Understanding the Role of Bronchodilator Reversibility in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases.¹ The spirometric criterion for airflow limitation is a postbronchodilator fixed ratio of forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) of <0.70.¹ (Screening for, and diagnosis of, COPD have been previously reviewed in this e-newsletter series.) Chronic airflow limitation is the diagnostic hallmark of COPD.

Reversal of airflow obstruction refers to the change in FEV₁ or FVC before and after bronchodilator or corticosteroid treatment.¹ Historically, it was believed that the presence of reversibility to bronchodilators differentiated asthma from COPD (eg, people with asthma had a 12% to 15% and 200 mL improvement in FEV₁ or FVC after bronchodilator use).² Evidence now shows that many COPD patients demonstrate clinically significant bronchodilator reversibility.³ Therefore, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) no longer recommends using the degree of reversibility of airflow limitation for the diagnosis of COPD, differential diagnosis with asthma, or to predict response to treatment.¹

Case Lorenzo is a 48-year-old construction worker who visits the clinician's office because of suspected bronchitis. His chief complaint is: “Doc, I have this bronchitis again, and this time it is really bad.” You learn that Lorenzo has experienced coughing, shortness of breath, and wheezing intermittently for the past 3 to 4 weeks. He was unable to go to work yesterday or today because he felt exhausted and was coughing too much. He even gave up his daily cigar beginning 3 days ago. Lorenzo is a 15 pack-year cigarette smoker who quit cigarettes 10 years ago and substituted a daily cigar. He has worked as a ceiling plasterer for many years, but wears a mask now because the dust makes him cough. He believes that he may be getting asthma like both of his kids. He was going to try their medications, but they both told him to go to the doctor and get his own. On exam, Lorenzo has scattered wheezes and expectorates greenish phlegm. He is afebrile and his pulse oximetry reading is 94% on room air. His chest x-ray shows some basilar fuzziness, but he has no convincing infiltrate. You decide to treat Lorenzo as if he were having a COPD exacerbation, prescribing oral corticosteroids, antibiotics, and a long-acting β2-adrenergic agonist (LABA). You ask Lorenzo to call you in a few days, make an appointment for a follow-up visit in 2 weeks, and return for lung function testing in 6 weeks. Note: This is a hypothetical case description for teaching purposes.

Role of Bronchodilator Therapy in COPD

Bronchodilators are central to the treatment of COPD. These agents exert their mechanism of action through bronchial smooth muscle relaxation.¹ Bronchodilators are used as needed or as daily therapy to prevent and reduce symptoms, improve FEV₁, and improve exercise capacity.¹ Recently updated guidelines from GOLD recommend use of as-needed short-acting or daily long-acting bronchodilators based on a combined assessment of a patient’s symptoms and risk of future exacerbations.¹

The approach to combined symptom-based and risk-based assessment is shown in the Figure, which describes 4 patient symptom/risk profiles.¹ Validated questionnaires that are recommended for the assessment of symptoms are the Modified British Medical Research Council (mMRC) scale, which is a measure of breathlessness, and the COPD Assessment Test (CAT), which is a measure of health status impairment. An mMRC score of 0-1 or a CAT score <10 indicates few symptoms; higher scores indicate more symptoms. Exacerbation risk can be evaluated based on either the GOLD spirometric classification or on the patient’s past exacerbation history. Spirometric classifications are used to describe 4 grades of airflow limitation based on postbronchodilator FEV₁, with GOLD grades 1 and 2 indicating low risk (Table 1).¹ Using the past history method, 0-1 exacerbations in the past year indicates low risk, whereas ≥2 exacerbations indicates high risk. If results from the spirometric or history assessments differ, the method yielding the highest risk should be used to classify the patient.¹ For example, a patient with 2 exacerbations but an FEV₁ of 64% predicted would qualify as high risk for exacerbations.

The Figure and Table 2 show the pharmacologic approach to therapy in stable COPD based on the 4 symptom/risk patient profiles.¹ In patients who have a low level of symptoms and a low level of exacerbation risk, as-needed short-acting bronchodilator therapy is the first choice based on its effect on lung function and breathlessness.¹ In patients with low risk but more substantial symptoms, daily long-acting bronchodilator therapy is recommended over as-needed short-acting medications.¹ In patients with a high risk of exacerbations, regardless of symptom frequency, addition of an inhaled corticosteroid to a long-acting bronchodilator (eg, LABA or long-acting muscarinic agent/anticholinergic [LAMA]) is recommended, with fixed combinations preferred.¹ For all but the low-symptom/low-risk patient profile, LAMAs or LABAs are recommended as a first choice; each has been shown to reduce exacerbations.¹ The combination of LAMAs and LABAs is recommended as a second choice, particularly if single-agent bronchodilator therapy does not improve symptoms.¹ Combining different classes of bronchodilators vs increasing the dose of one agent may minimize adverse events and improve bronchodilation.¹

In addition to these treatment recommendations, the GOLD guidelines provide additional recommendations for management of COPD exacerbations.¹ Briefly, inhaled short-acting β₂-agonists, with or without short-acting anticholinergics, are preferred for the treatment of an exacerbation. Systemic corticosteroids and antibiotic treatment also are used to treat COPD exacerbations.


