We compared the predictive value of prebronchodilator and postbronchodilator spirometry for chronic obstructive pulmonary disease (COPD) features and outcomes.

We analysed COPDGene data of 10 192 subjects with smoking history. We created regressions models with the following dependent variables: clinical, functional and radiographic features, and the following independent variables: prebronchodilator airflow obstruction (PREO) and postbronchodilator airflow obstruction (POSTO), prebronchodilator and postbronchodilator FEV_{1}% predicted. We compared the model performance using the Akaike information criterion (AIC).

The COPD prevalence was higher using PREO. About 8.5% had PREO but no airflow obstruction in postbronchodilator spirometry (POSTN) (PREO-POSTN) and 3% of all subjects had no aiflow obstruction in prebronchodilator spirometry (PREN) but POSTO (PREN-POSTO). We found no difference in COPD features and outcomes between PREO-POSTN and PREN-POSTO subjects. Although, both prebronchodilator and postbronchodilator spirometries are both associated with chronic bronchitis, dyspnoea, exercise capacity and COPD radiographic findings, models that included postbronchodilator spirometric measures performed better than models with prebronchodilator measures to predict these COPD features. The predictive value of prebronchodilator and postbronchodilator spirometries for respiratory exacerbations, change in forced expiratory volume in 1 s, dyspnoea and exercise capacity during a 5-year period is relatively similar, but postbronchodilator spirometric measures are better predictors of mortality based on AIC.

Postbronchodilator spirometry may be a more accurate predictor of COPD features and outcomes.

The chronic obstructive pulmonary disease (COPD) prevalence was higher using prebronchodilator spirometry.

We found no difference in COPD features and outcomes between subjects with discordance in prebronchodilator and postbronchodilator spirometry.

Although both prebronchodilator and postbronchodilator spirometries are associated with COPD features and outcomes, postbronchodilator spirometry may be a more accurate predictor.

Chronic obstructive pulmonary disease (COPD) diagnosis is based on a spirometric definition according to Global Initiative for Chronic Obstructive Lung Diseases guidelines._{1})/forced vital capacity (FVC) below the lower limit of normal (LLN) or 0.7._{1}/FVC<LLN with FEV_{1}/FVC <0.7 as a diagnostic criterion for AFO._{1}/FVC <0.7. The rationale is based on its simplicity, independence of reference values and the fact that it is used in numerous clinical trials.

COPD prevalence is lower when postbronchodilator spirometry is used compared with when prebronchodilator spirometry is used.

Subjects with significant hyperinflation, and therefore with more dyspnoea,_{1}/FVC ratio._{1} increase after bronchodilator,_{1}/FVC <0.7 (POSTO) may be more sensitive to diagnose symptomatic patients with clinically significant hyperinflation than prebronchodilator FEV_{1}/FVC <0.7 (PREO).

We compared the predictive value of prebronchodilator and postbronchodilator FEV_{1}/FVC <0.7 and FEV_{1}% predicted for chronic bronchitis, dyspnoea, exercise capacity and COPD radiographic findings at phase 1 (baseline); respiratory exacerbations, change in dyspnoea, FEV_{1} and exercise capacity from phase 1 to phase 2 visit (about 5 years apart); and mortality. We also examined whether subjects with discordance in prebronchodilator and postbronchodilator spirometry have different clinical, functional and radiographic features.

We conducted the study using data from the COPDGene database. GOPDGene is an ongoing study that enrolled subjects in several clinical centres through the USA (

We included all subjects who participated in COPDGene study with at least 10 or more pack-years of smoking and who completed a phase 1 visit (n=10 192). Subjects were contacted every 6 months and completed a validated questionnaire regarding respiratory exacerbations. About 5 years after the phase 1 visit, a portion of subjects had a phase 2 visit that included questionnaire as in phase 1, a prebronchodilator and postbronchodilator spirometry and 6 min walk test. We also collected all-cause mortality data. We excluded those with incomplete prebronchodilator and postbronchodilator spirometric data.

