Lung Function Decline in Relation to Diagnostic Criteria
This cohort study was based on all available spirometry tests from the period October 2001 to March 2010 from three regional primary care diagnostic centres in the Netherlands (the General Practice Laboratory Foundation Etten-Leur/Breda (SHL), the Diagnostic Centre Eindhoven (DCE), and the General Practice Laboratory East (SHO)). These diagnostic centres offer a range of diagnostic tests (including spirometry) and other healthcare services to hundreds of general practitioners (GPs) in the south-western and south-eastern parts of our country since the mid- or late nineteen-nineties. When a patient consults with respiratory symptoms and the GP suspects an underlying chronic respiratory condition (e.g., COPD or asthma), he or she can refer the patient to the diagnostic centre for spirometry testing. When a chronic respiratory condition is diagnosed or still suspected, the majority of patients enter the diagnostic centre's monitoring service and return for reassessment every six to twelve months.
Spirometry test results and accompanying demographic (gender, age), anthropometric (height, weight) and medical history information (self-reported smoking status and history, respiratory symptoms, medication) are recorded during each visit using a standardized electronic format. Every spirometry test is assessed by a respiratory consultant whose interpretation of the test and — if applicable — diagnostic advice is sent to the GP, together with the actual test results. Further details about the spirometry tests performed in the diagnostic centres are described elsewhere. Since only routine lung function and respiratory medical history data were used for our analyses and the investigators had no access to the patients' medical records or information on patients' identity, no written informed consent was obtained.
We selected all data from Caucasian subjects aged ≥ 40 years with complete data regarding height, history of cigarette smoking, and respiratory medication use for whom at least three postbronchodilator spirometry tests were available during a minimum follow-up of one year (see Figure 1). We used postbronchodilator FEV1/FVC values to determine whether or not airflow obstruction was present in the study subjects. The following two definitions for airflow obstruction applied:
1) Fixed cutpoint definition: postbronchodilator FEV1/FVC < 0.70. This is the definition for airflow obstruction that is currently recommended in clinical COPD guidelines.
2) LLN cutpoint definition: postbronchodilator FEV1/FVC below the subjects' age-specific LLN value. When the resulting standard deviation (SD) score (also known as 'standardized Z score') was < -1.645, airflow obstruction was present according to this definition. This corresponds with the 5th percentile.
(Enlarge Image)
Figure 1.
Selection of Study Subjects From the Initial Primary Care Diagnostic Centres' Spirometry Databases. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; LLN: lower limit of normal. * based on Swanney prediction equations for FEV1/FVC † subgroups D, E, and F in Figure 2b ‡ subgroups A, B, and C in Figure 2b.
The principal prediction equations used to calculate LLN values for FEV1/FVC were those recently published by Swanney et al, which have been derived from an appropriate Dutch general population cohort. We also used several other LLN equations as alternatives to calculate age and gender specific cutpoints: European Community for Steel and Coal (ECSC), Falaschetti et al, Brandli et al, Kuster et al, and Hankinson et al. We selected these LLN equations from an extensive list of reference equations based on the following criteria: Caucasian race; includes age > 40 years; published in the last ten years. One additional set of equations that was more recently published was added to the selection post-hoc.
Before further analysis we subdivided the study population into four categories based on the presence of airflow obstruction at baseline as defined by the LLN and the fixed 0.70 FEV1/FVC cutpoint definitions:
- 'LLN-Fixed-': absence of airflow obstruction according to both definitions (further referred to as 'non-obstructed' subjects);
- 'LLN-Fixed+': absence of airflow obstruction according to the LLN definition, but presence of airflow obstruction according to the fixed definition (further referred to as 'discordant' subjects);
- 'LLN + Fixed+': presence of airflow obstruction according to both definitions (further referred to as 'obstructed' subjects);
- 'LLN + Fixed-': presence of airflow obstruction according to the LLN definition, but absence of airflow obstruction according to the fixed definition.
Figure 2a illustrates these categories. Only two subjects had obstruction according to the LLN definition but not according to the fixed 0.70 definition ('LLN + Fixed-'). These subjects were excluded from further analysis.
