Abstract
Rationale: International guidelines promote the use of post-bronchodilator spirometry values in the definition and severity classification of chronic obstructive pulmonary disease. However, post-bronchodilator reference values have not yet been developed.
Objectives: To derive reference values for post-bronchodilator forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC, and to compare these reference values with locally derived and existing pre-bronchodilator reference values.
Methods: Based on a random sample of a general adult population, 2,235 subjects (70% of invited subjects) performed spirometry with reversibility testing. A reference population of healthy never-smokers constituted 23% of the study population (n = 515). Reference values for median and lower-limit-of-normal pre- and post-bronchodilator lung function and bronchodilator response were modeled using quantile regression analyses.
Main Results: The reference population had equal proportions of men and women in the age range 26–82 yr. Both FEV1 and FVC decreased with age and increased with height. FEV1/FVC decreased with age, although this trend was not statistically significant for men after bronchodilatation. Linear models gave the best overall fit. Lower-limit-of-normal post-bronchodilator FEV1/FVC exceeded 0.7 for both sexes. Post-bronchodilator prediction equations gave higher predicted FEV1 and FEV1/FVC than both locally derived and existing pre-bronchodilator equations. The bronchodilator response decreased with age.
Conclusions: The present study is the first to develop reference values for post-bronchodilator lung function. Post-bronchodilator prediction equations can facilitate better management of patients with chronic obstructive pulmonary disease by avoiding falsely high FEV1% predicted with a subsequent underestimation of disease severity.
Recent international guidelines have emphasized the importance of post-bronchodilator lung function measurements in the diagnosis and severity classification of chronic obstructive pulmonary disease (COPD) (1, 2). The use of post-bronchodilator spirometry facilitates the distinction between fully reversible asthma and poorly reversible COPD, and may lead to a reduction in misclassification of individuals with reversible obstruction as COPD cases.
COPD is defined as a post-bronchodilator ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) < 0.7, and disease severity is categorized based on post-bronchodilator FEV1 in percent of predicted (1).
Predicted FEV1 is calculated based on reference values for normal lung function. Reference values are derived from healthy subsamples of general populations, and age and height are considered essential equation components (3). Because populations change over time regarding both anthropometric characteristics and environmental exposures, it is recommended to update reference values regularly (3). During the last 30 yr numerous sets of spirometry reference values have been published (4–17). However, none of them were based on spirometry after reversibility testing. It is unlikely that the difference between pre- and post-bronchodilator lung function is constant. Recent studies have shown that reversibility decreases with age in adults (18, 19), indicating a different relationship between lung function and age before and after bronchodilatation. In addition to the need for regularly updated reference values, there is thus also a need for specific post-bronchodilator reference values.
The main objective of our study was to develop reference values for median and lower-limit-of-normal (LLN) post-bronchodilator FEV1, FVC, and FEV1/FVC. We furthermore wanted to examine bronchodilator response, and to compare pre- and post-bronchodilator lung function in our reference population with regards to sex, age, and height; as well as to compare locally derived pre- and post-bronchodilator prediction equations with previously published pre-bronchodilator prediction equations. Equations were selected for comparative purposes based on common use (4) and population size (5, 6).
The present study was based on participants in the second phase of the Hordaland County Cohort Study. Information on sampling procedures and data collection in this longitudinal epidemiological study has been reported previously (20, 21). The second phase took place in 1996–1997. Of 3,181 invited subjects, 2,819 (89%) answered questionnaires, and 2,235 (70%) also performed spirometry with reversibility testing. The study population was white, and age ranged from 26 to 82 yr. The participants supplied information on disease history, respiratory symptoms, occupational exposure to airborne agents, and smoking history. Standing height and weight was measured at the clinical examination.
FVC and FEV1 were measured with a dry wedge spirometer (Vitalograph S-model; Vitalograph Ltd., Buckingham, UK) according to the American Thoracic Society (ATS) criteria (22). The subject breathed in from room air and then exhaled into the spirometer. The wedge opened as air was blown into the spirometer, and a marker moved accordingly along a sheet of paper for 6 s. The spirometer was computerized and printed the FEV1 and FVC values after the forced expiration had been performed. There was no time lag between the onset of forced expiration and the onset of timing for FEV1. No extrapolation was performed. However, if the patient hesitated at the beginning of the expiration or if the patient started the expiration too early, the maneuver was not accepted.