Prebronchodilator AFO (PREO) was defined as prebronchodilator FEV_{1}/FVC <0.7. Postbronchodilator AFO (POSTO) was defined as postbronchodilator FEV_{1}/FVC <0.7. Prebronhodilator FEV1% predicted (Pre-FEV_{1}%) and postbronchodilator FEV1% predicted (post-FEV_{1}%) were calculated using predicted equations by Hankinson _{1} or FVC equal to or greater than 0.2 L and 12% according to ATS-ERS guidelines.

Emphysema was defined by using the percentage of lung volume at TLC with attenuation less than −950 Hounsfield units (HU).

Exacerbations were defined as episodes of worsening respiratory symptoms requiring use of antibiotics and systemic steroids since the phase 1 visit. Severe exacerbations were defined as those requiring hospitalisations. Other variables definitions have been previously described.

We performed a McNemar test for paired binary data to compare the prevalence rate of AFO using PREO and POSTO as diagnostic criteria.

We stratified the subjects by prebronchodilator and postbronchodilator FEV_{1}/FVC to:

Prebronchodilator FEV_{1}/FVC ≥0.7 (PREN) and postbronchodilator FEV_{1}/FVC ≥ 0.7 (POSTN) = (PREN-POSTN).

Prebronchodilator FEV_{1}/FVC <0.7 (PREO) and postbronchodilator FEV_{1}/FVC <0.7 (POSTO) =(PREO-POSTO).

Prebronchodilator FEV_{1}/FVC <0.7 (PREO) and postbronchodilator FEV_{1}/FVC ≥ 0.7 (POSTN) = (PREO-POSTN).

Prebronchodilator FEV_{1}/FVC ≥ 0.7 (PREN) and postbronchodilator FEV_{1}/FVC <0.7 (POSTO) = (PREN-POSTO).

We compared characteristics at the phase 1 visit, number of exacerbations per year, changes in FEV_{1}, dyspnoea score and distance covered in 6 min walk from the phase 1 to the phase 2 visit between PREO-POSTN and PREN-POSTO using Fischer’s exact or χ^{2} test for categorical variables and Student’s t-test or Wilcoxon rank sum test for normal and non-normal continuous variables, respectively. When we found a significant difference in the above measures between PREO-POSTN and PREN-POSTO in unadjusted analysis, we created multivariable regression models with PREO-POSTN versus PREN-POSTO as an independent variable.

We performed multivariable logistic regression models with chronic bronchitis at baseline as the dependent variable (outcome) and PREO, POSTO, pre-FEV_{1}% and post-FEV_{1}% as the independent variables. Similarly, we performed multivariable linear regression models with the following dependent variables: (1) dyspnoea scores, emphysema%, gas trapping% and distance covered in 6 min walk at phase 1; (2) number of respiratory exacerbations and severe exacerbations per year; and (3) changes in FEV_{1}, dyspnoea and distance covered in 6 min walk between phase 1 and phase 2 visit, and prebronchodilator and postbronchodilator measures as the independent variables.

We used a Cox proportional hazard regression analysis to examine the association of spirometric measures and patterns with mortality.

All regression models included the following covariates: age, sex, race, smoking status, pack-years, history of asthma (per questionnaire), diabetes, high blood pressure, stroke and sleep apnoea. We used the Akaike information criterion (AIC) to compare the performance of the various models.

Of 10 192 subjects with at least 10 or more pack-years of smoking, we excluded 192 with incomplete prebronchodilator and postbronchodilator spirometric data. Ten thousand subjects were included in in the analysis. We had available data regarding respiratory exacerbations for 8479 subjects. Of the 10 000 subjects, 4857 completed a phase 2 visit that included respiratory questionnaires, spirometry and 6 min walk test. We also had available mortality data for 8221 subjects.

