travel via car or public transportation?

•Do you shop for your own food and clothes?

•Who prepares your food for you?

•How much of your own housework do you perform?

•Can you make your own bed?

•Who ensures you take your medication on time and in the correct dose?

•Do you manage your own money?

•Are you able to engage in sexual activity?

•Do you care for others?

•Do you care for a pet?

•Are you caring for children?

•How do you get around?

•Do you require a device to communicate with others?

Reprinted with permission from: Belfer MH, Reardon JZ. Improving exercise tolerance and quality of life in patients with chronic obstructive pulmonary disease. J Am Osteopath Assoc. 2009;109:268-278.18



to movies, recreational travel, social activities, sporting or recreational ac-tivities, volunteer work).18 Patients with moderate dyspnea on exertion should be able to perform most of the activities listed as “instrumental” in the Table, while patients with se-vere COPD may be able to perform only the most basic activities or re-quire assistance completing them.18 Patient responses to these questions can assist in determining the appro-priate treatment.3

APPROPRIATE COPD MANAGEMENT

Traditionally, there has been a nihilistic view of COPD management; however, recent guidelines empha-size that this disease is preventable and treatable.3

Currently available COPD treatment options, including pharmacologic and nonpharmacolog-ic therapies, can control and prevent COPD symptoms, reduce exacerba-tions, and improve exercise tolerance, quality of life, and functional abili-ties.3,18 Smoking cessation may be the only way to slow the progressive pul-monary function decline in patients with COPD; therefore, primary care physicians should encourage all pa-tients who smoke to quit.3

CONCLUSIONSSymptoms of COPD, including

dyspnea, sputum production, wheez-ing, and chest tightness, negatively affect patients’ ability to perform ac-tivities of daily living, which are criti-cal to maintaining quality of life. The chronic and progressive nature of COPD results in gradual decrements to exercise tolerance, health status, and quality of life, which may not al-ways be recognized by the patient. Appropriate COPD management can reduce symptoms and improve pa-tients’ functional abilities, exercise tolerance, and quality of life, under-scoring the importance of diagnos-ing COPD, initiating appropriate

treatments, and encouraging smok-ing cessation as early as possible. As the first point of contact for many pa-tients with COPD, primary care phy-sicians play a critical role in identify-ing symptoms of COPD in their pa-tients, evaluating patients for disease progression, educating them on their disease and management op-tions, and optimizing treatment. ■

AcknowledgmentsThe author thanks Anny Wu, PharmD, and Cynthia Gobbel, PhD, from Scientific Connexions (Newtown, PA) who provided medical writing support funded by AstraZeneca LP (Wilmington, DE).

REFERENCES:1. Miniño AM, Xu JQ, Kochanek KD. Deaths: pre-liminary data for 2008. Natl Vital Stat Rep. 2010;59:1-52.2. National Heart, Lung, and Blood Institute. Morbidity & Mortality: 2009 Chart Book on Cardio-vascular, Lung, and Blood Disease. http://www.nhlbi.nih.gov/resources/docs/2009_ChartBook_508.pdf. Accessed September 23, 2011.3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2010. http://www.goldcopd.org. Accessed September 23, 2011.4. American Lung Association. Trends in COPD (Chronic Bronchitis and Emphysema): Morbidity and Mortality. Washington, DC: American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division; February 2010.5. National Heart, Lung, and Blood Institute. Diseases and Conditions Index: COPD. Revised June 2010. http://www.nhlbi.nih.gov/health/dci/Diseases/Copd/Copd_WhatIs.html. Accessed September 23, 2011.6. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev. 2010;19:113-118.7. Rennard SI, Farmer SG. Exacerbations and progression of disease in asthma and chronic ob-structive pulmonary disease. Proc Am Thorac Soc. 2004;1:88-92.8. Tanabe N, Muro S, Hirai T, et al. Impact of exac-erbations on emphysema progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183:1653-1659.9. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847-852.10. Kumar S, Gross NJ. The global initiative for COPD: what you need to know. J Respir Dis. 2002;23:549-556.11. O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164:770-777.12. Bestall JC, Paul EA, Garrod R, et al. Usefulness of the Medical Research Council (MRC) dyspnea

scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54:581-586.13. Confronting COPD in America: Executive Summary. http://www.aarc.org/resources/confronting_copd/exesum.pdf. Accessed Septem-ber 23, 2011.14. Rennard SI, Decramer M, Calverley PMA, et al. Impact of COPD in North America and Europe in 2000: subjects’ perspectives of Confronting COPD International Survey. Eur Respir J. 2002;20:799-805.15. Partridge MR, Karlsson N, Small IR. Patient insights into the impact of COPD on morning symptoms, activities and daily life. Curr Med Res Opin. 2009;25:2043-2048.16. Kessler R, Partridge MR, Miravitlles M, et al. Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J. 2011;37:264-272.17. Tsiligianni I, Kocks J, Tzanakis N, et al. Factors that influence disease-specific quality of life or health status in patients with COPD: a review and meta-analysis of Pearson correlations. Prim Care Respir J. 2011;20:257-268.18. Belfer MH, Reardon JZ. Improving exercise tolerance and quality of life in patients with chronic obstructive pulmonary disease. J Am Osteopath Assoc. 2009;109:268-278.19. Sin DD, Man SFP. Skeletal muscle weakness, reduced exercise tolerance, and COPD: is systemic inflammation the missing link? Thorax. 2006;61:1-3.20. Pitta F, Troosters T, Spruit MA, et al. Charac-teristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171:972-977.21. Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax. 2001;56:880-887.22. Katz PP, Julian LJ, Omachi TA, et al. The impact of disability on depression among individuals with COPD. Chest. 2010;137:838-845.23. Rodriguez Gonzalez-Moro JM. Impact of COPD severity on physical disability and daily living activi-ties: EDIP-EPOC I and EDIP-EPOC II studies. Int J Clin Pract. 2009;63:742-750. 24. Barr RG, Celli BR, Martinez FJ, et al. Physician and patient perceptions in COPD: the COPD Resource Network Needs Assessment Survey. Am J Med. 2005;118:1415.e9-1415.e17.25. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic ob-structive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respira-tory Society. Ann Intern Med. 2011;155:179-191.26. Mintz ML, Yawn BL, Mannino DM, et al. Prevalence of airway obstruction assessed by Lung Function Questionnaire. Mayo Clin Proc. 2011;86:375-381.27. Kaptein AA, Scharloo M, Fischer M, et al. Illness perceptions and COPD: an emerging field for COPD patient management. J Asthma. 2008;45:625-629.28. Scharloo M, Katpetin A, Weinman JA, Willems LNA, Roojimans HGM. Physical and psychologic cor-relates of function in patients with chronic obstructive pulmonary disease. J Asthma. 2009;37:17-19.29. Scharloo M, Kaptein AA, Schlösser M, et al. Illness perceptions and quality of life in patients with chronic obstructive pulmonary disease. J Asthma. 2007;44:575-581.30. George J, Kong DCM, Thoman R, Stewart K. Factors associated with medication nonadherence in patients with COPD. Chest. 2005;128:3198-3204.

ABSTRACT: Chronic obstructive pulmo-nary disease (COPD) typically is consid-ered a disease of the lungs, but in actual-ity, it is a complex, multicomponent dis-ease that can affect different systems. An abnormal inflammatory response of the lungs to noxious substances, such as cigarette smoke, is the primary factor contributing to development of airflow limitation characteristic of the disease. However, COPD also is associated with systemic inflammation, which may be linked to the observed significant extra-pulmonary effects, including muscle wasting and cachexia, cardiovascular dis-ease, osteoporosis, depression and anxi-ety, and anemia, which contribute to poor outcomes in some patients. These comorbidities have to be considered and managed in conjunction with COPD treat-ment for a more holistic approach in order to improve patients’ overall health. Because systemic inflammation may be an important contributor to the comor-bidities associated with the disease, future systemic anti-inflammatory thera-pies may play a role in targeting the extrapulmonary effects of COPD.

