|Year : 2017 | Volume
| Issue : 1 | Page : 26-30
Asthma and chronic obstructive pulmonary disease
Department of Pulmonary Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata, West Bengal, India
|Date of Web Publication||29-Dec-2016|
Dr. Supriya Sarkar
Department of Pulmonary Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Asthma and chronic obstructive pulmonary disease (COPD) have striking differences but the similarities are also striking. Some scientists consider them as different expression of same disease. Some COPD patients show reversibility; on the other hand, asthma, a basically reversible disease, may lose its reversible nature by the process of airway remodeling and thereby blurring their differences. Although both are inflammatory diseases, they differ in the nature of inflammation and spectrum of inflammatory mediators. Clinically, most physicians can differentiate between two diseases, but the overlap also is widely recognized. The question remains whether any physiological test, among plethora available, can definitely differentiate asthma from COPD. Apart from overlap between asthma and COPD, it is now a well-established fact that asthma is a risk factor for the development of COPD. Only future can say, “whether Dutch or British hypothesis is right.”
Keywords: Asthma, chronic obstructive pulmonary disease, differences, similarities
|How to cite this article:|
Sarkar S. Asthma and chronic obstructive pulmonary disease. J Assoc Chest Physicians 2017;5:26-30
| Introduction|| |
Asthma and chronic obstructive pulmonary disease (COPD) have striking similarities. Both are chronic inflammatory diseases of airways initiated by gene-environment interactions and both cause airflow obstruction manifested by shortness of breath, cough, expectoration, and wheeze. The striking similarities are the basis of “Dutch hypothesis.” In 1961, during the first Bronchitis Symposium held in Groningen, the Netherlands, Orie et al. hypothesized that the various forms of airway obstruction, such as asthma, chronic bronchitis, and emphysema, should be considered not as separate diseases but as different expressions of one disease entity, chronic nonspecific lung disease. That hypothesis was latter on became famous as Dutch hypothesis. They proposed that various forms of obstructive lung disease (OLD) have overlapping clinical features, and one form of OLD (asthma) may evolve into another form (COPD). They also proposed that the development of OLD is based on allergy (i.e., inflammation) and bronchial hyper-responsibility, and endogenous (host) factors determined by heredity (genes) but is modulated by exogenous (i.e., environmental) factors (e.g., allergens, infections, smoking, pollution, age, and airway geometry).
On the other hand, the differences between asthma and COPD are also striking and distinct, and those features are sufficient to establish them as separate diseases. Asthma affects only the airways while COPD affects both the small airways and lung parenchyma. Perhaps the most important difference between asthma and COPD is the nature of inflammation, which is primarily eosinophilic and CD4-driven in asthma and neutrophilic and CD8-driven in COPD. That was the basis of “British hypothesis,” where asthma and COPD were seen as distinct entities generated by different mechanisms.
As our knowledge improves, we can now recognize that there is an overlap between asthma and COPD, both can coexist and most interestingly asthma can be a risk factor for the development of COPD. Hence, let us discuss where both diseases differ and where they converge blurring their differences.
| Pathological Differences|| |
Pathologically, both diseases have striking similarity as well as differences. Structural changes in the airway wall are different between asthma and COPD. In asthma, there is shedding of airway epithelial cells due to epithelial fragility and a characteristic deposition of collagen under the airway epithelia (subepithelial fibrosis). Subepithelial fibrosis is unique in asthma and it is not a feature of COPD. Airway smooth muscle hypertrophy and hyperplasia and increased bronchial vascularity may be seen in both asthma and COPD, but they are much less noticeable in COPD. Whereas COPD is characterized by squamous metaplasia, mucus glands and goblet cell hyperplasia, small airways fibrosis, parenchymal destruction, and pulmonary vascular remodeling.
