Chronic obstructive pulmonary disease (COPD) is primarily preventable, certainly treatable, and characterized by airflow limitation (postbronchodilator forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC] <0.70) that is not fully reversible [1, 2]. The magnitude of reversibility of airflow limitation is based on the change in FEV1 after administration of a bronchodilator or corticosteroid . Chronic inflammation present in the lungs of patients with COPD leads to narrowing of small airways, destruction of parenchymal tissues, and other structural changes that may result in air trapping, hyperinflation, and mucus hypersecretion (Figure 1) .
Figure 1. Physiological and Health Status Changes Resulting From Chronic Progressive Airflow Obstruction
Data from Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2009. Available at: http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=989. Accessed June 2010 .
P.R., a 50-year-old woman with a previous history of smoking, presents to her health care practitioner (HCP) with shortness of breath, cough, and wheeze. Because of her young age, fair tolerance for exercise, and family history of allergies, the HCP suspects that P.R. is suffering from asthma but cannot rule out COPD considering her symptoms and previous smoking habit.
In turn, hyperinflation of the lungs leads to chronic dyspnea and limited exercise tolerance . During an exacerbation, inflammation increases and leads to dyspnea worsening and further reduction in exercise tolerance. Evidence has shown that even mild to moderate chronic airflow obstruction has a substantial affect on work productivity and overall quality of life . Extrapulmonary effects of COPD, including weight loss, nutritional abnormalities, and skeletal muscle dysfunction, may increase the risk of cardiovascular disease, osteoporosis and bone fractures, respiratory infection, depression, diabetes, and other disorders . Pathological changes, chronic airflow limitation, extrapulmonary effects, and comorbidities all contribute to the severity of the disease .
As a standardized, reproducible, objective measurement of airflow obstruction, spirometry is the “gold standard” for diagnosing and monitoring the progression of COPD . In particular, FEV1/FVC and FEV1 measurements are recommended for diagnosis and assessment of severity of COPD . Spirometry can provide a description of the severity of pathological changes associated with COPD and forms the basis for conventional classifications of disease severity (Table 1 ).
Table 1. Spirometric GOLD Classification of COPD Severity Based on Postbronchodilator FEV1
aOr FEV1 <50% predicted plus chronic respiratory failure.
FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease.
Data from GOLD .
Spirometry is obtained to help differentiate between diagnoses of asthma and COPD for P.R. Her prebronchodilator FEV1/FVC ratio is 65%, which is suggestive of airflow limitation consistent with COPD.
While the use of peak flow meters may be considered if access to spirometry is limited, a clear understanding of the limited predictive value for COPD diagnosis due to low specificity also must be considered. Peak flow meters should not be used as a substitute for spirometry . Periodic spirometry measurements also are recommended to identify decline in pulmonary function and to provide important information about the severity of a patient’s condition when substantial increases in symptoms and complications are observed . For more in-depth information on the basics of spirometry, click here
Bronchodilators, which physiologically reverse airflow obstruction by relaxing airway smooth muscle and improving lung emptying during tidal breathing , play an important role in the pharmacological treatment of COPD. As such, they are often prescribed on an as-needed or regular basis to prevent or reduce symptoms of COPD (Figure 2) . This group of medications, which may include β2-agonists, anticholinergics, or methylxanthines, relaxes smooth muscle tone, resulting in an increase in FEV1 or change in other spirometric variables .
Figure 2. Bronchodilators Play an Important Role in COPD Treatment Algorithms, as Evidenced by the ATS/ERS Guidelines
Copyright 2004. Reprinted with permission from the European Respiratory Society .
Short-acting bronchodilators, such as albuterol and ipratropium, have a duration of effect of approximately 4−6 hours and have been shown to improve exercise tolerance by decreasing lung hyperinflation caused by airway obstruction [1, 4, 5]. Long-acting β2- agonists (LABAs), such as formoterol and salmeterol, have a duration of effect of approximately 12 hours and are effective in reducing chronic symptoms and improving long-term quality of life. [6, 7]. The use of combination therapy may result in improved efficacy compared with monotherapy , as demonstrated in clinical studies [8, 9]. For example, treatment with an inhaled corticosteroid (ICS) combined with a LABA has resulted in improved pulmonary function and symptom control compared with placebo and monotherapy in patients with moderate to very severe COPD [8, 9].
Bronchodilator reversibility historically has been used to differentiate asthma from COPD . Patients with COPD are generally thought to have little or no reversibility of airway obstruction, while airway obstruction in asthma patients is often fully reversible [1, 10]. One of the challenges inherent in evaluating acute reversibility of airflow obstruction in patients with COPD is the lack of a single “gold standard.” In clinical studies, the assessment of reversibility typically is based on definitions from 4 of the major respiratory guidelines (Table 2).