Airflow limitation that is characteri-stic of chronic obstructive pulmo-nary disease (COPD) results from a variety of contributing factors in the lungs, including mucociliary dysfunc-tion, pulmonary structural changes, and airway inflammation.1 Airway in-flammation in patients with COPD most commonly originates from chronic exposure to noxious stimuli, including cigarette smoke, air pollu-

tion, and burning of wood or biomass fuels.2 It involves activated neu-trophils, macrophages, and CD8� T-cell lymphocytes, and increased levels of inflammatory mediators, in-cluding leukotriene B4, interleukin (IL)-8, and tumor necrosis factor-� (TNF-�).2 COPD is also associated with clinically relevant extrapulmo-nary effects, including poor nutritio-nal status, muscle wasting, and im-paired skeletal muscle function,3 which may further contribute to di-sease severity in some patients.2 Se-veral other comorbidities also can contribute to disease severity and/or complicate COPD management.2 Systemic inflammation has been pro-posed as a pathogenic link between COPD and some of these comorbidi-ties, such as osteoporosis and cardio-vascular disease.4-7

EVIDENCE AND ORIGINS OF SYSTEMIC INFLAMMATION

Although it is well known that COPD is associated with chronic air-way and lung inflammation,2 in-creased levels of oxidative stress,8,9 activated inflammatory cells,10-12 and proinflammatory cytokines13 are also seen in the systemic circulation of COPD patients compared with healthy individuals.3 Serum levels of C-reactive protein (CRP), a marker of inflammation that has been shown to predict cardiovascular events,14 and of TNF-�, a marker of muscle wasting in patients with cancer,15 are elevated in COPD patients compared with smokers without COPD,16,17 and

NICOLA A. HANANIA, MD, MSBaylor College of Medicine

Chronic Obstructive Pulmonary Disease:Is It a Systemic Disorder?

Dr Hanania is associate professor of medicine in the section of pulmo-nary and critical care medicine, Baylor College of Medicine, Houston, TX.


DisclosuresNicola A. Hanania, MD, MSConsultant/Advisor: Dey, Forest, GlaxoSmithKline, PfizerRecipient of research grant support to institution: Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, SunovionSpeaker: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck


these levels appear to rise with in-creasing COPD severity.18 Increased CRP levels have also been shown to be associated with COPD-related hospitalization and death.19

Several origins of the systemic inflammation in COPD have been proposed. In the “spillover hypothe-sis” (Figure), inflammation begins in the lungs following the exposure to tobacco smoke or other oxidants, worsens with increasing airflow ob-struction,20 and spreads to the sys-temic circulation via inflammatory cells and mediators, potentially caus-ing the extrapulmonary manifesta-tions.20 Although chronic exposure to cigarette smoke is the most com-mon risk factor for COPD,2 genetic predisposition and gene-environ-ment interactions also may contrib-

ute to COPD susceptibility.2 Accord-ing to the “susceptible host hypoth-esis,” injury from tobacco smoke or other oxidants propagates inflamma-tion in multiple organs including the lung, leading to small airway narrow-ing and other COPD manifestations in susceptible individuals.21 Other potential origins for systemic inflam-mation include lung hyperinflation, tissue hypoxia, and sympathetic and neurohormonal activation.20

SYSTEMIC COMORBIDITIES OF COPD

Systemic comorbidities are com-mon in patients with COPD and can lead to an increase in the level of disability associated with the dis-ease.2 Categories of comorbidities include those with common path-

ways, including other smoking-re-lated diseases such as ischemic heart disease and lung cancer, and those considered to be complications of COPD, including pulmonary hyper-tension and heart failure.2 Coexisting coincidental comorbidities, such as bowel or prostate cancer, depression, diabetes, dementia, Parkinson’s di-sease, and arthritis, are pathogeni-cally unrelated, but they can compli-cate COPD management.2 Intercur-rent comorbidities, including upper respiratory tract infections, are acute illnesses that may have a more se-vere impact in COPD patients com-pared with those without COPD.2

In a large study of 2 population-based National Institutes of Health cohorts, patients with severe or very severe COPD were more likely to


Figure – The “spillover hypothesis” for comorbid conditions in patients with COPD.20

CRP, C-reactive protein; GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; TNF-�, tumor necrosis factor alpha.

Reprinted with permission from: Kao CC, Hanania NA. Co-morbidities of COPD: systemic inflammation. In: Crapo J, ed. Atlas of Chronic Obstructive Pulmonary Disease. Philadelphia, PA: Current Medicine Group; 2009:169-177.


have 1, 2, or 3 comorbid conditions compared with participants with nor-mal lung function.22 In a case-control study, only 6% of 200 patients with COPD did not have another chronic medical condition. Patients with COPD and healthy controls had an average of 3.7 and 1.8 chronic medical conditions, respectively (P < .001).23 Frequent comorbidities of patients with COPD include arthritis, cardiac disorders, hypertension, diabetes mel-litus, lipid disorders, psychiatric con-ditions, gastrointestinal diseases, can-cer, and osteoporosis (Table).24-28

Muscle wasting and cachexia. The prevalence of nutritional deple-tion and associated weight loss has been shown to increase with increas-ing severity of COPD,29 and low and normal weight is associated with de-creased sur vival compared with overweight and obese patients with COPD.30 Loss of muscle mass is a primary reason for weight loss in pa-tients with COPD.3 A study of mus-cle biopsies from 15 patients with COPD and 8 healthy participants showed an increased percentage of

apoptotic cells in patients with COPD versus healthy controls and in COPD patients with low versus normal body mass index (BMI).31

Skeletal muscle dysfunction has many potential causes, including physical inactivity, nutritional deple-tion, tissue hypoxia, oxidative stress, and systemic inflammation.3 In-creased levels of circulating CRP, IL-6, TNF-�, and other inflammatory mediators have been detected in COPD patients with skeletal muscle wasting versus normal skeletal mus-cle mass.32 Increased circulation of TNF-� leads to apoptosis and loss of protein in skeletal muscle cells.33,34 Patients with COPD often have an increased basal metabolic rate3,34 and commonly experience cachexia, which is a “wasting syndrome” involv-ing weight loss, skeletal muscle atrophy, and weakness that is associ-ated with systemic inflammation.33 Cachexia is an important predictor of mortality and is associated with functional impairment and reduced quality of life.34 These findings high-light the importance of implement-

ing and maintaining pulmonary re-habilitation programs, including exercise training and nutrition counseling, in appropriate patients early in the disease process.2

Cardiovascular disease. The lung and the heart are physiologi-cally integrated and functionally in-terdependent.35 The increased work of breathing associated with COPD is particularly problematic in pa-tients with compromised cardiac function because greater cardiac out-put is required.35 In addition, the pres-ence of COPD can impair cardiac function because pulmonary hyper-tension leads to increased cardiac strain.35 Evidence suggests a connec-tion between cardiovascular compli-cations and systemic inflammation associated with COPD.36 Circulating levels of TNF-� or CRP as a result of chronic lung inflammation may acce-lerate development of atherosclero-sis.35 High levels of circulating CRP and severity of airflow obstruction have also been correlated with in-creased risk of cardiac infarction in patients with COPD.5

Table – Prevalence of common comorbidities in COPD24

% of Patients

Source n Arthritis Cardiac HTN Diabetes Lipids Psych GI Cancer Osteoporosis

Van Manen 1145 36 13 23 5 — 9 15 6 —and colleagues24

Mapel and 200 22 65 45 12 — 17 32 18 —colleagues22

Soriano and 2699 28 22 — — — 10 26 4 —colleagues25

Sidney and 45,966 — 18 18 2 9 — — — —colleagues26

Walsh and 3000 70 50 52 16 51 38 62 4 32Thomashow27

—, no available data; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal disturbances; HTN, hypertension.

Reprinted with permission from: Chatila WM, Thomashow BM, Minai OA, Criner GJ, Make BJ. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5:549-555.


