EDITORIALS 10. Wayne LG. Dormancy of Mycobacterium tuberculosis and latency of disease. Eur J Clin Microbiol Infect Dis 1994;13:908–914. 11. Donald PR, Diacon AH. The early bactericidal activity of antituberculosis drugs: a literature review. Tuberculosis (Edinb) 2008;88: S75–S83. 12. Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, van Niekerk C, Everitt D, Winter H, Becker P, et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 2012;380:986–993. 13. Aung KJM, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, Rieder HL. Successful ‘9-month Bangladesh regimen’ for multidrugresistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis 2014;18:1180–1187. 14. Tang S, Yao L, Hao X, Liu Y, Zeng L, Liu G, Li M, Li F, Wu M, Zhu Y, et al. Clofazimine for the treatment of multidrug-resistant tuberculosis: prospective, multicenter, randomized controlled study
in China. Clin Infect Dis [online ahead of print] 20 Jan 2015; DOI: 10.1093/cid/civ027. 15. Tyagi S, Ammerman NC, Li SY, Adamson J, Converse PJ, Swanson RV, Almeida DV, Grosset JH. Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis. Proc Natl Acad Sci USA 2015;112:869–874. 16. Yano T, Kassovska-Bratinova S, Teh JS, Winkler J, Sullivan K, Isaacs A, Schechter NM, Rubin H. Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxidoreductase: a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem 2011;286:10276–10287. 17. Grant SS, Kaufmann BB, Chand NS, Haseley N, Hung DT. Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proc Natl Acad Sci USA 2012;109:12147–12152.
Copyright © 2015 by the American Thoracic Society
Exercise Limitation in Chronic Obstructive Pulmonary Disease The O’Donnell Threshold Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. It is defined by the presence of expiratory airflow limitation that is only partially reversible. Consistent with the defining feature, the reduction in expiratory airflow, generally measured as FEV1, is widely used as a gauge of disease severity. Paradoxically however, dyspnea, the symptomatic result of the compromised physiology of COPD, is not a result of airflow limitation but an effect of airflow limitation on lung volumes. These effects are amplified during exercise; as a consequence, dyspnea on exertion is often the chief complaint of patients with COPD. Work from several groups has established that the reduced expiratory airflow in COPD leads to incomplete lung emptying, particularly with the rapid respiratory rates and large tidal volumes seen during exercise. When respiratory rate rises, the time for exhalation is progressively constrained. Slow expiratory airflow means that as the time for exhalation is reduced, a point is reached when the exhalation cannot be completed and end-expiratory lung volume must rise. Eventually, as exercise intensity increases, the combination of rising end-expiratory lung volume and rising tidal volume brings the end-inspiratory lung volume close to the maximum lung volume that can be inhaled: the total lung capacity. At volumes near total lung capacity, the work of breathing increases and the overstretched chest wall receptors send signals to the brain, contributing to the sensation of dyspnea. Thus, the resulting overexpansion of the lungs, termed “dynamic hyperinflation,” is a regular feature of exercise and is a major driver of dyspnea. It likely also explains the frequent complaint of patients: “I can’t get air in.” This contrasts with the never-heard complaint of “My air goes out too slowly,” which would be directly attributable to reduced FEV1. The laboratory of Denis O’Donnell has been the leader among those demonstrating the importance of dynamic hyperinflation in driving dyspnea on exertion in patients with COPD (1, 2). A recent paper from this group has expanded this concept to demonstrate that dynamic hyperinflation occurs in mild COPD as well, which leads to inspiratory volumes reaching a limit at which symptoms of dyspnea begin to become intolerable (3). Specifically, by stimulating ventilation through adding dead space during an
Editorials
exercise test, this group demonstrated that exercise terminates when a specific inspiratory reserve volume is reached (Figure 1). That is, when the difference between total lung capacity and endinspiratory lung volume shrinks to below a critical value in the face of increasing respiratory drive, dyspnea becomes intolerable. These concepts have their roots in the work of previous generations of physiologists. For example, Hey and colleagues (4) demonstrated that in healthy subjects, increasing exercise ventilation is accomplished mostly by tidal volume increase only up to about 50% of vital capacity, after which respiratory rate increase is predominant. Importantly, at rest, normal individuals and patients with COPD can easily increase respired volumes to values greater than the tidal volumes seen at peak exercise; they routinely do so when performing vital capacity maneuvers. It is the combination of elevated tidal volume demand and elevated end-inspiratory lung volume that brings the patient to a threshold at which their dyspnea becomes intolerable. The dynamic hyperinflation that occurs in COPD (even mild COPD) causes this threshold, the O’Donnell threshold, to be reached much earlier than would be predicted from maximal voluntary ventilation measured at rest. This is a fundamental concept, with direct clinical relevance for understanding the physiology and symptomology of COPD. It is also a concept that is difficult to teach and is (in our experience) not easy for trainees to remember. Perhaps this is because of the primacy of expiratory airflow limitation (and FEV1 specifically) in our thinking about COPD. Whatever the reason, we believe that providing a name for the inspiratory reserve volume at which patients experience intolerable dyspnea in the face of the ventilatory demand of exercise helps with communicating and remembering this concept. We have termed this the O’Donnell threshold. We believe that this is easy to remember and appropriately acknowledges Dr. O’Donnell’s work in defining this concept. The O’Donnell threshold: The inspiratory reserve volume at which intolerable dyspnea limits exercise.