(Enlarge Image)
Figure 2.
A. Categories Based on the Lower Limit of Normal) and Fixed 0.70 FEV1/FVC Definitions. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; LLN: lower limit of normal Red diagonal line: LLN FEV1/FVC cutpoint (position and slope of this line will vary depending on the reference equation used and the height and age of the subject); black horizontal line: fixed FEV1/FVC cutpoint at 0.70 LLN-Fixed-: absence of obstruction according to both LLN and Fixed FEV1/FVC cutpoints (non-obstructed subjects) LLN-Fixed+: absence of obstruction according to LLN cutpoint, but presence of obstruction according to fixed cutpoint (discordant subjects) LLN+Fixed+: presence of obstruction according to both LLN and Fixed FEV1/FVC cutpoints (obstructed subjects) LLN+Fixed-: presence of obstruction according to LLN cutpoint, but absence of obstruction according to fixed cutpoint. Only two subjects were present in this category, who were excluded from further analysis (see Figure 1) B. Categories Based on the Lower Limit of Normal and Fixed 0.70 FEV1/FVC Definitions, and Subgroups of Subjects Who Showed a Downward Shift (A, B And C, N = 711) or an Upward Shift (D, E And F, N = 530) Between Categories Over Time. Subgroups A: no obstruction at baseline visit, obstruction according to fixed FEV1/FVC cutpoint at last available visit. B: no obstruction at baseline visit, obstruction according to both fixed and LLN FEV1/FVC cutpoints at last available visit. C: obstruction according to baseline FEV1/FVC cutpoint at first visit, obstruction according to both fixed and LLN cutpoints at last available visit. D: obstruction according to fixed and LLN FEV1/FVC cutpoints at baseline visit, obstruction according to fixed cutpoint at last available visit. E: obstruction according to fixed FEV1/FVC cutpoint at baseline visit, no obstruction at last available visit. F: obstruction according to fixed and LLN FEV1/FVC cutpoints at baseline visit, no obstruction at last available visit.
During the process of analysis we found that a substantial number of subjects (36% of the initial study cohort) shifted to another category after their initial visit. Because we considered consistency in classification to be essential for the 'proof of concept' that underlies the aim of this paper, we limited the analysis to subjects who were consistently classified in the same category (i.e., non-obstructed, discordant, or obstructed) throughout their entire follow-up ('base case population', see Figure 1).
The primary outcome to compare the clinical course of the subjects in the three categories was the annual rate of postbronchodilator FEV1 decline. We analyzed prebronchodilator FEV1 decline and pre- and postbronchodilator FVC decline as secondary outcomes.
SAS® Proprietary Software 9.2 (SAS Institute Inc., Cary, NC, USA) was used for all analyses. p < 0.05 was considered statistically significant. Baseline differences between the non-obstructed, discordant, and obstructed categories were tested with analysis of variance (Anova), Kruskal-Wallis, and Pearson Chi-square tests. A random coefficient regression model with random intercept and random slope was used to estimate the annual decline of postbronchodilator and prebronchodilator FEV1 and FVC in baseline smokers and non-smokers separately (PROC MIXED in SAS). Comparison of the discordant and obstructed categories was the principal part of the analyses, but we also compared lung function decline between discordant and non-obstructed subjects. We did not include age and gender in the regression models. Because of its known (but marginal) effect on FEV1 decline, use of inhaled corticosteroids (regardless of the dose being prescribed) during each subsequent visit was included in the model as a time-dependent dichotomous (yes/no inhaled corticosteroid use) covariate. As the proportion of subjects who reported to have changed smoking status during follow-up was small (4% of all baseline ex-smokers reported to have taken up smoking again, 5% of all baseline smokers reported to have stopped smoking) and very similar for the respective categories, we did not include changes in smoking status during follow-up in the respective regression models for smokers and non-smokers. In order to assess the sensitivity of our findings, we repeated the base case analysis after categorization of the study subjects using the selected alternative LLN prediction equations.