Patients with COPD are indeed at increased risk for cardiovascular complications and cardiovascular dis-ease.37,38 Compared with healthy controls, patients with COPD have increased arterial stiffness,38 which is an independent predictor of car-diovascular complications.39 In addi-tion, COPD patients have a signifi-cantly higher prevalence of and greater risk of hospitalization for arrhythmia, angina, acute myocardi-al infarction, congestive heart fail-ure, stroke, and pulmonary embolism compared with controls.37 In the To-wards a Revolution in COPD Health (TORCH) trial,40 27% of all deaths were due to cardiovascular disease,41 which is consistent with findings from other studies in patients with COPD (see Chatila and colleagues24 for a summary of studies). More-over, patients with COPD who have cardiovascular disease are at signifi-cantly increased risk for COPD exac-erbations and increased costs com-pared with patients with COPD who do not have cardiovascular disease.42 Together, these findings provide strong support for careful monitor-ing of cardiovascular health in pa-tients with COPD.

Osteoporosis. Results from the Third National Health and Nutri-tion Examination Survey show that risk of osteoporosis increases with disease severity in both men and women with COPD.6 Reduced physi-cal activity and skeletal muscle mass, changes in body composition, and mediators of chronic systemic in-flammation (ie, IL-1 and TNF-�) may contribute to the pathogenesis of osteoporosis in patients with COPD.43,44 Risk factors for osteopo-rosis also may include low vitamin D levels, smoking, increased alcohol intake, genetic factors, and treat-ment with systemic or inhaled corti-costeroids (ICS).44

Corticosteroids are known to reduce calcium absorption, increase

calcium excretion, stimulate bone re-sorption, and reduce bone forma-tion.44 Evidence suggests a strong association between a cumulative prednisone dose of ≥ 1000 mg and reduced bone mineral density (BMD).45 However, studies evaluat-ing the effects of ICS treatment on BMD and osteoporosis have shown inconsistent results.40,46-49 Patients with COPD should be screened for osteopenia, which indicates an in-creased risk for osteoporosis, and regular monitoring of BMD should be conducted in patients who are re-ceiving intermittent courses of oral corticosteroids or long-term ICS therapy.44

Depression and anxiety. Mood disorders, including depression and anxiety, are more prevalent in patients with COPD than in the general popu-lation.20 In a study of 1334 patients with COPD and other chronic breath-ing disorders, 65% of patients had both depression and anxiety at screen-ing.50 In the Evaluation of COPD Lon-gitudinally to Identify Predictive Sur-rogate Endpoints (ECLIPSE) obser-vational study, depression requiring treatment was more prevalent in women than men with moderate to very severe COPD (P ≤ .004).51 More-over, COPD patients with comorbid major depressive disorder or anxiety have higher rates of COPD-related emergency department visits or hos-pitalizations and health care costs compared with patients with COPD only.52 Other variables associated with depression and anxiety in patients with COPD include physical disability, fatigue, long-term oxygen therapy, low BMI, severe dyspnea, percentage of predicted forced expiratory volume in 1 second < 50%, poor quality of life, presence of comorbidity, living alone, current smoking, and low social class status.53

Depression and anxiety in-crease the severity of disease symp-toms,54 decrease levels of physical

activity,20 increase functional impair-ment,55 and worsen quality of life.20,56,57 In the National Emphysema Treatment Trial (NETT) (N = 610), approximately 41% of patients were mildly to moderately depressed; these patients had a greater 3-year risk of mortality compared with non-depressed patients.58 Anxiety and depressive disorders are underrec-ognized (< 40%) and undertreated (approximately 30%) in patients with COPD.50 The adverse clinical conse-quences of anxiety and depression in patients with COPD highlight the need to implement screening proce-dures and initiate appropriate treat-ment, such as antidepressants and/or pulmonary rehabilitation.57

Anemia. Putative mechanisms for anemia in chronic diseases in-clude shortened red blood cell sur-vival time, dysregulation of iron ho-meostasis, and impaired bone mar-row erythropoietic response.59 These changes may occur as a result of sys-temic inflammation involving in-creased circulating IL-1, TNF-�, in-terferon-�, and other cytokines and chemokines, supporting a mechanis-tic link between COPD and anemia.59 Anemia occurs in 13% to 17% of pa-tients with COPD60,61 and is associat-ed with worsening of COPD symp-toms, decreased exercise capacity, and greater risk of mortality in pa-tients with COPD.60 Although a caus-al relationship between COPD and anemia has not been established, findings support screening and ap-propriate treatment in patients with COPD.60 It should be noted that poly-cythemia can also occur in patients who have arterial hypoxemia and in continuing smokers, and it is identi-fied by a hematocrit of > 55%.2

EFFECTS OF COMORBIDITIES ON CLINICAL OUTCOMES

Comorbidities of COPD are as-sociated with poor clinical outcomes, although their severity and impact



on patient health vary with time and among patients.2 Data from the Na-tional Hospital Discharge Survey from 1979 to 2001 indicate that rates of in-hospital mortality due to vari-ous cardiovascular, pulmonary, and thoracic conditions are higher in pa-tients with, versus without, COPD.62 COPD currently is the third leading cause of death in adults in the United States63; however, results from sev-eral studies suggest that patients with COPD may be more likely to die of comorbid conditions than of COPD,64-66 in particular those related to cardiovascular disease.65,66

THERAPEUTIC IMPLICATIONS

Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend that significant comorbidities should be considered during a comprehensive diagnostic assessment of disease sever ity and determination of appro-priate treatment2; however, neither the GOLD guidelines nor the Ameri-can Thoracic Society/European Res pi-ratory Society (ATS/ERS) guide lines give integrated recommendations for management of specific comorbid conditions.2,67 The ATS/ERS guide-lines recommend referral to a special-ist for patients who have cormorbid illness, including osteoporosis, heart failure, bronchiectasis, and lung can-cer.67 Considering that 20% of Medi-care beneficiaries have ≥ 5 chronic conditions, and half are prescribed ≥ 5 medica tions for comorbid disea-ses, it is critical that physicians make efforts to screen for comorbidities and implement disease management programs that consider the “whole patient.”68 The central role of syste-mic inflammatory process in COPD and its comorbidities supports a need for further research evaluating novel targets for suppression of pulmonary and systemic inflammation, such as phosphodiesterase-4, p38 mitogen–

activated protein kinase, and nuclear factor-�B.69

CONCLUSIONSCOPD is associated with chron-

ic airway and systemic inflammation; the latter is a likely mechanism for the many clinically relevant extrapul-monary effects associated with the disease. Systemic comorbidities of COPD may affect multiple physio-logic systems and often are associat-ed with poor outcomes in COPD pa-tients. Disease management pro-grams that consider the pulmonary and nonpulmonary effects of COPD and its comorbidities and treat the “whole patient” are critically needed. Research on novel targets for reduc-ing systemic inflammation is also needed in COPD patients with or without existing comorbidities. ■

AcknowledgmentsThe author thanks Kristen Quinn, PhD, and Cynthia Gobbel, PhD, from Scientific Connexions (Newtown, PA) who provided medical writing support funded by AstraZeneca LP (Wilmington, DE).

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ABSTRACT: A central feature of chronic obstructive pulmonary disease (COPD) is airflow obstruction that is not fully re-versible, defined as a postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of < 0.70. Although airflow obstruction in COPD is not fully reversible, patients can still exhibit clinically significant bron-chodilator reversibility (or responsive-ness), based on changes from prebron-chodilator values in FEV1 and/or FVC. The FVC component is particularly impor-tant in patients with more severe COPD who have greater hyperinflation, as these patients often show clinically meaningful improvement in FVC without a significant FEV1 response after bron-chodilator treatment. Confusion exists surrounding the concept of bronchodilator reversibility because of the lack of a standardized definition of and methodol-ogies for assessing reversibility, inherent day-to-day variability in bronchodilator response, and similarities with asthma in some cases. This article reviews the role of spirometry in COPD diagnosis and ongoing monitoring, definitions of bron-chodilator reversibility, and clinical rele-vance of bronchodilator responsiveness in patients with COPD.