Both diseases are characterized by airway inflammation and it is basically neutrophilic in COPD, whereas it is mainly eosinophilic in asthmatics but in severe asthma it may be neutrophilic. COPD is a heterogeneous disease with chronic bronchitis with mucous metaplasia, goblet cell hyperplasia, and mucous gland enlargement on the one side, and emphysema with elastin degradation associated with loss of elastic recoil and distension of airway distal to terminal bronchioles with destruction of alveolar septum, on the other hand. Similarly, some scientists opined that asthma should not be considered as a disease but should be considered as a syndrome. Pathologically, also there are striking differences between asthma and severe asthma where neutrophils and CD8+ T-cells dominate.
The inflammatory cells and mediators involved in COPD defer from that of asthma [Table 1]. The inflammatory mediator profile of asthma and COPD is different. In asthma, there is a predominance of bronchoconstrictor mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2 as well as cytokines derived from Th2 cells, such as interleukin (IL)-5 and IL-13, etc. In COPD, neutrophil chemotactic mediators, such as leukotriene B4 and IL-8 gamma interferon (IFN-γ) are predominant, along with and enhanced expression of IFN-γ and tumor necrosis factor.
|Table 1: Difference between chronic obstructive pulmonary disease and asthma|
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| Physiological Differences|| |
The airflow limitation of COPD results from structural changes of small airways and lung parenchyma and those are not reversible. The narrowing of small airways is the result of disrupted alveolar attachments and disruption of alveolar septa, loss of elastic recoil, and distal shifting of equal pressure point causing dynamic airflow obstruction. By contrast, the airway narrowing of asthma is predominantly due to contraction of airway smooth muscle as a result of multiple bronchoconstrictor mediators released from inflammatory cells, blockage of lumen by cellular debris and mucus, and mucosal edema as a result of inflammation. All changes are reversible resulting in reversible airway obstruction.
However, airway remodeling can occur in long-standing asthma, and some nonreversible components are added to a basically reversible disease. Ultimately, airway obstructions in asthma become at least partially nonreversible. Therefore, many (but not all) patients with asthma may not show variability and reversibility with short-acting bronchodilators and oral/inhaled corticosteroids. As a result, the lines distinguishing asthma and COPD are blurred particularly in older adults.
Both dynamic hyperinflation and loss of elastic recoil, well-accepted finding in COPD, may be observed in asthmatics. Although 58% asthmatics were “flow responders” characterized by an improvement in large airway resistance, the other 42% were “volume responders,” reflecting dilation of the peripheral airways. It was also observed that 34% of the decrease, in expiratory flow in asthmatics, was due to loss of recoil rather than airway disease.
| Clinical Differences|| |
Asthma is characterized by the early age of onset; presents with dyspnea, wheeze, cough with little tenacious expectoration that is difficult to bring out; symptoms at night/early morning; episodic symptoms with day-to-day variability; symptom-free period in between episodes; manifestation of other atopic disease such as allergic rhinitis and/or eczema; positive family history; largely reversible airflow limitation and good response to treatment with bronchodilators and corticosteroids.
On the other hand, COPD is characterized by onset in mid-life; symptoms slowly progressive with cough, mucoid or mucopurulent expectoration and dyspnea with or without wheeze; symptoms do not vary significantly over days; progressive dyspnea that increases with exertion; no symptom-free period; long smoking history or exposure to other etiological factors; associated with complications such as cor pulmonale and systemic manifestations; incompletely reversible airflow limitation, and poor response to treatment.
Age of onset
Asthma usually begins in early childhood, and COPD patients are diagnosed in their 60s. However, the prevalence of asthma is estimated to be 3.8–7.1% in elderly population (older than 65). Asthma in elderly, mainly includes subjects with long-standing disease. However, the first asthmatic symptoms may occur in late adulthood or after 65 years of age. It is now increasing recognized that COPD may start at an earlier age. Above the age of 40 years, both asthma and COPD have to be considered.