Defining Bronchodilator Reversibility

Different estimates of the prevalence of bronchodilator reversibility among COPD patients stem from variability in definitions, testing methodologies, and intraindividual patient response. Findings from recent clinical studies suggest that one- to two-thirds of patients with COPD exhibit bronchodilator reversibility, depending on the definition of FEV₁ response used (Table 3).^4-8 No single criterion is considered to be a “gold standard” for assessment of acute bronchodilator reversibility.³ Instead, various definitions based on absolute or percentage increases in FEV₁ or FVC exist (Table 4).^7-10

Certain patients may exhibit responsiveness to bronchodilator therapy when one threshold for FEV₁ reversibility is employed, but not another. Anthonisen et al¹¹ assessed responsiveness to 2 inhalations of 200 μg isoproterenol in smokers with airway obstruction (n = 4194) aged 35 to 59 years in the 11-year Lung Health Study cohort. In that study, approximately 20% of patients exhibited reversibility when defined as a >200 mL increase in FEV₁ from baseline; however, when defined as >15% improvement from prebronchodilator FEV₁ or ≥12% of the predicted normal FEV₁ value, only 3% and 1% of patients, respectively, exhibited reversibility.¹¹ In a post hoc analysis of 5756 patients with moderate to severe COPD in the Understanding Potential Long-term Impacts of Function with Tiotropium study, the percentage of patients exhibiting bronchodilator reversibility varied between 39% and 73%, depending on the FEV₁ criteria used.^3,7

Measurements of lung volume, and not just FEV₁, should be considered when measuring bronchodilator responsiveness.^12,13 Pulmonary hyperinflation occurs in COPD because of excessive air trapping, resulting in an increased functional residual capacity (volume of air in lung after exhalation) and decreased lung volume inspiratory capacity.^1,14 Bronchodilator therapy reduces hyperinflation and improves inspiratory capacity in patients with COPD.^1,15,16 Patients who do not meet reversibility criteria based on FEV₁, particularly those with increasing COPD severity, may exhibit reversibility based on lung volume measurements, including FVC and inspiratory capacity (Table 5).^12,13,17-19

Case (continued) When Lorenzo returns for his 2-week follow-up visit, he shows improvement; he says that he thinks that you were right that he has some lung problems, and he will continue taking his inhaler. In 6 weeks he takes the spirometry test. The results demonstrate what you anticipated—his FEV1 is 72% of predicted and his FEV1/FVC ratio is 0.66, consistent with moderate COPD (ie, GOLD grade 2). Because this is a new diagnosis of COPD, assessment is based more on symptom than on risk. Lorenzo is currently a “2” on the mMRC. Therefore, you ask Lorenzo to continue to take his daily long-acting bronchodilator with a short-acting bronchodilator, as a “rescue” medication. In addition to the FEV1/FVC ratio of 0.66 on his postbronchodilator spirometry, you note that there is a 240 mL and a 16% increase in FEV1. Considering his history of never having had respiratory symptoms before his long-term smoking history, you stay with the diagnosis of COPD knowing that the reversibility is still consistent with your diagnosis. The reversibility may be helpful as a teaching point to show Lorenzo that his lungs do improve with the type of medication you are asking him to use daily. While we do not have evidence to confirm that reversibility is associated with clinical response to daily long-acting bronchodilator therapy, it is not inappropriate to use reversibility to help enhance adherence to treatment. Note: This is a hypothetical case description for teaching purposes.

Reversibility also varies based on the choice of bronchodilator and dose used. In one study of 813 patients with COPD, 11.2% of patients demonstrated bronchodilator reversibility after ipratropium only, 27.4% with albuterol only, and 34.6% with both bronchodilators.² Moreover, initial lack of reversibility to a bronchodilator therapy does not predict long-term response to treatment with a maintenance bronchodilator. In a retrospective analysis of 2 randomized, placebo-controlled studies of patients with COPD (N = 921), improvements in FEV₁ following 1 year of treatment with tiotropium were observed, regardless of initial responsiveness to the bronchodilator therapy.²⁰ Importantly, guidelines from the American Thoracic Society (ATS) and European Respiratory Society state that a single test of bronchodilator response is inadequate for assessment of potential therapeutic benefits of bronchodilator therapy.¹³

An individual patient’s degree of bronchodilator responsiveness also may vary with time.¹³ In a randomized, placebo-controlled study of 751 patients with COPD, 42% of patients were initially considered reversible following bronchodilation with albuterol and ipratropium according to ATS FEV₁ criteria.^12,21 Of these, only 37% were also classified as reversible on 2 subsequent study visits.²¹ Similarly, 32% of patients initially classified as “not reversible” exhibited acute responsiveness to bronchodilation by the second visit.²¹ Variability within and between patients in response to 250 μg of isoproterenol over 2.5 to 3 years was reported by Anthonisen et al²² and was correlated with baseline FEV₁.

Conclusions

Although by definition patients with COPD have airflow obstruction that is not fully reversible, many patients exhibit substantial bronchodilator response. Many factors can affect determination of bronchodilator reversibility status, including individual variability, choice of bronchodilator, and criteria used to assess responsiveness. Patients who do not exhibit FEV₁ reversibility can demonstrate significant lung volume response (eg, FVC improvement). Bronchodilators are the mainstay of therapy, and reversibility of airflow obstruction helps to explain their benefit in treating patients with COPD.

References

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