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(Chest. 2004;126:117S-124S.)
© 2004 American College of Chest Physicians

Physiologic Similarities and Differences Between COPD and Asthma*

Frank C. Sciurba, MD, FCCP

* From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

Correspondence to: Frank C. Sciurba, MD, FCCP, Associate Professor of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 1211 Kaufmann Bldg, Pittsburgh, PA 15213; e-mail: sciurbafc{at}upmc.edu


   Abstract
TOP
 Abstract
Introduction
 Variations in COPD and...
 Physiologic Comparison of Asthma...
 Lung Elastic Recoil/Parenchymal...
 Exercise Response/Systemic...
 Conclusion
 References
 
The structural and physiologic findings in asthma and COPD appear, on average, and in the extremes of presentation, to be easily distinguished. A closer inspection of the literature reveals that significant overlap exists in individual patients with respect to airway wall thickening and low-attenuation parenchymal regions on CT scans, and in reversibility, airway hyperresponsiveness, lung diffusion, resting and dynamic hyperinflation, lung elastic recoil, exercise response, and a "pharmaceutical volume reduction" effect following therapy with bronchodilators. In particular, the subgroup of COPD patients having an airway-dominant phenotype becomes indistinguishable from asthmatic subjects with reversible disease that evolves into an incompletely reversible pattern.

Key Words: asthma • COPD • emphysema • exercise • hyperinflation • lung elastic recoil


   Introduction
TOP
 Abstract
 Introduction
Variations in COPD and...
 Physiologic Comparison of Asthma...
 Lung Elastic Recoil/Parenchymal...
 Exercise Response/Systemic...
 Conclusion
 References
 
In its purest form, asthma is a condition of youthful onset in nonsmokers that is associated with episodic, completely reversible airway obstruction and airway hyperresponsiveness (AHR). Pure COPD, on the other hand, is characterized by tobacco-related, gradually progressive, fixed airflow obstruction that is associated with airway as well as emphysematous parenchymal components inducing the loss of lung elastic recoil, resting and dynamic lung hyperinflation, and abnormalities in gas diffusion. Although these physiologic and anatomic extremes of COPD and asthma are easily separated into distinct categories of disease, in practice a significant proportion of patients have characteristics that are classically associated with both conditions. In fact, the physiologic findings in individual patients with clinical asthma and COPD, when isolated from the context of the environmental and clinical history, may be insufficient to distinguish between the conditions.12 Such inability to clearly separate these conditions can lead to frustration in both the clinical and research settings. The clinician is often faced with two very different treatment paradigms,34 depending on the diagnostic choice. The researcher is often forced to exclude subjects from clinical trials who cannot be purely categorized, with the consequence that therapeutic interventions may not be adequately tested in large subgroups of patients.


   Variations in COPD and Asthma Phenotype
TOP
 Abstract
 Introduction
 Variations in COPD and...
Physiologic Comparison of Asthma...
 Lung Elastic Recoil/Parenchymal...
 Exercise Response/Systemic...
 Conclusion
 References
 
Before a specific comparison can be made between COPD and asthma, it is important to acknowledge the variations in structure and physiology observed within each disease. Such differences in disease structure and function are not only found between individuals but may evolve within a given individual over time. The dominant classification paradigm for COPD identifies the extreme categories of chronic bronchitis vs emphysema but acknowledges that there are often components of each process present in any individual. This common classification, however, fails to emphasize the substantial literature suggesting an important, potentially independent contribution of the small peripheral conducting airways to the increased airways resistance, resulting in airflow obstruction in patients with advanced disease.56789 Significantly, individuals exhibit considerable variability in the degree of small airway involvement relative to the severity of emphysema and large airway bronchitis.1011 Detailed morphologic evaluations11 have revealed that 79% of patients with COPD had evidence of parenchymal emphysema, while 85% had significant airway involvement including mucosal hyperplasia (75%) and bronchiolitis (47%). Of note, 11% had evidence of bronchiolitis but no mucosal hypertrophy consistent with chronic bronchitis. Such observations provide an explanation for apparent discrepancies in anatomy and physiology between certain individuals (Fig 1 ). The patient in Figure 1, left, A, has had 66% of his lung destroyed by emphysema (FEV1, 25% of predicted), whereas the patient in Figure 1, right, B, is an individual with minimal emphysema but a lower FEV1 (23% of predicted). Both patients had a similar history of tobacco use, and neither had symptomatic bronchitis or bronchodilator reversibility, thus indirectly supporting the disproportionate contribution of small airways disease in the second patient.