873
EDITORIALS 0.0
TLC
Inspiratory reserve volume at which intolerable dyspnea limits exercise
0.5
IRV (L)
O’Donnell threshold
1.0
* *
1.5
*
2.0 2.5 0
20
40
60
80
100 120 140 160 180
Work rate (watts) Figure 1. The figure illustrates the inspiratory reserve volume (IRV), expressed as a difference between total lung capacity (TLC) and end-inspiratory lung volume in patients with mild chronic obstructive pulmonary disease (COPD) (circles) performing an incremental exercise test compared to healthy control subjects (triangles). Exercise terminates at the same IRV, the O’Donnell threshold (shaded area). Exercise terminates at the same volume in the face of added dead space in patients with COPD, indicating that there is a mechanical limit to ventilation in the face of exercise-induced drive (not shown, see Reference 3). This limit is determined by lung volume. Adapted by permission from Chin and colleagues (3). *P , 0.05, patients with COPD compared to healthy control subjects.
The concept of the O’Donnell threshold is far more than an advance in understanding the physiology of dyspnea in patients with COPD. The conventional approach to assessing ventilatory limitation during cardiopulmonary exercise testing is to estimate the breathing reserve (5). This is determined by calculating the difference between the maximal voluntary ventilation (often estimated as from the maximum ventilation determined at rest during a 12-second maneuver, or estimated as a multiple of the FEV1) and peak ventilation during cardiopulmonary exercise testing. However, as O’Donnell and colleagues have shown, the ability to increase ventilation at rest is not a direct determinant of maximal exercise ventilation in COPD. It is the O’Donnell threshold that limits maximal exercise. It seems likely that a large number of patients with mild COPD being evaluated for dyspnea have been incorrectly diagnosed as “poor effort” or “detraining” when, in fact, ventilatory limitation is present. These concepts have direct clinical implications. For individuals whose exercise is limited on reaching the O’Donnell threshold, treatments that deflate the lung should be considered. Conversely, not all patients with COPD will develop limiting hyperinflation. Many patients with COPD, especially those with mild disease, are limited by leg fatigue, not breathlessness. In others whose exercise terminates because of dyspnea, but who fail to reach the O’Donnell threshold, alternate causes for dyspnea should be considered. The O’Donnell threshold concept raises a number of important physiologic questions, the answers to which have considerable potential for improving COPD therapy: What determines the inspiratory reserve volume at which intolerable dyspnea develops? Can the O’Donnell threshold be changed with interventions? Should the O’Donnell threshold be routinely assessed to determine which patients with exercise limitation should be treated with bronchodilators? How does respiratory drive interact with lung mechanics to yield the sensation of dyspnea? It is also unknown whether individuals perceive the volume attained (the end-inspiratory lung volume) or the volume remaining (the inspiratory reserve volume). We believe the inspiratory reserve
874
volume is more likely to be important physiologically than the end-inspiratory volume, which is the way it is plotted by Dr. O’Donnell (Figure 1). In practice, assessing the O’Donnell threshold in individual patients is most readily achieved by serial measurement of the inspiratory reserve volume during exercise testing. This can be done by having the subject perform serial inspiratory capacity maneuvers (the difference between inspiratory capacity and the contemporaneously determined tidal volume is the inspiratory reserve volume). Alternately, optoelectronic plethysmography allows