ORIGINAL RESEARCH A New Bronchodilator Response Grading Strategy Identifies Distinct Patient Populations James E. Hansen1†, Asli G. Dilektasli1,2, Janos Porszasz1, William W. Stringer1, Youngju Pak3, Harry B. Rossiter1,4, and Richard Casaburi1; for the COPDGene Investigators 1Rehabilitation Clinical Trials Center and 3UCLA Clinical and Translational Science Institute, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California; 2Department of Pulmonary Medicine, Faculty of Medicine, Uludağ University, Bursa, Turkey; and 4Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom ORCID IDs: 0000-0001-7099-9647 (A.G.D.); 0000-0002-8851-8589 (R.C.). Abstract Results: Twenty percent met mild and 31%met moderate or marked BDR-FEV1 criteria, whereas 12% met mild and 33% met moderate or Rationale: A positive bronchodilator response (BDR) according marked BDR-FVC criteria. In contrast, only 20.6% met ATS/ERS to American Thoracic Society/European Respiratory Society positive criteria. Compared with the negative BDR-FEV1 category, the (ATS/ERS) guidelines require both 200 ml and 12% increase in minimal, mild, moderate, and marked BDR-FEV1 categories were forced expiratory volume in 1 second (FEV1) or forced vital capacity associated with greater 6-minute-walk distance and lower St. George’s (FVC) after bronchodilator inhalation. This dual criterion is Respiratory Questionnaire and modified Medical Research Council insensitive in those with high or low FEV1. dyspnea scale scores. Compared with negative BDR, moderate and marked BDR-FEV1 categories were associated with fewer exacerbations,Objectives: To establish BDR criteria with volume or percentage and minimal BDR was associated with lower computed tomography FEV1 change. airway wall thickness. Compared with the negative category, all BDR- Methods: The largest FEV1 and FVCwere identified from three pre- FVC categories were associated with increasing emphysema percentage and three post-bronchodilator maneuvers in COPDGene (Genetic and gas trapping percentage. Moderate and marked BDR-FVC Epidemiology of COPD) participants. A total of 7,741 individuals categories were associated with higher St. George’s Respiratory with coefficient of variation less than 15% for both FEV and FVC Questionnaire scores but fewer exacerbations and lower dyspnea scores.1 formed bronchodilator categories of FEV1 response: negative Conclusions: BDR grading by FEV1 volume or percentage (<0.00% or <0.00 L), minimal (.0.00% to <9.00% or .0.00 L to response identified subjects otherwise missed by ATS/ERS criteria. <0.09 L), mild (.9.00% to <16.00% or .0.09 L to <0.16 L), BDR grades were associated with functional exercise performance, moderate (.16.00% to<26.00% or.0.16 L to<0.26 L), and marked quality of life, exacerbation frequency, dyspnea, and radiological (.26.00% or .0.26 L). These response size categories are based on airway measures. BDR grades in FEV1 and FVC indicate different empirical limits considering average FEV1 increase of approximately clinical and radiological characteristics. 160 ml and the clinically important difference for FEV1. To compare flow and volume response characteristics, BDR-FEV1 category Keywords: airflow obstruction; bronchodilator responsiveness; assignments were applied for the BDR-FVC response. forced expiratory volume in 1 second (Received in original form January 15, 2019; accepted in final form August 8, 2019 ) †Deceased. Supported by the National Center for Advancing Translational Sciences through UCLA CTSI Grant UL1TR001881-01 (Y.P.). COPDGene is funded by awards R01HL089856 and R01HL089897 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Author Contributions: R.C. is the guarantor of the manuscript. R.C., A.G.D., J.P., W.W.S., and J.E.H. contributed to study design. J.E.H. and A.G.D. conducted data analysis. J.P. and Y.P. contributed to data analysis and statistical support. J.E.H., A.G.D., J.P., R.C., W.W.S., Y.P., and H.B.R. contributed to interpretation of the data. J.E.H., A.G.D., J.P., R.C., H.B.R., and W.W.S. contributed to the writing of the manuscript. J.E.H., J.P., R.C., W.W.S., Y.P., and H.B.R. contributed critical review of the manuscript. J.E.H., A.G.D., J.P., R.C., Y.P., H.B.R., and W.W.S. contributed review of the drafts of the manuscript. A.G.D., J.P., W.W.S., Y.P., H.B.R., and R.C. approved the final version of the manuscript. Correspondence and requests for reprints should be addressed to Richard Casaburi, Ph.D., M.D., Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Building CDCRC, Torrance, CA 90502. E-mail: casaburi@ucla.edu. This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org. Ann Am Thorac Soc Vol 16, No 12, pp 1504–1517, Dec 2019 Copyright © 2019 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201901-030OC Internet address: www.atsjournals.org 1504 AnnalsATS Volume 16 Number 12| December 2019 ORIGINAL RESEARCH Current criteria for identifying a positive African American subjects, 45–80 years old, percentage change from baseline FEV1 spirometric bronchodilator response (BDR) with a greater than or equal to 10–pack-year (DFEV1%). BDR is a continuous variable based on American Thoracic Society (ATS) smoking history. Key exclusion criteria were with a unimodal, not bimodal, response and European Respiratory Society (ERS) (1) history of other lung disease (except asthma) pattern (12). Using fixed population-based guidelines require both 200 ml and 12% or previous lung resection (see online criteria for both volume and percentage increase in forced expiratory volume in supplement) (7). Participants underwent change in BDR is not optimal, especially 1 second (FEV1) or forced vital capacity spirometry, 6-minute-walk test, quantitative considering differences in drug, dosage, (FVC). If these dual criteria are not met, computed tomography (CT), and standard and administration methods in published BDR is categorized as negative. These questionnaires to assess symptoms and studies (4). We used five bronchodilator guidelines may not identify many medical history. From this population, categories of FEV1-BDR by using volume or individuals with potentially clinically participants who did not have FEV1, percentage FEV1 change: negative (<0.00% important BDR, especially those with low FEV6, and FVC values from three or <0.00 L), minimal (.0.00% to <9.00% baseline FEV1 who do not meet change prebronchodilator and three post- or .0.00 L to <0.09 L), mild (.9.00% to greater than or equal to 200 ml or those with bronchodilator maneuvers were excluded <16.00% or .0.09 L to<0.16 L), moderate high baseline FEV1 who do not meet change (n= 2,084), as were those with coefficient of (.16.00% to<26.00% or.0.16 L to<0.26 greater than or equal to 12% (2–4). Both variation (standard deviation [SD]/mean) L), and marked (.26.00% or .0.26 L). Pellegrino and Brusasco (5) and Calverley of either prebronchodilator or post- The rationale for the 5-point grading and colleagues (6) emphasized that FEV1 bronchodilator blows greater than 15% system including nonresponders BDR is a continuous variable; no threshold (n= 486) (9), reducing the study population (negative) and minimal, mild, moderate, adequately separates responders from to 7,741. The COPDGene protocol was and marked responders is based on several nonresponders. Hansen and colleagues (4), approved by institutional review boards at considerations: ΔFEV1L less than or equal to analyzing BDR in a sample of clinical pre- 21 participating centers. Written informed 0 clearly defines the nonresponder and and post-bronchodilator tests, showed that consent was obtained from all participants. negative responder category. We have 224 (71.6%) of 313 patients failed ATS/ERS previously asserted that ΔFEV1% of 6% or FEV1 criteria, but 89 (39.7%) of those 224 Spirometry and Proposed 7% might be clinically important because it who failed showed statistically significant BDR Grades is associated with about a 90- to 100-ml ΔFEV1 greater than or equal to 100 ml or Spirometry was performed in accordance increase in FEV1 (3), which has been greater than or equal to 6.0% improvement. with ATS/ERS recommendations and using suggested as the minimal clinically Of those with baseline FEV1 less than 1 L an ultrasound-based spirometer (EasyOne; important difference (MCID) for ΔFEV1 (n= 44), 52.3% had ΔFEV1 greater than or ndd Medical Technologies) before and after (13). We use 90 ml or 9% to separate equal to 100 ml or greater than or equal to two puffs of albuterol using a spacer (10). minimal from mild response. A 9% 6.0%, whereas only 11.4% were ATS/ERS Before bronchodilator reversibility testing, threshold, corresponding to the upper 95th positive (3). These results suggest the need short-acting and long-acting inhaled percentile of BDR in FEV1, was previously to revise BDR evaluation. bronchodilators were withheld 4 and 12 proposed to define clinical “abnormality,” The COPDGene (Genetic hours; short-acting and long-acting oral based on BDR in a large group of Epidemiology of COPD) population, with