The highest FVC and the highest FEV1 were used in the ratio FEV1/FVC. Spirometry was performed before and 15 min after inhalation of 0.3 mg salbutamol powder from a Turbuhaler (AstraZeneca AS, Skårer, Norway). Room temperature ranged from 19 to 24°C, with a mean (standard deviation—SD) of 22 (0.5).
According to the ATS guidelines, subjects examined to generate reference values should be lifetime nonsmokers without respiratory symptoms and disease (3). In the present study, we excluded ever-smokers from the reference population, as well as never-smokers reporting physician-diagnosed respiratory disease, dyspnea grades 1 to 4, morning cough, or wheeze.
Assumption of distributional normality in lung-function variables was tested with the Shapiro-Wilk W-test (23). Each lung-function variable was plotted against age, height, weight, and body mass index (kg/m2; BMI). Curve-estimation analyses were performed to test for linear, quadratic, cubic, logarithmic, and exponential associations.
After analyzing interactions between sex and age/height, we modeled separate reference equations for men and women, for median and LLN (five percentile) pre- and post-bronchodilator FVC, FEV1, and FEV1/FVC. In addition, reference equations for men and women combined were also modeled for bronchodilator response measured in FEV1 change (L), FEV1 change (% from baseline), and FEV1/FVC (× 100) change. All reference values were modeled with nonparametric quantile regression analysis (24). Linear models with age and height as predictors gave the best overall fit for FEV1 and FVC. A linear model with age as predictor gave the best fit for the bronchodilator response in FEV1 and FEV1/FVC, for pre-bronchodilator FEV1/FVC, and for post-bronchodilator female FEV1/FVC, whereas the association between age and male post-bronchodilator ratio did not reach statistical significance. When plotting the modeled reference values for FEV1 and FVC against age, we standardized height using mean values (1.80 m for males and 1.65 m for females).
We used a general linear model with repeated measures to compare pre- and post-bronchodilator FEV1, FVC, and FEV1/FVC with regard to sex, age, and height. We investigated both between-subject and within-subject main effects to assess the effects of the independent variables on both pre- and post-bronchodilator lung function separately as well as on the bronchodilator response.
We compared the post-bronchodilator prediction equations with existing equations from the European Community for Coal and Steel (ECSC), the Third National Health and Nutrition Examination Survey (NHANES3), and the Health Survey of England (HSE) (4–6). We assessed the differences between observed and predicted lung function values. Differences were given as mean differences, mean differences in percent of observed values, and mean squared differences. Goodness of fit was ranked according to mean squared difference. We produced Bland-Altman plots (25) to examine the differences between the post-bronchodilator prediction equations and each of the other three equations. Paired t tests, stratified by sex and age, were performed to assess the significance of these observed differences. To assess whether the observed differences between post-bronchodilator equations and existing equations were due to bronchodilator effect, methodologic differences or population differences, we also examined differences between locally derived pre-bronchodilator equations and the three existing equations in the same manner. Statistical analyses were performed using SPSS for Windows version 13.0 (26) and Stata SE9 (27).
There were 864 (39%) never-smokers in the study population. After exclusion of never-smokers with respiratory disease and symptoms, the remaining reference population comprised 515 subjects (23%). Men and women were evenly distributed, and height, weight, and BMI were comparable in the study population and the reference population (Table 1). Women had similar age distribution in the two populations, but men were on average 4 yr younger in the reference population than in the study population. Age range for both sexes was 26–82 yr. Occupational exposure to dust or gas was reported by 47% of the men and 22% of the women in the reference population, compared with 64% and 31%, respectively, in the study population. More subjects had obtained a higher educational level in the reference population than in the study population. University education was reported by 45% of the men in the reference population versus 25% of the men in the general study population.
