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The Pathophysiology of Airway Dysfunction

Dennis E. Doherty, MD

Asthma and chronic obstructive pulmonary disease (COPD) are distinct inammatory disorders with differing pathophysiologic mechanisms, different clinical courses, and, therefore, distinct treatment strategies. Whereas in asthma airow limitation is typically episodic and reversible, airow limitation in COPD is progressive and only partially reversible. In contrast to asthma, which is characterized by an elevated number of eosinophils in the blood and the accumulation of elevated numbers of activated eosinophils, mast cells, and CD4 TH2-lymphocytes in the lungs, the primary inammatory cells present in the lungs of patients with stable COPD are neutrophils, macrophages, and CD8 lymphocytes. Bronchoconstriction in COPD is largely regulated by cholinergically mediated vagal tone, and the pathologic processes of COPD further reduce airway patency. Bronchodilators, most notably anticholinergics, are recommended as rst-line pharmacologic therapy for COPD. Proper use of inhaled anticholinergic medications has been shown to lead to signicant reversibility of acetylcholine-mediated bronchoconstriction during both stable disease and exacerbations of COPD. For patients with asthma, current guidelines recommend anti-inammatory medications, specically inhaled corticosteroids and leukotriene-modiers, as rst-line therapy, making these agents the mainstay of asthma therapy. In contrast, the current guidelines for COPD management recommend that inhaled anti-inammatory agents be tried in patients with COPD only as second-line therapy for patients who have severe to very severe airow obstruction with frequent exacerbations and who remain symptomatic despite maximized bronchodilation with multiple inhaled bronchodilators. Hence, it is extremely important to understand the differences between the underlying pathogenesis and pathophysiology of COPD and those of asthma, as these differences dictate the implementation of distinctly different treatment options for these 2 diseases. Am J Med. 2004;117(12A):11S23S. 2004 by Elsevier Inc.

From the Chandler Medical Center, Division of Pulmonary and Critical Care Medicine, University of Kentucky, Lexington, Kentucky, USA and the Lexington Veterans Administration Medical Center, Lexington, Kentucky, USA. Requests for reprints should be addressed to Dennis E. Doherty, MD, Division of Pulmonary and Critical Care Medicine, Chandler Medical Center, University of Kentucky, Room K528, 740 South Limestone, Lexington, Kentucky 40536-0284. 2004 by Elsevier Inc. All rights reserved.

hronic obstructive pulmonary disease (COPD) is characterized by airow limitation that is not fully reversible, is usually progressive, and is associated with an abnormal inammatory response of the lungs to noxious particles or gases.1 In the United States, 85% of COPD cases arise after prolonged exposure of the airways and lungs to tobacco smoke. The airow limitation associated with the disease worsens over a period of many years and is only partially reversed to age-appropriate levels with maintenance bronchodilator therapy and sustained smoking cessation. The key symptoms of COPD are chronic cough, excess sputum production, and exertional dyspnea out of proportion to that expected for a patients level of activity and age. Patients slowly develop exercise intolerance and experience decreased quality of life; some individuals with severe COPD may even exhibit dyspnea at rest, hypoxemia, hypercapnia, pulmonary hypertension, and cor pulmonale.1 In addition to the considerable morbidity caused by this condition, COPD is associated with signicant premature mortality. In 2000, COPD was the fourth leading cause of death in the United States, with 120,000 persons dying of the disease.2 Also in 2000, for the rst time, the number of deaths in women with COPD exceeded the number in men. By 2020, COPD is expected to be the third leading cause of death, not only in the United States but also worldwide.2,3 Although guidelines for appropriate diagnosis and treatment are available, COPD continues to be underdiagnosed. The disease is often misdiagnosed as well. It is particularly common for patients with COPD to receive an incorrect diagnosis of asthma.4,5 Although both COPD and asthma involve chronic airway inammation, inhaled corticosteroids, which are the mainstay of asthma therapy because they effectively reverse that diseases inammatory component, are not very effective in controlling the chronic inammation associated with COPD. Accordingly, the use of inhaled corticosteroids in the management of COPD remains controversial.4 The most recent comprehensive guidelines for the identication and management of COPD, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines1 and the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines,6 state that bronchodilators are the most effective therapeutic agents for COPD and should be used as rst-line pharmacologic therapy. Anti-inammatory agents, specically inhaled corticosteroids, are relegated to second-line therapy only in those patients with severe COPD who remain symp1548-2766/04/$22.00 11S doi:10.1016/j.amjmed.2004.10.017

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tomatic and have frequent exacerbations despite maximized bronchodilation.1,6 The purpose of this review is to provide an evidenced-based rationale for the diagnosis and treatment of COPD, in part by distinguishing it from asthma on the bases of clinical characteristics, pathogenesis, pathophysiology, and pharmacologic treatment options.