direct determination of thoracic volumes from which end-inspiratory lung volume can be estimated (6). Such measurements are not routinely performed in clinical exercise laboratories but have found good use in COPD research studies. Studies using these methods have defined the mechanisms by which, for example, bronchodilators, supplemental oxygen, and exercise training enhance exercise tolerance (7–11). The key point is that the O’Donnell threshold can be determined, at least in the investigational setting, and that the further exploration of the underlying physiology holds promise to improve the understanding of activity limitation in COPD and the care of patients with this disorder. At a minimum, the concept that it is lung volume, not airflow, that limits ventilation in exercising COPD patients is a crucial one. We expect that others also will find that use of the term “O’Donnell threshold” helps communicate this concept; we propose it for general use. n Author disclosures are available with the text of this article at www.atsjournals.org. Richard Casaburi, M.D., Ph.D. Rehabilitation Clinical Trials Center Los Angeles Biomedical Research Institute at Harbor–University of California, Los Angeles, Medical Center Torrance, California Stephen I. Rennard, M.D. Pulmonary, Critical Care, Sleep & Allergy University of Nebraska Medical Center Omaha, Nebraska
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 8 | April 15 2015
EDITORIALS References 1. 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. 2. O’Donnell DE, Banzett RB, Carrieri-Kohlman V, Casaburi R, Davenport PW, Gandevia SC, Gelb AF, Mahler DA, Webb KA. Pathophysiology of dyspnea in chronic obstructive pulmonary disease: a roundtable. Proc Am Thorac Soc 2007;4:145–168. 3. Chin RC, Guenette JA, Cheng S, Raghavan N, Amornputtisathaporn N, Cortes-T ´ elles ´ A, Webb KA, O’Donnell DE. Does the respiratory system limit exercise in mild chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2013;187:1315–1323. 4. Hey EN, Lloyd BB, Cunningham DJ, Jukes MG, Bolton DP. Effects of various respiratory stimuli on the depth and frequency of breathing in man. Respir Physiol 1966;1:193–205. 5. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp B. Principles of exercise testing and interpretation. Philadelphia, PA: Lippincott Willliams and Wilkins; 2005. 6. Aliverti A, Stevenson N, Dellac a` RL, Lo Mauro A, Pedotti A, Calverley PM. Regional chest wall volumes during exercise
Editorials
in chronic obstructive pulmonary disease. Thorax 2004;59: 210–216. 7. O’Donnell DE, Fluge ¨ T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23: 832–840. 8. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24:86–94. 9. Peters MM, Webb KA, O’Donnell DE. Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnoea in normoxic COPD. Thorax 2006;61:559–567. 10. Somfay A, Porszasz J, Lee SM, Casaburi R. Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. Eur Respir J 2001;18:77–84. 11. Porszasz J, Emtner M, Goto S, Somfay A, Whipp BJ, Casaburi R. Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD. Chest 2005;128:2025–2034.
Copyright © 2015 by the American Thoracic Society
875
in China. Clin Infect Dis [online ahead of print] 20 Jan 2015; DOI: 10.1093/cid/civ027. 15. Tyagi S, Ammerman NC, Li SY, Adamson J, Converse PJ, Swanson RV, Almeida DV, Grosset JH. Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis. Proc Natl Acad Sci USA 2015;112:869–874. 16. Yano T, Kassovska-Bratinova S, Teh JS, Winkler J, Sullivan K, Isaacs A, Schechter NM, Rubin H. Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxidoreductase: a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem 2011;286:10276–10287. 17. Grant SS, Kaufmann BB, Chand NS, Haseley N, Hung DT. Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proc Natl Acad Sci USA 2012;109:12147–12152.
