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      Bronchodilator responsiveness or reversibility in asthma and COPD – a need for clarity

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          Abstract

          Asthma and COPD present with multiple overlapping phenotypes,1–3 making a simplified diagnostic separation between the two disease states difficult. From a practical standpoint, the difficulty in differentiating between asthma and COPD has been a limitation and a foundation for criticism of large prospective trials.4 Multiple attempts to better define the population of patients with features of both diseases have been made,5,6 yet a common consensus about the best way to approach this problem is missing. Part of this problem relates to our reliance on oversimplified and relatively crude spirometric definitions of asthma and COPD7 and an incomplete understanding of how to interpret changes after bronchodilator administration. Imprecise definitions of the terms “bronchodilator responsiveness” and “reversibility” add to the confusion in the attempts to distinguish between COPD and asthma. Although the two terms are often used interchangeably in the published literature,8 and their difference may seem to be an issue of semantics, appropriately defining “bronchodilator responsiveness” and “reversibility” is essential for understanding the role of bronchodilator administration in the diagnostic workup of obstructive lung disease. A diagnosis of COPD is currently defined by demonstrating the presence of persistent airflow obstruction postbronchodilator, which implies the lack of “reversibility” of the airflow obstruction following administration of the bronchodilator. Thus, based on their definitions, reversibility of airflow obstruction and COPD are mutually exclusive terms.7 In the narrowest sense, “reversibility” implies that the abnormality, in this case, airflow obstruction, returns to normal after bronchodilator administration. Clearly, this determination depends on the accepted definition of “abnormal,” with Global Initiative for Chronic Obstructive Lung Diseases (GOLD) guidelines9 choosing a fixed ratio of FEV1/FVC<70%, a subject that has generated much debate.10 Individuals with “reversible” obstruction are at higher risk of future development of COPD.11,12 The latest GOLD guidelines recommend the need to retest symptomatic subjects at risk of COPD with an FEV1/FVC ratio between 60% and 80% to account for variability of this measurement on repeated spirometry as “reversible” airflow obstruction on postbronchodilator spirometry may turn into a persistent airflow obstruction on follow-up testing. At the same time, the same subject with a reduced FEV1/FVC ratio of <70% which normalizes after bronchodilator administration may have asthma. Nevertheless, “reversibility” is neither necessary nor sufficient for an asthma diagnosis. Spirometry in asthma may be completely normal between exacerbations, yet persistent, uncontrolled asthma may lead to “irreversible” airflow obstruction, where the degree of obstruction may be a function of the duration and severity of the disease.13 By contrast, “bronchodilator responsiveness” can be defined in multiple ways,8 but it is inevitably based on measuring volume changes after bronchodilator administration. The American Thoracic Society (ATS) and European Respiratory Society (ERS) have adopted a definition of bronchodilator responsiveness as being an increase following bronchodilator of either FEV1 or FVC of ≥12% and ≥200 mL.14,15 Bronchodilator administration can also affect FEV1/FVC ratio, but the presence or absence of a change from <70% to ≥70% is not used to categorize the bronchodilator response into positive or negative. While “reversibility” is occasionally used as a criterion distinguishing between COPD and asthma-COPD overlap, often what is meant is “bronchodilator responsiveness.”6,16 Such references may relate to the definition of the term “reversibility” in the seminal paper by Miller et al,14 on the standardization of spirometry. However, it is important to emphasize that lack of clarification of this term has a significant impact on our interpretation of multiple published studies. A majority of patients with COPD (52%) demonstrate bronchodilator responsiveness, depending on its definition (FEV1 vs FVC) and disease stage.8 However, in the study by Prentice et al,17 among those with reversibility of airflow obstruction, only 28.1% had bronchodilator responsiveness. The repeatability of bronchodilator responsiveness is modest, with about 50% of patients with moderate to severe COPD changing their bronchodilator responsiveness status on a follow-up testing.18 In addition, oversimplified analysis of bronchodilator responsiveness as present or absent, based on defined ATS/ERS criteria of ≥200 mL and ≥12%,14 further diminishes the clinical usefulness of this spirometric measure in the evaluation of obstructive lung disease. In reality, bronchodilator responsiveness in COPD and asthma differ both quantitatively8 and in the pattern that reflects pathophysiological processes.19 In COPD, especially in advanced disease, FVC responsiveness dominates, likely implicating the effect of bronchodilator on reduction of hyperinflation and air trapping, as opposed to the FEV1 responsiveness, which is usually seen as a marker of bronchoreactivity in larger airways. What should we do then, in order to derive the best value from spirometry and to help us better understand airway pathophysiology? First, we need to recognize its limitations. Currently used metrics such as FEV1 and FEV1/FVC are not sufficiently sensitive to diagnose early or mild airway disease,20–22 and, while spirometric staging can be helpful with regard to prognosis, it is well accepted that spirometry alone does not fully characterize the many clinical manifestations of COPD.9 What spirometry does reflect well is the physiology of respiratory system and the dynamic changes that occur over time. While the forced expiratory and inspiratory maneuver is an artificial concept and sometimes difficult for patients to perform, the maximal flow volume curves do provide a rich source of physiological data. Large observational studies,23,24 along with digital technology and machine learning, offer the opportunity to explore novel spirometric indices of airway disease and to compare these indices with early structural abnormalities (eg, parametric response mapping) noted on high-resolution computed tomography scans. “Reversibility” and “bronchodilator responsiveness” are important spirometric features of a patient with obstructive airway disease, and they may provide useful information about the underlying pathobiology in a given patient. Nevertheless, distinguishing the two terms and better understanding of the limitations derived by their current and widely accepted definitions is of crucial importance as we try to use spirometry as a reference for building more sophisticated diagnostic models.6,25 In this regard, it is worth noting that uncertainty as to whether a patient has an overlap of asthma and COPD is unlikely to be resolved on the basis of spirometric criteria alone. We believe the term “reversibility” should be dropped from position statements and guidelines in the future. On the other hand, bronchodilator responsiveness, linked to evidence-based minimum clinically important differences, is a distinct clinical feature in comparison to reversibility and it occurs frequently in both asthma and COPD.