The clinical characteristics of COPD differ from those of asthma in a number of ways (Table 1).1,7 Notwithstanding the differences, however, distinguishing between these 2 inammatory diseases in the clinic remains a challenge, largely because of the supercial similarities in symptomatology and clinical presentation that tend to override their more subtle differences. Developing an accurate differential diagnosis is further complicated by the fact that 10% to 15% of patients with obstructive pulmonary disease have both COPD and asthma.7 An additional complication is that some individuals with asthma often continue to smoke and later develop COPD in addition to their asthma. Therefore, in determining whether a patient with obstructive pulmonary disease has COPD, asthma, or a combination of these 2 diseases, it is essential to consider the totality of symptoms and risk factors. The age of presentation for a patients rst episode of dyspnea often provides a potential distinguishing characteristic between asthma and COPD. Asthma typically develops at a young age, often during childhood, and it can appear and disappear. On the other hand, the dyspnea of COPD is almost always initially recognized or acknowledged after age 40, predominantly in individuals who have a 20 pack-year history of smoking tobacco.1,8 The age differentiator is not foolproof, however, because asthma occasionally develops in older patients as well. More likely than not, patients aged 40 years presenting without a history of asthma in youth and with current symptoms consistent with a chronic obstructive lung disease, a signicant smoking history, and their rst breathing difculties are more likely experiencing COPD than asthma. Certainly the patient must be evaluated for other nonobstructive causes of shortness of breath, i.e., congestive heart failure, restrictive lung disease, chronic pulmonary embolisms, and so forth must be ruled out. The older average age of the typical COPD patient highlights a second characteristic differentiating it from asthma: it is mainly the result of long-term and heavy tobacco use.9 The association between COPD and long-standing tobacco use reects the slow and irreversible changes in lung structure that underpin the disease (see below, Pathophysiology of Chronic Obstructive Pulmonary Disease and Asthma). Although it is true that smoking is a risk factor for both diseases, some persons with asthma

develop xed airways obstruction without ever having smoked.8 It should be noted that, in addition to certain environmental factors, patients of any age with a rare hereditary deciency of 1-antitrypsin also can develop COPD,1,10 and tobacco smoking often hastens the associated loss of lung function. However, the primary characteristic common to patients with COPD is long-term tobacco use. Asthma is characterized by acute increased responsiveness (or hyperresponsiveness) of the tracheobronchial tree. Although airway hyperresponsiveness can be present in COPD, its magnitude is often less than that occurring in asthma. Because asthma can be triggered by allergic responses, it is often associated with increased levels of serum immunoglobulin E (IgE), i.e., atopy. Consequently, patients with asthma may also present with rhinitis or eczema.8 In contrast, the COPD patient does not typically display atopy.9 Ironically, however, nonatopic asthma (i.e., normal serum levels of IgE) can occur despite the presence of similar inammatory cell inltrates and activated cytokine pathways in pulmonary mucosa of both clinical phenotypes of asthma.11,12 Individuals with asthma can often identify triggers or events that bring on their episodic symptoms, whereas patients with COPD often fail to acknowledge the symptoms associated with disease. Frequently, patients with COPD slowly modify their lifestyles over time to engage in fewer dyspnea-inducing events. Consequently, bouts of dyspnea often are not reported to the physician during an ofce visit. This delays the diagnosis of COPD unless the clinician specically questions the patient regarding changes he or she has made in lifestyle or day-to-day activities over time. Another important consideration is that whereas the airow limitation in patients with asthma tends to occur episodically, COPD symptoms tend to progress slowly, with little day-to-day variation. It must be recognized, however, that patients with COPD can experience exacerbations that are often misinterpreted as asthma episodes. These are triggered by upper respiratory infections and environmental factors such as air pollution, temperature changes, or exposure to tobacco smoke.13,14 On the other hand, some patients with asthma fail to display either an initial treatment response or the strong episodic course characteristic of the disease. This reects the fact that chronic mucus plug formation occurs in some individuals with asthma, and, as a result, airow limitation can take weeks or longer to resolve after anti-inammatory therapy.8 Long-standing and severe asthma also can be associated with structural remodeling of the airways such that airow limitation has a xed component and is not fully reversible.8 As a result of all of these characteristics, differentiating between an asthmatic episode and a COPD exacerbation can be a challenge for the clinician. In the simplest of
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Table 1. Clinical Differences Between Chronic Obstructive Pulmonary Disease (COPD) and Asthma Characteristic Age at onset Symptoms Allergic etiology Treatment response Bronchodilators Corticosteroids Smoking status Airow limitation (FEV1) Asthma Younger (often during childhood) Variable dyspnea Cough and/or wheeze Allergies present in 50% of patients Reversible Good Nonsmokers affected Can normalize after resolution of episode Older (age 40 yr) Progressive dyspnea Cough and sputum None Partial reversibility Poor Usually history of heavy smoking Cannot normalize; always reduced; deteriorates with advancing disease COPD

FEV1 forced expiratory volume in 1 second. Adapted from Global Initiative for Chronic Obstructive Lung Disease.1,8

cases, the differential diagnosis can be made on the basis of airow quantitation, after the episode of acute shortness of breath has resolved. Such measurements are made using spirometry, a test that can help differentiate COPD from asthma. The key measurements necessary for the early detection and monitoring of obstructive lung diseases are the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and in asthma but not in COPD, the peak expiratory ow (PEF). Normal airow, as assessed by spirometry, typically resumes in the patient with asthma after therapy (the provisos in the preceding paragraph notwithstanding) or during exacerbation-free periods. In the COPD patient, however, airow never returns to an age-appropriate level; therapy only partially reverses the airow obstruction. In these latter patients, postbronchodilator values of FEV1/FVC 70% indicate COPD. These values are used as the diagnostic cut-offs for normal versus obstructive lung disease (Table 2). Finally, a consideration of risk factors should play a role in differentially diagnosing asthma and COPD. In addition to atopy, risk factors for asthma include exposure to allergens, occupational sensitizers, active and passive smoking, air pollution, and respiratory infections.8 Asthma also has a strong familial component, whereas COPD, in general, does not.15 As mentioned previously, the primary risk factor for COPD is cigarette smoking, and it is a fact that individuals are more likely to smoke if their parents or a sibling smoke. Cigarette smoking is a learned behavior. The only well-established genetic risk factor for COPD is 1-antitrypsin deciency.1 Other risk factors for COPD include chronic exposure to occupational dust and other irritants such as noxious vapors and fumes, as well as air pollution (chronic exposure to biomass fuels). Thus, distinguishing between asthma and COPD is rarely simple because symptoms and risk factors can overlap. Therefore, it is essential to consider the entire clinical picture when making a diagnosis.


