Abstract
Rationale: Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes.
Objectives: To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity.
Methods: A total of 279 eligible patients with COPD (stages I–IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient.
Measurements and Main Results: Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was −32 ± 24 (SD) ml/yr (n = 261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (−63 ± 2, −31 ± 1, and −2 ± 1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils.
Conclusions: Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.
Although the rate of annual decline in FEV1 is an important outcome measure in chronic obstructive pulmonary disease, little is known about intersubject variability based on clinical phenotypes.
The rate of annual change in post-bronchodilator FEV1 is highly variable over a period of 5 years among patients with chronic obstructive pulmonary disease who receive appropriate therapy. Emphysema severity is independently associated with a rapid annual decline in FEV1.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, and represents a substantial economic and social burden worldwide. COPD is characterized by progressive airflow limitation that is not fully reversible (1). FEV1 and the rate of annual decline in FEV1 are the most widely used outcome measures for clinical trials of pharmacotherapy or other interventions, such as smoking cessation, for COPD (2). To date, the factors that have been shown to convincingly affect annual decline in FEV1 are smoking status (3, 4) and frequency of exacerbation (5), although some pharmacotherapies (6, 7) have only recently been shown to have the potential to alleviate this natural decline.
The airflow limitation in COPD is caused by a mixture of abnormal inflammatory responses in small airways and parenchymal destruction of the lungs (emphysema), the relative contributions of which vary from person to person (1, 8). However, there have been few studies clearly demonstrating an independent effect of emphysema severity on annual decline in FEV1 in patients with COPD (9–11), although the emphysema phenotype is reportedly associated with poor quality of life, osteoporosis, arterial stiffness, lung cancer, and poor prognosis (12–16). In addition to emphysema severity, there are many other phenotypes based on clinical parameters, such as spirometry, nutritional status, exercise tolerance, and exacerbation, which have recently attracted attention (17, 18).
The Hokkaido COPD cohort study is a carefully designed multicenter observational cohort, which primarily aims to examine the annual decline in FEV1 over a period of 5 years based on clinical phenotypes in patients with smoking-related COPD. At baseline, we found that emphysema severity varied widely, even in patients with the same spirometric stage of COPD, and emphysema phenotype was associated with poorer quality of life and lower body mass index (BMI) independently of pulmonary function (19). Thus, we were particularly interested in the independent effects of emphysema phenotype on the annual decline in FEV1.
In this study, we evaluated emphysema severity in two ways: by computed tomography (CT) (20, 21) and by annual measurements of carbon monoxide diffusing capacity (DlCO) (22, 23). We measured pulmonary function every 6 months before and after inhaling a short-acting bronchodilator, whereas we monitored other confounding factors, such as smoking status, exacerbation, and pharmacotherapy, during the study period. We here demonstrate that emphysema severity is independently associated with a rapid decline in FEV1 in COPD. Some of the results in this manuscript have been previously reported in the form of an abstract (24).
A total of 330 patients with respiratory physician-diagnosed COPD were recruited at Hokkaido University Hospital, Sapporo, Japan, and nine affiliated hospitals from May 2003 to May 2005. All were aged 40 years or older, and were either current or former smokers with a smoking history of at least 10 pack-years. Subjects with asthma diagnosed clinically, but not based on any bronchodilator reversibility, at the time of study entry were excluded. Details of enrolment of the subjects and other exclusion criteria are listed in the online supplement. Thirty patients were excluded for consent withdrawal or were ineligible for inclusion before visit 1, and a total of 300 patients were followed. During the first follow-up year (visits 1–3), the diagnosis was reconfirmed based on the spirometric criteria of the Global Initiative for Chronic Obstructive Lung Disease guidelines (1) (a ratio of post-bronchodilator FEV1 to FVC <0.70), and included those subjects for later analysis who fulfilled the criteria even once among the three visits. As a result, a total of 279 subjects with COPD (stage I, 26%; stage II, 45%; stage III, 24%; and stage IV, 5%) were eligible for subsequent follow-up (Figure 1). The Ethics Committee of Hokkaido University School of Medicine approved the study protocol and written informed consent was obtained from all participants.
Figure 1. Flow chart for subject selection. COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease. * Subjects with three or more measurements of pulmonary function for the 5-year study period (n = 261) were included in the analysis of annual changes in FEV1 using a mixed effects model after confirming normal distribution of subjects with seven or more measurements of pulmonary function.