In adult, the prevalence of asthma is equal in both sexes. Late-onset asthma is common in females. COPD was considered to be a disease of men mainly because of smoking habits. However, smoking is not uncommon in female, and other risk factors (indoor air pollution) may be an important factor, particularly in developing countries. A male dominance in COPD group with female-male ratio (F/M ratio) was 1:2.29, and female dominance of asthma (F/M ratio was 3.5:1) was observed in elderly population.
Dyspnea and wheeze
In asthma, shortness of breathing is usually episodic, occurs at night or early morning, and may show a diurnal, day-to-day, and seasonal variation. Dyspnea in asthmatics is commonly associated with wheezing and a feeling of chest tightness. In COPD, dyspnea is usually progressive (worsen over time), persistent (present everyday), and usually worsen with exercise. Wheezing is thought to be less common in COPD; probably it is often attributed to and misdiagnosed as asthma.
Cough and expectoration
In asthmatics, cough is usually dry or there may be thick, tenacious expectoration that is difficult to bring out. Cough may be the sole presenting symptom, particularly in children (cough variant of asthma). In COPD, cough is usually productive with mucoid or mucopurulent expectoration, but sometimes, cough may be intermittent and unproductive. Any pattern of chronic sputum production may indicate COPD.
Smoking is the most important etiologic factor for COPD, but COPD can occur in nonsmokers and only 15–20% of smokers develop COPD. On the other hand, smoking may be a precipitating factor for asthma. The prevalence of smoking among patients with asthma is surprisingly similar to that in the general population, and there is evidence indicating asthma is more severe in smokers. It is also observed that asthma patients who smoke have a more and additive decline in lung function.
Atopy and allergy
Atopic individuals are constitutionally inclined to produce more IgE in response to different antigens. Atopic individuals can be identify by the history of other allergic disorders such as eczema, allergic rhinitis, positive family history, positive skin prick test, and increased level of IgE. It is a well-known fact that asthma is more common in atopic individuals. However, skin test reactivity or high IgE levels may not be useful for differentiating asthma from COPD, particularly in the elderly people. Although elderly asthmatic patients are indeed less atopic than younger ones but it is well-documented that they have more evidence of atopy than age-matched controls without asthma (29% at age 65 or over). Skin prick test positivity was found in 37% in asthmatics, whereas it was found in 8.3% of COPD patients. Total serum IgE levels were higher in asthmatic than COPD patients, but that did not reach the level of statistical significance.
Clinical and physical findings
The clinically silent nature of early COPD and the indolent course of the disease allow patients to accommodate their growing disability with lifestyle modification. Therefore, most patients presenting to their health-care provider for symptoms related to their COPD when forced expiratory volume in 1st s (FEV1) falls below 50% of predicted value. On auscultation, wheezing in asthma and distant or reduced breath sounds in COPD are the characteristic findings. A barrel-shaped chest due to the air-trapping, evidence of pulmonary arterial hypertension, cor-pulmonale, and right ventricular failure are more characteristic of COPD than asthma.
| Lung Function Test|| |
Peak expiratory flow rate and variability
Peak expiratory flow rate (PEFR) is measured by peak flow meter, an inexpensive, portable, plastic, and user-friendly instrument. PEFR varies for each meter and for each person and it is not interchangeable to FEV1. Ideally, PEFR should be compared with patients own values at normal asymptomatic stage. Variability refers to improvement or deterioration of symptoms and lung function occurring over times (over the course of 1 day, from day-to-day, from month-to-month, or seasonally). Variability is a characteristic feature of asthma. Variability is usually assessed by (i) early morning dipping – a more than 20% fall of PEFR in the morning, (ii) diurnal variation – more than 20% of diurnal variation measured by (maximum PEFR − minimum PEFR)/½ (maximum PEFR + minimum PEFR) (maximum [maximum] and minimum [minimum] are the average over 1–2 weeks), and (iii) minimum % maximum – the best PEFR index, calculated by taking the minimum morning prebronchodilator PEFR over 1 week, expressed as % of the recent best.