The pathophysiology of asthma has been studied extensively, and within the last decade our understanding of the inammatory mechanisms underlying COPD has advanced considerably. Several studies have established that the respective anatomic sites of pathology, the pathologic features, and the immunologic mechanisms (pathogenesis) underlying COPD and asthma differ in a number of aspects that have important functional consequences and implications for therapy.16 Anatomy and Pathology Both asthma and COPD are inammatory diseases, but they differ in their respective inammatory cell inltrates. Asthma is primarily characterized by an accumulation of activated eosinophils, mast cells, and TH2 CD4 lymphocytes in the alveolar capillaries, interstitium, and alveoli. In contrast, COPD, in the absence of an acute exacerbation, is characterized primarily by an accumulation of macrophages, neutrophils, and CD8 lymphocytes in the same distribution. The mediators released by these cells are also distinctly different, with interleukin (IL)-4, IL-5, and IL-13 predominating in asthma, and tumor necrosis factor (TNF-), leukotriene B4 (LTB4), and IL-8 predominating in COPD. These different cell types and inammatory mediators lead to different pathophysiologic consequences in these diseases (Table 3). Hence, in asthma, inammation results in epithelial shedding, enlargement of bronchial smooth muscle in large airways, hyaline thickening of the basement membrane, and mucus secretion. In COPD, protease activity (i.e., macrophage tryptase, elastases, and other metalloproteinases), free radicals, cytokines and chemokines, and other factors in the inammatory inltrate result in irreversible remodeling of lung tissue, consequent narrowing of airways, and a loss of alveolar tethering. Remodeling includes squamous metaTHE AMERICAN JOURNAL OF MEDICINE Volume 117 (12A) 13S

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Table 2. Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) Severity-Stage Treatment Guidelines for Patients With Chronic Obstructive Pulmonary Disease GOLD Guidelines* Severity Stage 0 Stage Description At risk Characteristics Treatment




Chronic symptoms Exposure to risk factors Normal spirometry FEV /FVC 70% FEV 80% With or without symptoms FEV /FVC 70% 50% FEV 80% With or without symptoms
1 1 1 1

Avoidance of risk factors; inuenza


IIA (2001) IIB (2001)

Moderate Moderate

Same as stage II FEV1/FVC 70% 30% FEV150% With or without symptoms

Avoidance of risk factors; inuenza vaccination Add short-acting bronchodilator when needed Avoidance of risk factors; inuenza vaccination Add short-acting bronchodilator when needed Add regular treatment with 1 long-acting bronchodilator Add rehabilitation Same as stage II Avoidance of risk factors; inuenza vaccination Add short-acting bronchodilator when needed Add regular treatment with 1 long-acting bronchodilator Add rehabilitation Add inhaled corticosteroids if repeated
exacerbations Same as 2001 stage IIB Avoidance of risk factors; inuenza vaccination Add short-acting bronchodilator when needed Add regular treatment with 1 long-acting bronchodilator Add rehabilitation Add inhaled corticosteroids if repeated exacerbations Add long-term oxygen therapy if chronic respiratory failure Consider surgical treatments Same as 2001 stage III

III (2004) III (2001)

Severe Severe

Same as 2001 stage IIB FEV1/FVC 70% FEV130% or FEV150% predicted chronic respiratory failure

IV (2004)

Very severe

Same as 2001 stage III

FEV1 forced expiratory volume in 1 second; FVC forced vital capacity. * Recommendations and staging descriptions are the same for GOLD 2001 and 2004 guidelines unless otherwise indicated. Adapted with permission from Global Initiative for Chronic Obstructive Pulmonary Disease.1

plasia, brosis, goblet cell hyperplasia, and some smooth muscle hypertrophy.17,18 In contrast to the disease course of asthma, the lung parenchyma is destroyed in COPD.17 The resulting emphysema may manifest itself as focal damage to the central areas of the acinus (centriacinar or centrilobular emphysema) or as uniform destruction of the walls of airspaces distal to the terminal bronchiolus (panacinar or panlobular emphysema).17 Functional elastic tissue in the parenchyma (and airways) is replaced by inelastic brotic tissue, such that elastic recoil of the lung is lost, and patients experience hyperination, a premature collapse of airways mid exhalation that results in air trapping, a decrease in inspiratory capacity, and in some cases impaired gas exchange.19 In the advanced stages of COPD,

impaired gas exchange may result in alveolar hypoxia, which can lead to pathologic changes in the pulmonary circulation and respiratory muscles. Ultimately, this can lead to right ventricular hypertrophy, pulmonary hypertension, and cor pulmonale.17 Inammatory Mechanisms in Asthma The inammatory inltrate in the pulmonary tissue of individuals with asthma consists primarily of TH2 CD4 lymphocytes (T-helper cells) and activated eosinophils; macrophages, mast cells, and other cell types also appear to play a role in the disease.18,20 22 Elevated levels of CD4 lymphocytes have been observed in the bronchial mucosa of biopsy samples, bronchoalveolar lavage, and sputum from patients with asthma.21,23 Activated eosinVolume 117 (12A)

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Table 3. Pathologic Changes and Inammatory Mediators in Asthma and Chronic Obstructive Pulmonary Disease (COPD) Asthma Pathology Airways Parenchyma Airway hyperresponsiveness Bronchial smooth muscle Epithelium Basement membrane Mucous cell metaplasia/hyperplasia Mucus secretion Inammatory cells All Not involved Present Enlarged mass in large airways Shedding Thickened with hyaline deposition Metaplasia debated Present Eosinophils (degranulated) CD4, CD3, CD25, CD45 Mast cells Macrophages Histamine IL-4, IL-5, IL-13 LTB4 Eotaxin RANTES Positive COPD Central (bronchitis) Peripheral (emphysema) Destruction May or may not be present Enlarged mass in small airways Metaplasia May or may not be affected Present Present, heavy Neutrophils Eosinophils (mild elevation, not degranulated) CD8, CD3, CD68, CD45 VLA-1, HLA-DR Macrophages IL-8, IL-4 TNF- LTB4 GRO- GM-CSF Mildly positive/negative

