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Lung Function Decline in Male Heavy Smokers Relates to Baseline Airflow Obstruction Severity
CHEST
Original Research COPD
Lung Function Decline in Male Heavy Smokers Relates to Baseline Airflow Obstruction Severity Firdaus A. A. Mohamed Hoesein, MD, PhD; Pieter Zanen, MD, PhD; H. Marike Boezen, PhD; Harry J. M. Groen, MD, PhD; Bram van Ginneken, PhD; Pim A. de Jong, MD, PhD; Dirkje S. Postma, MD, PhD; and Jan-Willem J. Lammers, MD, PhD
Background: Recent evidence indicates that the rate of lung function decline is steepest in mild COPD and slower in moderate to severe COPD. The current study assessed whether lung function decline relates to baseline airflow obstruction severity in male heavy smokers. Methods: In total, 2,003 male smokers with a mean (SD) age of 59.8 (5.3) years underwent pulmonary function testing at baseline and after 3-year follow-up. Participants were classified by entry FEV1/FVC as follows: group 1, .70%; group 2, ,70%, but greater than lower limit of normal (LLN); and group 3, less than LLN. Differences in lung function decline among the groups were assessed using multiple regression after adjustment for pack-years, smoking status (current or former smoker), presence or absence of mucus production, medical center, height, age, CT scan-derived emphysema severity (15th percentile), observation time (years in study), and the baseline values. Results: Over 3 years, the mean (SD) FEV1/FVC, FEV1, and maximum expiratory flow at 50% of FVC decreases in group 1 were 3.1% (1), 0.21 L (0.07), and 0.40 L/s (0.26), respectively. In group 3, these decreases were 2.4% (1.1), 0.15 L (0.08), and 0.06 L/s (0.19), respectively. All lung function parameters showed the greatest decline in group 1 (P , .001). Conclusions: Diagnosing COPD based on the presence of more severe airflow obstruction (as defined by FEV1/FVC less than LLN) means that, at the time of such a diagnosis, subjects had passed the phase of strong lung-function decline. Trial registry: ISRCTN Register; No.: ISRCTN63545820; URL: www.trialregister.nl CHEST 2012; 142(6):1530–1538 Abbreviations: ATS 5 American Thoracic Society; ECLIPSE 5 Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; ERS 5 European Respiratory Society; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; LLN 5 lower limit of normal; MEF50 5 maximum expiratory flow at 50% of FVC; NELSON 5 DutchBelgian Lung Cancer Screening Trial; Perc15 5 15th percentile; PFT 5 pulmonary function test; TORCH 5 Towards a Revolution in COPD Health; UPLIFT 5 Understanding the Potential Long-term Impacts With Tiotropium
will be the third leading cause of death by COPD 2020 and is the only chronic disease with increas-
ing morbidity and mortality rates.1 COPD includes emphysema and chronic bronchitis, which can coincide, and both contribute to airflow obstruction. According to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria, COPD is present when the FEV1/FVC is , 70%, but the European Respiratory Society (ERS) and the American Thoracic Society (ATS) recommend the lower limit of normal (LLN) as the threshold for diagnosing COPD.2,3 No consensus exists as to which of these thresholds is more suitable.4,5
An accelerated lung function decline is an important hallmark of COPD and is already present before the FEV1/FVC ratio falls below either of the two thresholds. Often the diagnosis of COPD is based on a onetime pulmonary function test (PFT), and so COPD can be missed when such testing is performed “too early.” Emphysema, assessed with chest CT scan-based lung densitometry, can be present before airflow obstruction manifests.6 Two large, randomized, clinical trials, the Understanding the Potential Long-term Impacts With Tiotropium (UPLIFT) and Towards a Revolution in COPD Health (TORCH) studies, assessed the effect
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Figure 1. Flowchart of inclusion.
of pharmacologic treatment on lung function in patients with COPD.7,8 In the placebo-treated groups, the rate of decline was steepest in mild COPD and slower in moderate to severe COPD. However, differences in the dropout rates between the COPD stages offered an alternative explanation for this phenomenon, and no further analyses were performed to investigate this effect in more detail. We hypothesized that pulmoManuscript received November 7, 2011; revision accepted May 23, 2012. Affiliations: From the Division of Heart and Lungs, Department of Respiratory Medicine (Drs Mohamed Hoesein, Zanen, and Lammers), Image Sciences Institute, Department of Radiology (Dr van Ginneken), and Department of Radiology (Dr de Jong), University Medical Center Utrecht, Utrecht; Department of Epidemiology (Dr Boezen), and Department of Pulmonology (Drs Groen and Postma), University Medical Center Groningen, University of Groningen, Groningen; and Diagnostic Image Analysis Group, Department of Radiology (Dr van Ginneken), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Funding/Support: Funding was received from European Union FP7 [Grant 201379 COPACETIC (COPD Pathology: Addressing Critical Gaps, Early Treatment and Innovative Concepts)]. Correspondence to: Pieter Zanen, MD, PhD, University Medical Center Utrecht, HP F.02.333, PO Box 85500, 3508 GA Utrecht, The Netherlands; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-2837
nary function decline indeed is steeper in mild COPD stages and could be steepest in heavy smokers with only mild or absent airflow obstruction. The aim of the current study, therefore, was to assess the magnitude of lung function decline in relation to baseline airflow obstruction severity in a cohort of relatively healthy heavy smokers. We compared three groups: group 1 with FEV1/FVC . 0.70; group 2 with FEV1/FVC between 70% and LLN, and group 3 with FEV1/FVC less than LLN, representing increasing degrees of airflow obstruction. Materials and Methods Participants The study was conducted among participants of the Dutch Belgian Lung Cancer Screening Trial (NELSON) by the University Medical Centers in Utrecht and Groningen, The Netherlands. The NELSON study included only subjects with a high risk of developing lung cancer or COPD.9,10 Male subjects (aged ⱖ 50 years) with a smoking history of ⱖ 20 pack-years and fit enough to undergo surgery when lung cancer was potentially found were invited to participate. Subjects should not have quit smoking . 10 years before inclusion. Only men were included, as fewer women in the Dutch population accrued long-term tobacco exposure. Patients with a moderate or poor self-reported health status or who were unable to climb two flights of stairs were excluded. Detailed
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Table 1—Baseline Demographics of Included Participants for the Total Population and According to Groups Characteristics Age, y Current smokers, % Pack-years FEV1, L FEV1, % predicted FEV1/FVC, % MEF50, L/s Mucus production present, %d CT scan-derived emphysema, Perc15
Total (N 5 2,003)
Group 1a (n 5 1,337)
Group 2b (n 5 317)
Group 3c (n 5 349)
P Value for Group Differences
59.8 (5.3) 55.6 40.2 (17.6) 3.4 (0.73) 98.5 (18.5) 72.2 (9.3) 3.2 (1.4) 28.7 2935 (19)
59.5 (5.2) 54.1 39.3 (17.9) 3.65 (0.6) 105.1(14.3) 77.3(4.7) 3.80 (1.2) 23.8 2931 (19)
61.1(5.4) 53.7 41.7 (15.6) 3.22 (0.6) 94.4(13.1) 67.4(1.8) 2.36(0.5) 31.9 2939 (15)
60.0 (5.5) 63.0 42.2 (17.8) 2.63 (0.7) 76.4 (17.9) 56.8 (7.4) 1.49 (0.6) 45.2 2946 (19)
,.001 .005 .004 ,.001 ,.001 ,.001 ,.001 ,.001 ,.001
All data given in mean (SD) unless otherwise indicated. LLN 5 lower limit of normal; MEF50 5 maximum expiratory flow at 50% of FVC; Perc15 5 15th percentile. aGroup 1: FEV /FVC . 70% and greater than LLN. 1 bGroup 2: FEV /FVC , 70%, but greater than LLN. 1 cGroup 3: FEV /FVC , 70% and less than LLN. 1 dx2 test; all other cases: analysis of variance.