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  		Figure 1. CT scans of two subjects with clinical histories that are consistent with COPD are shown. Left, A: a patient with 66% emphysema by quantitative analysis (FEV1, 25% of predicted). Right, B: an individual with minimal emphysema but a lower FEV1 (23% predicted). Both patients had a similar history of tobacco use, and neither had symptomatic bronchitis or bronchodilator reversibility, thus indirectly supporting the disproportionate contribution of small airways disease in the second patient. The pattern found in the right, B, panel may be indistinguishable from that of a long-term asthma patient.

 
Advances in quantitative CT scanning may allow us to more accurately separate subjects into unique subgroups using noninvasive techniques.1213 Such CT scanning techniques have been validated by comparison with tissue histology for both emphysema volume and airway wall thickness measurements.1415 By quantifying the percentage of low-attenuation area (LAA%), that is, emphysema, and the percentage of airway wall thickness relative to airway perimeter (WA%) using quantitative CT scanning, we can stratify patients into airway-dominant phenotype, parenchyma-dominant phenotype, or combined phenotypes (Fig 2 ). In fact, such measurements of LAA% and WA% are independent predictors of expiratory flow rates.



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  		Figure 2. Using quantitative CT scan analyses, Nakano et al15 evaluated the relationship between emphysema and airway wall thickness in 94 COPD subjects and 20 smokers. By quantifying the percentage of low LAA% (ie, emphysema) and WA%, we can stratify patients into airway-dominant phenotype, parenchyma-dominant phenotype, or combined phenotypes. In fact, such measurements of LAA% and WA% are independent predictors of expiratory flow rates. The pattern (ie, phenotype) represented in the right lower quadrant of the graph is similar to the pattern found in patients with severe asthma that is incompletely reversible. Reprinted with permission from Nakano et al.15

 
Although asthma has traditionally been described as a reversible disease of the large airways, an increasing body of knowledge describes an often progressive process with an incompletely reversible component that often involves the small peripheral airways as well as the large airways.161718 CT scan studies19 performed in asthma populations have identified increases in airway wall thickness that are similar to those found in the airway-dominant subgroup of COPD subjects. While early studies in patients with milder asthma suggested that airway luminal diameter was preserved in patients with asthma compared to those with COPD, studies1920 evaluating more severe asthma demonstrate decreased airway luminal diameter associated with the airway-wall thickening as is found in COPD. Furthermore, increases in LAA% that are consistent with emphysema are observed in nonsmoking asthmatic patients. The volume of lung in the density range that is consistent with emphysema is associated with increasing asthma severity and age. One study21 found 5.1% of the lung volume in the emphysema density range in patients with mild asthma, and 23% in those with severe disease. The higher percentage of emphysema found in patients with more severe asthma is more than would be expected simply from the hyperinflation of healthy lung tissue. Importantly, studies2122 have shown a significantly greater percentage of CT scan-detected emphysema in asthmatic patients who are smokers compared with nonsmokers. Consistent with these observations, high-resolution CT scans that have been interpreted by expert observers have been shown to have poor discriminative value between clinical asthma and COPD.23


   Physiologic Comparison of Asthma and COPD
TOP
 Abstract
 Introduction
 Variations in COPD and...
 Physiologic Comparison of Asthma...
Lung Elastic Recoil/Parenchymal...
 Exercise Response/Systemic...
 Conclusion
 References
 
The Physiologic Dogma: Asthma vs COPD
The most common working definitions of COPD and asthma in most clinical and research settings consistently incorporate the following physiologic attributes. While, on average, populations separate based on these characteristics, as will be discussed below, frequent exceptions occur to these classic patterns in individual patients.

Degree of Variability and Reversibility of Spirometry:
Both asthma and COPD are defined by decreases in the FEV1/FVC ratio. FEV1 in asthma patients is considered to be at least partially (12% change in FEV1) or completely reversible and to vary significantly throughout the day.24 COPD, by definition, is never completely reversible, and significant reversibility often leads to exclusion from clinical trials. Both chemically induced and exercise-induced hyperresponsiveness are defining characteristics of asthma but are not traditionally associated with COPD.

Diffusing Capacity:
Measurements of the diffusing capacity of the lung for carbon monoxide (DLCO) are typically normal or increased in asthma patients. In COPD patients, they are typically decreased. The decreases are thought to be directly related to the loss of alveolar-capillary surface area that is associated with emphysema.