Cytokines and other factors

Response to corticosteroids

GM-CSF granulocyte/macrophage colony-stimulating factor; GRO- growth-related oncogene; HLA-DR human leukocyte antigenDR; IL interleukin; LTB4 leukotriene B4; RANTES regulated on activation, normal T-cell expressed; TNF- tumor necrosis factor; VLA-1 very late activation antigen1. Adapted from Chest7,18 and Thorax.17

ophils also have been found in signicantly greater numbers in the bronchial mucosa of patients with asthma than in those with stable COPD.24 In addition, levels of activated eosinophils correlate with the extent of airway hyperresponsiveness and symptoms in patients with asthma.25,26 TH2 CD4 cells secrete a number of cytokines, of which IL-4, IL-5, and IL-13 are of particular importance in asthma (Table 3).7,13,27,28 Allergen challenge has been associated with cellular activation and upregulation of mRNA for IL-4 and IL-5 by CD4 in cells obtained by bronchoalveolar lavage from patients with asthma.29 IL-4 promotes B-cell isotype switching to IgE production, the stimulation of T-cell differentiation to the TH2 subtype, and the activation of eosinophils.15,21,30 IL-5 is a chemoattractant and inducer of differentiation for eosinophils.15,21,30 IL-13 also induces B-cell isotype switching with resultant IgE production; it promotes mast cell development, increases eosinophil number, stimulates mucus hypersecretion, induces production of metalloproteinases by macrophages, and promotes airway hyperresponsiveness.15,21,30 The pathophysiologic consequences attributed to these cells and mediators of asthma have been shown to be responsive and inhibited by the use of inhaled corticosteroids.

Inammatory Mechanisms in COPD In contrast to the inammation of asthma, a signicant accumulation of activated eosinophils, often responsive to glucocorticoids, in the lungs of patients with COPD has generally been observed only in those patients experiencing an acute exacerbation or in those with concomitant asthma.31,32 This in part explains why patients with stable COPD receive minimal if any benet from maintenance glucocorticoids, whereas patients with COPD experiencing an exacerbation often show improvement with a short course of systemic corticosteroids: systemic corticosteroids inhibit the asthma-like cells transiently located in the lungs of COPD patients. Moreover, no eosinophils have been observed in the degranulated state in pulmonary tissue from patients with stable COPD, suggesting that activation of eosinophils does not occur in the disease in the absence of an exacerbation.33 In further contrast to asthma, the glucocorticoid-sensitive TH2 pathway does not play a major role in COPD.18 Hence, the distinctly different underlying inammatory inltrate in stable COPD compared with that in asthma in part explains the rationale for current treatment guidelines recommending the use of inhaled corticosteroids only as second-line therapy in the maintenance treatment of COPD.

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The predominant cytokines that contribute to COPD are TNF- and the potent neutrophil chemoattractants IL-8 and LTB4 (Table 3).7,13 TNF- is produced primarily by macrophages; it induces release of neutrophils from the bone marrow, stimulates production of other cytokines such as IL-8, and promotes broblast growth.34 IL-8 is produced by a variety of cell types, including monocytes and macrophages, epithelial cells, and smooth muscle cells in the airway. IL-8 is not only a neutrophil chemoattractant but also an activator of neutrophils.35 LTB4, also produced by macrophages, is a chemoattractant for neutrophils.7,13 The results of several well-designed and controlled studies provide the evidence-based data supporting the concepts and mechanisms stated above and illustrate the underlying cellular mechanisms of both COPD and asthma. In a study by Fabbri and colleagues,36 patients with COPD were shown to have more neutrophils and macrophages in bronchoalveolar lavage and sputum samples; fewer eosinophils in airway mucosa, bronchoalveolar lavage, and sputum; and a lower ratio of CD4 to CD8 lymphocytes in the airway mucosa. Signicantly greater neutrophil counts and IL-8 levels were found in sputum from patients with COPD compared with those measured in sputum from patients with asthma or from healthy control subjects, including smokers and nonsmokers. Patients with COPD also had signicantly greater levels of TNF- compared with smokers and healthy nonsmoking subjects.37 Neutrophil counts were elevated in bronchoalveolar uid samples from patients with COPD compared with patients with asthma and healthy control subjects. Finally, although eosinophils were increased in bronchial biopsy specimens and bronchoalveolar lavage of patients with asthma and patients with COPD compared with healthy control subjects, the eosinophils seen in samples from patients with COPD were not degranulated, unlike those seen in samples from patients with asthma.33 The preceding studies, as well as others not summarized here, demonstrate that the key inammatory lung cells involved in the pathogenesis of COPD are CD8 T lymphocytes, neutrophils, and macrophages.13,17,20,31,38 In asthma, the numbers of CD8 lymphocytes in lung tissue are low and CD4 lymphocytes predominate39; the involvement of CD8 lymphocytes in the pathogenesis of asthma is thought to be minor at most.21 Moreover, changes in neutrophil number in the bronchial mucosa of patients with asthma are minimal in comparison with the increase seen in lung tissue eosinophils in these patients.39,40 To further support the model that COPD is caused primarily by macrophage, CD8 lymphocyte, and neutrophilic inammation as well as the mediators released by these cells, a number of studies have attempted to correlate the presence of these specic inammatory cells