information on smoking habits (duration of smoking, number of cigarettes per day), smoking status (current or former smoker) and self-reported respiratory symptoms (cough, mucus, dyspnea, and wheezing) were collected via questionnaires at baseline. The NELSON trial was approved by the Dutch Ministry of Health on December 23, 2003, and by the institutional review boards of the University Medical Centre Utrecht (approval number 03/040) and the University Medical Centre Groningen, The Netherlands. Informed consent was obtained from all participants. Pulmonary Function Testing PFTs were performed at baseline and after 3 years according to ERS/ATS guidelines and with standardized equipment.11 No bronchodilatation was applied. PFT measurements included FEV1, FEV1/FVC ratio, and maximum expiratory flow at 50% (MEF50) as a measure for peripheral airway function. LLN was calculated using the reference equations of the European Community of Coal and Steel.12 CT Scanning All participants received low-dose CT imaging as described before.13 In brief, 16-detector multidetector CT scanners were used (Mx8000 IDT or Brilliance 16P; Philips Medical Systems or Sensation-16; Siemens AG). Detailed information about the CT scan acquisition, exposure settings, and reconstruction methods are reported in the supplementary file (e-Appendix 1). Emphysema severity was computed for the entire lung. The airways were excluded to ensure that only lung parenchyma was analyzed.14 Severity of CT scan-quantified emphysema was calculated using the 15th percentile (Perc15) technique.15-17 Perc15 provides the Hounsfield unit point below which 15% of all voxels are distributed. The lower the Perc15 values are (ie, the closer to 21,000 Hounsfield unit), the more CT scan-quantified emphysema is present. The use of Perc15 for emphysema quantification has been validated against pathology18 and applied in multiple studies.19,20
participants with an FEV1/FVC , 70%, but greater than LLN; and group 3 included participants with airflow obstruction according to both criteria (FEV1/FVC lower than LLN and , 70%). Statistical Analysis Mean and SD values were calculated for normally distributed data and median values and interquartile range (Q1-Q3) were calculated for nonnormally distributed data. The distribution of normality was confirmed using probability plots. Previous research has shown that lung function decline can be assumed to have a linear course over a time span of 3 years.7 Lung function parameters (ie, FEV1/FVC, FEV1, MEF50) at the end of the observation period were analyzed using multiple linear regression analysis with adjustment for pack-years, smoking status (current or former smoker), presence or absence of mucus production, medical center, height, age at baseline, CT scan-derived emphysema severity (ie, Perc15), observation time (ie, years in study), and the appropriate baseline values of FEV1/FVC, FEV1, and MEF50. The observation time was the time-related parameter in the analysis. The decline was calculated via simple subtraction of the baseline and follow-up values and one-way analysis of variance (ANOVA) was used to compare declines among the three groups of airflow classifications. Statistical significance was set at P , .05. All statistical
Table 2—P Values for the Adjustment Factors in the Regression Model of Follow-up Lung Function Valuesa Covariate
FEV1/FVC
FEV1
MEF50
,.001 .421 .005 .293 ,.001 .086 ,.001 .029 .011
.124 .002 ,.001 .086 ,.001 .088 ,.001 .116 .013
,.001 .997 ,.001 .311 ,.001 .010 ,.001 .083 .001
Baseline Classification of Airflow Obstruction
Study center Years in study Age, y Height, cm Smoking status (current or former) Pack-years, No. Baseline lung function Presence of mucus CT scan-derived emphysema severity, perc15
At baseline, participants were classified according to FEV1/FVC. Group 1 comprised participants without airflow obstruction (FEV1/FVC . 70% and greater than LLN); group 2 included
See Table 1 legend for expansion of abbreviations. aOnly statistically significant adjustment factors were retained in the final model (see Tables 3-5).
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Table 3—Results of Multiple Linear Regression Analyses: Estimated Effects of Specified Changes in Covariates on FEV1/FVC During 3-y Follow-upa Covariate Study center Age, y Smoking status FEV1/FVC at baseline, % Presence of mucus CT scan-derived emphysema severity, Perc15
Increment or Comparison
Change in FEV1/FVC, %
95% CI
Utrecht vs Groningen 110 current vs former 11 present vs absent 21 point
1.77 20.51 21.06 0.94 20.50 20.015
1.33-2.21 20.87 to 20.15 21.43 to 20.68 0.92-0.96 20.95 to 20.05 20.027 to 20.004
See Table 1 legend for expansion of abbreviation. aOnly the statistically significant factors from Table 2 were retained in this model.
analyses were performed using SPSS, version 18 for Windows (IBM).
Results Demographics and Lung Function at Baseline In total, 2,003 participants were included, with a mean (SD) age of 59.8 (5.3) years and 40.2 (17.6) pack-years smoked (see Fig 1). Additional baseline demographics for the population are provided in Table 1. Baseline FEV1, FEV1/FVC, and MEF50 values for groups 1, 2, and 3 are shown in Table 1. Lung Function After Follow-up After 3 years of follow-up, the mean (SD) FEV1/FVC was 69.3% (9.9). The FEV1 was 3.21 L (0.72), or 95.4% (19.0) of the predicted value. The MEF50 was 2.88 L/s (1.33), or 64.2% predicted (29.1). The data show a 2.9% (1.2) mean decline in the FEV1/FVC; a 0.21 L (0.07) decline, or 3.2% predicted (2.1) for FEV1; and a 0.32 L/s (0.29) decline, or 5.5% predicted (15.1) in MEF50. The significance levels of the adjustment factors in the models are listed in Table 2. The final model and the change in FEV1/FVC, FEV1, and MEF50 per covariate unit change are given in Tables 3-5, respectively. Values for adjusted lung function decline according to airflow obstruction classification (groups 1-3) are provided in Table 6 and depicted in Figures 2-4. The declines in FEV1/FVC, FEV1, and MEF50 were significantly greater in group 1 than in group 3 (P , .001).