Using PREO, the AFO prevalence was 50.2% (5016 of 10 000), whereas using POSTO, the prevalence was 44.5% (4451 of 10 000; P<0.001). There were 1167 subjects with discordant spirometry: 866 (8.7%) with PREO-POSTN and 301 (3%) with PREN-POSTO (

_{1}% and shorter distance covered in 6 min walk. Bronchodilator response was more common in PREN-POSTO subjects than in PREN-POSTN subjects. Change in FEV_{1}% predicted after bronchodilator was smaller, but change FVC% predicted after bronchodilator was larger in PREN-POSTO subjects compared with subjects with PREO-POSTN.

Baseline characteristics

All | PREO-POSTO | PREN-POSTN | PREO-POSTN | PREN-POSTO | P value* | |

Age, year±SD | 59.6±9 | 63.4±8.5 | 56.4±8.2 | 59.3±8.9 | 59.1±8.9 | 0.72 |

Female, % (n) | 46.7 (4668) | 43.9 (1823) | 49.4 (2315) | 44.6 (386) | 47.8 (144) | 0.36 |

Non-white race, % (n) | 32.9 (3287) | 21.6 (895) | 42.9 (2010) | 31.4 (272) | 36.5 (110) | 0.12 |

BMI, kg/m^{2}±SD | 28.8±6.3 | 27.8±6.1 | 29.7±6.3 | 28.6±6.3 | 29.5±6.4 | 0.023 |

PPY±SD | 44.3±24.9 | 52.2±27.2 | 37.8±20.8 | 41.9±22.8 | 43.2±24.3 | 0.57 |

Active smoking, % (n) | 52.8 (5279) | 42.1 (1746) | 60.9 (2853) | 57.4 (497) | 60.8 (183) | 0.33 |

Chronic bronchitis, % (n) | 19.2 (1922) | 26.5 (1101) | 13.3 (621) | 16.6 (144) | 18.6 (56) | 0.48 |

Asthma, % (n) | 19.4 (1943) | 25.3 (1049) | 14.4 (674) | 18.5 (160) | 19.9 (60) | 0.59 |

CAD, % (n) | 6.5 (648) | 9 (375) | 4.4 (207) | 5.4 (47) | 6.3 (19) | 0.67 |

CHF, % (n) | 3.2 (320) | 4.6 (192) | 2 (96) | 2.3 (20) | 4 (12) | 0.18 |

DM, % (n) | 13 (1301) | 11.9 (494) | 13.6 (638) | 14.2 (123) | 15.3 (46) | 0.64 |

HTN, % (n) | 43.2 (4322) | 48.4 (2008) | 39 (1830) | 39.7 (344) | 46.5 (140) | 0.046 |

OSA, % (n) | 14.6 (1459) | 16 (665) | 13.3 (624) | 14 (121) | 16.3 (49) | 0.39 |

Stroke, % (n) | 2.6 (258) | 3.4 (139) | 1.9 (90) | 2.1 (18) | 3.7 (11) | 0.19 |

SaO_{2},%±SD | 96.1±2.9 | 94.9±3.5 | 97±2.1 | 96.8±2.4 | 96.5±2.5 | 0.15 |

MMRC±SD | 1.4±1.4 | 1.9±1.5 | 0.9±1.3 | 1±1.3 | 1.3±1.5 | 0.0011 |

SGRQ±SD | 27.4±22.9 | 37.6±22.7 | 19.5±19.8 | 21.3±20.8 | 27.2±23.1 | <0.001 |

Post-FEV_{1}, %±SD | 76.3±25.6 | 55.9±22.4 | 92.6±15.4 | 84.7±15.9 | 77.3±17.4 | <0.001 |

Post-FVC, %±SD | 86.9±18.3 | 81.2±20.3 | 91.4±15.1 | 89±16.7 | 91.6±18.8 | 0.087 |

BDR, % (n) | 21.5 (2146) | 33.9 (1408) | 9.2 (432) | 19.5 (169) | 45.5 (137) | <0.001 |

Delta FEV_{1}, %±SD | 5.8±10.3 | 8.8±12.1 | 3±6.6 | 7.7±10.8 | 1.5±15.5 | <0.001 |