bronchodilators were withheld 8 and 12 asymptomatic never-smokers (14). After 10,311 current smokers or ex-smokers with hours before testing, respectively. The excluding nonresponders, when we ordered or without spirometrically defined chronic largest of three acceptable FEV1 and FVC responses by baseline FEV1, average ΔFEV1 obstructive pulmonary disease (COPD), measurements was reported. Spirometric in groups of 100 persons seemed to stabilize is uniquely positioned to evaluate BDR measurements were graded (range, 0–4) by a at approximately 160 ml (ΔFEV1L and (7) and formed the basis of the present centralized quality control process: grade ΔFEV1% profiles in Figure 1). This value evaluation. We aimed to 1) develop a new 4 = fully met ATS criteria, reproducible to (and the corresponding 16% change) was grading system based on BDR volume or within 50 ml; grade 3 = fully met ATS chosen to separate the mild and moderate percentage increase for comparison with criteria, reproducible to between 50 and categories. Previously, absolute increase in ATS/ERS guidelines, 2) evaluate ATS/ERS 100 ml; grade 2 = fully met ATS criteria, FEV1 required to exclude natural variability recommended ΔFEV1 versus ΔFVC values, reproducible between 100 and 150 ml; grade with 95% confidence was reported as 160 ml and 3) explore the clinical relevance of the 1 = partly meeting ATS criteria and/or in obstructive airway disease (OAD) (15). In new BDR grades by comparing them with reproducible between 150 and 200 ml; grade distinguishing between moderate and clinical outcomes and pulmonary structural 0 = failure to meet ATS criteria and/or marked response, it seemed practical to use characteristics. Some of the results of this reproducible greater than 200ml (11). In the a further 100-mlMCID step size and use 260 study have been reported previously in the study group, prebronchodilator quality ml or 26% increase. For ATS/ERS guideline form of an abstract (8). control grades for FEV1 and FVC were comparison, we placed participants into 3.546 0.78 and 3.356 0.92, respectively, ATS/ERS groups for ΔFEV1: 1) positive, whereas post-bronchodilator quality control defined as ΔFEV1L greater than or equal to Methods grades were 3.626 0.70 and 3.466 0.81, 0.2 L and ΔFEV1% greater than or equal to respectively. These grades did not differ 12% and 2) negative, defined as all others. We used the COPDGene cohort enrolled markedly among BDR categories (Table 1). To compare flow and volume response between 2007 and 2011 (7). This cohort BDR was evaluated as absolute characteristics in bronchodilator testing, we included 10,311 non-Hispanic white and change from baseline FEV1 (DFEV1L) and also evaluated BDR in FVC (BDR-FVC). Hansen, Dilektasli, Porszasz, et al.: A New Bronchodilator Response Grading Strategy 1505 ORIGINAL RESEARCH Table 1. Demographic characteristics, spirometry, functional exercise capacity, and quantitative CT measures of airway abnormality among FEV1 BDR grades (N=7,741) Negative Minimal Mild Moderate Marked Category range for DFEV1L (L) DFEV1 <0 0,DFEV1< 0.09 0.09,DFEV1< 0.16 0.16,DFEV1<0.26 0.26.DFEV1 Category range for DFEV1% (%) D%FEV1 <0 0,D%FEV1<9 9,D%FEV1<16 16,D%FEV1< 26 26.D%FEV1 n (%) 1,634 (21.1) 2,159 (27.9) 1,549 (20) 1,399 (18.1) 1,000 (12.9) Demographics Age, yr 59.168.6 60.868.9 60.969.0 60.669.1 59.06 8.7 BMI, kg/m2 28.866.2 28.566.3 28.566.1 28.766.1 28.76 6.0 Smoking history, pack-years 39.1 (27.7–54.2) 40.0 (28.0–55.5) 40.0 (27.0–55.5) 40.0 (28.5–55.5) 40.5 (30.0–58.0) Sex, male, % 55.3 48.1 47.8 57.2 66.8 Race, white, % 64.8 72.7 76.2 76.6 74.8 ICS use, % 6.7 6.2 5.5 6.9 9.3 Spirometry Pre-BD FEV1, L 2.3760.95 2.076 0.92 2.056 0.88 2.1360.91 2.0860.95 Post-BD FEV1, L 2.2860.93 2.126 0.93 2.176 0.88 2.3260.93 2.4360.98 Pre-BD FVC, L 3.4661.03 3.176 0.99 3.176 0.96 3.2961.04 3.3661.14 Post-BD FVC, L 3.3361.01 3.186 0.97 3.296 0.93 3.5061.00 3.7861.12 DFEV1, L 20.0960.09 0.046 0.02 0.126 0.02 0.2060.04 0.3660.12 DFVC, L 20.1460.24 0.026 0.19 0.126 0.21 0.2160.24 0.4160.37 DFEV1, % 23.9363.99 2.646 1.96 6.956 3.18 11.1765.13 21.12611.65 DFVC, % 23.8167.04 1.096 6.63 4.616 7.78 7.9569.68 14.84613.86 Pre-BD FEV1/FVC, % 66.87615.29 63.596 16.14 63.136 15.21 63.02614.73 59.87614.21 Post-BD FEV1/FVC, % 67.09615.98 64.836 16.89 64.806 15.99 65.65615.19 63.21614.63 Pre-BD FEV1, QC 3.1561.05 3.606 0.67 3.716 0.59 3.6660.65 3.6160.72 Post-BD FEV1, QC 3.6860.68 3.746 0.58 3.686 0.60 3.5560.69 3.2660.97 Pre-BD FVC, QC 3.0761.14 3.426 0.82 3.486 0.77 3.4360.85 3.3460.89 Post-BD FVC, QC 3.4660.82 3.576 0.68 3.516 0.73 3.4160.86 3.2161.02 Functional exercise performance, quality of life, and exacerbation frequency 6MWD, m 4136123 4086 123 4186 118 4296120 4316117 SGRQ score 20.61 (5.96–43.27) 22.55 (6.30–44.79) 21.74 (7.12–43.50) 20.53 (6.45–40.82) 25.35 (8.36–46.27) mMRC 1.3461.48 1.386 1.44 1.316 1.42 1.2361.41 1.3861.43 Exacerbations/yr 0.3961.00 0.426 0.93 0.436 0.99 0.3860.93 0.3860.89 Quantitative CT WAsegmental, % 61.1363.32 61.1763.21 61.2663.19 61.4063.14 62.126 3.38 Pi15 5.1460.19 5.136 0.19 5.146 0.20 5.1560.20 5.2160.21 Emphysema % 1.75 (0.56–6.17) 2.40 (0.74–9.49) 2.70 (0.76–7.93) 2.61 (0.79–8.01) 2.81 (0.97–7.12) Gas trapping % 13.54 (6.01–29.90) 15.10 (6.99–35.47) 16.06 (7.54–34.46) 16.47 (7.77–34.14) 19.35 (9.99–36.12) Definition of abbreviations: 6MWD=6-minute-walk distance; BD=bronchodilator; BDR=bronchodilator response; BMI =bodymass index; CT=computed tomography; FEV1= forced expiratory volume in 1 second; FVC= forced vital capacity; ICS= inhaled corticosteroids; mMRC=modified Medical Research Council dyspnea scale; Pi15 = square root wall area of a 15-mm diameter airway; QC=quality control grades for spirometry maneuver (ranging from 0 to 4); SGRQ=St. George’s Respiratory Questionnaire; WA=wall area. Data are presented as mean6SD or median (25th–75th interquartile range) or as percentages. BDR-FVC was evaluated as absolute distance (6MWD) to assess functional wall area of a 15-mm diameter airway (Pi15) change from baseline FVC (DFVCL) and exercise performance. The 6-minute-walk (20). Emphysema percentage on CT was percentage change from baseline FVC test was performed according to ATS defined as the percentage of low-attenuation (DFVC%). We used the same BDR category standards (18) and at least 20 minutes areas below2950 Hounsfield units (HU) on assignments we derived for FEV1 for the after albuterol administration for post- an end-inspiratory CT scan (21). Gas BDR-FVC response. bronchodilator spirometry. Exacerbation trapping percentage was defined as percentage frequency in the prior year was recorded at of lung voxels below2856 HU on expiratory Clinical and Functional Correlates enrollment, with exacerbations defined as scans (22). As clinical and functional correlates, acute worsening of respiratory symptoms we used the St. George’s Respiratory requiring antibiotics and/or systemic Statistical Analyses Questionnaire (SGRQ) to assess health- corticosteroids (19). CT scans were acquired IBM SPSS Statistics version 22.0 (IBM) and related quality of life (scores ranging from at full inspiration and end expiration (see Stata version 15 (StataCorp) software was 0 to 100, with a greater score indicating online supplement). CT scans were obtained used. Univariate analyses were performed worse health status) (16), modified Medical after bronchodilator testing. Airway wall between BDR grades using chi-square test Research Council (mMRC) dyspnea scale to thickness was assessed by segmental airway for proportions and one-way analysis quantify dyspnea (scores ranging from 0 to 4, wall area percentage (segmental WA%= of variance or Kruskal-Wallis test for with a greater score indicating worse dyspnea [outer bronchus area2 airway luminal continuous variables (Table 1; see also Table perception) (17), and 6-minute-walk area]/outer bronchus area) and square root E1 in the online supplement). P values for 1506 AnnalsATS Volume 16 Number 12| December 2019 ORIGINAL RESEARCH 0.20 20 ΔFEV1% distributions were dramatically different (Figure 3). This emphasizes that 0.18 18 volume and percentage changes need to be considered separately from each other. 0.16 16 Table 1 shows study participants graded by BDR intensity categories. Total BDR 0.14 14 positives were 78.9%. 0.12 12 DFEV1L andDFVCL after bronchodilator inhalation are presented in Figure 4. 0.10 10 Despite similarity of mean and SD (Table 4), ΔFVCL increased more rapidly than 0.08 8 ΔFEV1L above a BDR of 0.1 L (Figure 4A). In contrast, ΔFEV1% and ΔFVC% 0.06 6 increased similarly over the full BDR range (Figure 4B). 