Hyperinflation:
COPD is typically associated with more severe increases in resting lung volume that are accentuated during exertion. Asthma is conventionally thought to be associated with resting hyperinflation only during attacks.

Lung Elastic Recoil/Lung Compliance:
Increased lung elastic recoil (ie, decreased compliance) is characteristic of COPD and is considered to be normal in asthma.

Simple Measures of Pulmonary Function in Asthma and COPD
The excessive rate of decline in expiratory flow rates in susceptible smokers has been welldescribed.25 Long-term results from the Lung Health Study25 have demonstrated a decline of 66 mL per year in men and 54 mL per year in women compared with the expected normal decline of 20 to 30 mL per year. Given that the Lung Health Study only included subjects with known pulmonary dysfunction, the rate of decline in all smokers is expected to be significantly less than these values. The impact of asthma on the rate of decline in FEV1 is more controversial, ranging between 0 and 95 mL per year, and depends on disease definition, concomitant smoking, age, and severity of disease in the populations studied.262728 It is clear, however, that asthma in a significant subgroup of patients evolves into incompletely reversible disease, thus becoming more difficult to distinguish from subgroups of patients with tobacco-related COPD.

Three articles1229 have compared the spirometry, lung volume, and DLCO of COPD patients to subjects who had never smoked and had incompletely reversible asthma. All three studies compared patients with similar FEV1 severity. These studies demonstrated significantly lower DLCO and significantly greater residual volume (RV), functional residual capacity, and total lung capacity (TLC) in the COPD subgroup compared with the asthma subgroup. There was, however, significant overlap between groups. The DLCO was the single best physiologic discriminator between the two groups, with values in COPD patients ranging from 58 to 67% predicted and those in patients with incompletely reversible asthma ranging from 85 to 99% predicted. Unfortunately, even DLCO was inadequate as a discriminator in individual subjects. A DLCO value of 80% predicted was only 77% sensitive and 71% specific in discriminating COPD from asthma.

Bronchodilator Reversibility and AHR
The acute improvement in expiratory flow rates, such as FEV1 following bronchodilator use, is on average greater in asthma patients than in COPD patients (16% vs 11%, respectively). However, despite the common use of bronchodilator reversibility in the clinical and research setting to distinguish asthma from COPD, the diagnostic effectiveness of this parameter is poor in unselected patients.3031 One large study,32 using a threshold bronchodilator FEV1 change of 15%, determined only a 44% sensitivity for detecting asthma and a 72% specificity in distinguishing asthma from COPD. Increasing the minimum FEV1 threshold change to 20% increased the specificity to 84% but dramatically decreased the sensitivity.31 A large population-based analysis32 found that 30% of individuals with fixed airflow obstruction have a history of asthma.

While there is a correlation between bronchodilator reversibility and AHR to methacholine, the relationship is not strong.33 Tests of AHR are useful in distinguishing patients with asthma from healthy persons.343536 A 20% reduction in expiratory flow rates in response to 8 mg/mL methacholine occurs in nearly all patients with active asthma and in < 5% of healthy individuals. On the other hand, these tests are not useful in distinguishing asthma from COPD, since 68% of patients with COPD (85% of women and 59% of men) also exhibit AHR. In fact, in COPD patients, poorer pulmonary function is associated with a greater magnitude of AHR, and increasing severity of AHR is associated with greater rates of decline in lung function in continuing smokers.37

Twenty-seven percent of patients with {alpha}1-antitrypsin deficiency who are enrolled in the National Heart, Lung, and Blood Institute registry have significant bronchodilator reversibility, although the prevalence of AHR in one series39 (16%) was not significantly different from that of the control group (11%).3839

Resting and Dynamic Hyperinflation
The impact of lung hyperinflation on symptoms and impairment at rest and during exertion is increasingly recognized in COPD patients.404142 The consequences of hyperinflation include a shortened diaphragm with less efficient neuromechanical coupling, and constraints on inspiratory reserve volume within the limitations of the thoracic cage expansion. "COPD is a disease of resistance during expiration with the consequence of restriction during inspiration" (M. Younnes, MD; personal communication; May 1994). It has been shown in COPD patients that inspiratory capacity (the difference between TLC and end-expiratory lung volume) correlates better than FEV1 with steady-state bicycle endurance.