Copyright © 2015 by the American Thoracic Society
Exercise Limitation in Chronic Obstructive Pulmonary Disease The O’Donnell Threshold Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. It is defined by the presence of expiratory airflow limitation that is only partially reversible. Consistent with the defining feature, the reduction in expiratory airflow, generally measured as FEV1, is widely used as a gauge of disease severity. Paradoxically however, dyspnea, the symptomatic result of the compromised physiology of COPD, is not a result of airflow limitation but an effect of airflow limitation on lung volumes. These effects are amplified during exercise; as a consequence, dyspnea on exertion is often the chief complaint of patients with COPD. Work from several groups has established that the reduced expiratory airflow in COPD leads to incomplete lung emptying, particularly with the rapid respiratory rates and large tidal volumes seen during exercise. When respiratory rate rises, the time for exhalation is progressively constrained. Slow expiratory airflow means that as the time for exhalation is reduced, a point is reached when the exhalation cannot be completed and end-expiratory lung volume must rise. Eventually, as exercise intensity increases, the combination of rising end-expiratory lung volume and rising tidal volume brings the end-inspiratory lung volume close to the maximum lung volume that can be inhaled: the total lung capacity. At volumes near total lung capacity, the work of breathing increases and the overstretched chest wall receptors send signals to the brain, contributing to the sensation of dyspnea. Thus, the resulting overexpansion of the lungs, termed “dynamic hyperinflation,” is a regular feature of exercise and is a major driver of dyspnea. It likely also explains the frequent complaint of patients: “I can’t get air in.” This contrasts with the never-heard complaint of “My air goes out too slowly,” which would be directly attributable to reduced FEV1. The laboratory of Denis O’Donnell has been the leader among those demonstrating the importance of dynamic hyperinflation in driving dyspnea on exertion in patients with COPD (1, 2). A recent paper from this group has expanded this concept to demonstrate that dynamic hyperinflation occurs in mild COPD as well, which leads to inspiratory volumes reaching a limit at which symptoms of dyspnea begin to become intolerable (3). Specifically, by stimulating ventilation through adding dead space during an
Editorials
exercise test, this group demonstrated that exercise terminates when a specific inspiratory reserve volume is reached (Figure 1). That is, when the difference between total lung capacity and endinspiratory lung volume shrinks to below a critical value in the face of increasing respiratory drive, dyspnea becomes intolerable. These concepts have their roots in the work of previous generations of physiologists. For example, Hey and colleagues (4) demonstrated that in healthy subjects, increasing exercise ventilation is accomplished mostly by tidal volume increase only up to about 50% of vital capacity, after which respiratory rate increase is predominant. Importantly, at rest, normal individuals and patients with COPD can easily increase respired volumes to values greater than the tidal volumes seen at peak exercise; they routinely do so when performing vital capacity maneuvers. It is the combination of elevated tidal volume demand and elevated end-inspiratory lung volume that brings the patient to a threshold at which their dyspnea becomes intolerable. The dynamic hyperinflation that occurs in COPD (even mild COPD) causes this threshold, the O’Donnell threshold, to be reached much earlier than would be predicted from maximal voluntary ventilation measured at rest. This is a fundamental concept, with direct clinical relevance for understanding the physiology and symptomology of COPD. It is also a concept that is difficult to teach and is (in our experience) not easy for trainees to remember. Perhaps this is because of the primacy of expiratory airflow limitation (and FEV1 specifically) in our thinking about COPD. Whatever the reason, we believe that providing a name for the inspiratory reserve volume at which patients experience intolerable dyspnea in the face of the ventilatory demand of exercise helps with communicating and remembering this concept. We have termed this the O’Donnell threshold. We believe that this is easy to remember and appropriately acknowledges Dr. O’Donnell’s work in defining this concept. The O’Donnell threshold: The inspiratory reserve volume at which intolerable dyspnea limits exercise.
873
EDITORIALS 0.0
TLC
Inspiratory reserve volume at which intolerable dyspnea limits exercise
0.5
IRV (L)
O’Donnell threshold
1.0
* *
1.5
*
2.0 2.5 0
20
40
60
80
100 120 140 160 180
Work rate (watts) Figure 1. The figure illustrates the inspiratory reserve volume (IRV), expressed as a difference between total lung capacity (TLC) and end-inspiratory lung volume in patients with mild chronic obstructive pulmonary disease (COPD) (circles) performing an incremental exercise test compared to healthy control subjects (triangles). Exercise terminates at the same IRV, the O’Donnell threshold (shaded area). Exercise terminates at the same volume in the face of added dead space in patients with COPD, indicating that there is a mechanical limit to ventilation in the face of exercise-induced drive (not shown, see Reference 3). This limit is determined by lung volume. Adapted by permission from Chin and colleagues (3). *P , 0.05, patients with COPD compared to healthy control subjects.