0.04 FEV1 L 4  In Figure 1, DFEV L and DFEV %FEV 1 11 % of positive BDR participants are ordered 0.02 2 by increasing prebronchodilator FEV 0.0 1.0 2.0 3.0 4.0 5.0 1 volumes to compare volume and percentage Baseline FEV1 L increase patterns. Conspicuously, BDR patterns expressed as ΔFEV1L and ΔFEV %Figure 1. Mean forced expiratory volume in 1 second (FEV 11) bronchodilator response in volume (in L) and as a percentage by clusters of 100 individuals at each point as baseline FEV percent predicted differed markedly as prebronchodilator1 value increases for the 6,107 participants with positive bronchodilator response. Changes in volume FEV1 increased. Below prebronchodilator (left axis, ΔFEV1L) and percent predicted (right axis, ΔFEV1%) differ markedly. Although ΔFEV1L FEV1 percent predicted of 40% (FEV1, increases rapidly to approximately 0.16 L and stabilizes at that level (represented with the dashed line z1 L), ΔFEV1L increased rapidly up to on the graph), ΔFEV1% fraction gradually declines in a hyperbolic fashion from 16% to 4%. approximately 0.160 L and then stabilized, whereas ΔFEV1% averaged approximately 16%, then gradually declined in a hyperbolic pairwise comparisons were adjusted for DFVC% were coded using a restricted cubic fashion to approximately 4% as FEV1 overall type II error rate (5%) using Tukey’s spline function with three knots located at increased. method. Relationships between BDR grades the 5th, 50th, and 95th percentiles (Figures (independent variable) and quantitative CT, 2A and 2B ). All these models were adjusted BDR Categories by FEV1 Response SGRQ, and 6MWD (dependent variables) for age, sex, race, smoking history, body Using proposed BDR cutoffs, 27.9%, 20.0%, were assessed by generalized linear mass index, baseline FEV1 or FVC, and CT 18.1%, and 12.9% of the population had regression models using age, sex, race, scanner type (for CT measures). minimal, mild, moderate, and marked BDR, smoking history, body mass index, baseline Analyses were performed for the respectively (Table 1). One hundred percent FEV1, and CT scanner type (only for CT whole study population. ATS/ERS criteria of the minimal responders had a minimal measures) as covariates (separately for BDR- identified most of the participants in the FEV1-BDR by both DFEV1L and DFEV1%. FEV1 and BDR-FVC response) (Tables 2 marked BDR category as positive BDR. Of the mild responders 93.1% and 25.6% and 3 ). A proportional odds model was used Accordingly, analyses were performed in the had mild BDR by DFEV1L and DFEV1%, for mMRC (Tables 2 and 3). A generalized subgroup after excluding ATS/ERS positives respectively. Of the moderate responders, linear regression model with negative (Table 3). Excluding ATS/ERS positives 91.6% and 20.7% had moderate BDR by binomial link function assessed BDR grade’s causes a substantial loss in sample size of the DFEV1L and DFEV1%, respectively. Of the independent effect on exacerbation marked BDR group, however; for that marked responders, 91.0% and 27.7% had frequency (23) (Tables 2 and 3). SGRQ, reason, marked BDRs were excluded from marked BDR by DFEV1L and DFEV1%, emphysema percentage, and gas trapping the subgroup analysis. respectively. However, 21.1% of the percentage were natural log transformed; population had a negative BDR. Mean ages regression coefficients for natural log– of marked bronchodilator responders and transformed variables were back Results nonresponders were lower than those of transformed, and exponentiated b-values minimal, mild, and moderate responders. were presented to aid interpretation. Finally, Characteristics of the 7,741 participants are Female sex was more prominent in minimal to assess the relationship between BDR summarized in Table 4. Within-subject and mild BDR, whereas male sex was more (DFEV1L, DFEV1%, DFVCL, DFVC% as coefficients of variation for pre- and post- prominent in marked and nonresponse separate continuous variables) and 6MWD, bronchodilator FEV1 were 4.126 2.77% and categories. Negative responders had greater SGRQ, and quantitative CT measures, we 3.526 2.54%, respectively. Distributions of pre- and post-bronchodilator FEV1/FVC modeled 6MWD, SGRQ, and quantitative absolute and percentage FEV1 BDR are than all other response categories. CT measures against DFEV1L, DFEV1%, presented in Figure 3. Mean DFEV1L and In the univariate analyses, there was DFVCL, and DFVC% in the whole study DFVCL were 0.099 L and 0.092 L, progressive increase in segmental WA% population. DFEV1L,DFEV1%, DFVCL, and respectively. However, ΔFEV1L and from negative to marked BDR (P, 0.0001). Hansen, Dilektasli, Porszasz, et al.: A New Bronchodilator Response Grading Strategy 1507 FEV1 L FEV1 % ORIGINAL RESEARCH 1508 AnnalsATS Volume 16 Number 12| December 2019 Table 2. Adjusted multivariable analysis for functional exercise performance, QOL, exacerbation frequency, dyspnea, and quantitative CT measures with increasing FEV1 and FVC BDR grades Bronchodilator Response Grades, FEV1 Response Negative Minimal (n=2,159 [27.9%]) Mild (n=1,549 [20.0%]) Moderate (n=1,399 [18.1%]) Marked (n=1,000 [12.9%]) (n=634 [21.1%]) 6MWD Mean difference 1 (ref) 8.46* (2.01 to 14.91) 17.60† (10.61 to 24.58) 26.94† (19.81 to 34.07) 37.00† (29.14 to 44.86) (95% CI) SGRQ % Difference 1 (ref) 27.30* (213.00 to 21.20), 0.927 28.30* (214.40 to 21.80), 0.917 212.20† (218.20 to 25.80), 0.878 212.40† (218.90 to 25.30), 0.876 (95% CI), eb mMRC OR (95% CI) 1 (ref) 0.81* (0.71 to 0.93) 0.74† (0.64 to 0.86) 0.62† (0.53 to 0.73) 0.63† (0.53 to 0.75) Exacerbations/yr RR (95% CI) 1 (ref) 0.89 (0.78 to 1.01) 0.91 (0.79 to 1.05) 0.86* (0.74 to 0.99) 0.74† (0.63 to 0.87) WAsegmental, % Mean difference 1 (ref) 20.24* (20.43 to 20.06) 20.18 (20.38 to 0.01) 20.08 (20.28 to 0.12) 0.29* (0.06 to 0.51) (95% CI) Pi15 Mean difference 1 (ref) 20.01* (20.03 to 20.00) 20.00 (20.02 to 0.01) 20.00 (20.01 to 0.01) 0.03 † (0.01 to 0.04) (95% CI) Emphysema % % Difference 1 (ref) 7.62 (21.62 to 12.71), 1.08 5.30 (24.41 to 15.99), 1.05 3.75 (26.06 to 14.60), 1.04 26.00 (215.83 to 4.97), 0.95 (95% CI), eb Gas trapping, % % Difference 1 (ref) 22.69 (28.57 to 3.57), 0.97 1.54 (25.06 to 8.60), 1.01 4.00 (22.92 to 11.41), 1.04 10.50 (2.37 to 19.28), 1.10* (95% CI), eb Bronchodilator Response Grades, FVC Response Negative Minimal (n=1,273 [16.4%]) Mild (n=928 [12.0%]) Moderate (n=935 [12.1%]) Marked (n=1,720 [22.2%]) (n=2,885 [37.3%]) 6MWD Mean difference 1 (ref) 4.65 (22.17 to 11.48) 2.38 (25.27 to 10.03) 4.42 (23.26 to 12.10) 13.91† (7.56 to 20.27) (95% CI) SGRQ % Difference 1 (ref) 4.97 (22.28 to 12.63), 1.05 4.37 (23.50 to 12.89), 1.04 9.39 (1.16 to 18.29), 1.09* 14.33 (7.19 to 21.95), 1.14* (95% CI), eb mMRC OR (95% CI) 1 (ref) 20.03 (20.09 to 0.03) 0.07 (20.01 to 0.15) 0.12* (0.03 to 0.21) 0.20† (0.09 to 0.30) Exacerbations/yr RR (95% CI) 1 (ref) 0.06 (20.07 to 0.19) 0.16* (0.01 to 0.30) 0.20* (0.05 to 0.34) 0.17* (0.05 to 0.29) WAsegmental, % Mean difference 1 (ref) 20.10 (20.29 to 0.09) 0.11 (20.10 to 0.33) 0.27 (0.05 to 0.49) 0.67 † (0.49 to 0.85) (95% CI) Pi15 Mean difference 1 (ref) 20.02* (20.03 to 20.01) 20.01 (20.02 to 0.01) 0.12 (20.00 to 0.03) 0.04 † (0.03 to 0.05) (95% CI) Emphysema, % % Difference 1 (ref) 23.82 (12.03 to 36.84), 1.24† 27.44 (13.99 to 42.47), 1.27† 40.50 (25.70 to 57.04), 1.40† 50.29 (37.00 to 64.88), 1.50* (95% CI), eb Gas trapping, % % Difference 1 (ref) 10.33 (2.90 to 18.31), 1.10* 19.83 (10.75 to 29.65), 1.20† 26.51 (17.07 to 36.71), 1.26† 46.21 (37.09 to 55.94)†, 1.46 (95% CI), eb Definition of abbreviations: 6MWD=6-minute-walk distance; BDR=bronchodilator response; CI = confidence interval; CT= computed tomography; FEV1 = forced expiratory volume in 1 second; FVC= forced vital capacity; mMRC=modified Medical Research Council dyspnea scale; OR=odds ratio; Pi15 = square root wall area of a 15-mm diameter airway; QOL=quality of life; ref = reference; RR= relative risk; SGRQ=St. George’s Respiratory Questionnaire; WA=wall area. Mean value of the outcome is modeled; regression coefficient corresponds to mean difference of the outcome. The mean value of the outcome variables (6MWD, WA%, and Pi15) increases/ decreases by the amount of the regression coefficient in the particular BDR category compared with the reference category (negative response to bronchodilator). SGRQ, emphysema percentage, and gas trapping percentage were natural log transformed. The displayed coefficients (percentage difference and 95% CI) for SGRQ, emphysema percentage, and gas trapping percentage were back-transformed regression coefficients (eb) that correspond to the relative ratio between the two groups in percent. For example, for SGRQ, the mean SGRQ total score of marked bronchodilator responders is 12.4% lower than that of the reference category. OR indicates the relative odds increase for a higher score of mMRC between the two groups. For example, the estimated odds of having a one-unit-higher score of mMRC dyspnea score for marked bronchodilator responders is 0.63 of the odds compared with participants with a negative bronchodilator response. RR indicates the relative risk decrease in number of exacerbations per year between the risk group and the reference category. For example, relative risk of number of exacerbations per year is 26% decreased in marked bronchodilator responders compared with that of the reference category. Participants with a negative bronchodilator response are stated as the reference category. All models were controlled for sex, age, race, body mass index, smoking history, and initial prebronchodilator FEV1. In addition, models with CT outcomes were adjusted for CT scanner type. Significant associations are marked in bold. Negative response group was set as the reference category. *P,0.05. †P, 0.0001. ORIGINAL RESEARCH Pi15 increased from minimal to marked BDR (P, 0.0001). The marked BDR-FEV1 group had significantly greater segmental WA% and Pi15 than minimal, mild, and moderate BDR-FEV1 groups and nonresponders (adjusted P= 0.0005 for post hoc comparisons; not shown). 