and mediators directly with the incidence and clinical course of patients with COPD. The results show that the density of CD8 T lymphocytes in the basement membrane of tissue from patients with COPD (along with CD3 T lymphocytes, CD68 cells [monocytes/macrophages], and HLA-DR cells) was measurably higher than that seen in healthy subjects. Moreover, the density of CD8 cells in lung tissue from patients with chronic bronchitis with normal airow was not signicantly different from that observed in lung samples from healthy subjects. However, there was a negative correlation between the CD8 lymphocyte density in lung tissue of COPD patients with their lung functionthat is, the lower the FEV1, the higher the CD8 content.32 These data suggest an association between CD8 lymphocytes and airow limitation. In another study, CD8 lymphocyte counts in the parenchyma and arterial tissue of smokers with COPD was higher than in smokers without COPD and healthy controls, and the CD8 cell density correlated with airow limitation.41 Finally, a negative correlation between numbers of neutrophils in the bronchial mucosa and the extent of airway limitation in patients with COPD has been reported.39,42 Together, these ndings support a role for neutrophils and CD8 lymphocytes in the pathogenesis and severity of COPD.43 Other studies have gone a step further, attempting to dene specic mechanisms regulating the structural and functional changes to the airway and lung parenchyma in COPD. Specically, in COPD, neutrophils and macrophages are likely to synthesize and secrete proteins such as proteinases (neutrophil elastase, macrophage-derived tryptases) and other matrix metalloproteinases that potentially digest lung tissue, promote brosis and airway remodeling, and stimulate excessive secretion of mucus.13,44,45 Alveolar macrophages also appear to act as reservoirs for proteases, such as neutrophil elastase, that are secreted by other cell types.45 It is hypothesized that CD8 cells mediate apoptosis of epithelial cells on the walls of alveoli by means of perforins and TNF-,13,46 which in turn leads to a noninammatory loss of alveolar walls and the subsequent development of emphysematous lesions.


In general, physicians are more aware of appropriate diagnostic and treatment strategies for asthma than for COPD. At the time of initial evaluation, these 2 syndromes present to the clinician with a similar constellation of symptoms (cough, dyspnea, excess mucus production, and wheeze). Many of the treatments and therapeutic goals are similar for COPD and asthma (Table 4). Together, these facts can lead the healthcare provider to assume that the pharmacologic options for
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Table 4. Goals of Treatment for Asthma and Chronic Obstructive Pulmonary Disease (COPD) Asthma Risk factors Symptoms Pulmonary function/airow limitation Activity and exercise Exacerbations Drug-related adverse event Disease-related mortality Reduce exposure Control Maintain normal or close-to-normal pulmonary function; prevent development of irreversible airow limitation Maintain normal levels of activity and exercise Prevent and treat Avoid Prevent COPD Reduce exposure Relief Prevent progression of pulmonary dysfunction Improve exercise tolerance (strength, endurance) Prevent and treat Avoid Reduce

Adapted from Global Initiative for Chronic Obstructive Lung Disease.1,8

asthma are appropriate for COPD. Unfortunately, this assumption is incorrect, as might be expected after reviewing the data above and appreciating the signicant differences in the pathogenesis of these 2 obstructive lung diseases. If one approaches these diseases from the perspective of their unique cellular mechanisms and pathologic processes rather than from the perspective of their similar symptoms, it is easier to understand why some of the rst-line therapies that provide relief for asthma are not as efcacious for the rst-line maintenance treatment of COPD. Perhaps the best example of this is the use of inhaled corticosteroids, alone or in combination with other antiinammatory agents (leukotriene modiers) or with 2agonists in the treatment of asthma. Inhaled corticosteroids are the mainstay of rst-line asthma treatment.8 It is beyond the scope of this review to provide a detailed molecular explanation for the efcacy of these agents, but they are effective in asthma because they directly block the transcriptional induction of a number of proinammatory cellular mediators and gene products in cells that have been shown to cause the bronchospasm and airway remodeling of asthma, most notably, activated eosinophils, TH2 lymphocytes, and the mediators IL-4, IL-5, and IL-13. In contrast, the macrophage and neutrophilic inammation and elaboration of mediators (TNF-, IL-8, and LTB4) underlying COPD are not as effectively controlled with inhaled corticosteroids.47,48 Furthermore, the airow narrowing that occurs in COPD is a result of brotic changes in the airway wall, or a loss of alveolar units and elastic recoil. These processes are not altered by inhaled corticosteroid therapy. Efcacy of Inhaled Corticosteroids in COPD: FEV1 Decline and Disease Progression Because the use of inhaled corticosteroids in the treatment of patients with COPD is somewhat controversial, it is worthwhile to review a number of translational clinical trials that directly examine this issue and provide evidenced-based clinical data that bring the above-described

basic science mechanisms to the bedside of patients being treated for COPD. The following clinical studies examined the safety, efcacy, and long-term effects of inhaled corticosteroid therapy in patients with mild to very severe COPD (GOLD stages I through IV). In these studies, inhaled corticosteroids were administered in doses known to be anti-inammatory in patients with asthma. The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP) was a long-term (3-year), double-blind, randomized, placebocontrolled, multicenter study comparing the effects of budesonide 400 g b.i.d. with those of placebo. This trial included 1,277 patients (912 of whom completed the study) with mild COPD and a history of smoking, and included patients who continued smoking. Patients with a history of asthma, allergic eczema, or allergic rhinitis were excluded. The rate of smoking cessation during the trial was similar for the 2 groups. Patients receiving placebo exhibited a decline in FEV1 of 65 mL/year, which was similar to that observed in other long-term follow-up COPD trials. Patients receiving budesonide demonstrated improvement in FEV1 at the rate of 17 mL/year, but this only occurred during the rst 6 months of therapy. Changes in the rate of FEV1 from month 9 to the end of the study were not signicantly different between the budesonide and placebo groups (57 mL/year and 69 mL/year, respectively; P 0.39). The proportion of patients with a rapid decline in FEV1 (60 mL/year) was similar in both groups (55% for the budesonide group, 49% for the placebo group; P 0.06).49 The Copenhagen City Lung Study was a randomized, double-blind, placebo-controlled, single-center trial that included patients without asthma who had mild to moderate COPD. Patients received inhaled budesonide 400 g b.i.d. or placebo for 3 years. The minimum clinically relevant difference in rate of decline of FEV1 was dened as 20 mL/year. The crude annual rate of FEV1 decline for the placebo group was 41.8 mL/year. The mean rates of FEV1 decline from the regression model for the budesonide