Study Population | Reference Population | |
|---|---|---|
| (n = 2,235) | (n = 515) | |
| Men, n (%) | 1106 (49.5) | 237 (46.0) |
| Age, yr, mean, (SD) | 49.0 (14.4) | 45.1 (13.1) |
| 27–39 yr, n (%) | 342 (31) | 98 (41) |
| 40–49 yr, n (%) | 285 (26) | 65 (27) |
| 50–59 yr, n (%) | 195 (18) | 35 (15) |
| 60–69 yr, n (%) | 156 (14) | 26 (11) |
| 70–82 yr, n (%) | 128 (11) | 13 (6) |
| Height, m, mean (SD) | 1.78 (0.07) | 1.80 (0.07) |
| Weight, kg, mean (SD) | 82.0 (12.6) | 83.0 (12.1) |
| Body mass index, kg/m2, mean (SD) | 25.9 (3.4) | 25.7 (3.2) |
| Occupational exposure* | ||
| Yes, n (%) | 689 (64) | 108 (47) |
| No, n (%) | 393 (36) | 124 (53) |
| Educational level* | ||
| Primary, n (%) | 187 (17) | 15 (7) |
| Secondary, n (%) | 635 (58) | 113 (48) |
| University, n (%) | 273 (25) | 106 (45) |
| Women, n (%) | 1129 (50.5) | 278 (54.0) |
| Age, yr, mean (SD) | 50.6 (14.9) | 51.4 (15.1) |
| 27–39 yr, n (%) | 298 (26) | 68 (24) |
| 40–49 yr, n (%) | 287 (25) | 67 (24) |
| 50–59 yr, n (%) | 223 (20) | 61 (22) |
| 60–69 yr, n (%) | 157 (14) | 36 (13) |
| 70–82 yr, n (%) | 164 (15) | 46 (17) |
| Height, m, mean (SD) | 1.65 (0.06) | 1.65 (0.06) |
| Weight, kg, mean (SD) | 68.6 (12.9) | 67.9 (12.2) |
| Body mass index, kg/m2, mean (SD) | 25.3 (4.5) | 25.1 (4.5) |
| Occupational exposure* | ||
| Yes, n (%) | 344 (31) | 59 (22) |
| No, n (%) | 756 (69) | 210 (78) |
| Educational level* | ||
| Primary, n (%) | 213 (19) | 46 (17) |
| Secondary, n (%) | 667 (60) | 147 (54) |
| University, n (%) | 234 (21) | 79 (29) |
Initial analyses of FEV1 and FVC showed significant interactions between sex and height, and analysis of FEV1/FVC revealed significant interaction between sex and age (test of interaction p < 0.05). Subsequent analyses were performed separately for men and women.
Preliminary plots as well as curve-estimation analyses showed that FEV1 and FVC were associated with age (p < 0.05) and height (p < 0.05) in a linear manner, separately for men and women. Lung function decreased with age and increased with height. FEV1/FVC decreased linearly with age, but after bronchodilatation the trend was only statistically significant for women. Weight and BMI were not related to any of the lung function variables after adjustments for age and height. There was no significant interaction between age and height.
The median and LLN equations derived from the reference population explained from 38 to 55% of the variance in post-bronchodilator FEV1 and FVC (Table 2). Post-bronchodilator reference values for all lung function variables across age are presented in Figure 1 with standardized mean height (1.80 m for men and 1.65 m for women). We also calculated predicted post-bronchodilator lung function values for each subject in the reference population according to his or her age and height. Median (SD) predicted FEV1 decreased with age from 4.70 (0.39) L in men younger than 40 yr to 3.02 (0.36) L in men older than 70 yr. For women the corresponding decrease was from 3.48 (0.23) L in the youngest age group to 2.04 (0.27) L in the oldest age group (> 70 yr). Predicted FVC followed the same pattern (Figure 1). FEV1/FVC decreased with age for both men and women, but after bronchodilatation the association was not statistically significant for men (age coefficient for men was −0.0006 per year with standard error 0.0004, p = 0.114). Percentile estimations of post-bronchodilator FEV1/FVC in the male reference population gave a predicted median (95% confidence interval—CI) of 0.82 (0.82, 0.83) and LLN 0.72 (0.69, 0.73). For women, on the other hand, median (95% CI) predicted FEV1/FVC declined from 0.86 (0.86, 0.86) in subjects younger than 40 yr to 0.79 (0.78, 0.79) in subjects older than 70 yr. LLN exceeded 0.70 in all age groups for both sexes, being 0.72 across age for men and 0.71 at its lowest point among women older than 70 yr.
Figure 1. Predicted median (solid line) and lower limit of normal (dashed line) for post-bronchodilator forced expiratory volume in one second (FEV1) (a, b), forced vital capacity (FVC) (c, d), and FEV1/FVC (e, f) in men (height 1.80 m) (a, c, e) and women (height 1.65 m) (b, d, f). Observed values as underlying scatter plot.