6MWD increased from 4086 123 m to 4316 117 m as BDR-FEV1 increased from minimal to marked (P, 0.0001). We also observed significant differences in SGRQ and mMRC scores and in exacerbation frequency between BDR-FEV1 groups (Table 2). After adjusting for potential confounders, including sex, age, and baseline FEV1, patients with greater BDR- FEV1 had greater 6MWD, better SGRQ, fewer exacerbations, and lower mMRC (Table 2). There was a significant decrease in the odds of being in a higher mMRC category as BDR-FEV1 category increased from minimal to marked. Mean WA% and Pi15 of marked BDR-FEV1 were 0.29% and 0.03 mm greater than among negative responders, respectively. 6MWD was 37 m greater in marked BDR than in negative responders. SGRQ was 12% less in moderate and marked BDR-FEV1 groups than in negative responders. Relative risks of annualized exacerbation rates were 26% and 14% decreased in marked and moderate FEV1 bronchodilator responders compared with the negative category, respectively (relative risk, 0.86 [P= 0.044] and 0.74 [P, 0.00001], respectively). However, mean WA% and Pi15 were 0.24% and 0.01 mm less in minimal FEV1 bronchodilator responders than in negative responders. In models assessing the relationship between DFEV1L and DFEV1% as continuous variables (Figure 2A), 6MWD increased with an upward slope as DFEV1L increased, whereas 6MWD decreased with a downward slope as DFEV1% increased, in participants with a positive BDR. The relation between SGRQ score with DFEV1% had an upward slope in positive BDR. The relationship of DFEV1% with both WA segmental percentage and Pi15 was more pronounced with a steeper upward slope than for DFEV1L. Comparison of BDR-FEV1 Grading Strategy with BDR by ATS/ERS Criteria Comparison of BDR using ATS/ERS criteria with the proposed BDR grades shows striking differences (Table 5). ATS/ERS criteria identify only 20.6% of patients as Hansen, Dilektasli, Porszasz, et al.: A New Bronchodilator Response Grading Strategy 1509 Table 3. Adjusted multivariable analysis for functional exercise performance, QOL, exacerbation frequency, dyspnea, and CT measures with increasing FEV1 BDR grade in the subgroup excluding all marked bronchodilator responders and participants with a positive response by ATS/ERS BDR criteria (N=5,937) Number of Bronchodilator Response Grades participants Negative Minimal Mild Moderate 1,608 2,048 1,334 947 6MWD Mean difference (95% CI) 1 (ref) 7.94* (1.39 to 14.49) 18.50† (10.79 to 25.31) 24.97† (16.98 to 32.96) SGRQ % difference (95% CI), eb 1 (ref) 27.20* (213.20 to 20.08), 0.928 29.00* (215.40 to 22.00), 0.910 212.70† (219.60 to 25.30), 0.873 mMRC OR (95% CI) 1 (ref) 0.81* (0.70 to 0.93) 0.72† (0.61 to 0.84) 0.59† (0.49 to 0.72) Exacerbations/yr RR (95% CI) 1 (ref) 0.88 (0.77 to 1.00) 0.89 (0.76 to 1.03) 0.87 (0.73 to 1.04) WAsegmental, % Mean difference (95% CI) 1 (ref) 20.20 (20.42 to 0.03) 20.24 (20.49 to 0.01) 20.27 (20.55 to 0.02) Pi15 Mean difference (95% CI) 1 (ref) 20.01* (20.02 to 20.002) 20.00 (20.02 to 0.01) 20.01 (20.02 to 0.00) Emphysema, % Mean difference (95% CI) 1 (ref) 8.17 (21.33 to 18.57), 1.082 3.38 (26.59 to 14.41), 1.034 4.12 (26.92 to 16.53), 1.041 Gas trapping, % Mean difference (95% CI) 1 (ref) 22.18 (28.33 to 4.59), 0.97 20.01 (27.08 to 7.50), 0.99 5.86 (22.32 to 14.71), 1.06 Definition of abbreviations: 6MWD=6-minute-walk distance; ATS/ERS=American Thoracic Society/European Respiratory Society; BDR=bronchodilator responders; CI = confidence interval; CT= computed tomography; FEV1= forced expiratory volume in 1 second; mMRC=modified Medical Research dyspnea scale; OR=odds ratio; Pi15 = square root wall area of a 15-mm diameter airway; QOL=quality of life; ref = reference; RR= relative risk; SGRQ=St. George’s Respiratory Questionnaire; WA=wall area. Mean value of the outcome ismodeled; regression coefficient corresponds tomean difference of the outcome. The displayed coefficients (percentage difference and 95%CI) for SGRQ are back- transformed regression coefficients (eb) that correspond to the relative ratio between the two groups in percent. All models were controlled for sex, age, race, body mass index, smoking history, and initial prebronchodilator FEV1. In addition, models with CT outcomes were adjusted for CT scanner type. Significant associations aremarked in bold. Negative response groupwas set as the reference category. *P,0.05. †P,0.0001. ORIGINAL RESEARCH A 700 700 550 550 400 400 250 250 100 100 −1 −.5 0 .5 1 1.5 −50 0 50 100 150 BDR − FEV1 L BDR − FEV1 % 100 70 100 40 70 10 4010 −20 −20 −1 −.5 0 .5 1 1.5 −50 0 50 100 150 BDR − FEV1 L BDR − FEV1 % 74 74 70 70 66 66 62 62 58 58 −1 −.5 0 .5 1 1.5 −50 0 50 100 150 BDR − FEV1 L BDR − FEV1 % 6 6 5.8 5.8 5.6 5.6 5.4 5.4 5.2 5.2 5 5 −1 −.5 0 .5 1 1.5 −50 0 50 100 150 BDR − FEV1 L BDR − FEV1 % B 100 100 80 80 60 60 40 40 20 20 0 0 −2 −1 0 1 2 −50 0 50 100 BDR − FVC L BDR − FVC % 80 80 60 60 40 40 20 20 0 0 −2 −1 0 1 2 −50 0 50 100 BDR − FVC L BDR − FVC % 120 120 100 100 80 80 60 60 40 40 20 20 −2 −1 0 1 2 −50 0 50 100 BDR − FVC L BDR − FVC % Figure 2. Restricted cubic spline models of bronchodilator response (BDR; as separate continuous variables change in forced expiratory volume in 1 second in liters [DFEV1 L], change in forced expiratory volume in 1 second percent predicted [DFEV1%], change in forced vital capacity in liters [DFVC L], and change in forced vital capacity percent predicted [DFVC%]), with 95% confidence intervals (in gray), for 6-minute-walk distance (6MWD), total St. George’s Respiratory Questionnaire (SGRQ) score, and quantitative computed tomography (CT) measures in the total study population. (A) The adjusted models of BDR (FEV1L and BDR2 FEV1%) for 6MWD, SGRQ, wall area (WA) segmental percentage, and square root wall area of a 15-mm diameter airway (Pi15). (B) The adjusted models of BDR2 FVCL and BDR2 FVC% for SGRQ, emphysema percentage, and gas trapping percentage. DFEV1L, DFEV1%, DFVCL, and DFVC% were coded using a restricted cubic spline function with three knots, located at the 5th, 50th, and 95th percentiles. Models were adjusted for age, sex, race, smoking history, body mass index, baseline FEV1 or FVC, and CT scanner type (for CT measures). 1510 AnnalsATS Volume 16 Number 12| December 2019 SGRQ Total Gas trapping % Emphysema % SGRQ Total Score Pi15 WAsegmental, % Score 6MWD, meters SGRQ Total Gas trapping % Emphysema % SGRQ Total Score Pi 15 WA segmental % Score 6MWD, meters ORIGINAL RESEARCH Table 4. Characteristics of the study population and marked BDR-FVC categories were less likely than negative responders to Variables Study Population (N= 7,741) experience exacerbations. There were significantly decreased odds of being in a Age, yr 60.26 8.9 higher mMRC category in moderate and Sex, male, % 54.5 marked BDR-FVC categories. However, Race, white/African American, % 72.7/27.3 mean Pi15 was 0.02 mm less in minimal BMI, kg/m2 28.66 6.1 BDR-FVC group than in negative BDR- Smoking history, pack-years (IQR) 40.0 (28.0–55.5) Prebronchodilator spirometry FVC responders. FEV, L 2.146 0.93 In models assessing the relationship FEV1, % predicted 72.26 26.0 between DFVCL and DFVC% as continuous FVC, L 3.286 1.03 variables (Figure 2B), total SGRQ score, FVC, % predicted 85.46 19.2 FEV /FVC, % 63.66 15.4 emphysema percentage, and gas trapping1 FEV /FVC ,70%, n (%) 4,298 (55.5) percentage were lowest in the region of1 Post-bronchodilator spirometry DFVCL and DFVC% levels around FEV1, L 2.246 0.93 21.5 L and 240%, respectively. After FEV1, % predicted 75.66 25.8 those regions, there was a trend of FVC, L 3.376 1.01 FVC, % predicted 87.86 18.5 increasing total SGRQ score, emphysema FEV1/FVC, % 65.16 16.0 percentage, and gas trapping percentage FEV1/FVC ,70%, n (%) 3,864 (49.9) with an upward slope as DFVCL and Within-subject coefficient of variation among 3 forced exhalations DFVC% increased. CV for 3 pre-BD FEV1, % 4.126 2.77 CV for 3 pre-BD FVC, % 3.546 2.46 CV for 3 post-BD FEV1, % 3.526 2.54 CV for 3 post-BD FVC, % 3.026 2.18 Discussion Change after bronchodilator DFEV1, L 0.0996 0.015 Our approach of identifying distribution DFVC, L 0.0926 0.030 DFEV , % 6.046 9.34 characteristics of BDR is an improvement1 DFVC, % 3.786 10.48 in evaluating clinical and radiological associations of bronchodilator responsiveness. Definition of abbreviations: BD=bronchodilator; BMI =body mass index; CV= coefficient of variation; Grading systems using several categories FEV1 = forced expiratory