Chronic airflow obstruction is a cen-tral feature of chronic obstructive pul-monary disease (COPD).1 Often, pa-tients with COPD have a significant response to bronchodilator treat-ment,2-5 but the disease is not fully reversible.1 Airflow limitation that is not fully reversible is defined as a

postbronchodilator forced expiratory volume in 1 second/forced vital ca-pacity (FEV1/FVC) ratio of < 0.70.1 A common misconception is that pa-tients who exhibit a significant re-sponse to bronchodilators but are not fully reversible more likely have asth-ma than COPD. However, bronchodi-lator responsiveness is not sensitive or specific enough to differentiate asthma from COPD.6 According to current COPD management guide-lines, measurements of postbroncho-dilator FEV1/FVC and FEV1 are rec-ommended for COPD diagnosis and assessment of disease severity, re-spectively, but the degree of post-bronchodilator response (eg, change in FEV1) is not recommended for dif-ferentiation of COPD from asthma.1

DIFFERENTIATING BETWEEN COPD AND ASTHMA

Characteristic COPD symptoms include dyspnea, chronic cough, and sputum production.1 These symp-toms also may be present in patients with asthma, albeit with greater vari-ability.7 Several clinical features can help distinguish COPD from asthma (Table 1),1 although these distin-guishing features are not absolute. Fixed airflow obstruction is a defin-ing feature of COPD, but airway re-modeling occurs often in asthma and may lead to a fixed component of air-flow obstruction in some asthma pa-tients.7 In particular, patients with longstanding asthma may demon-strate irreversible airway obstruc-tion,1 and some patients with asthma

DONALD P. TASHKIN, MDUniversity of California, Los Angeles

Chronic Obstructive Pulmonary Disease:Bronchodilators and Reversibility

of Airflow Obstruction

Dr Tashkin is emeritus professor of medicine and medical director of the pulmonary function laboratory, David Geffen School of Medi-cine, University of California, Los Angeles, CA.


DisclosuresDonald P. Tashkin, MDConsultant/Advisor: AstraZeneca, Dey, Novartis, SunovionRecipient of grant support: Boehringer Ingelheim, GlaxoSmithKline, NovartisRecipient of research grant support to institution: AstraZenecaSpeaker: AstraZeneca, Boehringer Ingelheim, Dey, Pfizer


may have a pseudo-emphysematous pattern.8 While atopy is very com-mon in asthma,1 some COPD pa-tients also have atopy.9 Although smoking is the most common cause of COPD,1 10% to 15% of patients with COPD have never smoked.10 While inflammation in asthma is dominated by eosinophils,11 patients with severe asthma may have pre-dominantly neutrophils in their spu-tum,11,12 a characteristic more typical of COPD.11 Conversely, up-regula-tion of sputum eosinophils may occur in patients with COPD during exacerbations.11,13 It also is important to recognize that COPD and asthma can coexist in some patients.14

Some typical physiologic char-acteristics of COPD may help in fur-ther distinguishing COPD from asth-

ma.15 The diffusing capacity of the lung for carbon monoxide typically is decreased in patients with the em-physematous phenotype of COPD but is normal or increased in pa-tients with asthma.15,16 In addition, patients with COPD tend to have more severe hyperinflation at rest that increases with exertion, while resting hyperinflation usually is pres-ent in patients with asthma only dur-ing exacerbations.15 Patients with COPD with an emphysematous com-ponent have decreased lung elastic recoil.15 Lung elastic recoil generally is normal in patients with asthma,15 although it may be decreased in pa-tients with asthma who have fixed airflow obstruction8 or transiently decreased during an acute asthma exacerbation.17 Thus, several clinical

and physiologic features may factor into a diagnosis of COPD or asthma.

SPIROMETRY AND ASSESSING COPD

Spirometry is essential for con-firming a diagnosis of COPD,1 which should be suspected in current or ex-smokers aged ≥ 40 years with dyspnea, chronic cough, or sputum,1

particularly those with a smoking history of ≥ 20 pack-years.18 In addi-tion to a reduced FEV1/FVC ratio, patients with COPD generally have decreases in FEV1 and FVC, with greater declines in both measures as disease severity worsens.1

Performing conventional spi-rometry can be expensive and time-consuming, and it requires training and expertise.19 Handheld spirome-ters are an inexpensive, convenient, and practical alternative in the pri-mary care setting.20 They are also accurate,21 with good correlation in FEV1 measurements between hand-held spirometers and full spirome-try.19 If findings from handheld or smaller pocket spirometers are ab-normal, patients could be referred to a hospital-based pulmonary function laboratory or a specialist for more rigorous tests with conventional spi-rometry instruments.

If interpreted correctly, spirom-etry results can reveal important in-formation about the patient’s disease. An FEV1/FVC ratio of < 0.70 that re-mains < 0.70 after bronchodilator ad-ministration (eg, albuterol 90 µg × 2 to 4 inhalations) confirms airflow ob-struction that is not fully reversible, suggesting COPD.1 In patients who receive a diagnosis of COPD, spirom-etry findings also are used to assess disease severity and progression of the disease. Patients with FEV1 ≥ 80% predicted, FEV1 50% to < 80% predict-ed, 30% to < 50% predicted, or < 30% predicted are classified as having mild (Global Initiative for Chronic Obstructive Lung Disease [GOLD]

Chronic Obstructive Pulmonary Disease:Bronchodilators and Reversibility of Airflow Obstruction

Table 1 – Clinical features distinguishing asthma from COPD1,7,11,33

Clinical features COPD Asthma

Smoker or ex-smoker Nearly alla Possibly

Symptoms under age 35 years Rare Often

Progression of symptoms Chronic, slowly Episodic and progressive highly variable

Chronic productive cough Common Uncommon

Breathlessness Persistent and Variable progressive

Nighttime awakening with shortness Uncommon Commonof breath and/or wheezing

Atopic symptoms and Uncommon Commonseasonal allergies

Significant diurnal/day-to-day Uncommon Commonvariability

Airway inflammation Neutrophilic Eosinophilic

Favorable response to ICS Inconsistent Consistent

Response to bronchodilators Less More

aTen percent to 15% of patients with COPD have never smoked.10

COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid.


stage I), moderate (GOLD stage II), severe (GOLD stage III), or very se-vere (GOLD stage IV) COPD, re-spectively.1 In addition, spirometry findings are used to assess individual patients’ changes in pulmonary func-tion over time and after bronchodila-tor administration22; several criteria have been established for determin-ing a clinically meaningful bronchodi-lator response (Table 2).22-25

ASSESSING BRONCHODILATOR REVERSIBILITY (RESPONSIVENESS)

Confusion exists surrounding the concept of bronchodilator revers-ibility or responsiveness for several reasons, including the lack of stan-dardized definitions or methodolo-gies for determining bronchodilator reversibility. The American Thoracic Society/European Respiratory Soci-ety (ATS/ERS) criteria for broncho-dilator reversibility22 are the most cur-rent definition and include an FVC component, defining reversibility using FEV1, FVC, or both.22 The

FVC component of the ATS/ERS definition is often overlooked, and although FVC results are more diffi-cult to obtain, volume changes based on FVC may have a better correla-tion with improvements in exercise tolerance than measures of flow based on FEV1 and hence may be more clinically important.26 More-over, some patients who do not dem-

onstrate bronchodilator reversibility based on FEV1 do show a response based on FVC,5,27,28 particularly those with more severe COPD5 and great-er hyperinflation.28

It should be noted that a pa-tient’s acute response to bronchodila-tor treatment cannot be used to pre-dict a long-term response to mainte-nance bronchodilator therapy.3,29 In a

Table 2 – Definitions used to assess bronchodilator reversibility

Guideline Definitiona

ACCP23 Improvement in FEV1 of ≥ 15%

ATS25 Improvement in FEV1 or FVC of ≥ 12% and ≥ 200 mL

ERS24 Improvement in % predicted FEV1 of ≥ 10%

ATS/ERS22 Improvement in FEV1 and/or FVC of > 12% and > 200 mL

GOLD1 Improvement in FEV1 of > 12% and > 200 mL

aFor all definitions, improvement is referenced to the prebronchodilator value of FEV1 or FVC.

ACCP, American College of Chest Physicians; ATS, American Thoracic Society; ERS, European Respiratory Society; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Figure 1 – Mean FEV1 before and after treatment with tiotropium on (A) day 1 and (B) day 344.29

“Responders” and “poor responders,” respectively, included patients who did or did not meet American Thoracic Society reversibility criteria for FEV1 after tiotropium treatment on day 1.