The concept of the O’Donnell threshold is far more than an advance in understanding the physiology of dyspnea in patients with COPD. The conventional approach to assessing ventilatory limitation during cardiopulmonary exercise testing is to estimate the breathing reserve (5). This is determined by calculating the difference between the maximal voluntary ventilation (often estimated as from the maximum ventilation determined at rest during a 12-second maneuver, or estimated as a multiple of the FEV1) and peak ventilation during cardiopulmonary exercise testing. However, as O’Donnell and colleagues have shown, the ability to increase ventilation at rest is not a direct determinant of maximal exercise ventilation in COPD. It is the O’Donnell threshold that limits maximal exercise. It seems likely that a large number of patients with mild COPD being evaluated for dyspnea have been incorrectly diagnosed as “poor effort” or “detraining” when, in fact, ventilatory limitation is present. These concepts have direct clinical implications. For individuals whose exercise is limited on reaching the O’Donnell threshold, treatments that deflate the lung should be considered. Conversely, not all patients with COPD will develop limiting hyperinflation. Many patients with COPD, especially those with mild disease, are limited by leg fatigue, not breathlessness. In others whose exercise terminates because of dyspnea, but who fail to reach the O’Donnell threshold, alternate causes for dyspnea should be considered. The O’Donnell threshold concept raises a number of important physiologic questions, the answers to which have considerable potential for improving COPD therapy: What determines the inspiratory reserve volume at which intolerable dyspnea develops? Can the O’Donnell threshold be changed with interventions? Should the O’Donnell threshold be routinely assessed to determine which patients with exercise limitation should be treated with bronchodilators? How does respiratory drive interact with lung mechanics to yield the sensation of dyspnea? It is also unknown whether individuals perceive the volume attained (the end-inspiratory lung volume) or the volume remaining (the inspiratory reserve volume). We believe the inspiratory reserve
874
volume is more likely to be important physiologically than the end-inspiratory volume, which is the way it is plotted by Dr. O’Donnell (Figure 1). In practice, assessing the O’Donnell threshold in individual patients is most readily achieved by serial measurement of the inspiratory reserve volume during exercise testing. This can be done by having the subject perform serial inspiratory capacity maneuvers (the difference between inspiratory capacity and the contemporaneously determined tidal volume is the inspiratory reserve volume). Alternately, optoelectronic plethysmography allows direct determination of thoracic volumes from which end-inspiratory lung volume can be estimated (6). Such measurements are not routinely performed in clinical exercise laboratories but have found good use in COPD research studies. Studies using these methods have defined the mechanisms by which, for example, bronchodilators, supplemental oxygen, and exercise training enhance exercise tolerance (7–11). The key point is that the O’Donnell threshold can be determined, at least in the investigational setting, and that the further exploration of the underlying physiology holds promise to improve the understanding of activity limitation in COPD and the care of patients with this disorder. At a minimum, the concept that it is lung volume, not airflow, that limits ventilation in exercising COPD patients is a crucial one. We expect that others also will find that use of the term “O’Donnell threshold” helps communicate this concept; we propose it for general use. n Author disclosures are available with the text of this article at www.atsjournals.org. Richard Casaburi, M.D., Ph.D. Rehabilitation Clinical Trials Center Los Angeles Biomedical Research Institute at Harbor–University of California, Los Angeles, Medical Center Torrance, California Stephen I. Rennard, M.D. Pulmonary, Critical Care, Sleep & Allergy University of Nebraska Medical Center Omaha, Nebraska
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 8 | April 15 2015
EDITORIALS References 1. 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. 2. O’Donnell DE, Banzett RB, Carrieri-Kohlman V, Casaburi R, Davenport PW, Gandevia SC, Gelb AF, Mahler DA, Webb KA. Pathophysiology of dyspnea in chronic obstructive pulmonary disease: a roundtable. Proc Am Thorac Soc 2007;4:145–168. 3. Chin RC, Guenette JA, Cheng S, Raghavan N, Amornputtisathaporn N, Cortes-T ´ elles ´ A, Webb KA, O’Donnell DE. Does the respiratory system limit exercise in mild chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2013;187:1315–1323. 4. Hey EN, Lloyd BB, Cunningham DJ, Jukes MG, Bolton DP. Effects of various respiratory stimuli on the depth and frequency of breathing in man. Respir Physiol 1966;1:193–205. 5. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp B. Principles of exercise testing and interpretation. Philadelphia, PA: Lippincott Willliams and Wilkins; 2005. 6. Aliverti A, Stevenson N, Dellac a` RL, Lo Mauro A, Pedotti A, Calverley PM. Regional chest wall volumes during exercise
Editorials
in chronic obstructive pulmonary disease. Thorax 2004;59: 210–216. 7. O’Donnell DE, Fluge ¨ T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23: 832–840. 8. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24:86–94. 9. Peters MM, Webb KA, O’Donnell DE. Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnoea in normoxic COPD. Thorax 2006;61:559–567. 10. Somfay A, Porszasz J, Lee SM, Casaburi R. Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. Eur Respir J 2001;18:77–84. 11. Porszasz J, Emtner M, Goto S, Somfay A, Whipp BJ, Casaburi R. Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD. Chest 2005;128:2025–2034.
Copyright © 2015 by the American Thoracic Society
875