[More] [Minimize]Most subjects, except for those with stage I COPD, visited outpatient clinics at each hospital monthly or bimonthly for regular clinical checkups (see online supplement), and all were advised to participate in the follow-up study every 6 months for the following 5 years (from visits 1–11). Each physician was allowed to manage and treat subjects in such a way that he or she considered appropriate at all times, and thus changes in smoking status or pharmacotherapy often occurred in many subjects during the study period. Particularly, the subjects had been advised to cease smoking before they were enrolled in the study and those who could not give up smoking by entry were continuously encouraged to do so during the follow-up period. On the first visit, demographic information, including sex, age, height, weight, smoking history, medical history and any medications, and information on pulmonary symptoms were collected. Every 6 months, any changes in smoking status, medical history, and pharmacotherapy were monitored. Subjects were described as continuous, intermittent, or former smokers, depending on the smoking status during the study period. Actual use of any respiratory medicine was recorded on each visit, and usage was considered to be positive when any respiratory medicine was used for more than half of the entire follow-up period. Assessment of exacerbation during the study is described in detail in the online supplement (25). Health-related quality of life assessed by St. George's Respiratory Questionnaire (26) was examined every year, and blood was sampled also every year for measurements of circulating blood cell counts, serum IgE, erythrocyte sedimentation rate, or C-reactive protein. We confirmed at baseline that there were no subjects with α-antitrypsin deficiency. If permitted, blood samples for measurements of biomarkers or genetic samples were stored for later analysis.
Spirometry before and after inhalation of a bronchodilator was conducted on every visit, and DlCO was examined every 12 months (visits 1, 3, 5, 7, 9, and 11). On each visit, withdrawal of any respiratory medicine was confirmed before testing. DlCO was measured by the single breath method immediately after prebronchodilator spirometry and results were corrected by hemoglobin concentration, using the equation provided by American Thoracic Society guidelines (27), but not corrected by carboxyhemoglobin level. Transfer factor coefficient of the lung for carbon monoxide (Kco), which is DlCO corrected by alveolar volume, is used for later analysis. DlCO and Kco were expressed as percentages of predicted normal values (28). The reversibility of airflow limitation was evaluated before and at 30 minutes after inhalation of salbutamol (0.4 mg) at visits 1–5, 7, 9, and 11, or at 60 minutes after inhalation of oxitropium (0.4 mg) at visits 6, 8, and 10. Further details of pulmonary function tests and the reason for use of two classes of bronchodilators (29) are described in the online supplement.
Chest CT scans were performed in the supine position, with breath held at full inspiration. The CT scanners used in this study and details of technical parameters are described in the online supplement. Severity of emphysema was visually assessed by three independent pulmonologists according to the modified Goddard scoring system (19, 30). Computerized three-dimensional CT analysis of the lung (31, 32) was performed using custom software (AZE Ltd., Tokyo, Japan) only in those subjects who visited Hokkaido University Hospital (n = 108). Computerized analysis was not performed for all subjects because we could not obtain the Digital Imaging and Communications in Medicine images from some hospitals and it was considered to be hard to satisfactorily standardize quantitative computerized assessment of emphysema when the study was started. A good correlation was obtained between visually assessed severity of emphysema and severity based on computerized analysis (n = 108; r = 0.79; P < 0.0001) (see Figure E1 in the online supplement). Details for both visual assessment and computerized assessment are provided in the online supplement.
Summary statistics for subject characteristics were constructed using frequencies and proportions for categorical data, and mean ± SD for continuous variables, or median values with interquartile range for skewed continuous variables. Two types of analysis were performed for determination of individual annual changes in FEV1. First, linear regression analysis was used for each individual who underwent spirometric measurements more than seven times with a follow-up period of 3 to 5 years (n = 217). Normal distribution of intersubject variation in annual changes in FEV1 in the first analysis was confirmed by Kolmogorov-Smirnov tests. A mixed-effects model was then used for those subjects who had at least three spirometric measurements to accommodate loss-to-follow-up subjects, and the Best Linear Unbiased Prediction of the annual changes in post-bronchodilator FEV1 (milliliter per year) was estimated using the random coefficient regression model (33). Univariate analysis used chi-square tests for categorical variables, one-way analysis of variance for quantitative continuous variables with Tukey multiple comparison tests, and Kruskal-Wallis with Mann-Whitney U-tests for skewed continuous variables. Logistic regression analysis was performed where necessary (34). Data are shown as means ± SEM, unless otherwise specified. P value less than 0.05 was considered statistically significant.
The flow chart in Figure 1 depicts how the subjects were followed. Of 279 subjects with spirometry-confirmed COPD by the first year, 216 (77%) completed a 4-year follow-up period, and 195 (70%) completed a 5-year follow-up period (see Figure E2). The reasons for dropout (n = 84) during the study period are shown in Figure E3, and among these patients, 34 died.