FEV1, forced expiratory volume in 1 second.

Reprinted with permission from: Tashkin D, Kesten S. Long-term treatment benefits with tiotropium in COPD patients with and without short-term bronchodilator responses. Chest. 2003;123:1441-1449.

BA


study by Tashkin and Kesten,29 tiotropium resulted in significant im-provements in FEV1 from baseline compared with placebo after nearly a year of treatment, even in patients who did not show an initial short-term response to tiotropium (Figure 1). Similarly, responsiveness to sal-meterol treatment was demonstrated at day 84 in patients classified as ei-ther “reversible” or “nonreversible” based on the ATS criteria for FEV1 after albuterol administration at base-line.3 However, in both studies, the magnitude of response to bronchodi-lator treatment was greater in pa-tients classified as “reversible” or “a responder” at baseline.3,29

Further contributing to the con-fusion surrounding bronchodilator reversibility, bronchodilator re-sponse can vary based on the defini-tion of reversibility used,30 the bron-chodilator used,31 and day-to-day variability in bronchodilator re-sponse.30,32 In the Understanding Po-tential Long-Term Impacts on Func-tion with Tiotropium (UPLIFT) study, patients’ reversibility status (“responsive” or “poorly respon-sive”) varied depending on the crite-rion used.5 Similarly, findings from another study showed differences in the percentage of patients with

COPD who exhibited reversibility after maximal bronchodilation (al-buterol 400 µg followed 30 minutes later by ipratropium 80 µg) depend-ing on the criterion used, with 42% meeting the ATS criteria for FEV1 and 23% meeting the ERS criterion for % predicted FEV1.

30 Bronchodila-tor response also varies based on the bronchodilator used.31 Differences in the percentage of patients exhibiting reversibility have been shown when

using ipratropium alone, albuterol alone, or both (Figure 2).31

In addition, there is inherent day-to-day variability in bronchodila-tor response. In a study of 852 pa-tients with moderate to severe COPD, the percentage of patients exhibiting significant (≥ 15% FEV1 improve-ment) reversibility to albuterol, ip-ratropium, or both varied over 4 sepa-rate days, with > 90% of patients dem-onstrating significant reversibility on at least 1 occasion (Table 3).32 In an-other study, 52% of patients changed reversibility status to albuterol and ipratropium over the 3 study visits based on the combined ATS criteria.30 However, despite variability in bron-chodilator response, many patients with COPD do exhibit significant bronchodilator reversibility.

STUDIES SUPPORTING BRONCHODILATOR RESPONSIVENESS IN COPD

In a post hoc analysis of 5756 pa-tients in the UPLIFT study, more than half of the patients exhibited bronchodilator responsiveness after maximal or near-maximal bronchodi-


Figure 2 – Percent-ages of patients demonstrating reversibility based on FEV1 improve-ment threshold of ≥ 12% and ≥ 200 mL when using albuterol, ipratropium, or both.31

FEV1, forced expiratory volume in 1 second.

Reprinted with permis-sion from: Donohue JF. Therapeutic responses in asthma and COPD. Chest. 2004;126:125S-137S.

Table 3 – Percentage of patients with > 15% improvement in FEV1 30 minutes after drug administrationa,32

Number of Ipratropiumtest days with and albuterol Ipratropium Albuterolpositive responseb (n = 292) (n = 283) (n = 277)

0 Test days 3 8 9

≥ 1 Test day 97c 92 91

≥ 2 Test days 90c 80 79

≥ 3 Test days 76c 63 66

All 4 test days 56c 37 46

aStandard error of the mean < 3% for all data points.bPulmonary function test performed on days 1, 29, 57, and 86.cIpratropium and albuterol combination significantly better than individual agents (P < .05).Reprinted with permission from: Dorinsky PM, Reisner C, Ferguson GT, et al. The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD. Chest. 1999;115:966-971.


lation with ipratropium followed by albuterol treatment based on the combined ATS criteria for FEV1 im-provement of ≥ 12% and ≥ 200 mL.5 Similarly, in 2 studies of 1109 patients with moderate to very severe COPD, a large percentage of patients demon-strated meaningful improvements in FEV1 based on the combined ATS criteria after administration of for-moterol-containing treatment on the day of randomization (51% to 54%) and at the end of treatment (57% to

76%).4 Notably, at the screening visit, only 34% to 39% of patients exhibited reversibility to albuterol based on the combined ATS criteria for FEV1.4 These findings suggest that patients’ bronchodilator responsiveness may be underestimated if based on al-buterol reversibility testing alone.

A patient’s response to a bron-chodilator can be influenced by dis-ease severity, depending on the crite-rion used. Studies have shown that bronchodilator response based on

FEV1 may vary by disease severity, but response based on FVC remains more consistent across severity groups (Figure 3).4,5 In both the UP-LIFT study analysis and the study conducted by Celli and colleagues, the percentage of patients demon-strating a bronchodilator response (FEV1 improvement ≥ 12% and ≥ 200 mL) progressively decreased with increasing COPD severity.4,5 In con-trast, the percentage of patients ex-hibiting a bronchodilator response

Figure 3 – Percentage of patients demonstrating reversibility based on FEV1 and FVC improvement thresholds of ≥ 12% and ≥ 200 mL by COPD severity in (A) Tashkin et al 30 minutes after maximal bronchodilation with 4 inhalations of ipratropium (80 µg) followed by 4 inhalations of salbutamol (400 µg) and (B) Celli et al 15–30 minutes after administration of study treatments.4,5

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Figure 3A reprinted with permission from: Tashkin DP, Celli B, Decramer M, et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J. 2008;31:742-750.

Figure 3B reprinted with permission from: Celli BR, Tashkin DP, Rennard SI, et al. Bronchodilator responsiveness and onset of effect with budesonide/formoterol pMDI in COPD. Respir Med. 2011;105:1176-1188.

A

B


based on a FVC improvement of ≥ 12% and ≥ 200 mL generally was consistent across disease severities.4,5

BRONCHODILATORS FOR TREATING COPD

Bronchodilators are the main-stay of treatment for COPD.1 Com-bining different classes of bronchodi-lators may result in greater efficacy and a decreased risk of side effects compared with increasing the dose of a single bronchodilator.1 There also may be clinical benefits of add-ing an inhaled corticosteroid to long-acting bronchodilator therapy, in ad-dition to reducing exacerbations.1 Data from the 2 studies of 1109 pa-tients with moderate to very severe COPD showed that patients receiv-ing budesonide/formoterol pressur-ized metered-dose inhaler (pMDI) generally had numerically greater mean improvements in 1-hour post-dose FEV1 and FVC versus formoter-ol alone on the day of randomization.4 For the whole population (including all patients with moderate to very se-vere COPD), mean improvements in 1-hour postdose FEV1 and FVC on the day of randomization were 220 to 230 mL and 400 to 410 mL, respec-tively, in the budesonide/formoterol pMDI groups compared with 160 mL and 350 mL, respectively, in the for-moterol group.4

CONCLUSIONSCOPD is characterized by air-

flow obstruction that is not fully re-versible; however, confusion exists surrounding the concept of reversibil-ity. Although the disease is not fully reversible, patients with COPD often exhibit a clinically significant bron-chodilator response, as defined by several different published criteria for FEV1 and/or FVC improvement (eg, American College of Chest Physi-cians, ATS/ERS, ATS). In particular, patients with more severe COPD show benefits of reduced air trapping

and hyperinflation after bronchodila-tor treatment, as measured by FVC. Bronchodilators are central to COPD management, and although variability exists in bronchodilator response be-tween and within patients, patients with COPD do show a clinically meaningful response to bronchodila-tor therapy, administered alone or in combination. ■

AcknowledgmentsThe author thanks Anny Wu, PharmD, and Cynthia Gobbel, PhD, from Scientific Connexions (Newtown, PA) who provided medical writing support funded by AstraZeneca LP (Wilmington, DE).