Table 2. Measures of Bronchodilator Reversibility in Patients with COPD Based on ATS, ERS, ACCP, and GOLD Guidelines
ACCP, American College of Chest Physicians; ATS, American Thoracic Society; ERS, European Respiratory Society; GOLD; Global Initiative for Chronic Obstructive Lung Disease.
In addition to differences in definition, reversibility also may be assessed using various parameters of pulmonary function or lung volume, such as FVC  or inspiratory capacity [16, 17], or using different bronchodilators alone or in combination [10, 16]. Reversibility data are further complicated by the natural variation in FEV1 over time . These variations may lead to differences in data interpretation (eg, a patient may be classified as reversible according to one set of criteria and as irreversible according to another), making diagnosis and treatment even more difficult. However, despite the use of different definitions and methods to determine reversibility, evidence from several studies suggests that patients with COPD may have significant bronchodilator responsiveness [15, 19, 20-22].
In the Understanding Potential Long-Term Impacts of Function With Tiotropium (UPLIFT) trial, patients with moderate to very severe COPD (N=5756) were treated with 80 µg of ipratropium followed 60 minutes later by 400 µg of salbutamol (albuterol in the United States) . Evaluation of bronchodilator responsiveness, performed 30 minutes after the 400-μg salbutamol dose, showed that >50% of patients achieved reversibility based on the criteria from the American College of Chest Physicians (ACCP; ≥15% FEV1 increase over baseline ; Figure 3) and the American Thoracic Society (ATS; ≥12% and ≥200 mL FEV1 increase over baseline) , while 38.6% achieved the European Respiratory Society (ERS) criterion (≥10% absolute increase in percentage predicted value) . In a randomized double-blind trial in patients with COPD (N=411), approximately 65% of patients in each treatment arm (salmeterol 42 µg twice daily and ipratropium 36 µg 4 times daily) showed reversibility in response to 180 μg of albuterol at screening according to ATS criteria .
Figure 3. Percentage of Patients Showing FEV1 Responsiveness According to ≥15% Increase in FEV1 Over Baseline
(American College of Chest Physicians Criterion)
Copyright 2008. Reproduced with permission from the European Respiratory Society .
P.R. has an FEV1 percent of predicted normal value of approximately 55%, which reverses by ≥15% and ≥200 mL after administration of albuterol. Because of these spirometry results, she is diagnosed with moderate COPD that is reversible according to both the ATS and ACCP criteria. According to the Global Initiative for Chronic Obstructive Lung Disease GOLD guidelines for moderate COPD, the HCP prescribes treatment with a long-acting bronchodilator (anticholinergic) along with a short-acting bronchodilator when needed.
A post hoc analysis of 2 randomized, double-blind, parallel-group studies of patients with COPD (N=726) and no history of asthma evaluated the efficacy of fluticasone/salmeterol 250/50 µg twice daily compared with ipratropium/albuterol 36/206 µg 4 times daily according to reversibility status at baseline . Bronchodilator reversibility to 180 μg of albuterol, assessed per ATS criteria, was achieved in 44% of patients (all treatment groups combined) . In another post hoc analysis in 906 patients with moderate to very severe COPD, the common treatment arms of a 6-month study  and a 12-month study  (both randomized, double-blind studies) were pooled and included patients treated with budesonide/formoterol (BUD/FM) 160/9 µg or 320/9 µg twice daily or FM 9 µg twice daily [21, 22]. The percentage of patients at screening who exhibited acute reversibility to albuterol according to ATS criteria was 34%−39% across treatment groups . On the day of randomization, the percentage of patients who experienced reversibility according to the ATS criterion following treatment with BUD/FM pressurized metered-dose inhaler (pMDI) or FM dry powder inhaler (DPI) was 51%−54% [21, 22]. While COPD is often thought of as an irreversible disease, these studies show that the majority of patients are able to achieve significant improvements in FEV1 in response to bronchodilator treatment alone or in combination with an ICS.
Lung hyperinflation resulting from airway obstruction reduces lung volume inspiratory capacity (click here for illustration), resulting in dyspnea and exercise intolerance . By reducing air trapping, bronchodilators decrease lung volume, which results in improved dyspnea and exercise capacity [1, 24].
Reversibility as determined by changes in FEV1 does not always reflect changes in lung volume, and patients who are nonreversible according to FEV1 response criteria may still exhibit improvement in lung volume following bronchodilator treatment . Several studies have reported improvements in lung volume measures in the absence of a significant flow response, with the percentage of patients exhibiting such responses increasing with the severity of airflow obstruction [15, 17].