volume in 1 second; FVC= forced vital capacity; IQR= interquartile range. might be more useful than those yielding Mean6SD or median (25th–75th IQR) presented as appropriate. Reported pulmonary function values are based on largest measurements. only positive/negative categories. These data demonstrate the importance of separating volume and percentage BDR positive BDR, 79.4% in the marked category, in FVC. Prebronchodilator FEV1, FVC, and change rather than requiring both 32.3% in the moderate category, and only FEV1/FVC decreased as volume response simultaneously, which biases against 8.8% in minimal and mild BDR-FEV1 increased from minimal to marked FVC- identifying meaningful BDR in subjects categories. Almost four-fifths of the marked BDR. In the univariate analyses (Table with small or large FEV1. BDR group (794 of 1,000) was also ATS/ERS E1), total SGRQ and dyspnea scores, Our categorization employs identical positive. When we analyzed correlates of exacerbation frequency, segmental WA%, numerical fractions for ΔFEV1 in liters and BDR grades after excluding ATS/ERS emphysema percentage, and gas trapping in percentage units. It yields many more positives in the minimal, mild, and percentage increased as FVC-BDR increased positive responders than ATS/ERS positive moderate BDR categories, we observed from negative to marked (P, 0.0001). criteria do (Table 5). Logically, patients with that minimal, mild, and moderate BDR- After adjusting for potential low FEV1 should benefit more from small FEV1 were associated with greater confounders, including baseline FVC, FEV1 volume increases than those with large 6MWD and lower SGRQ than in the patients with greater BDR-FVC had greater FEV1. Advantageously, for the 7,741 negative BDR category. Odds of being emphysema and gas trapping and fewer individuals studied, our grading method in a higher mMRC category decreased exacerbations and lower mMRC (Table 2). identified 80% with at least minimal and as BDR-FEV1 increased from minimal Emphysema and gas trapping were 50% and 50% with moderate or greater FEV1 BDR, to moderate when compared with 46% greater, respectively, in marked BDR whereas the ATS/ERS method identified nonresponders (Table 3). than in negative responders. Mean WA% only 20.6% positive. and Pi15 of marked BDR-FVC were 0.67% Interpretation of BDR for patients BDR Grading Strategy Applied for and 0.04 mm greater than in negative with OAD in pulmonary laboratories has BDR in FVC responders, respectively. 6MWD was long been disputed. Nearly 50 years ago, By using proposed BDR cutoffs, 16.4%, approximately 14 m greater in marked Freedman and colleagues suggested that 12.0%, 12.1%, and 22.2% of the population BDR-FVC than in negative responders. most physicians would agree that an FEV1 had minimal, mild, moderate, and marked SGRQ was 9% and 14% higher in moderate increase less than 10% is valueless and FVC-BDR, respectively (Table 2). Of the and marked BDR-FVC than in negative that a 20–30% increase was likely useful study population, 37.3% had a negative BDR responders. Participants in mild, moderate, (24). In 1974, a Chest advisory committee Hansen, Dilektasli, Porszasz, et al.: A New Bronchodilator Response Grading Strategy 1511 ORIGINAL RESEARCH FEV1L FEV1% and as percentage change from baseline, so we employed this strategy. In addition, in NEGATIVE MIN MILD MOD MARKED the presence of severe airway disease such as 21.1% 27.9%20.0%18.1% 12.9% COPD, the baseline FEV1 may be far off the predicted value, which may cause an underestimation of the BDR as compared with performance of the subject variable (change in FEV1 as percent predicted) in relatively healthier or nonsmoker populations. BDR Category Assignments Dividing BDR data into grades has often used only mean and SD values. In our study population, using a grading approach based on DFEV1L or DFEV1% distribution and –0.4 –0.2 0.0 0.2 0.4 0.6 L means (Figure 3) might cause an unbalanced strategy, because 61 SD of volume change –40 –20 0 20 40 60 % would assimilate approximately 68% of FEV1 participants into one BDR class, with the remaining approximately 32% divided into Figure 3. Distribution of change in absolute volume for largest of three pre- to post-bronchodilator several much smaller classes (e.g., 62 SD, forced expiratory volume in 1 second (FEV1) differences (DFEV1L) and change in FEV1 percent predicted after bronchodilator in the whole study population (N=7,741). Dashed vertical lines represent 63 SD). Instead, our grading strategy is the limits of the new bronchodilator response (BDR) grading system (negative, <0.00% or <0.00 L; based on profile of changes in volume and minimal [MIN], .0.00% to <9.00% or .0.00 L to <0.09 L; mild, .9.00% to <16.00% or .0.09 L to percentage change in FEV1 (Figure 1) and <0.16 L; moderate [MOD], .16.00% to <26.00% or .0.16 L to <0.26 L; and marked, .26.00% or other considerations to establish grading .0.26 L). Percentages of participants in each BDR category are given between vertical lines that category cutoffs. This resulted in BDR of this represent the limits of the BDR grading system. Curves were constructed as Gaussian fits on the population being classified 21% negative, histogram points consisting of 24 bins with equal distance of 0.0905 L spanning from20.63 L to 1.45 L 28%minimal, 20%mild, 18%moderate, and forDFEV1L and 6.46%wide bins from231.8 to 116.8% forDFEV1% change. N.B.: To demonstrate the 13% marked. similarities and differences in distributions, only the segments from20.4 L to 0.6 L and from240% to Of the 7,741 participants, 21.1% had 60% changes are shown. negative BDR by FEV1 compared with 37.3% by BDR-FVC. Although BDR-FVC was reported more frequently than BDR- recommended positive BDR required FEV1 (American College of Chest Physicians [25]) FEV1 in patients with COPD (37, 38), we change in both percent and absolute volume and greater than 12% and 200-ml increase observed that BDR by FEV1 was more (25). In 1982, Reis recommended an FEV1 (ATS [28], ATS/ERS [1], and Global common than BDR by FVC in our study increase of both 15% and 200 ml (26). Initiative for Chronic Obstructive Lung population. FVC has the disadvantage of Eliasson and colleagues (27), reviewing 66 Disease [19]). In response to a letter by being dependent on expiratory time (39). asthma and COPD papers, found that 14 Hansen and colleagues (33), Hanania Therefore, evaluation of BDR by FVC may papers used seven different BDR criteria. In and colleagues agreed that BDR less be noisy (40). Figure 4 shows that, for 1991, an ATS committee recommended than 200 ml in those with low baseline FEV1 ΔFEV1L BDR greater than 100 ml, the increase in FEV1 or FVC greater than was clinically valuable (34). In 2005, number of individuals meeting any specific or equal to 200 ml and 12% (28). This Donohue (13) recommended that volume criterion is much greater for FVC criterion was reinforced in the 2005 greater than 100 ml FEV1 increase in than for FEV1, whereas for those meeting ATS/ERS guidelines (1). Considering patients with OAD is likely to be clinically ΔFEV1% criteria greater than 10% are that baseline FEV1 values of individuals important. similar for FVC and FEV1. In patients with assessed for BDR vary over a wide BDR may be expressed in alternate COPD, the magnitude of the flow (DFEV1) range (29), to exceed healthy population- ways: as absolute change in values, as and volume (DFVC) responses after based confidence intervals (30) for percentage change from baseline, or as administration of albuterol differs. A both volume and percentage values to change as a percentage of the subject’s particular flow response is accompanied by a establish positive BDR may be too predicted value (35, 36). Using change in higher volume response as the severity of restrictive. FEV1 as percent predicted was recently airflow obstruction worsens in COPD. In In a 2011 review, Hanania and shown to avoid sex and size bias in the our study,DFEV1 andDFVC responses were colleagues (31) examined the five most assessment of BDR (35). Although there is similar between BDR categories (Table 1). prevalent recommendations: including no consensus on how a BDR should be This finding may be a result of our study FEV1 percent predicted greater than 10% expressed in the literature, most guidelines population consisting of smokers, with (ERS [32]), FEV1 increase greater than 15% express BDR as absolute change in values almost 50% without airflow obstruction. 