REFERENCES:1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2010. htttp://www.goldcopd.org. Accessed September 23, 2011. 2. Bleecker ER, Emmett A, Crater G, et al. Lung function and symptom improvement with flutica-sone propionate/salmeterol and ipratropium bro-mide/albuterol in COPD: response by beta-agonist reversibility. Pulm Pharmacol Ther. 2008;21:682-688.3. Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest. 1999;115:957-965.4. Celli BR, Tashkin DP, Rennard SI, et al. Broncho-dilator responsiveness and onset of effect with budesonide/formoterol pMDI in COPD. Respir Med. 2011;105:1176-1188.5. Tashkin DP, Celli B, Decramer M, et al. Broncho-dilator responsiveness in patients with COPD. Eur Respir J. 2008;31:742-750.6. Kesten S, Rebuck AS. Is the short-term response to inhaled beta-adrenergic agonist sensitive or spe-cific for distinguishing between asthma and COPD? Chest. 1994;105:1042-1045.7. National Asthma Education and Prevention Pro-gram (NAEPP). Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: US Depart-ment of Health and Human Services, National Institutes of Health; 1997.8. Gelb AF, Zamel N. Unsuspected psuedophysio-logic emphysema in chronic persistent asthma. Am J Respir Crit Care Med. 2000;162:1778-1782.9. Sitkauskienne B, Sakalauskas R, Malakauskas K, Lötvall J. Reversibility to a ß2-agonist in COPD: relationship to atopy and neutrophil activation. Respir Med. 2003;97:591-598.10. Coultas DB. Passive smoking and risk of adult asthma and COPD: an update. Thorax. 1998;53:381-387.11. Yawn B. Differential assessment and manage-ment of asthma vs chronic obstructive pulmonary disease. Medscape J Med. 2009;11:20.12. Green RH, Brightling CE, Woltmann G, et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled cortico-steroids. Thorax. 2002;57:875-879.13. Wedzicha JA. Exacerbations: etiology and

pathophysiologic mechanisms. Chest. 2002;121:136S-141S.14. Soriano JB, Davis KJ, Coleman B, et al. The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest. 2003;124:474-481.15. Sciurba FC. Physiologic similarities and differ-ences between COPD and asthma. Chest. 2004;126:117S-124S.16. Snider GL. Distinguishing among asthma, chronic bronchitis, and emphysema. Chest. 1985;84:35S-39S.17. Gold WM, Kaufman HS, Nadel JA. Elastic recoil of the lungs in chronic asthmatic patients be-fore and after therapy. J Appl Physiol. 1967;23:433-438.18. Ohar JA, Sadeghnejad A, Meyers DA, et al. Do symptoms predict COPD in smokers? Chest. 2010;137:1345-1353.19. Rytila R, Helin T, Kinnula V. The use of micro-spirometry in detecting lowered FEV1 values in current or former cigarette smokers. Prim Care Respir J. 2008;17:232-237.20. Stoloff SW. Diagnosis and treatment of patients with chronic obstructive pulmonary disease in the primary care setting: focus on the role of spirome-try and bronchodilator reversibility. J Fam Pract. 2011;60(4 suppl):S9-S16.21. Buffels J, Degryse J, Heyrman J, et al. Office spirometry significantly improves early detection of COPD in general practice: the DIDASCO study. Chest. 2004;125:1394-1399.22. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948-968.23. Report of the Committee on Emphysema American College of Chest Physicians. Criteria for the assessment of reversibility in airway obstruc-tion. Chest. 1974;65:552-553.24. Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). Eur Respir J. 1995;8:1398-1420.25. American Thoracic Society. Lung function test-ing: selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991;144:1202-1218.26. O’Donnell DE, Lam M, Webb KA. Measure-ment of symptoms, lung hyperinflation, and endur-ance during exercise in chronic obstructive pulmo-nary disease. Am J Respir Crit Care Med. 1998;158:1557-1565.27. Ben Saad H, Préfaut C, Tabka Z, et al. The forgotten message from gold: FVC is a primary outcome measure of bronchodilator reversibility in COPD. Pul Pharmacol Ther. 2008;21:767-773.28. Newton MF, O’Donnell DE, Forkert L. Re-sponse of lung volumes to inhaled salbutamol in a large population of patients with severe hyperin-flation. Chest. 2002;121:1042-1050.29. Tashkin D, Kesten S. Long-term treatment benefits with tiotropium in COPD patients with and without short-term bronchodilator responses. Chest. 2003;123:1441-1449.30. Calverley PMA, Burge PS, Spencer S, et al, for the ISOLDE study investigators. Bronchodilator reversibility testing in chronic obstructive pulmo-nary disease. Thorax. 2003;58:659-664.31. Donohue JF. Therapeutic responses in asthma and COPD. Chest. 2004;126:125S-137S.32. Dorinsky PM, Reisner C, Ferguson GT, et al. The combination of ipratropium and albuterol opti-mizes pulmonary function reversibility testing in patients with COPD. Chest. 1999;115:966-971.33. Price DB, Yawn BP, Jones RCM. Improving the differential diagnosis of chronic obstructive pulmo-nary disease in primary care. Mayo Clin Proc. 2010;85:1122-1129.


ABSTRACT: Pharmacologic treatments and pulmonary rehabilitation improve symptoms, health status, and exercise tolerance in patients with chronic ob-structive pulmonary disease (COPD). Short-acting and long-acting bronchodila-tors are the mainstays of therapy for as-needed symptom relief and long-term maintenance, respectively. Disease sever-ity, device characteristics, medication costs, and patient preferences are factors to consider when making pharmacologic treatment decisions. Changes in symp-toms, adherence to treatment, and exis-tence of comorbidities should be assessed when evaluating the effectiveness of pharmacologic therapy. Pulmonary reha-bilitation, including exercise training, nu-tritional counseling, psychosocial support, and patient education, has shown clinical benefits at all COPD severity stages. Oxygen therapy and surgical options may be considered in carefully selected patients. Research is ongoing to develop novel therapies that can modify disease progression and to identify COPD pheno-types for greater individualization of therapy. This article reviews current COPD treatment recommendations and potential novel COPD treatment options for the future.

Patients with chronic obstructive pulmonary disease (COPD) can ex-hibit a significant response to bron-chodilator therapy1-5; as such, short-acting and long-acting bronchodila-tor therapies are the mainstays of COPD treatment.6 Goals of pharma-cotherapy and other elements of

COPD management (eg, pulmonary rehabilitation, smoking cessation) are to relieve symptoms; prevent dis-ease progression; improve exercise tolerance, health status, and quality of life; prevent and treat complica-tions and exacerbations; and reduce mortality.6 Identification of comor-bidities, which can complicate treat-ment and result in poor outcomes, also is necessary.6 COPD treatment is selected based on severity and exacerbation frequency, clinical pre-sentation, speed of lung function decline, extrapulmonary effects, co-morbidities, and patient factors.7

PHARMACOLOGIC TREATMENT OPTIONS

Table 1 summarizes available COPD medications.6 Regardless of other therapies, all COPD patients should have short-acting ß2-adrener-gic agonists (SABAs) and short-acting anticholinergics available for rapid symptom relief.6 SABAs relax air way smooth muscles,6 while short-acting anticholinergics block the bronchoconstrictive effects of acetylcholine on air way smooth muscle cells.6,8

Long-acting bronchodilators, in-cluding long-acting muscarinic an-tagonists (LAMAs) and long-acting ß2-adrenergic agonists (LABAs), are the mainstays of therapy for long-term COPD symptom management.6 Despite concerns stemming from asthma studies,9-11 the safety of LAMAs and LABAs has been shown in patients with COPD.8,12-14 The Un-

BARBARA P. YAWN, MD, MSc, FAAFPOlmsted Medical Center, Rochester, MN

Treatment Options in Chronic Obstructive Pulmonary Disease:

Current Recommendations and Recent Findings

Dr Yawn is director of research, Olmsted Medical Center, Rochester, MN, and adjunct professor, depart-ment of family and community health, University of Minnesota.