Methods
Study Setting and Cohort
This cohort study was based on all available spirometry tests from the period October 2001 to March 2010 from three regional primary care diagnostic centres in the Netherlands (the General Practice Laboratory Foundation Etten-Leur/Breda (SHL), the Diagnostic Centre Eindhoven (DCE), and the General Practice Laboratory East (SHO)). These diagnostic centres offer a range of diagnostic tests (including spirometry) and other healthcare services to hundreds of general practitioners (GPs) in the south-western and south-eastern parts of our country since the mid- or late nineteen-nineties. When a patient consults with respiratory symptoms and the GP suspects an underlying chronic respiratory condition (e.g., COPD or asthma), he or she can refer the patient to the diagnostic centre for spirometry testing. When a chronic respiratory condition is diagnosed or still suspected, the majority of patients enter the diagnostic centre's monitoring service and return for reassessment every six to twelve months.
Spirometry test results and accompanying demographic (gender, age), anthropometric (height, weight) and medical history information (self-reported smoking status and history, respiratory symptoms, medication) are recorded during each visit using a standardized electronic format. Every spirometry test is assessed by a respiratory consultant whose interpretation of the test and — if applicable — diagnostic advice is sent to the GP, together with the actual test results. Further details about the spirometry tests performed in the diagnostic centres are described elsewhere. Since only routine lung function and respiratory medical history data were used for our analyses and the investigators had no access to the patients' medical records or information on patients' identity, no written informed consent was obtained.
Subject Selection and Definitions for Airflow Obstruction
We selected all data from Caucasian subjects aged ≥ 40 years with complete data regarding height, history of cigarette smoking, and respiratory medication use for whom at least three postbronchodilator spirometry tests were available during a minimum follow-up of one year (see Figure 1). We used postbronchodilator FEV1/FVC values to determine whether or not airflow obstruction was present in the study subjects. The following two definitions for airflow obstruction applied:
1) Fixed cutpoint definition: postbronchodilator FEV1/FVC < 0.70. This is the definition for airflow obstruction that is currently recommended in clinical COPD guidelines.
2) LLN cutpoint definition: postbronchodilator FEV1/FVC below the subjects' age-specific LLN value. When the resulting standard deviation (SD) score (also known as 'standardized Z score') was < -1.645, airflow obstruction was present according to this definition. This corresponds with the 5th percentile.
(Enlarge Image)
Figure 1.
Selection of Study Subjects From the Initial Primary Care Diagnostic Centres' Spirometry Databases. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; LLN: lower limit of normal. * based on Swanney prediction equations for FEV1/FVC † subgroups D, E, and F in Figure 2b ‡ subgroups A, B, and C in Figure 2b.
The principal prediction equations used to calculate LLN values for FEV1/FVC were those recently published by Swanney et al, which have been derived from an appropriate Dutch general population cohort. We also used several other LLN equations as alternatives to calculate age and gender specific cutpoints: European Community for Steel and Coal (ECSC), Falaschetti et al, Brandli et al, Kuster et al, and Hankinson et al. We selected these LLN equations from an extensive list of reference equations based on the following criteria: Caucasian race; includes age > 40 years; published in the last ten years. One additional set of equations that was more recently published was added to the selection post-hoc.
Categorization of Airflow Obstruction
Before further analysis we subdivided the study population into four categories based on the presence of airflow obstruction at baseline as defined by the LLN and the fixed 0.70 FEV1/FVC cutpoint definitions:
- 'LLN-Fixed-': absence of airflow obstruction according to both definitions (further referred to as 'non-obstructed' subjects);
- 'LLN-Fixed+': absence of airflow obstruction according to the LLN definition, but presence of airflow obstruction according to the fixed definition (further referred to as 'discordant' subjects);
- 'LLN + Fixed+': presence of airflow obstruction according to both definitions (further referred to as 'obstructed' subjects);
- 'LLN + Fixed-': presence of airflow obstruction according to the LLN definition, but absence of airflow obstruction according to the fixed definition.
Figure 2a illustrates these categories. Only two subjects had obstruction according to the LLN definition but not according to the fixed 0.70 definition ('LLN + Fixed-'). These subjects were excluded from further analysis.