Delta FVC, %±SD | 3.9±12.6 | 7.5±13.2 | 0.9±7.5 | −2.1±9.3 | 17.7±34.4 | <0.001 |

Emphysema, %±SD†‡ | 7.6±10.6 | 14±12.9 | 2.2±2.8 | 2.9±3.1 | 3.4±5 | 0.45 |

Gas trapping, %±SD†‡ | 24.2±20.8 | 39.3±20.5 | 10.6±9 | 15±10 | 17.1±12.6 | 0.19 |

6-MWD, feet±SD | 1351±399 | 1224±408.2 | 1443±365.3 | 1447±370.1 | 1352±382.3 | <0.001 |

*Comparison between PREO-POSTN and PREN-POSTO using χ^{2} and Student’s t-test or Wilcoxon rank sum test.

†For emphysema and gas trapping analysis, data were available for 5553 and 4945 subjects, respectively.

‡Gas trapping was measured at functional residual capacity.

6-MWD, 6 min walk distance; BDR, bronchodilator response; BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; Delta FEV_{1}%, % change in FEV_{1} after bronnchodilator; Delta FVC%, % change in FVC after bronchodilator; DM, diabetes mellitus; FEV_{1}, forced expiratory volume in 1 s; FVC, forced vital capacity; HTN, hypertension; MMRC, modified Medical Research Council dyspnoea score; OSA, obstructive sleep apnoea; pre-FEV_{1}%, prebronchodilator FEV_{1}% predicted; post-FEV_{1}%, postbronchodilator FEV_{1}% predicted; PPY, pack per year; SaO_{2}, arterial oxygen saturation; SGRQ, St. George’s Respiratory Questionnaire score;6-MWD = 6-min walk distance.

PREN-POSTN: prebronchodilator FEV_{1}/FVC >0.7 and postbronchodilator FEV_{1}/FVC >0.7.

PREN-POSTO: prebronchodilator FEV_{1}/FVC >0.7 and postbronchodilator FEV_{1}/FVC <0.7.

PREO-POSTNO: prebronchodilator FEV_{1}/FVC <0.7 and postbronchodilator FEV_{1}/FVC <0.7.

PREO-POSTN: prebronchodilator FEV_{1}/FVC <0.7 and postbronchodilator FEV_{1}/FVC >0.7.

To investigate further the higher dyspnoea scores and shorter distance covered in 6 min walk in PREO-POSTN subjects compared with PREN-POSTO subjects, we performed multilinear regression analysis and found that PREN-POSTO is associated with increased dyspnoea and reduced exercise capacity. (_{1}% in the models, this association disappeared.

In the adjusted analysis, both PREO and POSTO were associated with chronic bronchitis, dyspnoea scores, radiographic percent emphysema and gas trapping and distanced covered in 6 min walk at the phase 1 visit, but based on the AIC, models that included POSTO performed better than models that included PREO to predict those outcomes (_{1}% and post-FEV_{1}%.

Association of prebronchodilator and postbronchodilator spirometric measures with chronic bronchitis, dyspnoea scores, chest CT emphysema and air trapping and distance covered in 6 min walk test

Prebronchodilator FEV_{1}/FVC <0.7 (PREO) | Postbronchodilator FEV_{1}/FVC <0.7 (POSTO) | |||||

OR (95% CI) | P value | AIC | OR (95% CI) | P value | AIC | |

Chronic bronchitis | 2 (1.78 to 2.25) | <0.001 | 8910 | 2.14 (1.9 to 2.41) | <0.001 | 8882 |

Coef (95% CI) | P value | AIC | Coef (95% CI) | P value | AIC | |

MMRC | 0.72 (0.66 to 0.77) | <0.001 | 4849 | 0.85 (0.79 to 0.9) | <0.001 | 4605 |

SGRQ | 13 (12.16 to 13.83) | <0.001 | 59 145 | 15.3 (14.5 to 16.14) | <0.001 | 58 811 |