1512 AnnalsATS Volume 16 Number 12| December 2019 ORIGINAL RESEARCH 1.2 50  FEV1 L  FEV1 % 1.0  FVC L 40  FVC % 0.8 30 0.6 0.4 20 0.2 10 0.0 0 –0.2 –0.4 –10 –0.6 –20 0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18 Number of individuals (n*500) Number of individuals (n*500) Figure 4. Response trend of change in forced expiratory volume in 1 second (DFEV1) and change in forced vital capacity (DFVC) after bronchodilator in the total study population (N=7,741). (A) Response trend of mean change in absolute volume of DFEV1L and DFVCL in 500 individuals at each point. (B) Response trend of mean change in DFEV1% and DFVC% in 500 individuals at each point. In both A and B, individuals are ordered by size of response. Clinical Implications of BDR Grades initial observations of a relatively well- in the UPLIFT (Understanding Potential Our results indicate that spirometric indices preserved exercise tolerance in patients Long-term Impacts on Function with and CT measures of airway wall thickness with COPD with large BDRs (43). The Tiotropium) trial (45). Moreover, to our increase as BDR increases. In accordance mechanism underlying this observation is knowledge, our analysis is the first to show with reports suggesting inverse correlation not known, but one possible explanation is exacerbation frequency reduction without between spirometric obstruction and BDR, that patients with a larger BDR are able to regard to baseline FEV1 in patients with baseline FEV1/FVC decreased as BDR bronchodilate during the hyperpnea of moderate and marked BDR compared increased (27). We observed significant exercise. Despite the relationship between with negative responders. Our analysis increase in segmentalWA% and Pi15 as BDR 6MWD and DFEV1L being similar to that of characterizes a group of marked BDR increased from minimal to marked 6MWD and BDR-FEV1 response grades, the with more airway disease, evidenced by (Table 1). Similar trends persisted when we relationship between 6MWD and DFEV1% greater segmental WA% and Pi15, better- adjusted CT outcomes for baseline FEV1 was inverse (Figure 2A). One possible preserved exercise performance and and other potential confounders. Kim and explanation for the difference between dyspnea, better quality of life, and fewer colleagues found that airway wall thickness results of continuous modeling of 6MWD exacerbations than in negative responders. independently predicted BDR in COPD and versus FEV1% and DFEV1% may be that Associations observed for 6MWD in the suggested that increased CT airway wall greater than 90% of the responders in multivariable models are greater than thickness in the BDR positive COPD group each BDR category were positive by their MCIDs (46, 47). Associations for represented airway pathology dominated volume change in FEV1. For that reason, exacerbations and CT measures can only by smooth muscle hypertrophy (41). associations with BDR grades may be be evaluated statistically, because validated Morphometric studies in patients with dominated by associations with volume MCIDs for those outcomes do not yet asthma revealed bronchial tree zones change in FEV1. exist (48). with significant muscular hypertrophy, Recently, Quanjer and colleagues When we applied a BDR grading reflecting hyperreactivity of these segments suggested that an ideal BDR measure strategy for an FVC-based BDR, we (42). Both the segmental WA% and Pi15 should be based on clinical outcomes, observed that emphysema percentage and mainly reflect large airways. We believe such as exacerbations, quality of life, and gas trapping percentage increased as BDR in that our findings showing significant BDR hospitalizations (12). Not long before, FVC increased from minimal to marked dependence in segmental WA% and Pi15 Albert and colleagues suggested that BDR category. Emphysema and gas trapping were may reflect an increased bronchomotor did not distinguish clinical outcomes such as prominent features of BDR-FVC responders tone due to smooth muscle hypertrophy mortality or exacerbation rates in the in accordance with previous reports (49– in the large airways of smokers with marked ECLIPSE COPD (Evaluation of COPD 51). Cerveri and colleagues have shown that BDR. Longitudinally to Identify Predictive FVC responder patients with COPD have To our knowledge, our results indicate Surrogate Endpoints) cohort (44). We more severe emphysema than both FEV1 for the first time that 6MWD, a marker observed a significant increase in quality of and FVC responders (49). Furthermore, of functional exercise performance, life as BDR grade increased fromminimal to Deesomchok and colleagues have shown significantly and continuously increases as marked. In support of this, a higher SGRQ that patients with COPD with greatest acute BDR grade increases. This finding is in score was reported in poorly responsive resting lung hyperinflation show the agreement with Anthonisen and Wright’s patients with moderate to very severe COPD largest bronchodilator-induced volume Hansen, Dilektasli, Porszasz, et al.: A New Bronchodilator Response Grading Strategy 1513 Change (Liters) Change (%) ORIGINAL RESEARCH Table 5. Comparison of bronchodilator responses using ATS/ERS guidelines and SGRQ, and mMRC in the adjusted proposed bronchodilator response grades multivariable analysis: Patients with greater BDR had greater exercise performance, BDR Grades better quality of life, and less dyspnea perception (Table 3). Negative Minimal Mild Moderate Marked We observed that 21.1% of our study group had a negative response (defined as Total number of participants 1,634 2,159 1,549 1,399 1,000 Δ <0.00% or <0.00 L FEV change) toOnly FEV1% >12% 0 0 146 489 769 1 Only ΔFVC% >12% 27 121 216 345 505 albuterol. Recently, Bhatt and colleagues Only ΔFEV1L >0.2 L 0 0 0 632 955 showed that a paradoxical response to Only ΔFVCL >0.2 L 88 269 448 663 761 b2-agonists resulting in bronchoconstriction ΔFEV1L >0.2L and ΔFEV1% >12% 0 0 0 224 724 was associated with respiratory morbidity ΔFVCL >0.2L and ΔFVC% >12% 26 111 215 338 501 BDR(1) by ATS/ERS ΔFEV L >0.2L and 26 111 215 452 794 measured by higher mMRC, frequent1 ΔFEV % >12% or ΔFVCL >0.2L and exacerbations, and lower 6MWD (53).1 ΔFVC% >12% Probably, some of the participants in the negative response category in our study can Definition of abbreviations: ATS/ERS=American Thoracic Society/European Respiratory Society; be regarded as having a paradoxical BDR=bronchodilator response; FEV1= forced expiratory volume in 1 second; FVC= forced vital capacity. response to b2-agonists. Despite the Number of participants in each category is presented. ATS/ERS guidelines (ΔFEV1L >0.2L and negative category being set as the reference ΔFEV1% >12% or ΔFVC > 0.2L and ΔFVC% >12%) and proposed BDR grades (based on range of category in our analyses, our results are ΔFEV1L or ΔFEV1%). All models were controlled for sex, age, race, body mass index, smoking history, partly in accordance with those of Bhatt and and initial pre-bronchodilator FEV1. In addition, models with computed tomography (CT) outcomes colleagues by showing a decreasing quality were adjusted for CT scanner type. of life and 6MWD as BDR decreased, increasing odds for experiencing a higher response in reversibility testing (50). The In this study, we demonstrate that dyspnea level as BDR decreased, and greater volume response than flow BDR-FEV1 and BDR-FVC are associated decreasing odds for frequency of response in patients with COPD was with different clinical, functional, and exacerbations in patients with marked and explained by the presence of a higher radiological characteristics. Although moderate BDR compared with the negative loss of lung elastic recoil due to emphysema increasing BDR in FEV1 is primarily response category. and compression of small airways by the associated with improving 6MWD, quality In the whole study group, patients with enlarged airspaces as the airflow obstruction of life, and dyspnea, increasing BDR in FVC minimal BDR-FEV1 compared with those worsened (49). In addition to previously is primarily associated with increasing with mild, moderate, and marked BDR- reported findings, the BDR grading strategy emphysema and gas trapping. Moderate or FEV1 had lower exercise performance, lower defined in the present study was successful marked BDR in both measures is associated quality of life, and more dyspnea perception in capturing an increasing trend in with a reduction in exacerbation frequency. (Table 2). It seems logical to assume that the emphysema and gas trapping extent as A very recent paper aimed to examine minimal BDR-FEV1 group is likely to have BDR in FVC increased from minimal to clinical, functional, and radiological fixed airway obstruction, because their marked response categories compared associations of BDR by ATS/ERS criteria airways respond minimally to albuterol with nonresponders. (51). In subjects with spirometrically inhalation. BDR-FVC is associated with gas defined COPD, the authors have shown that trapping. This finding is in agreement with ATS-BDR positive participants in the Relevance to Asthma–COPD literature findings (51, 52). Gas trapping on COPDGene population were associated Overlap Phenotype quantitative CT is accepted as a prominent with higher gas trapping percentage, Bronchodilator responsiveness is accepted sign of small airway disease. In support of Pi10, functional small airway disease, as the key feature of asthma–COPD overlap this, small airway diameter on spiral CT functional residual capacity and total lung (ACO) phenotype (54). Although