The FEV1 and MEF50 declines in group 2 were also significantly greater than in group 3 (all P , .001), but the decline in FEV1/FVC was significantly more substantial in group 3 than in group 2, at 2.4% and 2.2%, respectively (P ⱕ .001) (Table 6). Smoking status had comparable effects on the decline in lung-function parameters change in all three groups, and the interaction between smoking status and the groups was not significant (P 5 .55). The presence of mucus production and CT scan-derived emphysema severity proved to be significant covariates for decline in FEV1/FVC. For FEV1 and MEF50, CT scan-derived emphysema severity was a significant covariate, whereas mucus production was not (Tables 4, 5).
Discussion The results of this study show that lung function decline is most pronounced in former and current heavy smokers with FEV1/FVC . 70% and less so in those with more severe airflow obstruction. Our data suggest that diagnosing COPD based on the presence of more severe airflow obstruction (as defined by FEV1/FVC less than LLN) means that, at the time of such a diagnosis, subjects had passed the phase of strong lung-function decline. These findings demonstrate the importance of early recognition of disease. Our findings are in agreement with the results from the UPLIFT, TORCH, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints
Table 4—Results of Multiple Linear Regression Analyses: Estimated Effects of Specified Changes in Covariates on FEV1 Over 3-y Follow-upa Covariate Age, y Smoking status FEV1 at baseline, mL CT scan-derived emphysema severity, Perc15 Years in study
Increment or Comparison
Change in FEV1, mL
95% CI
110 current vs former 11 21 point 11
240.0 252 0.903 20.824 245
260.0 to 220.0 273 to 228 0.886-0.921 21.473 to 20.0174 219 to 272
See Table 1 legend for expansion of abbreviation. aOnly the statistically significant factors from Table 2 were retained in this model. journal.publications.chestnet.org
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Table 5—Results of Multiple Linear Regression Analyses: Estimated Effects of Specified Changes in Covariates on MEF50 Over 3-y Follow-upa Covariate Study center Age, y Smoking status Pack-y MEF50 at baseline, mL/s CT scan-derived emphysema severity, Perc15
Increment or Comparison
Change in MEF50, mL/s
95% CI
Utrecht vs Groningen 110 current vs former 110 11 21 point
308 110 2138 220 0.83 22.67
245-372 2160 to 260 2191 to 284 230 to 25 0.81-0.85 24.29 to 21.05
See Table 1 legend for expansion of abbreviations. aOnly the statistically significant factors from Table 2 were retained in this model.
(ECLIPSE) studies, but our data extend their observations, as we included also subjects with normal lung function.7,8,21 The patients in the UPLIFT study with GOLD stage I/II COPD and treated with placebo showed a greater decline in FEV1 than patients with stage III disease, and patients with stage III disease showed a stronger decline than those with GOLD stage IV COPD. The varying dropout rates among the UPLIFT GOLD groups, however, could explain the findings as well. A similar pattern of decline, however, was also found in the placebo groups of the TORCH study. Recent data from the ECLIPSE study, which is a large observational study of subjects with moderate to severe COPD, also showed that the level of lung function decline was inversely related to GOLD stage.21 Together, these three large and representative studies showed that lung function decline is greater in subjects with less severe disease. The main difference between our study and the UPLIFT, TORCH, and ECLIPSE studies is that those studies only included individuals with established COPD, whereas the majority of our subjects had either no or mild COPD. The studies by Donaldson et al22 and Higashomoto et al23, which investigated determinants of more rapid lung function decline in patients with moderate to severe COPD, also reported that an initially high baseline FEV1 predicts a faster decline. We confirmed all these observations, but also showed these phenomena to be present in subjects with an FEV1/FVC ⱖ 70%. The well-known Fletcher-Peto curve, which was originally published in 1977, has been used as the reference for lung function decline in smokers and ex-smokers.24 According to this curve, the FEV1 decline in smokers is initially slow and increases when lung function decreases, known as the horse-racing effect.25 The results of our and other studies indicate the opposite: Lung function decline is steep at first and then becomes less strong as the lung function decreases (an inverse horse-racing effect). Although the study by Fletcher and Peto24 has been extensively cited, some criticism was present. At the time, the spirometry equipment used in the study was not standardized;
thus, measurements errors are likely to have occurred. Additionally, there was a large loss to follow-up (ie, 344 subjects of 1,136 initially included), which may have led to under- and/or overestimation of the observed FEV1 decline. Thus, the actual decline in subjects with normal FEV1 values could have been underestimated if subjects with normal lung function were more likely to be absent from the follow-up data. Furthermore, it is recognized that it was not possible to appropriately and adequately estimate changes over time at that period, as proper statistical techniques (ie, linear mixed models) were not yet available.26 Taking all of these factors into account, it is at least debatable whether the findings by Fletcher and Peto24 are truly valid. The overall FEV1 decline in group 1 after a median 3-year follow-up period was 210 mL (70 mL/y), which was higher than the values found in the general population (ie, 29 mL/y, or 87 mL in 3 years). Even in group 3, the 3-year FEV1 decline exceeded the normal Table 6—Mean Adjusted Declines in Lung Function Parameters Over the 3-y Follow-up Period According to Baseline Classification of Airflow Obstruction Groupa 1 2 3 1 2 3 1 2 3
Lung Function Parameter FEV1/FVC, % 3.2 (1.0) 2.6 (1.0) 2.0 (1.2) FEV1, L 0.22 (0.05) 0.19 (0.05) 0.13 (0.06) MEF50, L/s 0.43 (0.25) 0.17 (0.20) 0.04 (0.20)
P Valueb ,.001 ,.001 Reference group ,.001 ,.001 Reference group ,.001 ,.001 Reference group
All data given as mean (SD) unless otherwise indicated. See Table 1 legend for expansion of abbreviation. aGroup 1: FEV /FVC . 70% and greater than LLN; group 2: 1 FEV1/FVC , 70%, but greater than LLN; group 3: FEV1/FVC , 70% and less than LLN. bSignificance levels indicate differences in comparison with group 3 (one-way analysis of variance).
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Figure 2. Mean (95% CI) adjusted FEV1/FVC decline over 3 y stratified by baseline classification of airflow obstruction. LLN 5 lower limit of normal.
Figure 3. Mean (95% CI) adjusted FEV1 (L) decline over 3 y stratified by classification of airflow obstruction. See Figure 2 legend for expansion of abbreviation. journal.publications.chestnet.org
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Figure 4. Mean (95% CI) adjusted (mL/s) decline over 3 y stratified by classification of airflow obstruction. MEF50 5 maximum expiratory flow at 50% of FVC. See Figure 2 legend for expansion of other abbreviation.