Emphysema, %* | 8.4 (7.9 to 8.9) | <0.001 | 24 259 | 9.79 (9.29 to 10.29) | <0.001 | 23 892 |

Gas trapping, %*† | 20.2 (19.24 to 21.18) | <0.001 | 27 241 | 23 (22 to 23.9) | <0.001 | 26 738 |

6-MWD, feet | −137.4 (−152.9 to 121.9) | <0.001 | 115 774 | −172.8 (−188.3 to 157.2) | <0.001 | 115 608 |

Prebronchodilator FEV_{1}% predicted | Postbronchodilator FEV_{1}% predicted | |||||

OR (95% CI) | P value | AIC | OR (95% CI) | P value | AIC | |

Chronic bronchitis | 0.98 (0.98 to 0.99) | <0.001 | 8833 | 0.98 (0.98 to 0.99) | <0.001 | 8833 |

Coef (95% CI) | P value | AIC | Coef (95% CI) | P value | AIC | |

MMRC | −0.026 (−0.027 to 0.025) | <0.001 | 3150 | −0.026 (−0.027 to 0.025) | <0.001 | 3065 |

SGRQ | −0.44 (−0.46 to 0.43) | <0.001 | 57 014 | −0.45 (−0.46 to 0.43) | <0.001 | 56 967 |

Emphysema, %* | −0.23 (−0.24 to 0.22) | <0.001 | 22 926 | −0.24 (−0.25 to 0.23) | <0.001 | 22 827 |

Gas trapping, %*† | −0.52 (−0.53 to 0.50) | <0.001 | 25 519 | −0.52 (−0.53 to 0.5) | <0.001 | 25 471 |

6-MWD, feet | 6.35 (6.07 to 6.64) | <0.001 | 114 300 | 6.61 (6.3 to 6.9) | <0.001 | 1 14 144 |

All regression models included the following covariates: age, sex, race, smoking status, pack per years, history (per questionnaire) of asthma, diabetes, high blood pressure, stroke and sleep apnoea.

*For emphysema and gas trapping analysis, data were available for 5553 and 4945 subjects, respectively.

6-MWD, 6 min walk distance; AIC, Akaike information criterion; FEV_{1}, forced expiratory volume in 1 s; FVC, forced vital capacity; MMRC, modified Medical Research Council dyspnoea score; SGRQ, St. George’s Respiratory Questionnaire score.

We found no difference in the number of exacerbations and severe exacerbations per year between PREO-POSTO and PREN-POSTO subjects followed in average for 4.5±1.8 years (_{1} between the phase 1 and 2 visits was greater in PREO-POSTN compared with the change in PREN-POSTO subjects, whereas the change in distance covered in 6 min walk was smaller in the PREO-POSTN compared with PREN-POSTO group. In adjusted analysis, PREN-POSTO subjects had a smaller reduction in FEV_{1} compared with PREO-POSTN subjects, but when we adjusted for postbronchodilator FEV_{1}% that association disappeared (

Number of exacerbations and severe exacerbations per year, change in FEV_{1}, dyspnoea scores and distance covered in 6 min walk test from phase 1 to phase 2 visit (5-year interval)

All | PREO-POSTO | PREN-POSTN | PREO-POSTN | PREN-POSTO | P value* | |

Exacerbations per year±SD | 0.42±0.99 | 0.68±1.22 | 0.21±0.70 | 0.27±0.74 | 0.26±0.79 | 0.3 |

Severe exacerbations per year±SD | 0.14±0.52 | 0.24±0.66 | 0.07±0.34 | 0.1±0.5 | 0.09±0.3 | 0.069 |

All | PREO-POSTO | PREN-POSTN | PREO-POSTN | PREN-POSTO | P value* | |

Change in FEV_{1}, mL±SD | −198.1±294.5 | −202.5±320.2 | −198.8±268.5 | −203.6±282.2 | −125.6±365.5 | <0.001 |

Change in MMRC | 0.06±1.24 | 0.19±1.26 | −0.04±1.22 | 0.03±1.08 | 0.05±1.36 | 0.42 |

Change in SGRQ | 0.15±15.3 | 1.5±15.2 | −0.8±15.4 | −0.88±14.6 | 0.98±16 | 0.86 |

Change in 6-MWD, feet±SD | −130.9±360.6 | −172.7±366.4 | −103.7±357 | −103±327.4 | −123.5±377 | <0.001 |

*Comparison between PREO-POSTN and PREN-POSTO using χ^{2} and Student’s t-test or Wilcoxon rank sum test.