[More] [Minimize]b0 | b1 | b2 | ||
|---|---|---|---|---|
| Intercept (SE) | Age (yr) (SE) | Height (m) (SE) | R2 | |
| FEV1 (L) | ||||
| Men | ||||
| Median | −4.261 (1.041) | −0.0296 (0.003) | 5.465 (0.553) | 0.40 |
| LLN | −1.905 (2.227)* | −0.0306 (0.007) | 3.757 (1.157) | 0.40 |
| Women | ||||
| Median | −1.747 (0.861) | −0.0263 (0.002) | 3.619 (0.489) | 0.49 |
| LLN | −0.581 (0.992)* | −0.0268 (0.003) | 2.632 (0.533) | 0.55 |
| FVC (L) | ||||
| Men | ||||
| Median | −6.142 (1.142) | −0.0281 (0.003) | 7.000 (0.606) | 0.38 |
| LLN | −2.607 (2.355)* | −0.0264 (0.005) | 4.507 (1.240) | 0.38 |
| Women | ||||
| Median | −4.040 (1.060) | −0.0259 (0.002) | 5.364 (0.603) | 0.45 |
| LLN | −3.992 (1.466) | −0.0242 (0.006) | 4.942 (0.794) | 0.47 |
| FEV1/FVC (× 100) | ||||
| Men | ||||
| Median | 82 | — | — | — |
| LLN | 72 | — | — | — |
| Women | ||||
| Median | 91.127 (1.192) | −0.1684 (0.022) | — | 0.13 |
| LLN | 83.424 (3.186) | −0.1626 (0.060) | — | 0.13 |
| Median bronchodilator response | ||||
| Men and women combined | ||||
| FEV1 change (L) | 0.178 (0.015) | −0.002 (0.0003) | — | 0.05 |
| FEV1 change (%) | 4.388 (0.543) | −0.041 (0.011) | — | 0.02 |
| FEV1/FVC (× 100) change | 3.483 (0.317) | −0.0258 (0.006) | — | 0.02 |
Linear models with age and height as predictors gave the best overall fit for both pre-bronchodilator FEV1 and FVC, while linear models with age as predictor gave the best fit for FEV1/FVC (Table 3). Linear models for men and women combined with age as predictor gave the best fit for bronchodilator response of FEV1 and FEV1/FVC (Table 2).
b0 | b1 | b2 | ||
|---|---|---|---|---|
| Intercept (SE) | Age (yr) (SE) | Height (m) (SE) | R2 | |
| FEV1 (L) | ||||
| Men | ||||
| Median | −4.698 (1.133) | −0.0254 (0.003) | 5.563 (0.601) | 0.37 |
| LLN | −2.886 (2.876)* | −0.0218 (0.008) | 4.016 (1.543) | 0.40 |
| Women | ||||
| Median | −1.267 (1.075)* | −0.0256 (0.003) | 3.278 (0.610) | 0.45 |
| LLN | −0.839 (2.128)* | −0.0255 (0.005) | 2.711 (1.206) | 0.52 |
| FVC (L) | ||||
| Men | ||||
| Median | −6.852 (1.353) | −0.0271 (0.004) | 7.362 (0.720) | 0.38 |
| LLN | −4.318 (3.292)* | −0.0313 (0.008) | 5.583 (1.705) | 0.37 |
| Women | ||||
| Median | −3.859 (1.126) | −0.0255 (0.003) | 5.252 (0.639) | 0.43 |
| LLN | −4.146 (2.415)* | −0.0242 (0.008) | 5.035 (1.308) | 0.46 |
| FEV1/FVC (× 100) | ||||
| Men | ||||
| Median | 82.994 (1.293) | −0.0632 (0.023) | — | 0.01 |
| LLN | 70 | — | — | — |
| Women | ||||
| Median | 87.439 (1.330) | −0.1355 (0.025) | — | 0.10 |
| LLN | 79.127 (3.059) | −0.1191 (0.057) | — | 0.05 |
Age and height were important lung function predictors both before and after reversibility testing, and age had also a significant effect on bronchodilator response of FEV1 and FEV1/FVC (Tables 2 and 4). Bronchodilator response of FVC was not associated with age or height. Both pre- and post-bronchodilator lung function decreased with age in both sexes, but post-bronchodilator lung function had a steeper age-related decline. Consequently, also bronchodilator response of FEV1 and FEV1/FVC decreased with age (p < 0.05, Tables 2 and 4). Based on the bronchodilator response equations in the present study, a 25-yr-old subject would have a 3.4% increase in FEV1 and 2.8 percentage point increase in FEV1/FVC(× 100). A 75-yr-old subject, on the other hand, would have a 1.3% increase in FEV1 and 1.5 percentage point increase in FEV1/FVC(× 100) (Table 2).