DisclosuresBarbara P. Yawn, MD, MSc, FAAFPRecipient of research support: Boehringer Ingelheim, Novartis


Table 1 – Formulations and typical doses of COPD medicationsa,6

Solution for Vials for Duration nebulizer injection of actionDrug Inhaler (µg) (mg/mL) Oral (mg) (hours)

ß2-agonistsShort-acting

Fenoterol 100-200 (MDI) 1 0.05% (syrup) 4-6

Levalbuterol 45-90 (MDI) 0.21, 0.42 6-8

Salbutamol (albuterol) 100, 200 (MDI & DPI) 5 5 mg (pill), 0.1, 0.5 4-6 0.024% (syrup)

Terbutaline 400, 500 (DPI) 2.5, 5 (pill) 4-6

Long-actingFormoterol 4.5-12 (MDI & DPI) 0.01b 12+

Arformoterol 0.0075 12+

Indacaterol 150-300 (DPI) 24

Salmeterol 25-50 (MDI & DPI) 12+

AnticholinergicsShort-acting

Ipratropium bromide 20, 40 (MDI) 0.25-0.5 6-8

Oxitropium bromide 100 (MDI) 1.5 7-9

Long-actingTiotropium 18 (DPI), 5 (SMI) 24+

Combination short-acting ß2-agonists plus anticholinergic in 1 inhalerFenoterol/ipratropium 200/80 (MDI) 1.25/0.5 6-8

Salbutamol/ipratropium 75/15 (MDI) 0.75/0.5 6-8

MethylxanthinesAminophylline 200-600 mg (pill) 240 mg Variable, up to 24

Theophylline (SR) 100-600 mg (pill) Variable, up to 24

Inhaled glucocorticosteroidsBeclomethasone 50-400 (MDI & DPI) 0.2-0.4

Budesonide 100, 200, 400 (DPI) 0.20, 0.25, 0.5

Fluticasone propionate 50-500 (MDI & DPI)

Combination long-acting ß2-agonists plus glucocorticosteroids in 1 inhalerFormoterol/budesonide 4.5/160, 9/320 (DPI)

Salmeterol/fluticasone 50/100, 250, 500 (DPI)propionate 25/50, 125, 250 (MDI)

Systemic glucocorticosteroidsPrednisone 5-60 mg (pill)

Methylprednisolone 4, 8, 16 mg (pill)

Phosphodiesterase-4 inhibitorsRoflumilast 500 µg (pill) 24aNot all formulations are available in all countries; in some countries, other formulations may be available.bFormoterol nebulized solution is based on the united dose vial containing 20 µg in a volume of 2.0 mL.COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; MDI, metered-dose inhaler; SMI, soft-mist inhaler; SR, sustained release. Reprinted with permission from: Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of COPD. Updated 2010. http://www.goldcopd.org/uploads/users/files/GOLDReport_April112011.pdf.


Treatment Options in Chronic Obstructive Pulmonary Disease:Current Recommendations and Recent Findings

derstanding Potential Long-term Im-pacts on Function With Tiotropium (UPLIFT) study and a subsequent meta-analysis of 19 studies with tiotropium, including UPLIFT, showed no evidence of an increased risk of cardiovascular events.12,13 The safety of LABA monotherapy in COPD is well documented8,14; LAMAs and LABAs can be adminis-tered alone or as combination thera-py for bronchodilation and reduction of symptoms and exacerbations.6,14

Regular inhaled corticosteroid (ICS) therapy may further reduce exacerbation frequency for patients with severe or very severe COPD and a history of frequent exacerba-tions.6 ICS treatment has not been proven to slow lung function decline in patients with COPD,6,15-18 but To-wards a Revolution in COPD Health (TORCH) post hoc data suggest a slowing of lung function decline that

should be further evaluated.19 ICS use in persons with COPD has been shown to increase the risk of pneu-monia, which may var y by ICS type,6,20-23 and high-dose ICS therapy increases fracture risk.20 No in-creased risk of pneumonia was seen with inhaled budesonide (up to 640 µg/d) compared with placebo or for-moterol alone over 12 months.24 Oral corticosteroids are not recommend-ed for long-term therapy in patients with COPD.6 However, a 7- to 10-day burst of oral prednisone is a main-stay of COPD exacerbation therapy.6

HOW TO SELECT PHARMACOLOGIC THERAPY

Treatments should be selected based on the patient’s disease sever-ity and COPD exacerbation frequen-cy (Figure 1).6 The type of delivery device25 (eg, pressurized metered-

dose inhaler, dry powder inhaler, or nebulizer), the skills and ability of the individual patient,6 the cost of each treatment (commonly US$36 to $210 per month26), and the patient’s financial status also should be con-sidered. Patients with COPD rou-tinely take 4 to 10 medications daily for various indications.27,28 Use of multiple types of inhaler devices can lead to confusion and errors in medi-cation use29,30; therefore, it may be advantageous for physicians to keep the device consistent if possible.30 When used correctly, the device does not affect treatment efficacy31; however, it is important to ensure proper inhaler technique. At each clinic visit, a clinical team member should recheck the patient’s inhaler technique to ensure correct inhaler use.6 Information about inhaler de-vices, inhalation technique, and rec-ommendations for training can be

Figure 1 – Therapy at each stage of COPD.6

FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Reprinted with permission from: Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of COPD. Updated 2010. http://www.goldcopd.org/uploads/users/files/GOLDReport_April112011.pdf.


found here: http://advanceweb.com/web/AstraZeneca/focus_on_copd_issue3_DevicesForAerosol/focus_on_copd_issue3.html.32

CHANGING PHARMACOLOGIC THERAPY

Patients with COPD should be monitored carefully for treatment re-sponse and side effects,6 and therapy should be individualized.6 Over time, all patients will require additional treatments or an increase in dose as

disease severity worsens.6 However, COPD progression may not be rec-ognized by patients over time.33 It is important for physicians to evaluate patients for signs and symptoms of disease worsening,33 including de-creased exercise tolerance (what can the patient not do now that he/she could do last year?), impaired quality of life (what does the patient want to be able to do?), increased breathless-ness at rest or during exercise (how many stairs can the patient go up be-fore having to stop?), increased spu-

tum (tablespoon versus a shot glass versus a cup full in a day), low or re-duced oxygen saturation (pulse ox-imetry testing), change in ability to perform activities of daily living inde-pendently, and increased wheeze.34

Assessment tools may help dis-ease evaluations by providing physi-cians with clear and validated ques-tions to ask patients. The Modified Medical Research Council (MMRC) dyspnea scale35 (http://copd.about.com/od/copdbasics/a/MMRC-dyspneascale.htm) and the modified


Figure 2 – COPD assessment test.38


Reprinted with permis-sion from: Jones PW, Harding G, Berry P, et al. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34:648-654.


Borg scale36,37 (http://www.yourlung-health.org/testing/6min_walk/index.cfm) can be used to follow dis-ease progression if used repeatedly over time. The 8-item COPD Assess-ment Test (CAT) can be used to mea-sure overall COPD-related health status (Figure 2),38 and the 14-item Exacerbations of Chronic Pulmonary Disease Tool-Patient-Reported Out-come (EXACT-PRO)39,40 (http://www.exactproinitiative.com/default.php#) can be used to quantify the se-verity of a COPD exacerbation.39

IMPORTANCE OF PATIENT ADHERENCE TO COPD MANAGEMENT

COPD requires life-long medi-cation therapy, and adherence to therapy is critical to achieving treat-ment goals. Poor adherence is com-mon in patients with COPD, and ad-herence tends to decline over time.41,42 Thus, ef forts to improve treatment adherence are wor th-while. Data from the TORCH study showed that good adherence (> 80% of doses) to inhaled COPD medica-tion is associated with a significantly decreased risk of mortality and hos-pital admission for severe exacerba-tions over 3 years.43

Factors related to the patient (eg, health beliefs, self-efficacy, co-morbidities, psychologic profile), the treatment (eg, dosing regimen, poly-pharmacy, side effects, method of administration), society (eg, social support, patient-prescriber relation-ship, access to medication, inhaler technique training), and health pro-fessionals (eg, education, goal set-ting, regular follow-up visits) can af-fect adherence.41 In particular, de-pression is a major contributor to poor adherence in patients with COPD, and its treatment substantial-ly improves quality of life.44 Question-naires including the Hospital Anxiety and Depression Questionnaire44 and the Patient Health Questionnaire-945

(http://www.phqscreeners.com/pdfs/02_PHQ-9/English.pdf) can help to identify patients who have sig-nificant anxiety and depression.