value by nearly a factor two. In the Atherosclerosis Risk in Communities (ARIC) cohort, the annual decline in FEV1 was slightly lower (62 mL/y).27 The obvious explanation for this relatively high decline is that the NELSON trial included heavy smokers. Interestingly, in the Atherosclerosis Risk in Communities cohort, subjects without airflow obstruction, but with chronic cough and mucus (formerly GOLD stage 0), had a higher risk of COPD-related hospitalization and mortality compared with subjects at higher GOLD stages, which indicates the importance of recognizing patients exhibiting rapid decline without airflow obstruction. Participants in the Lung Health Study, all of whom had an FEV1/FVC , 70%, but a comparable number of pack-years smoked, showed a decline of 52.3 ml/y.28 Previous studies have shown that inflammation is present in smokers with normal lung function and that the number of inflammatory cells in the lungs is increased in these patients.29-31 Our findings are consistent with the results by Hogg et al,32 who showed that subjects with a FEV1 . 80% and a FEV1/FVC . 70% (formerly GOLD stage 0) already have an inflammatory response in the small airway walls. Pierrou et al33 found that the expression of genes involved in the oxidant/antioxidant response was higher in patients at former GOLD stage 0 and GOLD stage I compared with GOLD stages II-IV. Other studies showed that
the expression of matrix metalloproteinase 2, which is involved in extracellular matrix breakdown, decreased as FEV1 declined.34 Together, these studies indicate that part of the immune response and reaction to smoking exposure occurs in the early stages of the disease and also that this response declines in advanced COPD stages. The effects of this early immune response may elicit an FEV1 decline even when FEV1 values are normal. Regression toward the mean could be suggested as a possible explanation for our findings,35 as it can occur in longitudinal studies when subject dropout is nonrandom and when repetitive measurements are imperfectly correlated.36 We have examined the occurrence of both of these factors and concluded that regression toward the mean is unlikely in our study. The correlation coefficient between the baseline and follow-up lung function measurements was high (Pearson r 5 0.89). Furthermore, we analyzed the data with the preferred method for analyzing a continuous variable that is measured at baseline and again at the outcome.37 Results from a more detailed analysis of the probability of regression toward the mean are presented in the supplementary file (e-Appendix 1). One of the strengths of this study is that it included a large number of smokers with a high number of pack-years smoked. These patients were frequently
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in a pre-COPD phase, which allowed the observation of early phenomena not seen in patients diagnosed by physicians. Furthermore, all participants underwent both longitudinal PFTs and CT scanning, allowing us to correct for emphysema severity. Additionally, lung function was determined by well-qualified laboratory technicians and according to ATS/ERS standards, and the equipment used in both centers was shown to be interchangeable.38 This study has some limitations. First, the smoking status and the presence of symptoms were determined via questionnaires at baseline. As a result, we could not take into account that some patients who had quit smoking could have started smoking again, and conversely some smokers could have quit during the follow-up period. Second, no reversibility testing was applied, which could have led to lower FEV1/FVC values. However, because the follow-up spirometry was similarly performed without reversibility testing, we believe that this limitation did not bias our results. Third, no female patients were included. Previous studies have shown that emphysema scores in women are lower than in men, and women also show a slower progression of emphysema.39-41 Lastly, our follow-up time was 3 years; however, this interval is comparable to the follow-up period of the UPLIFT study. In addition, because we included a large number of former and current heavy smokers, we were able to report significantly large declines over the 3-year follow-up period. When relevant changes in factors such as lung function and CT scan-quantified emphysema are evident, additional observation time becomes unnecessary. In conclusion, lung function decline in heavy smokers is greatest in those patients with a normal lung function according to GOLD (,70%) or ERS/ATS (less than LLN) criteria. Both criteria classify these individuals as not having COPD, and these methods, therefore, miss the phase with the most rapid decline, which is the hallmark of COPD. These findings show that a diagnosis of COPD cannot be excluded in heavy smokers when based on an above-threshold PFT score at a single point in time. Acknowledgments Author contributions: Drs Mohamed Hoesein and Zanen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Mohamed Hoesein: contributed to the concept and design of the study, statistical analysis, writing of the first version of the manuscript, and approval of the final manuscript and served as principal author. Dr Zanen: contributed to the concept and design of the study, statistical analysis, writing of the first version of the manuscript, and approval of the final manuscript. Dr Boezen: contributed to the concept and design of the study, reviewing and revising the final manuscript for intellectual content, and approval of the final manuscript.
Dr Groen: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr van Ginneken: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr de Jong: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr Postma: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr Lammers: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Postma received funding for research from AstraZeneca, GlaxoSmithKline plc, and Takeda Pharmaceuticals International GmbH. Travel to ERS or ATS has been partially funded by AstraZeneca, GlaxoSmithKline plc, Chiesi Ltd, and Takeda Pharmaceuticals International GmbH. Dr Postma has been consultant to AstraZeneca, Boehringer Ingelheim GmbH, Chiesi Ltd, GlaxoSmithKline plc, Takeda Pharmaceuticals International GmbH, and Teva Pharmaceuticals USA. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript, or in the decision to submit for publication. Additional information: The e-Appendix can be found in the “Supplemental Materials” area of the online article.
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10. van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009;361(23):2221-2229. 11. Miller MR, Crapo R, Hankinson J, et al; ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005;26(1):153-161. 12. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC; Official Statement of the European Respiratory Society. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Eur Respir J Suppl. 1993;16:5-40. 13. Mohamed Hoesein FA, de Hoop B, Zanen P, et al. CT-quantified emphysema in male heavy smokers: association with lung function decline. Thorax. 2011;66(9):782-787. 14. van Rikxoort EM, Prokop M, de Hoop B, Viergever MA, Pluim JP, van Ginneken B. Automatic segmentation of the pulmonary lobes from fissures, airways, and lung borders: evaluation of robustness against missing data. Med Image Comput Comput Assist Interv. 2009;12(pt 1):263-271. 15. Coxson HO. Quantitative chest tomography in COPD research: chairman’s summary. Proc Am Thorac Soc. 2008; 5(9):874-877. 16. Coxson HO. Quantitative computed tomography assessment of airway wall dimensions: current status and potential applications for phenotyping chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5(9):940-945. 17. Newell JD Jr, Hogg JC, Snider GL. Report of a workshop: quantitative computed tomography scanning in longitudinal studies of emphysema. Eur Respir J. 2004;23(5):769-775. 18. Gould GA, MacNee W, McLean A, et al. CT measurements of lung density in life can quantitate distal airspace enlargement–an essential defining feature of human emphysema. Am Rev Respir Dis 1988;137(2):380-392. 19. Parr DG, Stoel BC, Stolk J, Stockley RA. Validation of computed tomographic lung densitometry for monitoring emphysema in alpha1-antitrypsin deficiency. Thorax 2006;61(6):485-490. 20. Parr DG, Sevenoaks M, Deng C, Stoel BC, Stockley RA. Detection of emphysema progression in alpha 1-antitrypsin deficiency using CT densitometry; methodological advances. Respir Res. 2008;9:21. 21. Vestbo J, Edwards LD, Scanlon PD, et al; ECLIPSE Investigators. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365(13):1184-1192. 22. Donaldson GC, Seemungal TA, Patel IS, et al. Airway and systemic inflammation and decline in lung function in patients with COPD. Chest. 2005;128(4):1995-2004. 23. Higashimoto Y, Iwata T, Okada M, Satoh H, Fukuda K, Tohda Y. Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease. Respir Med. 2009;103(8):1231-1238. 24. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ. 1977;1(6077):1645-1648. 25. Burrows B, Knudson RJ, Camilli AE, Lyle SK, Lebowitz MD. The “horse-racing effect” and predicting decline in forced
26. 27. 28.