p Value* | ||||||
|---|---|---|---|---|---|---|
| 27–39 yr | 40–59 yr | 60–82 yr | Age (yr) | Height (m) | ||
| Men | ||||||
| n | 101 | 98 | 38 | |||
| FEV1 | ||||||
| Pre-br. mean (SD) | 4.53 (0.61) | 4.04 (0.56) | 3.32 (0.65) | .000 | .000 | |
| Post-br. mean (SD) | 4.67 (0.61) | 4.12 (0.55) | 3.35 (0.66) | .000 | .000 | |
| Mean change (SD) | 0.145 (0.134) | 0.078 (0.120) | 0.034 (0.178) | .000 | .711 | |
| FVC | ||||||
| Pre-br. mean (SD) | 5.67 (0.78) | 5.08 (0.75) | 4.25 (0.73) | .000 | .000 | |
| Post-br. mean (SD) | 5.68 (0.79) | 5.06 (0.75) | 4.22 (0.72) | .000 | .000 | |
| Mean change (SD) | 0.010 (0.137) | −0.022 (0.131) | −0.026 (0.132) | .105 | .292 | |
| FEV1/FVC | ||||||
| Pre-br. mean (SD) | 0.80 (0.05) | 0.80 (0.05) | 0.78 (0.05) | .048 | — | |
| Post-br. mean (SD) | 0.83 (0.05) | 0.82 (0.05) | 0.79 (0.06) | .002 | — | |
| Mean change (SD) | 0.025 (0.018) | 0.019 (0.016) | 0.013 (0.034) | .003 | — | |
| Women | ||||||
| n | 72 | 130 | 76 | |||
| FEV1 | ||||||
| Pre-br. mean (SD) | 3.41 (0.43) | 2.90 (0.43) | 2.18 (0.45) | .000 | .000 | |
| Post-br. mean (SD) | 3.52 (0.43) | 2.95 (0.44) | 2.23 (0.46) | .000 | .000 | |
| Mean change (SD) | 0.115 (0.101) | 0.056 (0.095) | 0.046 (0.081) | .021 | .002 | |
| FVC | ||||||
| Pre-br. mean (SD) | 4.13 (0.56) | 3.60 (0.56) | 2.80 (0.56) | .000 | .000 | |
| Post-br. mean (SD) | 4.12 (0.55) | 3.58 (0.55) | 2.80 (0.55) | .000 | .000 | |
| Mean change (SD) | −0.009 (0.110) | −0.021 (0.111) | −0.001 (0.103) | .194 | .414 | |
| FEV1/FVC | ||||||
| Pre-br. mean (SD) | 0.83 (0.05) | 0.81 (0.04) | 0.80 (0.05) | .000 | — | |
| Post-br. mean (SD) | 0.86 (0.04) | 0.83 (0.04) | 0.80 (0.05) | .000 | — | |
| Mean change (SD) | 0.029 (0.020) | 0.021 (0.020) | 0.017 (0.021) | .000 | — | |
The post-bronchodilator equations gave higher values for FEV1 and FEV1/FVC than any of the other prediction equations studied (Table 5). The ECSC prediction equations were farthest away from observed post-bronchodilator lung function, underestimating FEV1, FVC, and FEV1/FVC in both sexes. Values predicted by equations from the HSE differed from observed values by less than 2% for men, while the discrepancy was larger for women, being almost 5% below observed post-bronchodilator FEV1. Values derived from NHANES3 differed 3% or less from observed values.