First, we examined the annual change in FEV1 for 217 subjects who had more than seven spirometric measurements, with a follow-up period of 3–5 years (see Figure E4). The annual changes in FEV1, either for prebronchodilator values (mean ± SD: −26 ± 41 ml/yr, n = 215) or for post-bronchodilator values (−31 ± 38 ml/yr, n = 217) varied widely among subjects with normal distribution. Of particular note is that a significant proportion of subjects maintained pulmonary function over the study period.
We then used a linear mixed-effects model to assess the annual changes in FEV1 for all subjects who had at least three spirometric measurements (n = 261), regardless of whether they dropped out during the study period. The calculated annual change in post-bronchodilator FEV1 was −32 ± 24 SD ml/yr (Figure 2A). We next classified the subjects into three groups based on the magnitude of annual change in FEV1 (Tables 1 and 2). We labeled those of less than the 25th percentile as Rapid decliners (−63 ± 2 SE ml/yr); the 25th to 75th percentile as Slow decliners (−31 ± 1 SE ml/yr); and greater than the 75th percentile as Sustainers (−2 ± 1 SE ml/yr). Figures 2B and 2C displays the chronologic course of the mean FEV1 and that expressed as percent change from baseline in the three groups.
| Rapid Decliners(N = 65) | Slow Decliners(N = 131) | Sustainers(N = 65) | P Value | |
| Age, yr | 69 ± 6 | 70 ± 8 | 68 ± 9 | 0.11 |
| Female sex, N (%) | 1 (1.5) | 10 (7.6) | 4 (6.2) | 0.22 |
| Body mass index, kg/m2 | 21 ± 3* | 22 ± 3 | 23 ± 4 | 0.017 |
| Current smoker at entry, N (%) | 13 (20) | 40 (31) | 20 (31) | 0.26 |
| Smoking index at entry, pack-years | 67 ± 27 | 64 ± 33 | 55 ± 25 | 0.05 |
| Lung function | ||||
| Prebronchodilator | ||||
| FEV1, L | 1.58 ± 0.65 | 1.55 ± 0.67 | 1.70 ± 0.73 | 0.36 |
| FEV1, % predicted | 57 ± 22 | 58 ± 22 | 61 ± 24 | 0.59 |
| FVC, % predicted | 95 ± 19 | 92 ± 20 | 92 ± 23 | 0.70 |
| Post-bronchodilator | ||||
| FEV1, L | 1.76 ± 0·62 | 1.71 ± 0.66 | 1.84 ± 0.67 | 0.42 |
| FEV1, % predicted | 64 ± 21 | 64 ± 22 | 66 ± 23 | 0.74 |
| FVC, % predicted | 103 ± 17 | 100 ± 19 | 99 ± 22 | 0.47 |
| FEV1/FVC | 0.50 ± 0·13 | 0.51 ± 0.12 | 0.53 ± 0.13 | 0.20 |
| Reversibility of FEV1, % | 14 ± 14 | 14 ± 12 | 11 ± 14 | 0.33 |
| Reversibility of FEV1, ml | 176 ± 152 | 167 ± 121 | 148 ± 141 | 0.47 |
| DlCO, mmol/min/mm Hg | 11.2 ± 5.2† | 12 ± 4.6* | 14 ± 4 | 0.003 |
| Kco, mmol/min/mm Hg/L | 2.5 ± 1.2† | 2.8 ± 1† | 3.3 ± 1 | <0.001 |
| Patient-reported outcomes | ||||
| Chronic bronchitis, N (%) | 7 (11) | 11 (8) | 11 (17) | 0.20 |
| MRC dyspnea score, ≥2 (%) | 56 (86) | 111 (85) | 52 (80) | 0.59 |
| SGRQ total score | 31 ± 17 | 32 ± 17 | 31 ± 19 | 0.84 |
| Laboratory values | ||||
| Blood neutrophil count, cells/mm3 | 3,597 (2,759–4,601) | 3,342 (2,704–3,953) | 3,534 (2,893–4,287) | 0.13 |
| Blood eosinophil count, cells/mm3 | 120 (80–221)† | 169 (94–248)* | 233 (131–353) | 0.001 |
| Serum total IgE, IU/ml | 62 (19–153) | 73 (19–184) | 86 (27–216) | 0.64 |
| All Patients(N = 261) | Rapid Decliners(N = 65) | Slow Decliners(N = 131) | Sustainers(N = 65) | P Value | |
| Smoking status* | |||||
| Continuous smoker, N (%) | 40 (15) | 4 (6) | 24 (18) | 12 (19) | 0.21 |
| Intermittent smoker, N (%) | 40 (15) | 12 (19) | 18 (14) | 10 (15) | 0.21 |
| Former smoker, N (%) | 181 (69) | 49 (75) | 89 (68) | 43 (66) | 0.21 |
| Exacerbation (events/person/yr)† | |||||
| Symptom definition | 0.22 ± 0.39 | 0.19 ± 0.33 | 0.24 ± 0.44 | 0.22 ± 0.33 | 0.64 |
| Prescription change | 0.17 ± 0.33 | 0.15 ± 0.32 | 0.18 ± 0.36 | 0.18 ± 0.28 | 0.87 |