6-6-MWD = 6-min walk distance; MMRC, modified Medical Research Council dyspnoea score; SGRQ, St. George’s Respiratory Questionnaire score.

PREN-POSTN: prebronchodilator FEV_{1}/FVC >0.7 and postbronchodilator FEV_{1}/FVC >0.7.

PREO-POSTNO: prebronchodilator FEV_{1}/FVC <0.7 and postbronchodilator FEV_{1}/FVC <0.7.

PREO-POSTN: prebronchodilator FEV_{1}/FVC <0.7 and postbronchodilator FEV_{1}/FVC >0.7.

PREN-POSTO: prebronchodilator FEV_{1}/FVC >0.7 and postbronchodilator FEV_{1}/FVC <0.7.

In multilinear regression analysis, both PREO and POSTO correlated significantly with number of exacerbations and severe exacerbations per year, dyspnoea scores and distance covered in 6 min walk between phase 1 and 2 visits (

Association of prebronchodilator and postbronchodilator spirometric measures with number of exacerbations and severe exacerbations per year, change in FEV_{1}, dyspnoea scores and distance covered in 6 min walk test from phase 1 to phase 2 visit (5-year interval)

Prebronchodilator FEV_{1}/FVC <0.7 (PREO) | Postbronchodilator FEV_{1}/FVC <0.7 (POSTO) | |||||

Coef (95% CI) | P value | AIC | Coef (95% CI) | P value | AIC | |

Exacerbations per year | 0.35 (0.31 to 0.4) | <0.001 | −893 | 0.38 (0.34 to 0.43) | <0.001 | −929 |

Severe exacerbations per year | 0.14 (0.11 to 0.16) | <0.001 | −11608 | 0.14 (0.12 to 0.16) | <0.001 | −11614 |

Change in FEV_{1}, mL | −2.25 (−20.3 to 15.8) | 0.81 | 54 317 | 10 (−7.26 to 29.3) | 0.24 | 54 315 |

Change in MMRC | 0.2 (0.12 to 0.27) | <0.001 | 1978 | 0.21 (0.13 to 0.29) | <0.001 | 1974 |

Change in SGRQ | 1.92 (0.99 to 2.85) | <0.001 | 26 399 | 2.56 (1.62 to 3.5) | <0.001 | 26 387 |

Change in 6-MWD, feet | −22.2 (−44.3 to 0.05) | 0.049 | 55 763 | −33.2 (−55.6 to 10.8) | 0.004 | 55 758 |

Postbronchodilator FEV_{1}% predicted | Postbronchodilator FEV_{1}% predicted | |||||

Coef (95% CI) | P value | AIC | Coef (95% CI) | P value | AIC | |

Exacerbations | −0.011 (−0.012 to 0.01) | <0.001 | −1233 | −0.011 (−0.01 to 0.0097) | <0.001 | −1222 |

Severe exacerbations | −0.004 (−0.0045 to 0.0036) | <0.001 | −11787 | −0.004 (−0.0045 to 0.0036) | <0.001 | −11777 |

Change in FEV_{1}, mL | −1.91 (−2.28 to 1.53) | <0.001 | 54 218 | −2.76 (−3.13 to 2.39) | <0.001 | 54 112 |

Change in MMRC | −0.002 (−0.0038 to 0.00065) | 0.006 | 1996 | −0.02 (−0.0036 to 0.00037) | 0.016 | 1998 |

Change in SGRQ | −0.01 (−0.03 to 0.0095) | 0.32 | 26 415 | −0.01 (−0.029 to 0.01) | 0.34 | 26 415 |

Change in 6-MWD, feet | 0.99 (0.53 to 1.46) | <0.001 | 55 749 | 0.9 (0.43 to 1.37) | <0.001 | 55 753 |

All regression models included the following covariates: age, sex, race, smoking status, pack per years, history (per questionnaire) of asthma, diabetes, high blood pressure, stroke and sleep apnoea.