Office spirometer and reversibility
Reversibility is defined as increase of FEV1 (ΔFEV1) ≥12% and 200 ml from baseline value after administration of 200 μg salbutamol. Reversibility can also be measured, though not ideal, with peck flow meter and defined as a 60 L/min (or 20% or more) improvement of PEFR after the use of bronchodilator. In general, airflow obstruction in asthmatics is reversible and in COPD is not reversible. However, Calverley et al. stated that reversibility may be found in up to 23–42% of patients with COPD. On the other hand, fixed obstruction has been reported to occur in 30% of a large population diagnosed as asthma.
Mannino et al. found that the reversibility could afford only 44% of sensitivity for detecting asthma and a quite modest 72% of specificity in distinguishing asthma from COPD. It was reported that only 53% of patients with late-onset asthma showed completely reversible airway obstruction. In long-standing asthmatics, a more striking decline in FEV1 and persistent airway obstruction were detected.
In elderly patients with OLD, it was found that the baseline FEV1 was lower in the COPD patients than in asthmatic patients (P < 0.01). Bronchial reversibility (ΔFEV1%) in asthmatics was significantly higher than in COPD patients (P < 0.05). The mean percentage increase in FEV1 after reversibility test was 26.00 ± 7.59% in asthmatics versus 11.50 ± 2.21% in COPD patients.
Lung volumes and capacities
Among lung volumes, functional residual capacity (FRC), residual volume (RV), and RV/total lung capacity ratio were increased in both asthmatic and COPD patients. The increase in lung volumes was found to be higher in COPD patients than asthmatics (131.8% vs. 106). The higher RV in COPD patients suggest parenchymal destruction. It was well-accepted that patients with the diagnosis of COPD exhibit resting and dynamic hyperinflation, and the inspiratory capacity does correlate better than the FEV1 with steady-state exercise bicycle endurance. Yet, these characteristics are also seen in asthmatics.
Diffusion capacity (DLCO) was significantly lower, and lung volumes (RV, FRC) were significantly higher in COPD patients compared to asthma even if they had similar FEV1 levels. COPD patients showed significantly low DLCO, whereas this value is normal or even high in patients with asthma and the differences were significant (DLCO % 49.16 vs. 69.70, P < 0.05). However, DLCO is inadequate to differentiate them, and DLCO of 80% was merely 77% sensitive and 71% specific in discriminating COPD from asthma.
Airway hyperresponsiveness (AHR) is measured as the dose of methacholine required to cause a 20% fall of FEV1 after a challenge by inhaled methacholine/histamine or exercise called provocation dose (PC-20). A PC-20 <8 mg/ml of methacholine is a feature of asthma. The test is sensitive for a diagnosis of asthma (high negative prediction value for patients not on steroid). However, it has limited specificity (false positive in allergic rhinitis, cystic fibrosis, bronchiectasis, and COPD). AHR is seen in patients with COPD as a result of the geometric effect of airway narrowing and this makes it impossible to determine whether AHR is the cause or the consequence of COPD.
Arterial blood gas analysis
Both asthmatics and COPD patients show hypoxia, but asthmatics usually have hypocapnia, whereas COPD patients have hypercapnia and increased level of bicarbonate. The level of both PaO2 and PaCO2 in patients with COPD significantly differed from asthmatics (P < 0.01). Hypoxemia in asthmatics is usually mild but is usually moderate in COPD patients. COPD patients usually have hypercapnia while the mean PaCO2 value was found to be 44.57 mmHg. Severe asthmatics may show hypercapnia, but increased bicarbonate level is unlikely to be present.
| Chest Radiology (Chest X-Ray and Computed Tomography-Thorax)|| |
Bronchial wall thickening (ring shadow and tram line opacity), characteristic radiological sign of chronic bronchitis, is found in 42% of cases of COPD but may be observed in asthma. Hyperinflation, a characteristic sign of emphysema, may be found in 39% of cases of asthma, hyperinflation in asthmatics is usually transient but may be seen in 19% cases of asthma during remission. The combination of low and flat diaphragm is more specific for emphysema while low diaphragm may be found in acute asthma. Flat diaphragm (>1.5 cm) was the best predictor of emphysema with false positive rate is around 4%. Bullae, transradiant, avascular area with hairline curvilinear margins, were found to be present in all severe, 66% of moderate, and 35% of mild emphysema with no false positive result. Computed tomography-thorax has proved very sensitive and specific in assessing emphysema and bullae. Chronic bronchitis patients may show lung plethora and other signs of cor-pulmonale.