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          Most cited references 16

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          • Article: not found

          Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function.

          Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms.
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            • Record: found
            • Abstract: found
            • Article: not found

            The Asthma-COPD Overlap Syndrome.

            Although in textbooks asthma and chronic obstructive pulmonary disease (COPD) are viewed as distinct disorders, there is increasing awareness that many patients have features of both. This article reviews the asthma-COPD overlap syndrome.
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              • Record: found
              • Abstract: found
              • Article: not found

              Bronchodilator reversibility testing in chronic obstructive pulmonary disease.

              A limited or absent bronchodilator response is used to classify chronic obstructive pulmonary disease (COPD) and can determine the treatment offered. The reliability of the recommended response criteria and their relationship to disease progression has not been established. 660 patients meeting European Respiratory Society (ERS) diagnostic criteria for irreversible COPD were studied. Spirometric parameters were measured on three occasions before and after salbutamol and ipratropium bromide sequentially or in combination over 2 months. Responses were classified using the American Thoracic Society/GOLD (ATS) and ERS criteria. Patients were followed for 3 years with post-bronchodilator FEV(1) and exacerbation history recorded 3 monthly and health status 6 monthly. FEV(1) increased significantly with each bronchodilator, a response that was normally distributed. Mean post-bronchodilator FEV(1) was reproducible between visits (intraclass correlation 0.93). The absolute change in FEV(1) was independent of the pre-bronchodilator value but the percentage change correlated with pre-bronchodilator FEV(1) (r=-0.44; p<0.0001). Using ATS criteria, 52.1% of patients changed responder status between visits compared with 38.2% using ERS criteria. Smoking status, atopy, and withdrawing inhaled corticosteroids were unrelated to bronchodilator response, as was the rate of decline in FEV(1), decline in health status, and exacerbation rate. In moderate to severe COPD bronchodilator responsiveness is a continuous variable. Classifying patients as "responders" and "non-responders" can be misleading and does not predict disease progression.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2018
                23 October 2018
                : 13
                : 3511-3513
                Affiliations
                [1 ]Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA, ibarjaktarevic@ 123456mednet.ucla.edu
                [2 ]Division of Pulmonary and Critical Care, Weill Cornell Medicine, NY, USA
                [3 ]Department of Genetic Medicine, Weill Cornell Medicine, NY, USA
                [4 ]Department of Health Policy and Management, Fielding School of Public Health at UCLA, Los Angeles, CA, USA
                [5 ]Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
                Author notes
                Correspondence: Igor Barjaktarevic, Division of Pulmonary and Critical Care, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS, 43233, Los Angeles, CA 90095, USA, Email ibarjaktarevic@ 123456mednet.ucla.edu
                Article
                copd-13-3511
                10.2147/COPD.S183736
                6207394
                30498341
                © 2018 Barjaktarevic et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Editorial

                Respiratory medicine

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