6-MWD, 6 min walk distance; AIC, Akaike information criterion; FEV_{1}, forced expiratory volume in 1 s; FVC, forced vital capacity; MMRC, modified Medical Research Council dyspnoea score; SGRQ, St. George’s Respiratory Questionnaire score.

Similarly, both prebronchodilator and postbronchodilator FEV_{1}% correlated significantly with the number of exacerbations and severe exacerbations per year, change in FEV_{1}, dyspnoea scores and distance covered in 6 min walk between phase 1 and 2 visits (_{1}% models performed better) and for change in FEV_{1} (pre-FEV_{1}% models performed better).

Of 377 subjects with PREO-POSTN at phase 1 who had both prebronchodilator and postbronchodilator spirometry at the phase 2 visit, the phase 2 spirometry showed PREO-POSTO in 167 (44.3%), PREN-POSTN in 120 (31.8%), PREO-POSTN in 72 (19.1%) and PREN-POSTO in 18 (4.8%) (

Of 166 PREN-POSTO at phase 1 who had both prebronchodilator and postbronchodilator spirometry at the phase 2 visit, the phase 2 spirometry showed PREO-POSTO in 82 (49.4%), PREN-POSTN in 51 (30.7%), PREO-POSTN in 24 (14.5%) and PREN-POSTO in 9 (5.4%) (

Subjects were followed in average for 1956±407 days, and there were 830 deaths (10.1%). All PREO, POSTO, pre-FEV_{1}%, and post-FEV_{1}% were associated with mortality (_{1}% performed better at predicting mortality than the rest. Furthermore, PREO-POSTO was associated with increased mortality, while PREO-POSTN and PREN-POSTO were not (

Mortality models

HR (95% CI) | P value | AIC | |

PREO | 2.46 (2.07 to 2.92) | <0.001 | 14 194 |

POSTO | 2.54 (2.15 to 3) | <0.001 | 14 181 |

Pre-FEV_{1}% | 0.97 (0.96 to 0.97) | <0.001 | 13 837 |

Post-FEV_{1}% | 0.97 (0.96 to 0.97) | <0.001 | 13 806 |

All regression models included the following covariates: age, sex, race, smoking status, pack per years, history (per questionnaire) of asthma, diabetes, high blood pressure, stroke and sleep apnoea.

AIC , Akaike information criterion; POSTO, postbronchodilator FEV_{1}/FVC <0.7; pre-FEV_{1}%, prebronchodilator FEV_{1}% predicted; post-FEV_{1}%, postbronchodilator FEV_{1}% predicted; PREO, prebronchodilator FEV_{1}/FVC <0.7.

In this report, AFO prevalence is higher when the PREO criterion is applied. About 8.5% of all subjects had PREO-POSTN, whereas 3% had a PREN-POSTO spirometric pattern. In adjusted analysis, we found no difference in COPD features and outcomes between PREO-POSTN and PREN-POSTO subjects. Although both prebronchodilator and postbronchodilator spirometry are associated with chronic bronchitis, dyspnoea, exercise capacity and COPD radiographic findings, models that include postbronchodilator spirometric measures perform better than those with prebronchodilator measures to predict those outcomes. The predictive value of prebronchodilator and postbronchodilator spirometries are relatively similar for respiratory exacerbations, change in FEV_{1} and dyspnoea from phase 1 to phase 2 visits. Both prebronchodilator and postbronchodilator spirometry are associated with mortality, but models that include postbronchodilator spirometric measures perform better than models with prebronchodilator spirometry. About half of PREO-POSTN and PREN-POSTN become PREO-POSTO at Phase 2. PREO-POSTO is associated with higher mortality compared with the other patterns.