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expiratory volume in one second from screening spirometry. Am Rev Respir Dis. 1987;135(4):788-793. Linn RL, Slinde JA. The determination of the significance of change between pre- and posttesting periods. Rev Educ Res. 1977;47(1):121-150. Mannino DM, Reichert MM, Davis KJ. Lung function decline and outcomes in an adult population. Am J Respir Crit Care Med. 2006;173(9):985-990. Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS. Smoking cessation and lung function in mild-tomoderate chronic obstructive pulmonary disease. The Lung Health Study. Am J Respir Crit Care Med. 2000;161(2 pt 1): 381-390. Cosio M, Ghezzo H, Hogg JC, et al. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med. 1978;298(23):1277-1281. Wright JL, Lawson LM, Paré PD, Kennedy S, Wiggs B, Hogg JC. The detection of small airways disease. Am Rev Respir Dis. 1984;129(6):989-994. Amin K, Ekberg-Jansson A, Löfdahl CG, Venge P. Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study. Thorax. 2003;58(2):135-142. Hogg JC, Chu F, Utokaparch S, et al. The nature of smallairway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645-2653. Pierrou S, Broberg P, O’Donnell RA, et al. Expression of genes involved in oxidative stress responses in airway epithelial cells of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(6):577-586. Gosselink JV, Hayashi S, Elliott WM, et al. Differential expression of tissue repair genes in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(12):1329-1335. Suissa S. Lung function decline in COPD trials: bias from regression to the mean. Eur Respir J. 2008;32(4):829-831. Davis CE. The effect of regression to the mean in epidemiologic and clinical studies. Am J Epidemiol. 1976;104(5): 493-498. Vickers AJ, Altman DG. Statistics notes: analysing controlled trials with baseline and follow up measurements. BMJ. 2001; 323(7321):1123-1124. Munnik P, Zanen P, Lammers JW. A comparison of lung function equipment with emphasis on interchangeability and methods. Physiol Meas. 2006;27(6):445-455. Bellomi M, Rampinelli C, Veronesi G, et al. Evolution of emphysema in relation to smoking. Eur Radiol. 2010;20(2): 286-292. Grydeland TB, Dirksen A, Coxson HO, et al. Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking. Eur Respir J. 2009;34(4):858-865. Soejima K, Yamaguchi K, Kohda E, et al. Longitudinal follow-up study of smoking-induced lung density changes by high-resolution computed tomography. Am J Respir Crit Care Med. 2000;161(4 pt 1):1264-1273.
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Original Research COPD
Lung Function Decline in Male Heavy Smokers Relates to Baseline Airflow Obstruction Severity Firdaus A. A. Mohamed Hoesein, MD, PhD; Pieter Zanen, MD, PhD; H. Marike Boezen, PhD; Harry J. M. Groen, MD, PhD; Bram van Ginneken, PhD; Pim A. de Jong, MD, PhD; Dirkje S. Postma, MD, PhD; and Jan-Willem J. Lammers, MD, PhD
Background: Recent evidence indicates that the rate of lung function decline is steepest in mild COPD and slower in moderate to severe COPD. The current study assessed whether lung function decline relates to baseline airflow obstruction severity in male heavy smokers. Methods: In total, 2,003 male smokers with a mean (SD) age of 59.8 (5.3) years underwent pulmonary function testing at baseline and after 3-year follow-up. Participants were classified by entry FEV1/FVC as follows: group 1, .70%; group 2, ,70%, but greater than lower limit of normal (LLN); and group 3, less than LLN. Differences in lung function decline among the groups were assessed using multiple regression after adjustment for pack-years, smoking status (current or former smoker), presence or absence of mucus production, medical center, height, age, CT scan-derived emphysema severity (15th percentile), observation time (years in study), and the baseline values. Results: Over 3 years, the mean (SD) FEV1/FVC, FEV1, and maximum expiratory flow at 50% of FVC decreases in group 1 were 3.1% (1), 0.21 L (0.07), and 0.40 L/s (0.26), respectively. In group 3, these decreases were 2.4% (1.1), 0.15 L (0.08), and 0.06 L/s (0.19), respectively. All lung function parameters showed the greatest decline in group 1 (P , .001). Conclusions: Diagnosing COPD based on the presence of more severe airflow obstruction (as defined by FEV1/FVC less than LLN) means that, at the time of such a diagnosis, subjects had passed the phase of strong lung-function decline. Trial registry: ISRCTN Register; No.: ISRCTN63545820; URL: www.trialregister.nl CHEST 2012; 142(6):1530–1538 Abbreviations: ATS 5 American Thoracic Society; ECLIPSE 5 Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; ERS 5 European Respiratory Society; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; LLN 5 lower limit of normal; MEF50 5 maximum expiratory flow at 50% of FVC; NELSON 5 DutchBelgian Lung Cancer Screening Trial; Perc15 5 15th percentile; PFT 5 pulmonary function test; TORCH 5 Towards a Revolution in COPD Health; UPLIFT 5 Understanding the Potential Long-term Impacts With Tiotropium
will be the third leading cause of death by COPD 2020 and is the only chronic disease with increas-
ing morbidity and mortality rates.1 COPD includes emphysema and chronic bronchitis, which can coincide, and both contribute to airflow obstruction. According to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria, COPD is present when the FEV1/FVC is , 70%, but the European Respiratory Society (ERS) and the American Thoracic Society (ATS) recommend the lower limit of normal (LLN) as the threshold for diagnosing COPD.2,3 No consensus exists as to which of these thresholds is more suitable.4,5
An accelerated lung function decline is an important hallmark of COPD and is already present before the FEV1/FVC ratio falls below either of the two thresholds. Often the diagnosis of COPD is based on a onetime pulmonary function test (PFT), and so COPD can be missed when such testing is performed “too early.” Emphysema, assessed with chest CT scan-based lung densitometry, can be present before airflow obstruction manifests.6 Two large, randomized, clinical trials, the Understanding the Potential Long-term Impacts With Tiotropium (UPLIFT) and Towards a Revolution in COPD Health (TORCH) studies, assessed the effect
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Figure 1. Flowchart of inclusion.