| Hospital admission | 0.06 ± 0.20 | 0.07 ± 0.21 | 0.06 ± 0.23 | 0.05 ± 0.11 | 0.84 |
| Medication for COPD (%)‡ | |||||
| Any medication | 190 (73) | 51 (78) | 97 (74) | 42 (65) | 0.19 |
| Anticholinergics | 135 (52) | 36 (55) | 71 (54) | 28 (43) | 0.27 |
| β-Receptor agonists | 92 (35) | 23 (35) | 47 (36) | 22 (34) | 0.96 |
| Theophylline | 116 (44) | 32 (49) | 58 (44) | 26 (40) | 0.57 |
| Inhaled corticosteroids | 36 (14) | 10 (15) | 18 (14) | 8 (12) | 0.88 |
Figure 2. Annual change in post-bronchodilator FEV1 among three groups classified by annual declines in post-bronchodilator FEV1. (A) Annual changes in post-bronchodilator FEV1 varied widely, with the mean (SD) post-bronchodilator FEV1 being −32 (24) ml/yr (n = 261). The subjects were categorized into three groups using the 25th percentile and the 75th percentile (lines in A): less than the 25th percentile as Rapid decliners (−63 ± 2 ml/yr, mean ± SEM); the 25th to 75th percentile as Slow decliners (−31 ± 1 ml/yr); and greater than the 75th percentile as Sustainers (−2 ± 1 ml/yr). (B) Mean post-bronchodilator FEV1 (with SEM) expressed as absolute values. (C) Mean post-bronchodilator FEV1 (with SEM) expressed as percent changes from baseline.
[More] [Minimize]There were no significant differences in spirometric data, reversibility of airflow limitation, or quality of life measurements among the three groups at baseline (Table 1). Furthermore, smoking status, exacerbation frequency, and pharmacotherapy during the study period did not significantly differ. Rather, there were fewer continuous smokers and pharmacotherapy was more intense in the Rapid decliners, although these differences were not statistically significant (Table 2). Among the clinical features, BMI was significantly lower in the Rapid decliners compared with the Sustainers. Interestingly, circulating eosinophil count was significantly higher in the Sustainers compared with the other two groups. Most markedly, emphysema score was significantly higher in the Rapid decliners on visual assessment of all subjects compared with the other two groups (P < 0.05) (Figure 3A). Computerized assessment of a limited number of subjects (n = 108) revealed the same results (Figure 3B). Consistent with this, %Kco at baseline was the lowest in the Rapid decliners, followed by the Slow decliners, and then the Sustainers (Figure 3C). Furthermore, the annual decline in DlCO or Kco expressed as percent change from baseline was significantly greater in the Rapid decliners compared with the other two groups (P < 0.05) (Figure 4A) or compared with the Slow decliners (P < 0.05) (Figure 4B).
Figure 3. Emphysema severity at baseline among three groups classified by annual declines in post-bronchodilator FEV1. Emphysema severity was assessed by (A) emphysema score visually assessed (n = 261), (B) percent low attenuation volume (n = 108), and (C) percent carbon monoxide transfer coefficient (%Kco, n = 257). Data show medians with interquartile range for skewed data (A and B) and means with SEM for quantitative continuous variables (C). See Figure 2 A for classification of the three groups.
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Figure 4. Annual declines in diffusing capacity of carbon monoxide and carbon monoxide transfer coefficient in three groups classified by annual declines in post-bronchodilator FEV1. Both diffusing capacity of carbon monoxide and carbon monoxide transfer coefficient were expressed as percent changes from baseline over a period of 5 years. See Figure 2 A for classification of the three groups. * P < 0.05 versus Slow decliners; † P < 0.05 versus Sustainers.