The prevalence of AFO and therefore COPD is higher using prebronchodilator spirometry in our cohort, although previous studies have shown mixed results.

When we examined the subjects with AFO discordance in prebronchodilator and postbronchodilator spirometry, which comprised 11.7% of our total cohort, PREN-POSTO subjects have a remarkable increase in FVC after bronchodilator spirometry compared with PREO-POSTN subjects, although they have similar postbronchodilator FVC%. PREN-POSTO subjects have likely more prebronchodilator air trapping than PREO-POSTN, which can be present in mild disease_{1}%, PREN-POSTO was not associated with worse dyspnoea or exercise capacity compared with PREO-POSTN, which means that PREN-POSTO does not represent a different phenotype with increased air trapping but rather a group with more severe disease and lower post-FEV_{1}%.

Prebronchodilator and postbronchodilator measures showed relatively similarly predictive value for long-term outcomes such as respiratory exacerbations, change of FEV_{1}, dyspnoea score and exercise capacity. Previous studies have shown that bronchodilator response is associated with clinical outcomes,_{1}% at baseline, and we found that the discordance groups had no difference in change of FEV_{1}, dyspnoea score and exercise capacity.

Postbronchodilator spirometry models perform better than prebronchodilator spirometry models to predict mortality, although both are strongly associated with mortality. This is in disagreement with a previous study by Mannino _{1}%.

In addition, we showed that about 50% of the subjects with AFO discordance between prebronchodilator and postbronchodilator spirometry progress to PREO-POSTO, which is a pattern with higher mortality than the rest of the groups. Interestingly, subjects with PREO-POSTN that progressed to PREO-POSTO had higher smoking rates than those that progressed to PREN-POSTN in the follow-up visit; this raises the question whether this group represents patients with early disease to whom we need to target interventions like smoking cessation. This finding suggest that using prebronchodilator spirometry may be a better diagnostic test for early (or future) disease although postbronchodilator spirometry correlates better with current symptoms, functional and radiographic measures and 5-year mortality.

Apart from the fact that chest CTs were performed after bronchodilator and gas trapping was measured at FRC our study is limited by the large variability of bronchodilator response. Although, we used albuterol and the same protocol for all the bronchodilations, greater bronchodilator response may occur when spirometric manoeuvres were performed >20 min after bronchodilator administration instead of 15–20 min.

In conclusion, PREO was more sensitive to diagnose AFO compared with POSTO. About half of the subjects with AFO discordance in their prebronchodilator and postbronchodilator spirometry, which compromise 11% of all subjects, progress to PREO-POSTO, which is a pattern with higher mortality compared with the other patterns. Although both prebronchodilator and postbronchodilator spirometries are associated with clinical, functional and radiographic features of COPD, and mortality, our findings suggest that postbronchodilator spirometry may be a more accurate measure of COPD burden and should be used for COPD diagnosis and classification. This raises the question of whether postbronchodilator spirometric reference values for the US population are needed.

We thank Paul Casella, MFA for editorial assistance and PatrickTen Eyck, PhD for statistical consult.

All authors made substantial contributions to the study. SF participated in study conception and design, data analysis and interpretation and drafting of the manuscript. ME participated in study design, data interpretation and drafting of the manuscript. DG participated in data interpretation. AC participated in study conception and design, data interpretation and drafting of the manuscript.

The project described was supported by Award Number R01 HL089897 and Award Number R01 HL089856 from the National Heart, Lung, and Blood Institute. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens and Sunovion.

None declared.

The institutional review boards at each participating center outlined below approved the study protocol. Details of the study protocol have been published previously.

Not commissioned; externally peer reviewed.

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_{1}is better than pre-bronchodilator FEV

_{1}in evaluation of COPD severity