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and placebo groups were not signicantly different (46.0 mL vs. 49.1 mL, respectively; P 0.7). No changes in symptoms, if present initially, were noted in this study between the control and inhaled corticosteroid groups.50 The Lung Health Study II was a long-term (4-year, with mean follow-up at 40 months), randomized, placebo-controlled, multicenter study that compared the effects on FEV1 of triamcinolone acetonide 600 g b.i.d. with those of placebo in 1,116 patients with mild to moderate COPD. Mean declines in FEV1 for the triamcinolone and placebo groups were not signicantly different (48.6 mL vs. 49.9 mL, respectively; P 0.78).51 In those patients with more severe COPD, there was a modest improvement in dyspnea and the onset of severe symptoms. However, bone mass density measurements obtained from some of these patients revealed that those on the inhaled corticosteroids were at an increased risk for the development of osteoporosis.51 The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study was a double-blind, placebocontrolled, multicenter trial of 990 patients without asthma who had severe COPD (387 of whom completed the study) randomized to inhaled uticasone propionate 500 g b.i.d. or placebo; follow-up was at 36 months. Mean annual declines in FEV1 were not signicantly different (50 mL/year for patients receiving uticasone and 59 mL/year for patients receiving placebo; 95% condence interval [CI], 3 to 20; P 0.161). However, on average, there was a 100-mL increase in FEV1 after 3 to 6 months of therapy that was maintained over the 3-year period and a decrease in exacerbations of 25% compared with placebo; the differences in exacerbation rates, however, were restricted to patients with severe COPD (FEV1 50% of predicted).52 In summary, investigators for the Copenhagen City Lung Study, ISOLDE, the Lung Health Study II, and EUROSCOP all concluded in their respective studies that inhaled corticosteroid therapy did not affect FEV1 decline over the long term. The Lung Health and ISOLDE studies also showed that inhaled corticosteroids slowed the onset of severe symptoms and decreased exacerbations, but these effects were only apparent in those patients with severe COPD and were not associated with clinical benets.49,5153 In addition, a recent meta-analysis of 6 randomized, double-blind, placebo-controlled trials that assessed the long-term effects of inhaled corticosteroid treatment on patients with COPD found that inhaled corticosteroids had no signicant effect on FEV1.54 Inhaled and Systemic Corticosteroids in COPD: Exacerbations Exacerbations of COPD are a common cause of visits to the emergency department.55,56 Although it has no effect on the overall decline in lung function, maintenance therapy with inhaled corticosteroids in patients with se18S December 20, 2004 THE AMERICAN JOURNAL OF MEDICINE