Age (yr) | n | Mean difference (L) (SE) | Mean difference (% of observed) (SE) | Mean squared difference (L) (SE) | Rank | |
|---|---|---|---|---|---|---|
| Men | ||||||
| FEV1 | ||||||
| Present study | 26–82 | 237 | 0.013 (0.030) | −0.856 (0.737) | 0.214 (0.022) | 1 |
| ECSC | 18–70 | 225 | 0.316 (0.032) | 6.143 (0.716) | 0.326 (0.034) | 4 |
| NHANES3 | 20–80 | 236 | 0.092 (0.030) | 1.023 (0.725) | 0.223 (0.024) | 2 |
| HSE | 16–94 | 237 | 0.101 (0.030) | 1.403 (0.723) | 0.227 (0.026) | 3 |
| FVC | ||||||
| Present study | 26–82 | 237 | 0.026 (0.038) | −0.806 (0.733) | 0.342 (0.032) | 2 |
| ECSC | 18–70 | 225 | 0.372 (0.040) | 5.751 (0.713) | 0.501 (0.050) | 4 |
| NHANES3 | 20–80 | 236 | −0.075 (0.038) | −2.905 (0.756) | 0.351 (0.031) | 3 |
| HSE | 16–94 | 237 | −0.009 (0.038) | −1.422 (0.735) | 0.340 (0.031) | 1 |
| FEV1/FVC (×100) | ||||||
| Present study | 26–82 | 237 | −0.315 (0.342) | −0.823 (0.445) | 27.689 (2.846) | 1 |
| ECSC | 18–70 | 225 | 2.465 (0.355) | 2.617 (0.444) | 34.267 (2.805) | 3 |
| NHANES3 | 20–80 | 236 | 2.932 (0.352) | 3.211 (0.439) | 37.720 (2.984) | 4 |
| HSE | 16–94 | 237 | 1.228 (0.337) | 1.109 (0.431) | 28.351 (2.538) | 2 |
| Women | ||||||
| FEV1 | ||||||
| Present study | 26–82 | 278 | 0.040 (0.020) | −0.339 (0.727) | 0.113 (0.010) | 1 |
| ECSC | 18–70 | 237 | 0.302 (0.022) | 9.042 (0.667) | 0.205 (0.018) | 4 |
| NHANES3 | 20–80 | 271 | 0.089 (0.020) | 1.595 (0.711) | 0.121 (0.011) | 2 |
| HSE | 16–94 | 278 | 0.157 (0.020) | 4.457 (0.686) | 0.135 (0.012) | 3 |
| FVC | ||||||
| Present study | 26–82 | 278 | 0.048 (0.025) | 0.133 (0.722) | 0.169 (0.015) | 2 |
| ECSC | 18–70 | 237 | 0.462 (0.027) | 11.658 (0.658) | 0.388 (0.033) | 4 |
| NHANES3 | 20–80 | 271 | −0.025 (0.025) | −2.344 (0.727) | 0.166 (0.015) | 1 |
| HSE | 16–94 | 278 | 0.125 (0.024) | 2.575 (0.695) | 0.181 (0.017) | 3 |
| FEV1/FVC (× 100) | ||||||
| Present study | 26–82 | 278 | 0.109 (0.268) | −0.159 (0.329) | 19.879 (1.681) | 1 |
| ECSC | 18–70 | 237 | 3.140 (0.284) | 3.519 (0.333) | 28.859 (2.507) | 4 |
| NHANES3 | 20–80 | 271 | 2.632 (0.270) | 2.936 (0.321) | 26.603 (2.237) | 3 |
| HSE | 16–94 | 278 | 1.733 (0.262) | 1.809 (0.317) | 21.977 (1.813) | 2 |
Predicted FEV1 from the post-bronchodilator equations were overall higher than values predicted both by the ECSC, the NHANES3, and the HSE for both sexes (Figure 2) (p < 0.05). Predicted FEV1 from the pre-bronchodilator equations, on the other hand, were in closer agreement with existing equations (Figure 3). Although predicted pre-bronchodilator FEV1 was also higher than values predicted by the ECSC (Figure 3) (p < 0.05), the predicted values were in agreement with NHANES3 for both sexes (p > 0.05), and were also in agreement with the HSE for both men and women with predicted FEV1 > 3.0 L and 3.5 l, respectively (p > 0.05).
Figure 2. Bland-Altman plots showing the difference between predicted post-bronchodilator FEV1 based on the present study and predicted FEV1 based on the European Community for Coal and Steel (ECSC) (a, b), the Third National Health and Nutrition Examination Survey (NHANES3) (c, d), and the Health Survey of England (HSE) (e, f) in men (a, c, e) and women (b, d, f). Broken line shows line of agreement; solid lines show lower limit of agreement, mean agreement difference, and upper limit of agreement.
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Figure 3. Bland-Altman plots showing the difference between predicted pre-bronchodilator FEV1 based on the present study and predicted FEV1 based on the ECSC (a, b), the NHANES3 (c, d), and the HSE (e, f) in men (a, c, e) and women (b, d, f). Broken line shows line of agreement; solid lines show lower limit of agreement, mean agreement difference, and upper limit of agreement.