(Enlarge Image)
Figure 2.
A. Categories Based on the Lower Limit of Normal) and Fixed 0.70 FEV1/FVC Definitions. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; LLN: lower limit of normal Red diagonal line: LLN FEV1/FVC cutpoint (position and slope of this line will vary depending on the reference equation used and the height and age of the subject); black horizontal line: fixed FEV1/FVC cutpoint at 0.70 LLN-Fixed-: absence of obstruction according to both LLN and Fixed FEV1/FVC cutpoints (non-obstructed subjects) LLN-Fixed+: absence of obstruction according to LLN cutpoint, but presence of obstruction according to fixed cutpoint (discordant subjects) LLN+Fixed+: presence of obstruction according to both LLN and Fixed FEV1/FVC cutpoints (obstructed subjects) LLN+Fixed-: presence of obstruction according to LLN cutpoint, but absence of obstruction according to fixed cutpoint. Only two subjects were present in this category, who were excluded from further analysis (see Figure 1) B. Categories Based on the Lower Limit of Normal and Fixed 0.70 FEV1/FVC Definitions, and Subgroups of Subjects Who Showed a Downward Shift (A, B And C, N = 711) or an Upward Shift (D, E And F, N = 530) Between Categories Over Time. Subgroups A: no obstruction at baseline visit, obstruction according to fixed FEV1/FVC cutpoint at last available visit. B: no obstruction at baseline visit, obstruction according to both fixed and LLN FEV1/FVC cutpoints at last available visit. C: obstruction according to baseline FEV1/FVC cutpoint at first visit, obstruction according to both fixed and LLN cutpoints at last available visit. D: obstruction according to fixed and LLN FEV1/FVC cutpoints at baseline visit, obstruction according to fixed cutpoint at last available visit. E: obstruction according to fixed FEV1/FVC cutpoint at baseline visit, no obstruction at last available visit. F: obstruction according to fixed and LLN FEV1/FVC cutpoints at baseline visit, no obstruction at last available visit.
During the process of analysis we found that a substantial number of subjects (36% of the initial study cohort) shifted to another category after their initial visit. Because we considered consistency in classification to be essential for the 'proof of concept' that underlies the aim of this paper, we limited the analysis to subjects who were consistently classified in the same category (i.e., non-obstructed, discordant, or obstructed) throughout their entire follow-up ('base case population', see Figure 1).
Outcomes and Statistical Analysis
The primary outcome to compare the clinical course of the subjects in the three categories was the annual rate of postbronchodilator FEV1 decline. We analyzed prebronchodilator FEV1 decline and pre- and postbronchodilator FVC decline as secondary outcomes.
SAS® Proprietary Software 9.2 (SAS Institute Inc., Cary, NC, USA) was used for all analyses. p < 0.05 was considered statistically significant. Baseline differences between the non-obstructed, discordant, and obstructed categories were tested with analysis of variance (Anova), Kruskal-Wallis, and Pearson Chi-square tests. A random coefficient regression model with random intercept and random slope was used to estimate the annual decline of postbronchodilator and prebronchodilator FEV1 and FVC in baseline smokers and non-smokers separately (PROC MIXED in SAS). Comparison of the discordant and obstructed categories was the principal part of the analyses, but we also compared lung function decline between discordant and non-obstructed subjects. We did not include age and gender in the regression models. Because of its known (but marginal) effect on FEV1 decline, use of inhaled corticosteroids (regardless of the dose being prescribed) during each subsequent visit was included in the model as a time-dependent dichotomous (yes/no inhaled corticosteroid use) covariate. As the proportion of subjects who reported to have changed smoking status during follow-up was small (4% of all baseline ex-smokers reported to have taken up smoking again, 5% of all baseline smokers reported to have stopped smoking) and very similar for the respective categories, we did not include changes in smoking status during follow-up in the respective regression models for smokers and non-smokers. In order to assess the sensitivity of our findings, we repeated the base case analysis after categorization of the study subjects using the selected alternative LLN prediction equations.
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