vere COPD appears, in some instances, to reduce the frequency of exacerbations in the COPD patient as outlined above. For example, a systematic review of 9 randomized, placebo-controlled trials of corticosteroid therapy of at least 6 months duration, including 3,976 patients (budesonide, n 1,730; uticasone, n 1,032; triamcinolone n 1,116; and beclomethasone, n 98), found that active therapy was associated with a reduction in exacerbations of about 30% compared with placebo in patients with severe COPD (relative risk, 0.70; 95% CI, 0.58 9.84).57 The administration of systemic corticosteroids may also positively affect COPD exacerbations. In 2 randomized trials, systemic corticosteroids appeared to prevent treatment failure and shorten the hospital stays for patients experiencing COPD exacerbations.58,59 Another randomized, double-blind, placebo-controlled trial examined the effect of a 10-day course of oral prednisone (40 mg) on relapse rates in 147 patients who were discharged from the hospital after experiencing an exacerbation of COPD. The overall rate of relapse at 30 days was signicantly lower in the prednisone group than in the placebo group (27% vs. 43%, P 0.05), and the time to relapse was signicantly prolonged in those taking prednisone (P 0.04).60 The authors conclude, however, that the short-term improvements in relapse rates must be balanced against the long-term cumulative risk and costs of side effects associated with corticosteroid use, which include suppression of the hypothalamic-pituitary-adrenal axis, bone demineralization, posterior subcapsular cataracts, and behavioral effects.61 The efcacy of systemic corticosteroids during an exacerbation of COPD is likely due to the fact that activated eosinophils, as well as other inammatory cells and mediators known to be involved in the pathogenesis of asthma, have been found in the lungs of COPD patients only during the acute phases of exacerbations. Therefore, these steroid-sensitive cells and mediators can be attenuated, thus relieving the bronchospasm occurring secondary to their presence and activation. Corticosteroids in COPD: Summary Given the data in the 2 preceding sections, questions remain concerning the use of inhaled and systemic corticosteroids in the maintenance therapy of stable COPD. Accordingly, the 2004 revised GOLD guidelines,1 as well as the recently published ATS/ERS COPD guidelines,6 recommend that a trial of high-dose inhaled corticosteroids should be considered as add-on therapy in the maintenance treatment of only those patients with severe stage III (FEV1 50% of predicted) or very severe stage IV (FEV1 30% of predicted) COPD who remain symptomatic and continue to have frequent exacerbations despite maximal bronchodilation with 1 inhaled bronchodilator. At this time, inhaled corticosteroids should be
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reevaluated after a 6-week to 3-month trial. They should be discontinued if, after that period of time, there is no evidence of clinical beneti.e., if the patients lung function has not improved according to evaluation by spirometry and dened as an increase in FEV1 of 200 mL and/or 12% from baseline, with FEV1 assessment conducted after bronchodilator use, no relief of chronic symptoms or exacerbations, and no improvements in activities of daily living.1 Acute exacerbations may be managed with a short course of a systemic corticosteroid (prednisone 30 to 40 mg/day for 10 to 14 days in addition to a bronchodilator). Long-term use of oral corticosteroids is not recommended because of an absence of data showing clinical benet and the increased risk of adverse events. The GOLD consensus workshop found that the existing data regarding the predictive value of a short-term (i.e., 2-week) trial of therapy with an oral corticosteroid for long-term response to inhaled corticosteroid therapy were unconvincing.1,52,62 Instead, after stabilization with bronchodilator therapy (discussed below), a 3-week to 6-month trial of therapy is recommended. If there is no evidence of clinical benet (dened as a 200 mL increase in FEV1 and a 12% increase in FEV1 from baseline, with FEV1 assessment conducted after bronchodilator use), inhaled corticosteroid therapy should be discontinued.1 Bronchodilators in COPD In the past, COPD has been characterized as an irreversible structural alteration that permanently narrows airways; however, a reversible component nonetheless remains in some patients. Even slight improvements in airow can have signicant clinical benets for the patient with COPD, and COPD is now dened as a partially reversible disease. Clinicians must start to think more optimistically about COPD and realize that they can slow the progression of the disease and improve their patients quality of life. Accordingly, the GOLD guidelines recommend that after avoidance of risk factors (smoking cessation), maximizing bronchodilation, with 1 inhaled agent if necessary, is rst-line maintenance therapy in COPD (stages I to IV).1,6 Residual airway patency is controlled primarily by parasympathetic innervation of smooth muscles surrounding bronchioles as well as by secretion of the bronchoconstricting mediator acetylcholine. Therefore, bronchodilators typically inhaled anticholinergics or 2-agonists, or the combination of both agentsare the preferred rst-line treatment to relieve the symptoms of COPD.1,6,16 Until recently, the anticholinergic ipratropium bromide has been the medication of choice for long-term maintenance therapy for patients with COPD. Short-acting 2-agonists, such as albuterol, which play a more important role in asthma therapy, have been reserved for the intermittent treatment of exacerbations. A retrospective

combined analysis of 7 studies including 1,445 patients with COPD compared the effects of ipratropium with 2-agonists (metaproterenol, n 474; albuterol sulfate, n 1,362). The combined analysis found that use of ipratropium was associated with signicant improvements in FEV1 and FVC from baseline compared with lung function measured before bronchodilator use (28 mL and 131 mL, respectively; both P 0.01). Changes in prebronchodilator FEV1 and FVC with 2-agonist treatment were not signicant (1 mL and 20 mL; both P 0.2).63 The use of ipratropium is hampered, however, by its relatively short duration of action (4 to 6 hours), which necessitates dosing 4 times daily.64 New, longer-acting anticholinergic agents recently have been developed to circumvent this issue. The effect of cholinergic tone of the airways of patients with COPD is magnied compared with normal controls due to preexisting airway narrowing, leading to a higher baseline airways resistance during periods of stable disease. Cranial nerve X, the vagus nerve, exits the brain and enters the lung at the area of the hilum. It courses posteriorly on airways, but this innervation ends at the terminal bronchioles. Therefore, the vagus innervates the larger airways within the lung. Along this neural pathway, acetylcholine is released from peribronchial ganglion cells, which interact with 3 muscarinic cholinergic receptors on the airways and mucus-secreting glands. The acetylcholine causes airway smooth muscle cells to constrict and mucous glands to secrete both of which narrow the caliber of the airway. There is a negative feedback loop to protect the lung from excessive bronchoconstriction. If too much acetylcholine is secreted, M2 muscarinic receptors are activated, and subsequent acetylcholine release is inhibited (Figure 1). An ideal agent to prevent acetylcholine-induced bronchoconstriction, therefore, would interrupt this mechanism by blocking M3 but not M2 receptors in the airways of COPD patients. Tiotropium bromide is a new anticholinergic agent that provides constant, 24-hour relief of symptoms. Available in Europe since 2002, Canada and Mexico since early 2003, and most recently in the United States in 2004, tiotropiums long-acting effects result from prolonged M3 receptor antagonism.65 Several large, long-term trials of tiotropium in the treatment of patients with COPD have been published.66 69 Casaburi and colleagues66 reported the ndings of 2 randomized, double-blind, placebo-controlled 1-year trials in which 921 patients received tiotropium 18 g q.d. or placebo. Patients receiving tiotropium demonstrated signicantly greater FEV1 response at trough (P 0.01), signicantly less dyspnea (P 0.001), and signicantly greater health status scores (P 0.05) compared with those receiving placebo. Trough FEV1 is dened as the FEV1 obtained immediately before the next scheduled

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Figure 1. Muscarinic receptor subtypes in airways. ACh acetylcholine; CNS central nervous system; cranial nerve X vagus cranial nerve. (Drawing by Dennis E. Doherty, MD.)