different scan was previously shown to narrow in capacity percent predicted, respiratory definitions for ACO are used in various FVC responder patients with COPD (49). exacerbations, and 6MWD than the non- studies, a spirometric component of a widely There was an inverse association with BDR- BDR group. In our study, in which we used ACO definition requires a marked FVC response and exacerbation frequency examined the responses of subjects BDR (.400 ml) or at least a positive BDR in patients with mild to marked BDR-FVC with smoking history with and without (>200 ml and 12%) in addition to persistent compared with negative responders. spirometric evidence of COPD, ATS/ERS airflow limitation (54–56). It might be Furthermore, quality of life was impaired in criteria identified most of the participants asked whether the characteristics of the moderate and marked BDR-FVC compared (79.4%) in the marked category as positive participants with marked BDR in our study with negative responders. We theorize that BDR. Despite this important clinical resembled clinical features of patients with impaired quality of life and increased association of the ATS/ERS BDR criteria ACO. Cosentino and colleagues found exacerbation frequency observed in these (51), when we excluded BDR positive that subjects with ACO had less severe patients may be a consequence of severe participants by ATS/ERS criteria, we spirometric and radiological findings (less hyperinflation and emphysema present in observed that clinical associations of BDR emphysema and gas trapping) but more moderate andmarked BDR-FVC responders. grading strategy persisted for 6MWD, segmental airway wall thickening and that 1514 AnnalsATS Volume 16 Number 12| December 2019 ORIGINAL RESEARCH they were more likely to experience frequent decisions (12). Therefore, we believe that the generalizability of the 100-ml MCID exacerbations than subjects with COPD this study’s findings are helpful to value to populations other than COPD (57). Although there are several published characterize clinical associations of (13). Fifth, we acknowledge that the studies aiming to characterize clinical bronchodilator responsiveness rather thresholds for the BDR grading system features of ACO phenotype in the than using them to make therapeutic were derived for FEV1 change. These COPDGene population (57–59), their decisions. We hope that our findings, in thresholds may not be fully applicable analysis is usually limited to comparing addition to recently reported studies that to FVC change. Further study will be features of patients with ACO with characterize BDR (12, 35), will spur necessary to determine whether different either COPD or asthma alone, rather guideline committees to revisit current BDR thresholds may perform better for FVC than comparing ACO characteristics criteria. response. with an overall smoker population. Our study has several limitations. Last, blood eosinophils have strong Having shown clinical implications of Although we used a large population, potential as a prognostic and therapeutic various degrees of BDR (much less than it includes only current smokers and biomarker in the clinical management 400 ml), we suggest considering the ex-smokers. A population-based sample of COPD. Evaluation of the association use of bronchodilator grading, rather of 3,922 healthy nonsmokers showed of bronchodilator responsiveness than an all-or-none evaluation that the upper 95% confidence limit for with blood eosinophil count would system, for further ACO phenotyping BDR was 284 ml for DFEV1 and 12% for be a promising analysis for further studies. DFEV1% (30). In the ECLIPSE cohort, FEV1 research. Tweeddale and colleagues (15) changes after an inhaled bronchodilator In conclusion, BDR in current smokers reported that, in patients with reduced in smoking control subjects and patients or ex-smokers can be graded by using either FEV1/FVC ratio, absolute FEV1 increase with COPD were significantly greater than volume or percentage change in FEV1 or required to exclude natural variability with in nonsmoking control subjects (35, 44). FVC. Our findings, based on the largest 95% confidence was 160 ml. In this context, Importantly, healthy never-smokers smoker population with quantitative minimal and mild categories in the were not included in our cohort, which CT data, suggest that this BDR grading proposed BDR grading system fall in restricts generalizability of our results system identified patients with clinically the range of this natural variability. In to this group. Second, whether other important differences in exercise our analysis, however, we observed that inhaled bronchodilators or other performance, quality of life, exacerbation minimal and mild BDR categories are albuterol doses should be similarly graded is frequency, dyspnea, and pulmonary associated with important patient-centered untested. Third, observations from various imaging. BDR-FEV1 and BDR-FVC outcomes in COPD (greater 6MWD, cohorts have shown that the presence of are associated with different clinical, lower SGRQ and mMRC dyspnea scores) BDR is variable over time (44, 60, 61). functional, and radiological characteristics. compared with negative BDR. The fact Unfortunately, our study does not include Whether these BDR categories have that BDR below variability thresholds may longitudinal analysis of the study cohort prognostic implications remains to be associate with symptom and performance to allow examination of long-term tested. n improvements (perhaps because BDR may implications of BDR categorization. Fourth, be unpredictably underestimated by FEV when defining thresholds for the BDR Author disclosures are available with the text1 and/or FVC changes in some cases) is also grading system, in distinguishing of this article at www.atsjournals.org. acknowledged in ATS/ERS 2005 guidelines between moderate and marked responses, (10). Furthermore, BDR to a short-acting a 100-ml MCID step size was used. Acknowledgment: This work is dedicated to bronchodilator is no longer recommended However, 100 ml as an MCID for FEV thememory of Dr. James E. Hansen, who died on1 May 7, 2017. He was our teacher, mentor, to predict long-term response and is not was based on a single study that enrolled colleague, and friend; we are much the poorer for believed to be helpful in making therapeutic only patients with COPD, which limits his passing. References 7 Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, et al. Genetic epidemiology of COPD (COPDGene) study design. COPD 1 Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. 2010;7:32–43. Interpretative strategies for lung function tests. Eur Respir J 2005;26: 8 Dilektasli AG, Porszasz J, Stringer WW, Pak Y, Rossiter HB, Casaburi R, 948–968. et al.; COPDGene Investigators. A new bronchodilator response 2 Hansen JE, Casaburi R, Goldberg AS. A statistical approach for grading strategy based on distribution of FEV1 increase identifies assessment of bronchodilator responsiveness in pulmonary function clinically distinct patient groups in the COPDGene cohort [abstract]. testing. Chest 1993;104:1119–1126. Am J Respir Crit Care Med 2018;197:A2450. 3 Hansen JE, Porszasz J. Rebuttal from Drs Hansen and Porszasz. Chest 9 Nickerson BG, Lemen RJ, Gerdes CB, Wegmann MJ, Robertson G. 2014;146:542–544. Within-subject variability and per cent change for significance of 4 Hansen JE, Sun XG, AdameD,WassermanK. Argument for changing criteria spirometry in normal subjects and in patients with cystic fibrosis. Am for bronchodilator responsiveness. Respir Med 2008;102:1777–1783. Rev Respir Dis 1980;122:859–866. 5 Pellegrino R, Brusasco V. Rebuttal from Drs Pellegrino and Brusasco. 10 Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Chest 2014;146:541–542. et al.; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir 6 Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW. J 2005;26:319–338. Bronchodilator reversibility testing in chronic obstructive pulmonary 11 Bhatt SP, Kim YI,Wells JM, BaileyWC, Ramsdell JW, ForemanMG, et al. disease. Thorax 2003;58:659–664. FEV1/FEV6 to diagnose airflow obstruction: comparisons with Hansen, Dilektasli, Porszasz, et al.: A New Bronchodilator Response Grading Strategy 1515 ORIGINAL RESEARCH computed tomography and morbidity indices. Ann Am Thorac Soc and management of chronic obstructive pulmonary disease (COPD). 2014;11:335–341. Eur Respir J 1995;8:1398–1420. 12 Quanjer PH, Ruppel GL, Langhammer A, Krishna A, Mertens F, 33 Hansen JE. A better way to assess bronchoreversibility. Chest 2012; Johannessen A, et al. Bronchodilator response in FVC is larger and 141:1118. more relevant than in FEV1 in severe airflow obstruction. Chest 2017; 34 Hanania NA, Celli BR, Donohue JF, Martin UJ. A better way to assess 151:1088–1098. bronchoreversibility: response. Chest 2012;141:1118–1119. 13 Donohue JF. Minimal clinically important differences in COPD lung 35 Ward H, Cooper BG, Miller MR. Improved criterion for assessing lung function. COPD 2005;2:111–124. function reversibility. Chest 2015;148:877–886. 