[More] [Minimize]To elucidate independent predictors for the Rapid decliners or the Sustainers we then used logistic regression models between the Rapid decliners and the Slow decliners, and between the Sustainers and the others (Tables 3 and 4). We included 10 items as potential confounding factors and treated emphysema score and %Kco separately, because they were mutually correlated. In addition, BMI was eliminated from this analysis because it was closely related to emphysema severity. As a result, higher emphysema score or lower %Kco was an independent predictor for the Rapid decliners compared with the Slow decliners. In addition, higher circulating neutrophil count was also a significant predictor for the Rapid decliners. However, the Sustainers were significantly associated with more chronic bronchitis symptoms, higher circulating eosinophil count, and lower emphysema score or higher %Kco.
| %Kco Excluded | Emphysema Scores Excluded | |||||
| Odds Ratio | 95% CI | P Value | Odds Ratio | 95% CI | P Value | |
| Emphysema score | 1.46 | 1.01–2.11 | 0.047 | |||
| %Kco, 10% | 0.84 | 0.73–0.96 | 0.014 | |||
| Post-bronchodilator FEV1, % predicted | 1.00 | 0.99–1.02 | 0.66 | 1.00 | 0.99–1.02 | 0.75 |
| Reversibility of airflow limitation | 1.01 | 0.98–1.05 | 0.45 | 1.02 | 0.98–1.06 | 0.36 |
| Blood neutrophil count, 100 cells/μl | 1.03 | 1.00–1.07 | 0.036 | 1.04 | 1.01–1.07 | 0.021 |
| Blood eosinophil count, 10 cells/μl | 0.98 | 0.95–1.01 | 0.12 | 0.98 | 0.95–1.01 | 0.12 |
| Chronic bronchitis symptom | 1.47 | 0.50–4.36 | 0.49 | 1.34 | 0.44–4.11 | 0.61 |
| MRC dyspnea scale ≥2 | 0.85 | 0.33–2.23 | 0.75 | 0.77 | 0.30–2.02 | 0.60 |
| Continuous vs. noncontinuous smokers | 0.84 | 0.35–1.98 | 0.68 | 0.70 | 0.30–1.76 | 0.42 |
| Exacerbation frequency, events/yr | 1.17 | 0.54–2.54 | 0.69 | 1.16 | 0.54–2.52 | 0.70 |
| Age, yr | 0.99 | 0.94–1.03 | 0.52 | 0.98 | 0.94–1.03 | 0.39 |
| Female sex | 0.20 | 0.02–1.67 | 0.14 | 0.22 | 0.03–1.85 | 0.16 |
| %Kco Excluded | Emphysema Scores Excluded | |||||
| Odds Ratio | 95% CI | P Value | Odds Ratio | 95% CI | P Value | |
| Emphysema score | 0.68 | 0.47–0.99 | 0.042 | |||
| %Kco, 10% | 1.21 | 1.06–1.38 | 0.004 | |||
| Post-bronchodilator FEV1, % predicted | 1.00 | 0.98–1.01 | 0.58 | 1.00 | 0.98–1.02 | 0.90 |
| Reversibility of airflow limitation | 0.98 | 0.95–1.01 | 0.23 | 0.98 | 0.94–1.01 | 0.19 |
| Blood neutrophil count, 100 cells/μl | 1.01 | 0.98–1.04 | 0.51 | 1.01 | 0.98–1.04 | 0.71 |
| Blood eosinophil count, 10 cells/μl | 1.04 | 1.01–1.06 | 0.007 | 1.03 | 1.01–1.06 | 0.013 |
| Chronic bronchitis symptom | 2.68 | 1.14–6.30 | 0.024 | 2.97 | 1.24–7.12 | 0.014 |
| MRC dyspnea scale ≥2 | 0.84 | 0.37–1.91 | 0.67 | 0.91 | 0.39–2.11 | 0.82 |
| Continuous vs. noncontinuous smokers | 0.99 | 0.48–2.07 | 0.99 | 1.23 | 0.59–2.57 | 0.58 |
| Exacerbation frequency, events/yr | 0.98 | 0.41–2.34 | 0.97 | 1.04 | 0.43–2.50 | 0.94 |
| Age, yr | 0.97 | 0.93–1.01 | 0.13 | 0.98 | 0.94–1.02 | 0.29 |
| Female sex | 1.14 | 0.31–4.20 | 0.84 | 1.01 | 0.27–3.72 | 0.99 |
Finally, the rate of annual decline in FEV1 was examined in subjects who were classified based on emphysema severity at baseline (19). As expected, the annual decline was significantly larger in subjects who were diagnosed as having severe emphysema (score ≥2.5) compared with those having no or mild emphysema (score <1; P < 0.001) or moderate emphysema (score ≥1, and <2.5; P < 0.05) (Figure 5A). The same trend was found when subjects were classified into three groups based on percent low attenuation volume at baseline; subjects who showed lower percent low attenuation volume (<25th percentile) demonstrated a larger annual decline in FEV1 compared with the other two groups (interquartile and >75th percentile) (Figure 5B).