dose of a bronchodilator; in the case of tiotropium this is approximately 23.5 hours after its last administration. Donohue and co-workers68 reported the results of a 6-month, randomized, double-blind, placebo- and active-controlled trial in which 623 patients received tiotropium 18 g q.d., salmeterol 50 g b.i.d., or placebo. Tiotropium was associated with signicantly greater increases in trough FEV1 versus placebo than salmeterol (140 mL vs. 90 mL; P 0.01). Signicantly greater improvements in dyspnea and health-related quality-of-life (HRQOL) measures versus placebo were also seen with tiotropium treatment compared with salmeterol therapy. However, in a combined analysis of 2 salmeterol- and placebo-controlled clinical trials, which included the aforementioned trial, transitional dyspnea index focal scores improved in both the tiotropium (1.1 0.3 U) and salmeterol (0.7 0.3 U) groups compared with placebo (P 0.001 and P 0.05, respectively), without a signicant difference between the tiotropium and salmeterol groups (P 0.17).69 Vincken and associates67 reported the results of 2 randomized, double-blind, active-controlled studies in which 535 patients received tiotropium 18 g q.d. or ipratropium 40 g q.i.d. for a period of 1 year. Patients receiving tiotropium had a signicantly greater mean change in trough FEV1 compared with patients receiving ipratropium (P 0.001) and signicantly greater improvements in dyspnea and HRQOL compared with

those receiving ipratropium (P 0.004 and P 0.05, respectively). Tiotropium also was associated with decreases in the frequency of exacerbations and hospitalizations in some of these trials. Casaburi and colleagues66 reported significantly fewer exacerbations and hospitalizations with tiotropium compared with placebo (P 0.05). Vincken and associates67 observed signicantly fewer exacerbations (P 0.01) as well as greater time to the rst exacerbation (P 0.01) and rst hospitalization owing to an exacerbation (P 0.05) with tiotropium than with ipratropium. The studies with the 2 long-acting 2-agonists, twicedaily formoterol and salmeterol, also have reported improved pulmonary function in patients with COPD. Dahl and co-workers70 reported clinically relevant improvements in FEV1 (120 mL) after formoterol treatment and signicantly greater increases in the area under the curve (AUC) for FEV1 measured over a 12-hour postdose period in the patients receiving formoterol compared with those taking placebo (P 0.001) or ipratropium (P 0.025). Similar improvements in lung function have been reported after treatment with salmeterol compared with placebo, but the comparisons with ipratropium have been variable. Mahler and colleagues71 reported statistically signicant improvements in the AUC FEV1 after treatment with salmeterol compared with placebo (P 0.001) at weeks 0, 4, 8, and 12, but the results were
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superior to ipratropium only at weeks 4 and 8 (P 0.005). In the trial by Rennard and associates,72 however, although the duration of action of salmeterol was signicantly longer than ipratropium, 1 dose of salmeterol and 2 doses of ipratropium (repeated after 6 hours) produced similar average improvements in FEV1 and FVC over the 12-hour dosing period.

Asthma and COPD are distinct obstructive pulmonary diseases with differing clinical courses, pathophysiologic proles, and treatment strategies. The symptomatology of the 2 diseases can overlap, making differential diagnosis challenging. In patients with COPD, bronchodilators are the foundation of rst-line pharmacologic therapy. In patients with asthma, inhaled corticosteroids (with or without a leukotriene modier) are rst-line therapy, with bronchodilators being used for relief of symptoms that persist despite adequate anti-inammatory treatment. In patients with COPD, however, the use of inhaled corticosteroids is recommended only in limited and specic circumstances as a second-line therapythat is, only for the COPD patient who has been bronchodilated with multiple agents in combination but who continues to experience symptoms (including frequent exacerbations). For patients with asthma, the underlying pathophysiology supports the use of inhaled corticosteroids, and the clinical evidence for the benet of these agents is unequivocal. The pathophysiologic basis of bronchoconstriction (cholinergic-mediated vagal tone acting in already narrowed airways) in COPD supports the use of anticholinergics as rst-line agents, with the addition of a 2-agonist if additional bronchodilation is needed. The theoretical benets of anticholinergics are borne out by evidenced-based clinical studies.

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A Symposium: The Pathophysiology of Airway Dysfunction/Doherty symptoms and bronchial responsiveness. Am Rev Respir Dis. 1992;146:500 506. Postma DS, Kerstjens HA. Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;158(Pt 3): S187S192. Foster PS, Martinez-Moczygemba M, Huston DP, Corry DB. Interleukins-4, -5, and -13: emerging therapeutic targets in allergic disease. Pharmacol Ther. 2002;94:253264. Robinson D, Hamid Q, Bentley A, Ying S, Kay AB, Durham SR. Activation of CD4 T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol. 1993; 92:313324. Oettgen HC. Regulation of the IgE isotype switch: new insights on cytokine signals and the functions of epsilon germline transcripts. Curr Opin Immunol. 2000;12:618 623. Saetta M, Di Stefano A, Maestrelli P, et al. 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Am J Respir Crit Care Med. 1999;160(Pt 2):S17S20. Stockley RA. Neutrophils and the pathogenesis of COPD. Chest. 2002;121(Suppl):151S155S. December 20, 2004 THE AMERICAN JOURNAL OF MEDICINE 45. Tetley TD. Macrophages and the pathogenesis of COPD. Chest. 2002;121(Suppl):156S159S. 46. Liu AN, Mohammed AZ, Rice WR, et al. Perforin-independent CD8() T-cellmediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand. Am J Respir Cell Mol Biol. 1999;20:849 858. 47. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glucocorticoids on inammatory indices in asthma and COPD. Am J Respir Crit Care Med. 1997;155:542548. 48. Culpitt SV, Maziak W, Loukidis S, Nightingale JA, Matthews JL, Barnes PJ. Effect of high-dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160(Pt 1):16351639. 49. Pauwels RA, Lofdahl CG, Laitinen LA, et al, for the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med. 1999;340:1948 1953. 50. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 1999;353:1819 1823. 51. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000;343: 19021909. 52. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double-blind, placebo-controlled study of uticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320:12971303. 53. Vestbo J, Hansen EF. 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