PULMONARY REHABILITATION

Pulmonary rehabilitation im-proves exercise capacity and health-related quality of life and reduces hospitalizations, perceived dyspnea intensity, anxiety, and depression in patients across all COPD severity levels.6 Components include exer-cise training, nutrition counseling, psychosocial support, and educa-tion.6,46 Exercise training programs generally range from 4 to 10 weeks, with greater benefits observed with longer programs.6,44 Strength train-ing is especially important for pa-tients with substantial muscle atro-phy,44 while inspiratory muscle train-ing may improve inspiratory muscle strength and decrease dyspnea.47 As part of nutrition counseling, physi-cians should ensure that patients with COPD who are underweight have adequate caloric intake and overweight patients have a diet that encourages fat loss.46 Maintenance of pulmonary rehabilitation is impor-tant, as benefits wane without contin-ued exercise.6

LONG-TERM OXYGEN THERAPY

Patients with very severe COPD may require oxygen therapy to en-sure that vital organs receive ade-quate oxygen.6 Supplemental oxygen therapy improves exercise capacity, ventilation, and neuropsychological performance (ie, memory and learn-ing).48 The need for long-term oxy-gen therapy (> 15 hours per day), which increases survival in patients with chronic respiratory failure,6 is determined by the patient’s arterial blood gas values. Treatment goals include increased baseline partial pressure of arterial oxygen to ≥ 60

mm Hg and/or production of ≥ 90% oxygen saturation.6

SURGICAL TREATMENTS AND NEW AND EMERGING PHARMACOLOGIC TREATMENTS

Certain surgical treatments may be considered in carefully selected patients. Bullectomy, which involves removal of a large bulla in select pa-tients with bullous emphysema, de-compresses pulmonary parenchyma and improves pulmonary function and dyspnea.6 Lung volume reduc-tion surgery improves expiratory flow rate by reducing hyperinflation and increasing lung elastic recoil.6 Compared with optimal medical ther-apy for severe COPD, lung volume reduction surgery has been shown to reduce the frequency of COPD exac-erbations and increase the time to first exacerbation49; it also has been shown to decrease mortality in pa-tients with upper-lobe predominant COPD and low exercise capacity.50 However, this costly procedure is recommended only in carefully se-lected patients.6 Lung transplantation is a rare therapy for COPD.6

Combinations of existing thera-pies and new pharmacological ap-proaches are available or are cur-rently in development. Data from a randomized, double-blind study of patients with COPD suggest that LABA/LAMA combination treat-ment may provide improved bron-chodilator efficacy versus LABA/ICS combination treatments.51 “Triple therapy” with a LAMA, LABA, and ICS can improve pulmonary function and COPD symptoms and reduce the rates of exacerbations versus an anticholinergic alone.6,52-54 The phos-phodiesterase-4 inhibitor roflumilast was US FDA-approved in 2011 as an oral medication.55 Patients with se-vere or very severe COPD and a his-tory of exacerbations have fewer moderate or severe exacerbations



Table 2 – Characteristics of and treatment recommendations for specific phenotypes of COPD

Phenotype Characteristics Recommendations for treatment

Bronchitic Mucus hypersecretion resulting in GOLD guidelines by disease severity6

chronic productive cough6 Treatment with mucolytic agents65

Emphysematous Gas exchange abnormalities6,67 GOLD guidelines by disease severity6

Limitations in functional capacity67

Rapid, recurrent Presence of chronic cough and sputum ICS and long-acting bronchodilatorexacerbations production70 therapy, according to GOLD 2010 Faster rates of lung function decline64 guidelines6

Addition of an ICS/LABA combination to a LAMA improves lung function and decreases symptoms and rates of exacerbations compared with an anticholinergic alone6,51-53

PDE-4 inhibitor (eg, roflumilast) reduces exacerbations in patients with severe COPD and history of exacerbations56

Antibiotics only for treating infectious exacerbations of COPD6

Acute treatment with oral corticosteroids during exacerbations; chronic treatment should be avoided6

Rapid decline in May be associated with chronic mucus GOLD guidelines by disease severity6

lung function hypersecretion71

May occur in patients with rapid, recurrent exacerbations64

Disease characteristics Patients with asthma who are exposed to GOLD guidelines by disease severity6

similar to asthma noxious agents (eg, cigarette smoke)6 In some patients with chronic asthma, Patients with long-standing asthma who clear distinction from COPD is not develop fixed airflow limitation6 possible, and management should be Patients with COPD who may have similar to that of asthma6

features of asthma, such as a mixed inflammatory pattern with increased eosinophils6

Patients with late-onset tobacco-related COPD with an airway-dominant phenotype and relatively little emphysema72

Systemic inflammation Presence of elevated biomarkers GOLD guidelines by disease severity6

(eg, C-reactive protein, serum amyloid A, interleukin-6, interleukin-8, tumor necrosis factor-�, leukocytes)7

Systemic involvement Extra-pulmonary manifestations, which GOLD guidelines by disease severity6

and multiple morbidities may be poorly related to the degree of Treatment specific to comorbidity67

airflow limitation67

COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting ß2-adrenergic agonist; LAMA, long-acting muscarinic antagonist; PDE-4, phosphodiesterase-4.


with roflumilast versus placebo,56 re-gardless of concomitant use of LABAs.57 Once-daily LABAs, termed “ultra-LABAs,” such as indacaterol (US FDA-approved in 2011),58 may help improve adherence,8 although this has not been shown in clinical trials. Ultra-LABA/LAMA combina-tions (eg, indacaterol/glycopyrroni-um59) are currently in development.

Existing pharmacologic thera-pies for COPD do not reduce long-term declines in lung function6; there is a need for novel therapies that modify disease progression.60 Poten-tial approaches for future COPD treatments may include agents that activate histone deacetylase-2 or in-hibit phosphoinositide 3-kinase to improve sensitivity to ICS and inhibi-tors of p38 kinase and cathepsin C to decrease inflammation.60

COPD PHENOTYPINGEarly studies suggest that

COPD clinical subpopulations, such as “frequent exacerbators,” may re-quire more aggressive COPD man-agement earlier in the disease.61-64 Data from the COPDGene study showed an association between chronic bronchitis and younger age, smoking, worse respiratory symp-toms, and a greater history of severe exacerbations.65 These findings sug-gest that for patients with COPD with chronic bronchitis, reducing mucus production and smoking ces-sation may be extremely important. Other research is ongoing in the Subpopulations and Intermediate Outcomes Measures in COPD Study (Spiromics; http://www.cscc.unc.edu/spir/), the COPDGene Study (http://www.copdgene.org/), and the Evaluation of COPD Longitudi-nally to Identify Predictive Surrogate Endpoints (ECLIPSE) study (http://www.eclipse-copd.com/) assessing mechanisms and identifying poten-tial measures of disease progression. Historical phenotypes (chronic bron-

chitis and emphysema)66 and those that have been proposed based on clinical manifestations67-69 are de-scribed in Table 2.

CONCLUSIONSSeveral pharmacological thera-

pies are available for the treatment of COPD. Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend treatment selection according to the patient’s disease severity.6 Within a severity category, patient pheno-types and other disease characteris-tics, device selection, and costs may influence the choice of therapy. Initi-ation and maintenance of pulmonary rehabilitation programs are impor-tant for optimal COPD management in all patients with COPD. Careful monitoring of patients during thera-py is necessary to recognize disease worsening and the need for changes in treatment. Improving patient ad-herence and screening for comor-bidities such as depression also con-tribute to better disease manage-ment. In the future, novel therapies may improve bronchodilator efficacy and reduce side effects compared with current treatments and modify disease progression. ■

AcknowledgmentsThe author thanks Kristen Quinn, PhD, Anny Wu, PharmD, and Cynthia Gobbel, PhD, from Scientific Connexions (Newtown, PA) who provided medical writing support funded by AstraZeneca LP (Wilmington, DE).

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