While the literature has focused little attention on such hyperinflation in asthma patients, RV is often elevated at rest even with mild, completely reversible disease and increases proportionately greater than the fall in FEV1 following bronchial challenge.43 Because such lung hyperinflation impacts on inspiratory capacity, it is not surprising, albeit not widely appreciated, that during asthma attacks four times as many patients perceive a greater discomfort during inspiration compared with expiration.44 Investigators have proposed that hyperinflation in asthma may be in part related to the persistent activity of the inspiratory muscles and to glottic closure during expiration, although it is not likely that with progressive disease the mechanisms are distinct from those in COPD.45

The change in resting and dynamic lung volumes following bronchodilator treatment appears to have relevance independent of changes in expiratory flow measurements in both asthma and COPD. A study of patients with moderate-to-severe COPD who did not exhibit reversibility in expiratory flow parameters revealed that 83% of these patients had significant improvements in lung volume indexes.46 Furthermore, patients with the most severe disease exhibited the greatest absolute improvements. Similarly, in another study47 15% of asthmatic patients exhibited reversibility in lung volume indexes, but not in FEV1, following bronchodilation.

Important past work4849 has suggested that different patterns of response to bronchodilation exist within both asthma and COPD populations, such that some individuals have dominant improvements in expiratory flow indexes while others have dominant improvements in lung volumes. Improvements in vital capacity (the difference between TLC and RV) should reflect improvements in hyperinflation if we assume that, following bronchodilation, changes in RV are usually very disproportionate to changes in TLC. In both COPD patients48 and asthma patients,49 it has been suggested that flow-dominated responses reflect improvement in large airway resistance, whereas volume-dominated responses reflect the dilation of peripheral airways (Fig 3 ). Paré et al49 used the {Delta}FEV1/{Delta}FVC bronchodilator response ratio to distinguish flow-dominant responders (ratio, > 1) from volume responders (ratio, < 1), and they identified 58% of subjects to be flow responders and 42% to be volume responders. Furthermore, they found that volume responders had significantly poorer baseline lung function than flow responders. This report supports the concept that asthma patients with advanced disease are more likely to exhibit a response pattern that until recently was associated with severe COPD. This pattern of disproportionate improvements in lung hyperinflation compared with expiratory flow parameters is consistent with disproportionate peripheral airway resistance. Furthermore, asthmatic patients who smoke have a disproportionate frequency of volume response, suggesting a greater degree of small airways disease. More recent work further supports the concept of the separation of expiratory flow and lung volume response by observing, in asthmatic patients during histamine challenge, that decreases in FVC are variable and are independent from changes in FEV1.50 These physiologic observations following pharmaceutical intervention in both COPD and asthma patients have been highlighted through physiologic observations following lung volume reduction surgery.5152 It is likely that the "pharmaceutical volume reduction" present in both COPD and asthma patients is not just an incidental finding that is of secondary importance to changes in expiratory flow rates, but rather is the dominant response to therapy. This concept is illustrated in Figure 3. The right panel reflects a theoretical response to therapy with bronchodilators, which reflects a volume response. In this model, the primary action would reside in improving expiratory time constants in the peripheral airways with highest resistance, such that they can empty more completely. The improvement in the flow-volume curve would be a consequence now of improved filling of the lower resistance units, thus improving the inspiratory capacity and vital capacity, and only secondarily resulting in improvements in expiratory flow rates. This contrasts with the left panel, in which improvements in expiratory flow rates are the primary process consequent to smooth muscle dilation and decreases in large airway resistance.



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  		Figure 3. Two patterns of responses to bronchodilator therapy include a predominant expiratory flow response (left), and a predominant volume response (right). The curves represent expiratory flow-volume loops before (red) and after (blue) bronchodilator use. The drawings represent a theoretical lung at full inspiration, with the white areas representing trapped air behind high-resistance peripheral airways. Left: improvements in expiratory flow rates are the primary process consequent to smooth muscle dilation and decreases in large-airway resistance. Right: a "volume response" is shown in which the dominant effect is improvement in expiratory time constants in the peripheral airways with highest resistance, such that they can empty more completely. This could theoretically occur uniformly throughout the lung or heterogeneously. In the latter case, illustrated in the right-hand drawing, improvement in expiratory flow is a consequence of improved filling of the lower resistance units following more complete emptying of the higher resistance units that now occupy less thoracic space at full inspiration. The effect of this includes improvement in the inspiratory capacity and vital capacity, with only secondary improvements in expiratory flow rates. This volume response represents the most common pattern in patients with COPD as well as severe, incompletely reversible asthma.