Although most patients with COPD exhibit some degree of bronchodilator reversibility, considerable variability exists in an individual patient’s responsiveness over time, making the assessment of pulmonary function and treatment effect more challenging.
In a study of 985 patients, variability in bronchodilator responsiveness was reported over time within the same individual and between individuals . Moreover, patients with greater initial bronchodilator response experienced greater variability in FEV1 over time . Bronchodilator reversibility also may vary according to the bronchodilator used . In a study of 813 patients with COPD, 11% of patients were reversible to ipratropium (according to the ATS criterion) and 27% of patients were reversible to albuterol, while 35% of patients showed reversibility when both drugs were used (Figure 4) .
On a subsequent office visit, the HCP determined that P.R.’s FEV1 measurement had decreased to 44% of predicted normal, which is indicative of severe COPD. P.R. also stated that she had experienced several episodes over the past year during which her COPD symptoms felt worse than normal and limited her daily activities substantially. Thus, the HCP added an ICS to P.R.’s current treatment, as recommended by the GOLD guidelines for patients with severe or very severe COPD with repeated exacerbations (Figure 6). The HCP will be certain to continue assessing P.R.’s response to treatment and COPD severity on future visits.
Figure 4. Patients With COPD Demonstrate Variable Reversibility Depending on the Bronchodilators Used
Copyright 2004. Reproduced with permission from The American College
of Chest Physicians .
Although patients who initially exhibit reversibility to short-acting bronchodilators typically show greater improvement in pulmonary function over time, evidence suggests initial reversibility status in response to a short- or long-acting bronchodilator does not always predict long-term benefits from maintenance bronchodilator therapy [19, 26]. A retrospective analysis of 2 identical randomized, placebo-controlled 1-year studies (N=921) evaluated the effect of maintenance bronchodilator therapy on pulmonary function and COPD symptoms in patients based on their initial response to 18 µg of tiotropium . In this analysis, patients at randomization whose FEV1 response to tiotropium met the ATS criterion were classified as responders; all other patients were considered poor responders . Over the 1-year study, improvements in FEV1 were observed regardless of responder status (Figure 5) .
Figure 5. Patients With COPD May Respond to Long-term Bronchodilator Therapy, Irrespective of Initial Reversibility Status
Mean FEV1 before and after treatment with tiotropium on day 1
Mean FEV1 before and after treatment with tiotropium on day 344
aP<.001 vs placebo at all time points following drug administration. Copyright 2003. Adapted with permission from the American College
of Chest Physicians .
In another retrospective analysis, pulmonary function improvements (determined by response to albuterol at screening based on the ATS criterion) were observed in both reversible and irreversible patients (N=726) treated with fluticasone/salmeterol 250/50 µg twice daily or ipratropium/albuterol 36/206 µg 4 times daily .
Figure 6. GOLD guidelines for therapy at each stage of COPD
Reversibility status also may change over time. In one study, the long-term reversibility status of 660 patients with COPD who were initially classified as “irreversible” per ERS criteria was assessed in response to treatment with salbutamol .
Over a 2-month period, reversibility status changed (to either reversible or irreversible) in 52% of patients according to ATS criteria and in 38% of patients according to the ERS criterion following treatment with 400 µg of salbutamol and 80 µg of ipratropium . These studies indicate that a patient’s initial bronchodilator response may not predict long-term responder status and that responder status may change over time.
Chronic, progressive airflow obstruction is a central feature of COPD and may lead to significant extrapulmonary comorbidities and reduced quality of life. Bronchodilators reverse airway obstruction and limitation and play a central role in the treatment of COPD. Reversibility to bronchodilators historically has been used to differentiate asthma from COPD; however, recent evidence suggests that patients with COPD may have significant bronchodilator reversibility. Although many patients with COPD do exhibit bronchodilator reversibility, patients’ responses may vary over time, between patients, and within the same patient.
Reversibility also may vary depending on the bronchodilator used. Although patients who exhibit acute reversibility to short-acting bronchodilators typically show greater improvement in pulmonary function over time, initial reversibility to short- or long-acting bronchodilators is not a reliable predictor of long-term response and initial responder status may change over time. In fact, many patients with COPD exhibit significant bronchodilator reversibility. Therefore, bronchodilator therapy should be considered for use in appropriate patients with COPD according to GOLD guidelines.
We thank Lisa Feder, PhD, and Kristen Quinn, PhD, from Scientific Connexions (Newtown, PA), who provided medical writing support funded by AstraZeneca LP (Wilmington, DE).