of pharmacologic treatment on lung function in patients with COPD.7,8 In the placebo-treated groups, the rate of decline was steepest in mild COPD and slower in moderate to severe COPD. However, differences in the dropout rates between the COPD stages offered an alternative explanation for this phenomenon, and no further analyses were performed to investigate this effect in more detail. We hypothesized that pulmoManuscript received November 7, 2011; revision accepted May 23, 2012. Affiliations: From the Division of Heart and Lungs, Department of Respiratory Medicine (Drs Mohamed Hoesein, Zanen, and Lammers), Image Sciences Institute, Department of Radiology (Dr van Ginneken), and Department of Radiology (Dr de Jong), University Medical Center Utrecht, Utrecht; Department of Epidemiology (Dr Boezen), and Department of Pulmonology (Drs Groen and Postma), University Medical Center Groningen, University of Groningen, Groningen; and Diagnostic Image Analysis Group, Department of Radiology (Dr van Ginneken), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Funding/Support: Funding was received from European Union FP7 [Grant 201379 COPACETIC (COPD Pathology: Addressing Critical Gaps, Early Treatment and Innovative Concepts)]. Correspondence to: Pieter Zanen, MD, PhD, University Medical Center Utrecht, HP F.02.333, PO Box 85500, 3508 GA Utrecht, The Netherlands; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-2837
nary function decline indeed is steeper in mild COPD stages and could be steepest in heavy smokers with only mild or absent airflow obstruction. The aim of the current study, therefore, was to assess the magnitude of lung function decline in relation to baseline airflow obstruction severity in a cohort of relatively healthy heavy smokers. We compared three groups: group 1 with FEV1/FVC . 0.70; group 2 with FEV1/FVC between 70% and LLN, and group 3 with FEV1/FVC less than LLN, representing increasing degrees of airflow obstruction. Materials and Methods Participants The study was conducted among participants of the Dutch Belgian Lung Cancer Screening Trial (NELSON) by the University Medical Centers in Utrecht and Groningen, The Netherlands. The NELSON study included only subjects with a high risk of developing lung cancer or COPD.9,10 Male subjects (aged ⱖ 50 years) with a smoking history of ⱖ 20 pack-years and fit enough to undergo surgery when lung cancer was potentially found were invited to participate. Subjects should not have quit smoking . 10 years before inclusion. Only men were included, as fewer women in the Dutch population accrued long-term tobacco exposure. Patients with a moderate or poor self-reported health status or who were unable to climb two flights of stairs were excluded. Detailed
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Table 1—Baseline Demographics of Included Participants for the Total Population and According to Groups Characteristics Age, y Current smokers, % Pack-years FEV1, L FEV1, % predicted FEV1/FVC, % MEF50, L/s Mucus production present, %d CT scan-derived emphysema, Perc15
Total (N 5 2,003)
Group 1a (n 5 1,337)
Group 2b (n 5 317)
Group 3c (n 5 349)
P Value for Group Differences
59.8 (5.3) 55.6 40.2 (17.6) 3.4 (0.73) 98.5 (18.5) 72.2 (9.3) 3.2 (1.4) 28.7 2935 (19)
59.5 (5.2) 54.1 39.3 (17.9) 3.65 (0.6) 105.1(14.3) 77.3(4.7) 3.80 (1.2) 23.8 2931 (19)
61.1(5.4) 53.7 41.7 (15.6) 3.22 (0.6) 94.4(13.1) 67.4(1.8) 2.36(0.5) 31.9 2939 (15)
60.0 (5.5) 63.0 42.2 (17.8) 2.63 (0.7) 76.4 (17.9) 56.8 (7.4) 1.49 (0.6) 45.2 2946 (19)
,.001 .005 .004 ,.001 ,.001 ,.001 ,.001 ,.001 ,.001
All data given in mean (SD) unless otherwise indicated. LLN 5 lower limit of normal; MEF50 5 maximum expiratory flow at 50% of FVC; Perc15 5 15th percentile. aGroup 1: FEV /FVC . 70% and greater than LLN. 1 bGroup 2: FEV /FVC , 70%, but greater than LLN. 1 cGroup 3: FEV /FVC , 70% and less than LLN. 1 dx2 test; all other cases: analysis of variance.
information on smoking habits (duration of smoking, number of cigarettes per day), smoking status (current or former smoker) and self-reported respiratory symptoms (cough, mucus, dyspnea, and wheezing) were collected via questionnaires at baseline. The NELSON trial was approved by the Dutch Ministry of Health on December 23, 2003, and by the institutional review boards of the University Medical Centre Utrecht (approval number 03/040) and the University Medical Centre Groningen, The Netherlands. Informed consent was obtained from all participants. Pulmonary Function Testing PFTs were performed at baseline and after 3 years according to ERS/ATS guidelines and with standardized equipment.11 No bronchodilatation was applied. PFT measurements included FEV1, FEV1/FVC ratio, and maximum expiratory flow at 50% (MEF50) as a measure for peripheral airway function. LLN was calculated using the reference equations of the European Community of Coal and Steel.12 CT Scanning All participants received low-dose CT imaging as described before.13 In brief, 16-detector multidetector CT scanners were used (Mx8000 IDT or Brilliance 16P; Philips Medical Systems or Sensation-16; Siemens AG). Detailed information about the CT scan acquisition, exposure settings, and reconstruction methods are reported in the supplementary file (e-Appendix 1). Emphysema severity was computed for the entire lung. The airways were excluded to ensure that only lung parenchyma was analyzed.14 Severity of CT scan-quantified emphysema was calculated using the 15th percentile (Perc15) technique.15-17 Perc15 provides the Hounsfield unit point below which 15% of all voxels are distributed. The lower the Perc15 values are (ie, the closer to 21,000 Hounsfield unit), the more CT scan-quantified emphysema is present. The use of Perc15 for emphysema quantification has been validated against pathology18 and applied in multiple studies.19,20
participants with an FEV1/FVC , 70%, but greater than LLN; and group 3 included participants with airflow obstruction according to both criteria (FEV1/FVC lower than LLN and , 70%). Statistical Analysis Mean and SD values were calculated for normally distributed data and median values and interquartile range (Q1-Q3) were calculated for nonnormally distributed data. The distribution of normality was confirmed using probability plots. Previous research has shown that lung function decline can be assumed to have a linear course over a time span of 3 years.7 Lung function parameters (ie, FEV1/FVC, FEV1, MEF50) at the end of the observation period were analyzed using multiple linear regression analysis with adjustment for pack-years, smoking status (current or former smoker), presence or absence of mucus production, medical center, height, age at baseline, CT scan-derived emphysema severity (ie, Perc15), observation time (ie, years in study), and the appropriate baseline values of FEV1/FVC, FEV1, and MEF50. The observation time was the time-related parameter in the analysis. The decline was calculated via simple subtraction of the baseline and follow-up values and one-way analysis of variance (ANOVA) was used to compare declines among the three groups of airflow classifications. Statistical significance was set at P , .05. All statistical
Table 2—P Values for the Adjustment Factors in the Regression Model of Follow-up Lung Function Valuesa Covariate
FEV1/FVC
FEV1
MEF50
,.001 .421 .005 .293 ,.001 .086 ,.001 .029 .011
.124 .002 ,.001 .086 ,.001 .088 ,.001 .116 .013
,.001 .997 ,.001 .311 ,.001 .010 ,.001 .083 .001
Baseline Classification of Airflow Obstruction
Study center Years in study Age, y Height, cm Smoking status (current or former) Pack-years, No. Baseline lung function Presence of mucus CT scan-derived emphysema severity, perc15
At baseline, participants were classified according to FEV1/FVC. Group 1 comprised participants without airflow obstruction (FEV1/FVC . 70% and greater than LLN); group 2 included
See Table 1 legend for expansion of abbreviations. aOnly statistically significant adjustment factors were retained in the final model (see Tables 3-5).