 

   Lung Elastic Recoil/Parenchymal Airway Interaction
TOP
 Abstract
 Introduction
 Variations in COPD and...
 Physiologic Comparison of Asthma...
 Lung Elastic Recoil/Parenchymal...
Exercise Response/Systemic...
 Conclusion
 References
 
Lung elastic recoil measurements such as maximal pulmonary elastic recoil pressure, the transpulmonary pressure at TLC, have traditionally been thought to distinguish asthma from COPD and to be unchanged following bronchial challenge or bronchodilator therapy in asthma patients.53 More recent studies have raised doubts concerning this distinction. One study54 showed that a significant subgroup of patients with clinical histories consistent with COPD had preserved lung elastic recoil, particularly those subjects with preserved DLCO values who were otherwise clinically indistinguishable. Furthermore, two reports5556 have described decreases in lung elastic recoil in patients with asthma. In these studies, the authors estimated that > 34% of the reduction in expiratory flow rate in asthmatic patients is due to the loss of lung elastic recoil rather than to intrinsic airways disease. It is unclear whether these changes were due to subtle emphysema or to other changes in lung tissue mechanical properties associated with stress relaxation.5758 In contrast, studies assessing parenchyma-airway interaction via deep inspiration and partial flow-volume analysis cannot distinguish asthma from COPD. Such observations have led the investigators to consider that intrinsic airway abnormalities may dominate both asthma and COPD, and that the parenchyma (emphysema) may be of less practical importance in altering airway function.59606162


   Exercise Response/Systemic Impairment
TOP
 Abstract
 Introduction
 Variations in COPD and...
 Physiologic Comparison of Asthma...
 Lung Elastic Recoil/Parenchymal...
 Exercise Response/Systemic...
Conclusion
 References
 
Although the primary site of involvement in COPD is the lungs, the poor relationship between lung function and quality of life may reflect variations in a systemic component including peripheral muscle deconditioning or myopathy.6364 Two studies6566 have highlighted the contribution of peripheral deconditioning very early in the course of both mild asthma and COPD. Each study compared the exercise response of patients with mild disease with that of healthy control subjects and found nearly identical results. Both mild asthma and COPD patients have a decreased maximal oxygen uptake and work rate. Both groups have decreased ventilatory reserve (ie, minute ventilation/maximal voluntary ventilation ratio) at maximal exertion but in general do not achieve ventilatory limitation. Both groups achieve near-maximal predicted heart rates. Both articles concluded that deconditioning occurs very early in the disease process to limit functional capacity. It is also possible that the chronic inflammatory state associated with elevated systemic inflammatory mediators, including tumor necrosis factor-{alpha}, may contribute to an early and progressive myopathic component in both conditions.6768


   Conclusion
TOP
 Abstract
 Introduction
 Variations in COPD and...
 Physiologic Comparison of Asthma...
 Lung Elastic Recoil/Parenchymal...
 Exercise Response/Systemic...
 Conclusion
References
 
While on average and in the extremes of presentation, asthma and COPD appear to be easily distinguished, in practice, significant proportions of patients are indistinguishable on the basis of structural and functional evaluations. A significant overlap exists in individual patients with respect to airway wall thickening and low-attenuation parenchymal regions seen on CT scans, reversibility, AHR, lung diffusion, resting and dynamic hyperinflation, lung elastic recoil, exercise response, and a pharmaceutical volume reduction effect following bronchodilator therapy. In particular, the substantial subgroup of patients with late-onset tobacco-related COPD who have an airway-dominant phenotype and relatively little emphysema become indistinguishable from the youthful-onset patients with reversible disease that evolves, with or without tobacco smoking, into an incompletely reversible pattern. Furthermore, data on ex-smoking COPD subjects and patients with severe asthma have suggested that these physiologic similarities also may be reflected by merging patterns of underlying inflammation and disease activity.6970


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; DLCO = diffusing capacity of the lung for carbon monoxide; LAA% = percentage of low-attenuation area; RV = residual volume; TLC = total lung capacity; WA% = percentage of wall thickness relative to airway perimeter

The author has received research grants from Amgen, Boehringer Ingelheim, Emphysis, GlaxoSmithKline, Hoffmann-La Roche, and Otsuka. He is also a consultant for Boehringer Ingelheim, GlaxoSmithKline, and Purdue.


   References
TOP
 Abstract
 Introduction
 Variations in COPD and...
 Physiologic Comparison of Asthma...
 Lung Elastic Recoil/Parenchymal...
 Exercise Response/Systemic...
 Conclusion
 References
 

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