[More] [Minimize]As observed in Table 4, there were only marginal differences between FVC before and after bronchodilatation. Consequently, pre- and post-bronchodilator equations for FVC were similar to each other. Both equations predicted higher FVC than values based on the ECSC for both sexes (Figures 4 and 5) (p < 0.05). Pre- and post-bronchodilator FVC was also higher than FVC predicted by the HSE for women. However, predicted pre- and post-bronchodilator FVC was lower than FVC predicted by NHANES3 for both sexes, and it was also lower than FVC predicted by the HSE for men (p < 0.05).
Figure 4. Bland-Altman plots showing the difference between predicted post-bronchodilator FVC based on the present study and predicted FVC based on the ECSC (a, b), the NHANES3 (c, d), and the HSE (e, f) in men (a, c, e) and women (b, d, f), against mean FVC predicted. Broken line shows line of agreement; solid lines show lower limit of agreement, mean agreement difference, and upper limit of agreement.
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Figure 5. Bland-Altman plots showing the difference between predicted pre-bronchodilator FVC based on the present study and predicted FVC based on the ECSC (a, b), the NHANES3 (c, d), and the HSE (e, f) in men (a, c, e) and women (b, d, f), against mean FVC predicted. Broken line shows line of agreement; solid lines show lower limit of agreement, mean agreement difference, and upper limit of agreement.
[More] [Minimize]Additional age-stratified analyses showed that post-bronchodilator FEV1/FVC predicted by the present study was higher than FEV1/FVC predicted by ECSC, NHANES3, and HSE for both sexes (p < 0.05), except for men younger than 40 yr who had higher FEV1/FVC predicted by HSE than by the present study. There were smaller differences between pre-bronchodilator FEV1/FVC predicted by the present study and FEV1/FVC predicted by ECSC, NHANES3, and HSE, although differences were still significant. Predicted pre-bronchodilator FEV1/FVC was higher than FEV1/FVC predicted by the ECSC and the NHANES3, and lower than FEV1/FVC predicted by the HSE (p < 0.05).
We estimated prediction equations for median and LLN pre- and post-bronchodilator FEV1, FVC, and FEV1/FVC, and for bronchodilator response in FEV1 and FEV1/FVC based on an asymptomatic never-smoking reference population aged 26– 82 yr. Lower limit of normal post-bronchodilator FEV1/FVC in all age groups exceeded the 0.7 cut-off point proposed by international guidelines to identify subjects with COPD (1, 2). The new post-bronchodilator prediction equations differed markedly from pre-bronchodilator prediction equations derived from the same reference population, as well as from other equations in common use today (4–6). Reversibility decreased with age, with elderly subjects having lower bronchodilator response than younger subjects.
The reference population in the present study was sampled from a general population and had a wide age span with subjects up to 82 yr of age. The inclusion of elderly is an important strength of this study, since equations should never be extrapolated beyond the age range they are based on (3). Several existing prediction equations have been based on younger reference populations, and thus have limited application in assessing normal lung function in the elderly (4, 9, 11, 12, 17).
All participants in the present study performed spirometry with reversibility testing, enabling us to derive both pre- and post-bronchodilator reference values. Post-bronchodilator reference values have not previously been derived, even though both the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines and the new joint guidelines from ATS and the European Respiratory Society (ERS) emphasize the importance of post-bronchodilator lung function testing in the assessment of COPD severity grades (1, 2). We have previously shown that both prevalence and incidence of COPD in a general population decreased substantially when COPD was defined with post-bronchodilator rather than pre-bronchodilator lung function values (18, 28). Similarly, calculating post-bronchodilator FEV1 in percent of predicted based on pre-bronchodilator reference values would result in an overestimation of achieved FEV1. Even healthy subjects experience improvement in lung function after reversibility testing (29). Such an improvement is not constant across age; our results showed that older subjects had lower reversibility than younger subjects. Such a decrease in reversibility with age has also been shown in previous studies (18, 19). A fixed increase added to pre-bronchodilator reference values would therefore not suffice; specific reference values for post-bronchodilator lung function are needed.
A linear model with age and height as predictors gave the best overall fit for FEV1 and FVC prediction equations in the present study. Traditionally, prediction equations have been based on such linear models (4, 7, 9, 10, 13, 30). However, the relation between lung function and age is not linear, but rather characterized by three phases: growth, plateau, and decline (3, 17). Thus, several recent studies have chosen models presenting a more curved relationship between lung function and predictors; either curvilinear or logarithmic models (5, 6, 11, 12, 14, 15, 31). In the present reference population study, we tested for linear, quadratic, cubic, logarithmic, and exponential associations between predictors and lung function. Linear associations gave the best fit for both age and height, probably because the youngest subjects were 26 yr old and had already passed both the growth and the plateau phases regarding lung function. A study with a larger age span including more young subjects would most likely necessitate a more complex prediction model.