Increased eosinophils in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer neutrophils in sputum and bronchoalveolar lavage fluid; and a higher CD4+/CD8+ ratio of T-cell were found in the patients with asthma than in the patients with COPD who had comparable airflow limitation and AHR. Fractional exhaled nitric oxide (NO) in asthma correlates with eosinophilic inflammation but it is less useful in COPD. However, peripheral NO (nitric oxide) correlates with disease severity in COPD. Inflammatory markers and biomarkers might prove useful to phenotypically characterize patients with coexisting asthma and COPD.
| Asthma Chronic Obstructive Pulmonary Disease Overlaps|| |
Overall, 17% and 19% overlapping between asthma and COPD were observed in the United States and in the United Kingdom, respectively, and the percentage was found to increase with increasing age. Administrative data reviewed over a 3-year period showed that 43% of “COPD population” were listed with the diagnosis of asthma, on the other hand, 46% of “asthma population” were at least once diagnosed as COPD. Clinical overlapping of COPD and late-onset asthma often lead to misdiagnosis in the elderly population.
The proportional Venn diagram showed significant overlaps among asthma, chronic bronchitis, and emphysema [Figure 1]. The subjects with features of both asthma and COPD exhibited an intermediate prognosis between the classical asthma and COPD phenotypes. The Third National Health and Nutrition Examination Survey observed that people who reported both asthma and COPD were more likely to have lower lung function and more symptoms.
|Figure 1: Proportional Venn diagram of obstructive lung disease in the United States (National Health and Nutrition Examination Survey III Surveys from 1988 to 1994) and United Kingdom (GPRD 1998) for all ages|
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| Asthma as a Risk Factor for Chronic Obstructive Pulmonary Disease|| |
In our study taking 3099 adult cohorts, it was established that subjects with active asthma had significantly higher hazard ratios than nonasthmatic subjects for acquiring COPD. As compared with nonasthmatics, active asthmatics had a ten-times higher risk for acquiring symptoms of chronic bronchitis (95% confidence interval [CI], 4.94–20.25), 17-times higher risk of receiving a diagnosis of emphysema (95% CI, 8.31–34.83), and 12.5-times higher risk of fulfilling COPD criteria (95% CI, 6.84–22.84), even after adjusting for smoking history and other potential confounders.
AHR in asthma is thought to contribute to the development of COPD; on the other hand, the presence of AHR is associated with a steeper decline in lung function in COPD.
| Conclusion|| |
The differences between asthma and COPD are so marked that most clinicians can easily distinguish between asthma and COPD based on clinical history and simple lung function tests. However, sometimes, the differences are not sufficient to distinguish them, particularly in elderly persons. The undeniable fact is that there is a significant pathological, physiological, and clinical overlap among the obstructive phenotypes of asthma and COPD. The key question remains unanswered, “Can any physiologic test distinguish asthma from COPD as obstructive phenotypes”? American Thoracic Society stated, “It may be impossible to differentiate patients with asthma whose airflow obstruction does not remit completely from persons with chronic bronchitis and emphysema with partially reversible airflow obstruction and bronchial hyper-responsiveness.”
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Orie NG, Sluite HJ, de Vries K, Tammeling GJ, Witkop J. The host factor in bronchitis. In: Orie NG, Sluiter HJ, editors. Bronchitis. Assen, The Netherlands: Royal Van Gorcum; 1961. p. 43-59.
Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A, et al.
Genomewide linkage analysis of quantitative spirometric phenotypes in severe early‑onset chronic obstructive pulmonary disease. Am J Hum Genet 2002;70:1229‑39.