Figure 5. Annual declines in post-bronchodilator FEV1 among three groups classified by emphysema severity at baseline. Emphysema severity on computer tomography was assessed (A) by visual assessment (n = 261) and (B) by computerized analysis (n = 108). Subjects with emphysema severity were defined as follows: no or mild emphysema (emphysema score <1, % of low attenuation area [LAA] in the assessed lung <12.5% on average); moderate emphysema (emphysema score <2.5, 12.5% <% of LAA <50%); and severe emphysema (emphysema score <2.5, 50% <% of LAA) (19.) In case of computerized assessment, subjects were classified as no or mild emphysema, less than the 25th percentile; moderate emphysema, the 25th to 75th percentile; and severe emphysema, greater than the 75th percentile of percent low attenuation volume (%LAV). Data show means with SEM.
[More] [Minimize]In this study, we demonstrated that there is a wide variability in the rate of annual change in FEV1, with normal distribution among the subjects with COPD, over a period of 5 years. Most importantly, we found that emphysema severity assessed by either CT or %Kco was independently associated with a rapid annual decline in FEV1 and that the Rapid decliners displayed an accelerated decline in DlCO and Kco over the 5-year follow-up period when expressed as percent change from baseline compared with the other two groups. Of additional note is that a significant proportion of subjects maintained FEV1 over a period of 5 years and they displayed increased levels of circulating eosinophils, although within normal limits.
This study has several strengths. First, it was a carefully designed, carefully conducted, prospective cohort, and the final follow-up rate of the subjects was very high (70%) at the 5th year, and even higher (82%) if one considers the number of the subjects who died. We accurately recorded confounding factors, such as smoking status, exacerbation, and pharmacotherapy during the study period. Second, assessment of annual change in FEV1 was based on measurements every 6 months over a period of 5 years; indeed, 217 subjects underwent more than seven measurements, and as many as 197 subjects underwent more than nine measurements. Burrows (35) noted in the early 1980s that the variability in FEV1 makes true rates of decline difficult to measure in individual patients, unless there are numerous time points over many years of follow-up. He also noted that intersubject variation in calculated rates of annual decline in FEV1 would be smaller with longer follow-up periods. Finally, emphysema severity was evaluated in this study using two methods: CT scans (20, 21) and annual measurements of DlCO and Kco (22, 23). This is important in the assessment of emphysema severity because neither of the two modalities is a perfect predictor of emphysema severity on a pathologic basis, and should thus be considered to be mutually complementary.
In most clinical trials of pharmacotherapy for COPD, including recently reported large-scale trials, annual decline in FEV1 is one of the most important outcome measurements (36, 37). Indeed, COPD is characterized by progressive airflow limitation, and thus an attempt to alleviate the annual decline in FEV1 is a major target of any therapeutic intervention. Smoking cessation is the best established and most effective intervention for this goal (3, 4). Recent studies have shown that some pharmacotherapy has the capacity to alleviate the annual decline in FEV1 by approximately 16 ml/yr (6, 7). However, no previous studies have considered clinical phenotype defined by emphysema severity in assessment of annual decline in FEV1. COPD is characterized by a combination of pulmonary emphysema and small airway disease (1, 8), both of which are known to vary substantially among patients even with the same spirometric COPD stages (8, 19), and emerging evidence exists to support the independent genetic influence on emphysema and airway disease (38–40). This study provides the first evidence that the phenotype defined by emphysema severity should be considered in future clinical trials when annual decline in FEV1 is a primary outcome measurement.
Few studies have examined the effects of emphysema on annual decline in lung function. In healthy smokers, Remy-Jardin and coworkers (9) reported that subjects with subtle morphologic abnormalities assessed by CT, including emphysema, at baseline showed a more rapid decline in lung function compared with those with normal CT findings. Another study by Yuan and coworkers (10) reported that quantitative assessment of overinflation of the lung by CT may be able to identify the “susceptible minority of smokers” who will eventually develop COPD. Only recently, Hoesein and coworkers (11) demonstrated that greater baseline severity of CT-detected emphysema is related to lower lung function and greater rates of lung function decline in a larger population. However, in these studies, the authors focused on the importance of early detection of emphysema in seemingly healthy subjects, not on emphysema phenotype in all stages of COPD. Unfortunately, they did not use post-bronchodilator values in FEV1, and calculated the annual decline with only two-point measurements. However, in another study examining emphysema severity and annual decline in FEV1 in patients with advanced COPD (41), only patients with moderate to severe COPD with the presence of significant emphysema were recruited because they were candidates for volume reduction surgery. Thus, it is understandable that no relationship between emphysema severity and annual decline in lung function was detected.