The ATS guidelines do not recommend defining a fixed FEV1/FVC as an LLN in adults due to an inverse relation of the ratio to age and height (32). We did not, however, find an association between FEV1/FVC and height in our study. This is in accordance with several other existing reference value studies (5, 10, 33). Age, on the other hand, is a widely recognized predictor of the FEV1/FVC ratio. Also in the present study, age was a significant predictor for pre-bronchodilator FEV1/FVC. Although the tendency remained the same after reversibility testing, the age coefficient was statistically significant only for women. It is likely that an association between post-bronchodilator FEV1/FVC and age would be confirmed statistically also for men if the reference population in the present study had included more elderly men. While 11% of the study population was older than 70 yr, only 6% (n = 13) of the reference population was included in this oldest age category.
The main limitation of this study was the small sample size, giving fewer observations especially among elderly men. However, the comparison of the reference population and the study population showed equal distribution of height, weight, and BMI for both men and women, and also equal age distribution for women. A previous study showed that the study population was representative of the Norwegian population within the same age range (18), indicating that the reference population reflects a larger population despite its limited sample size.
The dosage of 0.3 mg salbutamol applied in our study differed from the presently recommended dosage of 0.4 mg salbutamol by both the GOLD and the ATS/ERS guidelines (1, 32). When the Hordaland County Cohort Study was conducted in 1996–1997, there were no internationally uniform recommendations concerning bronchodilator reversibility testing. Our dosage of 0.3 mg was selected based on an ethical consideration regarding public safety. Later, a Norwegian study assessed that only 0.4% of a general population sample reported side effects after inhalation of 0.4 mg salbutamol (34). Consequences of differences in dosage between the Hordaland County Cohort Study and international recommendations have not been investigated in a general population. However, 0.3 mg salbutamol was administered by Turbuhaler in the Hordaland County Cohort Study, while international guidelines recommend 0.4 mg salbutamol with a metered dose inhaler. A study of patients with reversible obstructive airways disease have previously shown that 0.1 mg salbutamol given by Turbuhaler was equivalent to 0.2 mg salbutamol given by metered dose inhaler (35). Thus, the dose administered in the present study may in effect have been even larger than the recommended dose.
LLN FEV1/FVC for both men and women after reversibility testing exceeded 0.7 across all ages, reaching its lowest at 0.71 among the oldest women. The GOLD cut-off point of 0.7 for defining COPD has been criticized for overestimating COPD in healthy elderly in a recent Norwegian study, using simple spirometry without reversibility testing (33). The results from the present study suggest that the GOLD cut-off point is useful as long as FEV1/FVC is measured after bronchodilatation rather than before.
The implementation of correct post-bronchodilator prediction equations has important implications for COPD severity classification and patient treatment. With post-bronchodilator values, predicted lung function would be higher and consequently a lower COPD prevalence would be expected (18). However, among those with low FEV1/FVC after reversibility testing, disease will be classified as more severe when calculating percent of predicted based on post-bronchodilator equations than based on pre-bronchodilator equations. The use of post-bronchodilator reference equations will thus prevent underestimation of disease severity.
The implementation of reversibility prediction equations will furthermore ensure that bronchodilator response is evaluated based on the patient's age, preventing the practitioner from expecting the same bronchodilator response from a 25-yr-old patient as from a 75-yr-old patient. Both expected post-bronchodilator lung function and expected change in lung function with reversibility testing should be taken into account for optimal detection and management of COPD. Patients at risk for rapid lung function decline should be examined regularly and compared with reference values to detect disease early. Individuals who are more than 50 yr old and who are current smokers have been identified as being at risk of experiencing such rapid lung function decline (36) with smoking adding considerably to the age-related decline in FEV1 (37).
To conclude, we recommend implementation of both post-bronchodilator prediction equations and reversibility prediction equations derived from the present study in clinical practice. Due to the limited reference population size in the present study, however, we also recommend studies with larger reference populations to derive post-bronchodilator equations with more robust estimates.
The authors thank the Centre for Clinical Research at Haukeland University Hospital, respiratory laboratory technician Lene Svendsen, and the statisticians Matteo Bottai and Roy Miodini Nilsen.
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