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Table 3—Results of Multiple Linear Regression Analyses: Estimated Effects of Specified Changes in Covariates on FEV1/FVC During 3-y Follow-upa Covariate Study center Age, y Smoking status FEV1/FVC at baseline, % Presence of mucus CT scan-derived emphysema severity, Perc15
Increment or Comparison
Change in FEV1/FVC, %
95% CI
Utrecht vs Groningen 110 current vs former 11 present vs absent 21 point
1.77 20.51 21.06 0.94 20.50 20.015
1.33-2.21 20.87 to 20.15 21.43 to 20.68 0.92-0.96 20.95 to 20.05 20.027 to 20.004
See Table 1 legend for expansion of abbreviation. aOnly the statistically significant factors from Table 2 were retained in this model.
analyses were performed using SPSS, version 18 for Windows (IBM).
Results Demographics and Lung Function at Baseline In total, 2,003 participants were included, with a mean (SD) age of 59.8 (5.3) years and 40.2 (17.6) pack-years smoked (see Fig 1). Additional baseline demographics for the population are provided in Table 1. Baseline FEV1, FEV1/FVC, and MEF50 values for groups 1, 2, and 3 are shown in Table 1. Lung Function After Follow-up After 3 years of follow-up, the mean (SD) FEV1/FVC was 69.3% (9.9). The FEV1 was 3.21 L (0.72), or 95.4% (19.0) of the predicted value. The MEF50 was 2.88 L/s (1.33), or 64.2% predicted (29.1). The data show a 2.9% (1.2) mean decline in the FEV1/FVC; a 0.21 L (0.07) decline, or 3.2% predicted (2.1) for FEV1; and a 0.32 L/s (0.29) decline, or 5.5% predicted (15.1) in MEF50. The significance levels of the adjustment factors in the models are listed in Table 2. The final model and the change in FEV1/FVC, FEV1, and MEF50 per covariate unit change are given in Tables 3-5, respectively. Values for adjusted lung function decline according to airflow obstruction classification (groups 1-3) are provided in Table 6 and depicted in Figures 2-4. The declines in FEV1/FVC, FEV1, and MEF50 were significantly greater in group 1 than in group 3 (P , .001).
The FEV1 and MEF50 declines in group 2 were also significantly greater than in group 3 (all P , .001), but the decline in FEV1/FVC was significantly more substantial in group 3 than in group 2, at 2.4% and 2.2%, respectively (P ⱕ .001) (Table 6). Smoking status had comparable effects on the decline in lung-function parameters change in all three groups, and the interaction between smoking status and the groups was not significant (P 5 .55). The presence of mucus production and CT scan-derived emphysema severity proved to be significant covariates for decline in FEV1/FVC. For FEV1 and MEF50, CT scan-derived emphysema severity was a significant covariate, whereas mucus production was not (Tables 4, 5).
Discussion The results of this study show that lung function decline is most pronounced in former and current heavy smokers with FEV1/FVC . 70% and less so in those with more severe airflow obstruction. Our data suggest that diagnosing COPD based on the presence of more severe airflow obstruction (as defined by FEV1/FVC less than LLN) means that, at the time of such a diagnosis, subjects had passed the phase of strong lung-function decline. These findings demonstrate the importance of early recognition of disease. Our findings are in agreement with the results from the UPLIFT, TORCH, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints
Table 4—Results of Multiple Linear Regression Analyses: Estimated Effects of Specified Changes in Covariates on FEV1 Over 3-y Follow-upa Covariate Age, y Smoking status FEV1 at baseline, mL CT scan-derived emphysema severity, Perc15 Years in study
Increment or Comparison
Change in FEV1, mL
95% CI
110 current vs former 11 21 point 11
240.0 252 0.903 20.824 245
260.0 to 220.0 273 to 228 0.886-0.921 21.473 to 20.0174 219 to 272
See Table 1 legend for expansion of abbreviation. aOnly the statistically significant factors from Table 2 were retained in this model. journal.publications.chestnet.org
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Table 5—Results of Multiple Linear Regression Analyses: Estimated Effects of Specified Changes in Covariates on MEF50 Over 3-y Follow-upa Covariate Study center Age, y Smoking status Pack-y MEF50 at baseline, mL/s CT scan-derived emphysema severity, Perc15
Increment or Comparison
Change in MEF50, mL/s
95% CI
Utrecht vs Groningen 110 current vs former 110 11 21 point
308 110 2138 220 0.83 22.67
245-372 2160 to 260 2191 to 284 230 to 25 0.81-0.85 24.29 to 21.05
See Table 1 legend for expansion of abbreviations. aOnly the statistically significant factors from Table 2 were retained in this model.
(ECLIPSE) studies, but our data extend their observations, as we included also subjects with normal lung function.7,8,21 The patients in the UPLIFT study with GOLD stage I/II COPD and treated with placebo showed a greater decline in FEV1 than patients with stage III disease, and patients with stage III disease showed a stronger decline than those with GOLD stage IV COPD. The varying dropout rates among the UPLIFT GOLD groups, however, could explain the findings as well. A similar pattern of decline, however, was also found in the placebo groups of the TORCH study. Recent data from the ECLIPSE study, which is a large observational study of subjects with moderate to severe COPD, also showed that the level of lung function decline was inversely related to GOLD stage.21 Together, these three large and representative studies showed that lung function decline is greater in subjects with less severe disease. The main difference between our study and the UPLIFT, TORCH, and ECLIPSE studies is that those studies only included individuals with established COPD, whereas the majority of our subjects had either no or mild COPD. The studies by Donaldson et al22 and Higashomoto et al23, which investigated determinants of more rapid lung function decline in patients with moderate to severe COPD, also reported that an initially high baseline FEV1 predicts a faster decline. We confirmed all these observations, but also showed these phenomena to be present in subjects with an FEV1/FVC ⱖ 70%. The well-known Fletcher-Peto curve, which was originally published in 1977, has been used as the reference for lung function decline in smokers and ex-smokers.24 According to this curve, the FEV1 decline in smokers is initially slow and increases when lung function decreases, known as the horse-racing effect.25 The results of our and other studies indicate the opposite: Lung function decline is steep at first and then becomes less strong as the lung function decreases (an inverse horse-racing effect). Although the study by Fletcher and Peto24 has been extensively cited, some criticism was present. At the time, the spirometry equipment used in the study was not standardized;
thus, measurements errors are likely to have occurred. Additionally, there was a large loss to follow-up (ie, 344 subjects of 1,136 initially included), which may have led to under- and/or overestimation of the observed FEV1 decline. Thus, the actual decline in subjects with normal FEV1 values could have been underestimated if subjects with normal lung function were more likely to be absent from the follow-up data. Furthermore, it is recognized that it was not possible to appropriately and adequately estimate changes over time at that period, as proper statistical techniques (ie, linear mixed models) were not yet available.26 Taking all of these factors into account, it is at least debatable whether the findings by Fletcher and Peto24 are truly valid. The overall FEV1 decline in group 1 after a median 3-year follow-up period was 210 mL (70 mL/y), which was higher than the values found in the general population (ie, 29 mL/y, or 87 mL in 3 years). Even in group 3, the 3-year FEV1 decline exceeded the normal Table 6—Mean Adjusted Declines in Lung Function Parameters Over the 3-y Follow-up Period According to Baseline Classification of Airflow Obstruction Groupa 1 2 3 1 2 3 1 2 3
Lung Function Parameter FEV1/FVC, % 3.2 (1.0) 2.6 (1.0) 2.0 (1.2) FEV1, L 0.22 (0.05) 0.19 (0.05) 0.13 (0.06) MEF50, L/s 0.43 (0.25) 0.17 (0.20) 0.04 (0.20)
P Valueb ,.001 ,.001 Reference group ,.001 ,.001 Reference group ,.001 ,.001 Reference group
All data given as mean (SD) unless otherwise indicated. See Table 1 legend for expansion of abbreviation. aGroup 1: FEV /FVC . 70% and greater than LLN; group 2: 1 FEV1/FVC , 70%, but greater than LLN; group 3: FEV1/FVC , 70% and less than LLN. bSignificance levels indicate differences in comparison with group 3 (one-way analysis of variance).