Buist AD. Similarities and differences between asthma and chronic obstructive pulmonary disease: Treatment and early outcomes. Eur Respir J 2003;21 Suppl 39:30s‑5s.
Martin RJ. Small airway and alveolar tissue changes in nocturnal asthma. Am J Respir Crit Care Med 1998;157(5 Pt 2):S188‑90.
Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, et al.
CD8 T‑lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157(3 Pt 1):822‑6.
Paré PD, Lawson LM, Brooks LA. Patterns of response to inhaled bronchodilators in asthmatics. Am Rev Respir Dis 1983;127:680‑5.
Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Chest 2002;121:715‑21.
Burrows B, Barbee RA, Cline MG, Knudson RJ, Lebowitz MD. Characteristics of asthma among elderly adults in a sample of the general population. Chest 1991;100:935‑42.
Sin BA, Akkoca Ö, Saryal S, Öner F, Mısırlıgil Z. Differences between asthma and COPD in the elderly male. J Investig Allergol Clin Immunol 2006;16:44‑50.
Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur Respir J 2004;24:822‑33.
James AL, Palmer LJ, Kicic E, Maxwell PS, Lagan SE, Ryan GF, et al.
Decline in lung function in the Busselton Health Study: The effects of asthma and cigarette smoking. Am J Respir Crit Care Med 2005;171:109‑14.
Bauer BA, Reed CE, Yunginger JW, Wollan PC, Silverstein MD. Incidence and outcomes of asthma in the elderly. A population‑based study in Rochester, Minnesota. Chest 1997;111:303‑10.
Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW. Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax 2003;58:659‑64.
Kesten S, Rebuck AS. Is the short‑term response to inhaled beta‑adrenergic agonist sensitive or specific for distinguishing between asthma and COPD? Chest 1994;105:1042‑5.
Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: Data from the National Health and Nutrition Examination Survey, 1988‑1994. Arch Intern Med 2000;160:1683‑9.
Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987;70:171‑9.
Sin BA, Akkoca Ö, Saryal S, Öner F, Mısırlıgil Z. Differences between asthma and COPD in the elderly male. J Investig Allergol Clin Immunol 2006;16:44‑50.
Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:967‑75.
Sciurba FC. Physiologic similarities and differences between COPD and asthma. Chest 2004;126 2 Suppl: 117S‑24S.
Magnussen H, Richter K, Taube C. Are chronic obstructive pulmonary disease (COPD) and asthma different diseases? Clin Exp Allergy 1998;28 Suppl 5:187‑94.
Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am J Respir Crit Care Med 1996;153(6 Pt 1):1802‑11.
Hodson CJ, Trickery SE. Bronchial wall thickening in asthma. Clin Radiol 1960;11:183‑91.
Petheram IS, Kerr IH, Collins JV. Value of chest radiographs in severe acute asthma. Clin Radiol 1981;32:281‑2.
Nicklaus TM, Stowell DW, Christiansen WR, Renzetti AD Jr. The accuracy of the roentgenologic diagnosis of chronic pulmonary emphysema. Am Rev Respir Dis 1966;93:889‑99.
Mannino DM. Coexisting asthma and COPD: Confused clinicians or poor prognosticator? Chest 2008;134:1‑2.
Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB. The proportional Venn diagram of obstructive lung disease: Two approximations from the United States and the United Kingdom. Chest 2003;124:474‑81.
Shaya FT, Dongyi D, Akazawa MO, Blanchette CM, Wang J, Mapel DW, et al.
Burden of concomitant asthma and COPD in a Medicaid population. Chest 2008;134:14‑9.
Kitch BT, Levy BD, Fanta CH. Late onset asthma: Epidemiology, diagnosis and treatment. Drugs Aging 2000;17:385‑97.
Burrows B, Bloom JW, Traver GA, Cline MG. The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N Engl J Med 187;317:1309‑14.
Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004;126:59‑65.