14 Dales RE, Spitzer WO, Tousignant P, Schechter M, Suissa S. Clinical 36 Brand PL, Quanjer PH, Postma DS, Kerstjens HA, Koëter GH, interpretation of airway response to a bronchodilator: epidemiologic Dekhuijzen PN, et al.; Dutch Chronic Non-Specific Lung Disease considerations. Am Rev Respir Dis 1988;138:317–320. (CNSLD) Study Group. Interpretation of bronchodilator response in 15 Tweeddale PM, Alexander F, McHardy GJ. Short term variability in FEV1 patients with obstructive airways disease. Thorax 1992;47:429–436. and bronchodilator responsiveness in patients with obstructive 37 Newton MF, O’Donnell DE, Forkert L. Response of lung volumes to ventilatory defects. Thorax 1987;42:487–490. inhaled salbutamol in a large population of patients with severe 16 Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory hyperinflation. Chest 2002;121:1042–1050. Questionnaire. Respir Med 1991;85:25–31. [Discussion, pp. 33–37.] 38 Ben Saad H, Préfaut C, Tabka Z, Zbidi A, Hayot M. The forgotten 17 Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. message from GOLD: FVC is a primary clinical outcome measure of Usefulness of the Medical Research Council (MRC) dyspnoea scale bronchodilator reversibility in COPD. Pulm Pharmacol Ther 2008;21: as a measure of disability in patients with chronic obstructive 767–773. pulmonary disease. Thorax 1999;54:581–586. 39 Swanney MP, Jensen RL, Crichton DA, Beckert LE, Cardno LA, Crapo 18 ATS Committee on Proficiency Standards for Clinical Pulmonary RO. FEV6 is an acceptable surrogate for FVC in the spirometric Function Laboratories. ATS statement: guidelines for the six-minute diagnosis of airway obstruction and restriction. Am J Respir Crit Care walk test. Am J Respir Crit Care Med 2002;166:111–117. Med 2000;162:917–919. 19 Vestbo J, Hurd SS, Agustı́ AG, Jones PW, Vogelmeier C, Anzueto A, 40 Calverley PM, Albert P,Walker PP. Bronchodilator reversibility in chronic et al. Global strategy for the diagnosis, management, and prevention obstructive pulmonary disease: use and limitations. Lancet Respir of chronic obstructive pulmonary disease: GOLD executive summary. Med 2013;1:564–573. Am J Respir Crit Care Med 2013;187:347–365. 41 Kim V, Desai P, Newell JD, Make BJ, Washko GR, Silverman EK, et al.; 20 Patel BD, Coxson HO, Pillai SG, Agustı́ AG, Calverley PM, Donner CF, COPDGene Investigators. Airway wall thickness is increased in et al.; International COPD Genetics Network. Airway wall thickening COPD patients with bronchodilator responsiveness. Respir Res 2014; and emphysema show independent familial aggregation in chronic 15:84. obstructive pulmonary disease. Am J Respir Crit Care Med 2008;178: 42 Ebina M, Yaegashi H, Chiba R, Takahashi T, Motomiya M, Tanemura M. 500–505. Hyperreactive site in the airway tree of asthmatic patients revealed by 21 Gevenois PA, De Vuyst P, deMaertelaer V, Zanen J, Jacobovitz D, Cosio thickening of bronchial muscles: a morphometric study. Am Rev MG, et al. Comparison of computed density and microscopic Respir Dis 1990;141:1327–1332. morphometry in pulmonary emphysema. Am J Respir Crit Care Med 43 Anthonisen NR, Wright EC. Response to inhaled bronchodilators in 1996;154:187–192. COPD. Chest 1987;91(5, Suppl):36S–39S. 22 Zach JA, Newell JD Jr, Schroeder J, Murphy JR, Curran-Everett D, 44 Albert P, Agusti A, Edwards L, Tal-Singer R, Yates J, Bakke P, et al. Hoffman EA, et al.; COPDGene Investigators. Quantitative computed tomography of the lungs and airways in healthy nonsmoking adults. Bronchodilator responsiveness as a phenotypic characteristic of Invest Radiol 2012;47:596 602. established chronic obstructive pulmonary disease. Thorax 2012;67:– 23 Keene ON, Calverley PM, Jones PW, Vestbo J, Anderson JA. Statistical 701–708. analysis of exacerbation rates in COPD: TRISTAN and ISOLDE 45 Tashkin DP, Celli B, Decramer M, Liu D, Burkhart D, Cassino C, et al. revisited. Eur Respir J 2008;32:17 24. Bronchodilator responsiveness in patients with COPD. Eur Respir J– 24 Freedman BJ, Meisner P, Hill GB. A comparison of the actions of 2008;31:742–750. different bronchodilators in asthma. Thorax 1968;23:590 597. 46 Jones PW. St. George’s Respiratory Questionnaire: MCID. COPD 2005;– 25 Snider GL, Woolf CR, Kory RC, Ross J. Criteria for the assessment of 2:75–79. reversibility in airways obstruction: report of the Committee on 47 Puhan MA, Chandra D, Mosenifar Z, Ries A, Make B, Hansel NN, et al.; Emphysema American College of Chest Physicians. Chest 1974;65: National Emphysema Treatment Trial (NETT) Research Group. The 552–553. minimal important difference of exercise tests in severe COPD. Eur 26 Reis AL. Response to bronchodilators. In: Clausen JL, Abramon JF Respir J 2011;37:784–790. editors. Pulmonary function testing guidelines and controversies: 48 Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha equipment, methods, and normal values. New York: Academic Press; JA. Minimal clinically important differences in pharmacological trials. 1982. pp. 215–221. Am J Respir Crit Care Med 2014;189:250–255. 27 Eliasson O, Degraff AC Jr. The use of criteria for reversibility and 49 Cerveri I, Pellegrino R, Dore R, Corsico A, Fulgoni P, van de Woestijne obstruction to define patient groups for bronchodilator trials: influence KP, et al. Mechanisms for isolated volume response to a bronchodilator of clinical diagnosis, spirometric, and anthropometric variables. Am in patients with COPD. J Appl Physiol (1985) 2000;88:1989–1995. Rev Respir Dis 1985;132:858–864. 50 Deesomchok A, Webb KA, Forkert L, Lam YM, Ofir D, Jensen D, et al. 28 American Thoracic Society. Lung function testing: selection of reference Lung hyperinflation and its reversibility in patients with airway values and interpretative strategies. Am Rev Respir Dis 1991;144: obstruction of varying severity. COPD 2010;7:428–437. 1202–1218. 51 Fortis S, Comellas A, Make BJ, Hersh CP, Bodduluri S, Georgopoulos D, 29 Hansen JE, Porszasz J. Counterpoint: Is an increase in FEV1 and/or FVC et al.; COPDGene Investigators–Core Units: Administrative Center, > 12% of control and > 200 mL the best way to assess positive COPDGene Investigators–Clinical Centers: Ann Arbor VA. Combined bronchodilator response? No. Chest 2014;146:538–541. forced expiratory volume in 1 second and forced vital capacity 30 TanWC, VollmerWM, Lamprecht B, Mannino DM, Jithoo A, Nizankowska- bronchodilator response, exacerbations, and mortality in chronic Mogilnicka E, et al.; BOLD Collaborative Research Group. Worldwide obstructive pulmonary disease. Ann Am Thorac Soc 2019;16: patterns of bronchodilator responsiveness: results from the Burden of 826–835. Obstructive Lung Disease study. Thorax 2012;67:718–726. 52 Walker PP, Calverley PM. The volumetric response to bronchodilators 31 Hanania NA, Celli BR, Donohue JF, Martin UJ. Bronchodilator in stable chronic obstructive pulmonary disease. COPD 2008;5: reversibility in COPD. Chest 2011;140:1055–1063. 147–152. 32 Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J, Howard P, 53 Bhatt SP, Wells JM, Kim V, Criner GJ, Hersh CP, Hardin M, et al.; et al.; European Respiratory Society Task Force. Optimal assessment COPDGene Investigators. Radiological correlates and clinical 1516 AnnalsATS Volume 16 Number 12| December 2019 ORIGINAL RESEARCH implications of the paradoxical lung function response to b2 agonists: bronchodilator response and degree of emphysema. Ann Am Thorac an observational study. Lancet Respir Med 2014;2:911–918. Soc 2016;13:1483–1489. 54 Postma DS, Rabe KF. The asthma–COPD overlap syndrome. N Engl 58 Hardin M, ChoM, McDonald ML, Beaty T, Ramsdell J, Bhatt S, et al. The J Med 2015;373:1241–1249. clinical and genetic features of COPD–asthma overlap syndrome. Eur 55 Soler-Cataluña JJ, Cosı́o B, Izquierdo JL, López-Campos JL, Marı́n JM, Respir J 2014;44:341–350. Agüero R, et al. Consensus document on the overlap 59 Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, Make BJ, phenotype COPD-asthma in COPD. Arch Bronconeumol 2012;48: et al.; COPDGene Investigators. The clinical features of the overlap 331–337. between COPD and asthma. Respir Res 2011;12:127. 56 Sin DD, Miravitlles M, Mannino DM, Soriano JB, Price D, Celli BR, et al. 60 Hanania NA, Sharafkhaneh A, Celli B, Decramer M, Lystig T, Kesten S, What is asthma–COPD overlap syndrome? Towards a consensus et al. Acute bronchodilator responsiveness and health outcomes in definition from a round table discussion. Eur Respir J 2016;48: COPD patients in the UPLIFT trial. Respir Res 2011;12:6. 664–673. 61 Anthonisen NR, Lindgren PG, Tashkin DP, Kanner RE, Scanlon PD, 57 Cosentino J, Zhao H, Hardin M, Hersh CP, Crapo J, Kim V, et al.; Connett JE; Lung Health Study Research Group. Bronchodilator COPDGene Investigators. Analysis of asthma–chronic obstructive response in the lung health study over 11 yrs. Eur Respir J 2005;26: pulmonary disease overlap syndrome defined on the basis of 45–51. Hansen, Dilektasli, Porszasz, et al.: A New Bronchodilator Response Grading Strategy 1517