The magnitude of annual decline in FEV1 observed in this study may be relatively small compared with that reported in recently conducted clinical trials worldwide (36, 37). Possible reasons include that the subjects were allowed to receive pharmacotherapy during the study, as decided by their physicians, and that the percentage of continuous or intermittent smokers was as low as only about 15% in each during the follow-up period because of our intense advice of cessation of smoking before they entered the study. Another reason may be the unique clinical characteristics observed in Japanese patients with COPD, because Japanese subjects participating in the recent UPLIFT study also showed a much smaller annual decline in FEV1 (27 ml/yr with tiotropium) compared with the overall average (42). It is not clear whether this is caused by ethnic or genetic differences, or by environmental differences, including socioeconomic factors. Another unique finding of this study is the very low incidence of exacerbation during the study period in all subject groups. This was again observed in the Japanese participants in the UPLIFT study and another study only recently published (43). Whatever the reason, the low incidence of exacerbation during the study period may help to elucidate the independent effects of emphysema severity on annual decline in FEV1 in this study. It is of note that we have seen a dramatic decrease in chronic bronchitis symptoms in patients with COPD for the last two or three decades that certainly contributed low incidence of exacerbation in our population. It may be surprising that we did not see any deleterious effect of continuous smoking on annual decline of FEV1. We examined the background of the groups classified by smoking behavior (see Table E1); however, we could not identify any reasons. The results might be a simple consequence that Rapid decliners were more willing to quit smoking in response to physicians’ advice and their worsening symptoms.
It must be noted that a significant proportion of the subjects maintained pulmonary function over a period of 5 years (annual decline, −2 ± 1 ml/yr). Characteristics that significantly discriminate the Sustainers from the others were higher, but within the normal range, levels of eosinophils in blood and more frequent chronic bronchitis symptoms. They had lower levels of emphysema, and slightly but significantly greater BMI. Considering these clinical features, one can speculate that there were some patients with asthma in this group; however, we clinically excluded patients with asthma at entry (Table 1). Furthermore, we did not observe any significant differences in reversibility of airflow limitation among the three groups during the entire follow-up period (see Figure E5). Nevertheless, clinicians should pay closer attention to the presence of those patients with COPD who maintain pulmonary function over the long-term in daily practice and future clinical trials.
This study has several limitations. First, most of the subjects were male, and findings may not necessarily be extrapolated to female patients with COPD. This biased sex ratio simply reflects the marked difference in prevalence of smoking between men and women in Japanese society. Second, emphysema severity on CT was visually assessed. However, it was shown that visual emphysema scoring for three CT slices was strongly correlated with objective volume-based computerized assessment for the whole lung in a limited number of subjects (see Figure E1). We also found very similar findings (Figure 5), even for those subjects in whom computerized analysis could be performed. Both Kco and DlCO data are definitely complementary for evaluation of emphysema severity in this study. Finally, the sample size in this study was not so large compared with previous large-scale studies, such as the Lung Health Study (4) and the UPLIFT study (36) in which the rate of annual decline in FEV1 was also the primary endpoint. Thus, the lack of adequate power as a result of the small sample size may well explain some of the failures in detecting the factors, such as exacerbation and chronic bronchitis syndrome, which would potentially influence natural history of COPD.
In conclusion, we demonstrated that emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. We also confirmed the presence of Sustainers who can maintain pulmonary function over a period of 5 years provided that they receive appropriate therapy. Emphysema severity and presence of Sustainers should thus be considered in daily practice and in future clinical trials where annual decline in FEV1 is a primary outcome measurement.