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Figure 2. Mean (95% CI) adjusted FEV1/FVC decline over 3 y stratified by baseline classification of airflow obstruction. LLN 5 lower limit of normal.
Figure 3. Mean (95% CI) adjusted FEV1 (L) decline over 3 y stratified by classification of airflow obstruction. See Figure 2 legend for expansion of abbreviation. journal.publications.chestnet.org
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Figure 4. Mean (95% CI) adjusted (mL/s) decline over 3 y stratified by classification of airflow obstruction. MEF50 5 maximum expiratory flow at 50% of FVC. See Figure 2 legend for expansion of other abbreviation.
value by nearly a factor two. In the Atherosclerosis Risk in Communities (ARIC) cohort, the annual decline in FEV1 was slightly lower (62 mL/y).27 The obvious explanation for this relatively high decline is that the NELSON trial included heavy smokers. Interestingly, in the Atherosclerosis Risk in Communities cohort, subjects without airflow obstruction, but with chronic cough and mucus (formerly GOLD stage 0), had a higher risk of COPD-related hospitalization and mortality compared with subjects at higher GOLD stages, which indicates the importance of recognizing patients exhibiting rapid decline without airflow obstruction. Participants in the Lung Health Study, all of whom had an FEV1/FVC , 70%, but a comparable number of pack-years smoked, showed a decline of 52.3 ml/y.28 Previous studies have shown that inflammation is present in smokers with normal lung function and that the number of inflammatory cells in the lungs is increased in these patients.29-31 Our findings are consistent with the results by Hogg et al,32 who showed that subjects with a FEV1 . 80% and a FEV1/FVC . 70% (formerly GOLD stage 0) already have an inflammatory response in the small airway walls. Pierrou et al33 found that the expression of genes involved in the oxidant/antioxidant response was higher in patients at former GOLD stage 0 and GOLD stage I compared with GOLD stages II-IV. Other studies showed that
the expression of matrix metalloproteinase 2, which is involved in extracellular matrix breakdown, decreased as FEV1 declined.34 Together, these studies indicate that part of the immune response and reaction to smoking exposure occurs in the early stages of the disease and also that this response declines in advanced COPD stages. The effects of this early immune response may elicit an FEV1 decline even when FEV1 values are normal. Regression toward the mean could be suggested as a possible explanation for our findings,35 as it can occur in longitudinal studies when subject dropout is nonrandom and when repetitive measurements are imperfectly correlated.36 We have examined the occurrence of both of these factors and concluded that regression toward the mean is unlikely in our study. The correlation coefficient between the baseline and follow-up lung function measurements was high (Pearson r 5 0.89). Furthermore, we analyzed the data with the preferred method for analyzing a continuous variable that is measured at baseline and again at the outcome.37 Results from a more detailed analysis of the probability of regression toward the mean are presented in the supplementary file (e-Appendix 1). One of the strengths of this study is that it included a large number of smokers with a high number of pack-years smoked. These patients were frequently
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Original Research
in a pre-COPD phase, which allowed the observation of early phenomena not seen in patients diagnosed by physicians. Furthermore, all participants underwent both longitudinal PFTs and CT scanning, allowing us to correct for emphysema severity. Additionally, lung function was determined by well-qualified laboratory technicians and according to ATS/ERS standards, and the equipment used in both centers was shown to be interchangeable.38 This study has some limitations. First, the smoking status and the presence of symptoms were determined via questionnaires at baseline. As a result, we could not take into account that some patients who had quit smoking could have started smoking again, and conversely some smokers could have quit during the follow-up period. Second, no reversibility testing was applied, which could have led to lower FEV1/FVC values. However, because the follow-up spirometry was similarly performed without reversibility testing, we believe that this limitation did not bias our results. Third, no female patients were included. Previous studies have shown that emphysema scores in women are lower than in men, and women also show a slower progression of emphysema.39-41 Lastly, our follow-up time was 3 years; however, this interval is comparable to the follow-up period of the UPLIFT study. In addition, because we included a large number of former and current heavy smokers, we were able to report significantly large declines over the 3-year follow-up period. When relevant changes in factors such as lung function and CT scan-quantified emphysema are evident, additional observation time becomes unnecessary. In conclusion, lung function decline in heavy smokers is greatest in those patients with a normal lung function according to GOLD (,70%) or ERS/ATS (less than LLN) criteria. Both criteria classify these individuals as not having COPD, and these methods, therefore, miss the phase with the most rapid decline, which is the hallmark of COPD. These findings show that a diagnosis of COPD cannot be excluded in heavy smokers when based on an above-threshold PFT score at a single point in time. Acknowledgments Author contributions: Drs Mohamed Hoesein and Zanen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Mohamed Hoesein: contributed to the concept and design of the study, statistical analysis, writing of the first version of the manuscript, and approval of the final manuscript and served as principal author. Dr Zanen: contributed to the concept and design of the study, statistical analysis, writing of the first version of the manuscript, and approval of the final manuscript. Dr Boezen: contributed to the concept and design of the study, reviewing and revising the final manuscript for intellectual content, and approval of the final manuscript.
Dr Groen: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr van Ginneken: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr de Jong: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr Postma: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Dr Lammers: contributed to the concept and design of the study, review and revising the final manuscript for intellectual content, and approval of the final manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Postma received funding for research from AstraZeneca, GlaxoSmithKline plc, and Takeda Pharmaceuticals International GmbH. Travel to ERS or ATS has been partially funded by AstraZeneca, GlaxoSmithKline plc, Chiesi Ltd, and Takeda Pharmaceuticals International GmbH. Dr Postma has been consultant to AstraZeneca, Boehringer Ingelheim GmbH, Chiesi Ltd, GlaxoSmithKline plc, Takeda Pharmaceuticals International GmbH, and Teva Pharmaceuticals USA. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript, or in the decision to submit for publication. Additional information: The e-Appendix can be found in the “Supplemental Materials” area of the online article.
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Original Research