Hokkaido COPD Cohort Study Group Investigators: Yoshikazu Kawakami, Youichi Nishiura, Hiroshi Saito, Tetsuya Kojima, Kazuhiko Sakai, Yoriko Demura, Yukihiro Tsuchida, Motoko Tsubono, Kazuhiro Tsuboya, and Shinichi Kakimoto, KKR Sapporo Medical Center; Kiyonobu Kimura, Ikuo Nakano, Moto Katabami, Kouichi Itabashi, Kiyoshi Morikawa, Seiichi Tagami, Yoshihiro Otsuka, Rika Sato, Junichiro Kojima, Shinji Nigawara, Takashi Morioka, Ichiro Sakai, Shiro Fujii, Kazuyoshi Kanehira, Ryota Funakoshi, Yui Takashima, Masahiro Awaka, Hitoshi Ishii, Makoto Nakayama, Hiroki Honda, Ryo Kaneda, and Masahisa Takagi, Hokkaido Chuo Rosai Hospital; Hiroshi Yamamoto, Kenji Akie, Fumihiro Honmura, Shinichi Kusudou, Hiroshi Izumi, Kensuke Baba, Hiroki Goya, Kihoko Kitamura, Shiho Mineta, Takayo Takeda, Kiyoshi Kubo, Junko Yamaguchi, and Hiroshi Nara, Sapporo City General Hospital; Tsuyoshi Nakano, Chihiro Naka, Hiroko Sato, Teiji Yamamoto, Toshio Abe, and Nobuo Tomita, Otaru City Hospital; Kimihiro Takeyabu, Yuji Ootsuka, and Naoki Watanabe, Otaru Kyokai Hospital; Fujiya Kishi, Akihide Ito, Michihiro Fujino, Masashi Ohe, Toshiyuki Harada, Yasuko Noda, Teruyo Takahashi, Keiko Abe, Akira Nakajima, Tomonori Fujii, Hiroshige Mori, Hideo Taguchi, Takashi Kojima, Ryouji Minami, Shigeki Murakami, Yuzuri Oono, Osamu Ishigamori, Satoru Akimoto, Takashi Emoto, Daichi Takahashi, and Risa Ajioka, Hokkaido Social Insurance Hospital; Akira Kamimura, Nobuyuki Hakuma, Noriaki Sukou, Eriko Anada, Tamaki Numata, Teiko Itakura, Tomoko Iizawa, Rina Ohya, and Yoshihiro Honoki, Iwamizawa City General Hospital; Kazuo Takaoka, Isamu Doi, Miki Suzuki, Sachiko Komuro, Yoshiko Yoshida, Michiko Kobayashi, and Hitoshi Seki, Sapporo Social Insurance General Hospital; Atsushi Ishimine, Ryouji Nakano, Masako Ishihara, Fumiyo Itagaki, Naoya Matsuzaka, Takae Kosukegawa, Eriko Miyajima, Kimitsugu Nakamura, Wako Funayama, Katsumigi Tsuchiya, and Ryouji Kaihatsu, Kinikyo Chuo Hospital; Kaoru Kamishima and Yasushi Hasegawa, Tenshi Hospital; Kunio Hamada, Yoko Ito, Motoko Kobayashi, Takeshi Hosokawa, Nao Odajima, Chinatsu Moriyama, Takayuki Yoshida, Takashi Inomata, Kanako Maki, Eiji Shibuya, Yoshiko Obata, Kotomi Hosono, Kana Yoshikuni, and Tomoko Akiyama, First Department of Medicine/Hokkaido University School of Medicine; Yuya Onodera, Department of Radiology, Hokkaido University Graduate School of Medicine; Tsukasa Sasaki, Division of Radiology, Department of Diagnosis and Treatment Support Part, Hokkaido University Hospital; Katsuaki Nitta, Masafumi Yamamoto, and Shigetaka Mizuno, Division of Pulmonary Function, Department of Laboratory Medicine, Hokkaido University Hospital; Kenji Miyamoto, Division of Rehabilitation Science, Faculty of Health Sciences, Hokkaido University; and Nobuyuki Hizawa, Pulmonology, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba.
The authors thank Hideka Ashikaga, Ayako Kondo, and Yuko Takagi at the Central Office of Hokkaido COPD Cohort Study; the staff of Exam Co., Ltd.; Tatsuo Kagimura at the Medical Data Services Department Biostatistics Group in Nippon Boehringer Ingelheim; Takahiro Nakamura; Masaki Minami at the Medical Affairs Department Respiratory and Allergy Group in Nippon Boehringer Ingelheim; and the medical doctors, nurses, and technicians in all hospitals involved in the study.
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*These authors contributed equally to the entire study and writing of the manuscript.
†A complete list of members may be found before the beginning of the References.
Supported by a scientific research grant to the Hokkaido COPD Cohort Study from the Ministry of Education, Science, Culture and Sports of Japan (17390239 and 2139053 to M.N.); Nippon Boehringer Ingelheim; Pfizer, Inc.; and a grant to the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare, Japan. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Author Contributions: M.N. and H.M., study concept and design, acquisition of data, interpretation of data, and drafting and finalizing of the manuscript; K.N., S.K., Y.N., M.H., K.S., T.B., S.F., T.I., Y.A., and S.O., study design, acquisition of data, and interpretation of data; and Y.M.I., statistical analysis and interpretation of data.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201106-0992OC on October 20, 2011
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