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Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) is defined by fixed spirometric ratio, FEV1/FVC < 0.70 after inhaled bronchodilators. However, the implications of variable obstruction (VO), in which the prebronchodilator FEV1/FVC ratio is less than 0.70 but increases to 0.70 or more after inhaled bronchodilators, have not been determined.
Objectives: We explored differences in physiology, exacerbations, and health status in participants with VO compared with reference participants without obstruction.
Methods: Data from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort were obtained. Participants with VO were compared with reference participants without obstruction.
Measurements and Main Results: We assessed differences in baseline radiographic emphysema and small airway disease at study entry, baseline, and change in lung function by spirometry, functional capacity by 6-minute walk, health status using standard questionnaires, exacerbation rates, and progression to COPD between the two groups. All models were adjusted for participant characteristics, asthma history, and tobacco exposure. We assessed 175 participants with VO and 603 reference participants without obstruction. Participants with VO had 6.2 times the hazard of future development of COPD controlling for other factors (95% confidence interval, 4.6–8.3; P < 0.001). Compared with reference participants, the VO group had significantly lower baseline pre- and post-bronchodilator (BD) FEV1, and greater decline over time in post-BD FEV1, and pre- and post-BD FVC. There were no significant differences in exacerbations between groups.
Conclusions: Significant risk for future COPD development exists for those with pre- but not post-BD airflow obstruction. These findings support consideration of expanding spirometric criteria defining COPD to include pre-BD obstruction.
Clinical trial registered with www.clinicaltrials.gov (NCT 01969344).
Currently, chronic obstructive pulmonary disease (COPD) is defined by a postbronchodilator FEV1/FVC < 0.70. There are concerns that this results in misspecification of patients who still experience respiratory symptoms, exacerbations, and decline of lung function.
This study highlights the finding that those with prebronchodilator FEV1/FVC < 0.70 that corrects to ⩾ 0.70 with bronchodilator administration have a high prevalence of respiratory symptoms and greater radiographic emphysema and airway disease and progress to COPD and lung function loss at greater rates than those without.
The Global Initiative on Obstructive Lung Disease (GOLD) stipulates that a diagnosis of chronic obstructive pulmonary disease (COPD) must be predicated on demonstrating airflow obstruction defined as having a postbronchodilator (BD) ratio of FEV1/FVC < 0.70 (1). This has raised issues and concerns that have been debated in the literature.
First, it has been recognized that the use of a fixed ratio of FEV1/FVC < 0.70, as opposed to the lower limit of normal (LLN) calculated from reference values for FEV1 and FVC, leads to underdiagnosis of COPD in younger individuals and overdiagnosis in older individuals (2). Yet older individuals with FEV1/FVC of less than 0.70 but more than the LLN still appear to have worse health status (3). Second, reliance on post-BD FEV1/FVC raises concern that some individuals might have evidence of airflow obstruction on pre-BD testing that “corrects” following administration of bronchodilators. We have called this variable obstruction (VO) and chose this terminology to delineate differences in physiology and avoid conflation with “bronchodilator responsiveness” (4, 5). This category probably includes many symptomatic people with current or former tobacco exposure with so-called “preserved spirometry” who have been shown to have COPD symptoms and exacerbations (6).
One obvious question is whether individuals with VO actually have pre-COPD with early airway pathophysiologic changes (7, 8), and whether these changes eventually progress to fixed obstruction, with post-BD FEV1/FVC < 0.70. We sought to investigate individuals with variable obstruction using the SPIROMICS (Sub-Populations and Intermediate Outcomes in COPD Study) cohort of extensively characterized patients with COPD of varying severity as well as people with current or former tobacco exposure with preserved spirometry and nonsmoking controls (9). Our hypothesis is that individuals with VO may have numerous features of COPD, evidenced by radiographic abnormalities on computed tomography (CT) of the chest, and that they progress to fixed obstruction over time.
The SPIROMICS parent study was approved by the institutional review boards of each individual site before the enrollment of participants. All participants provided informed consent.
Participants were recruited into SPIROMICS as previously reported and followed longitudinally, with planned annual visits for up to 3 years after enrollment (9), and via SPIROMICS II, a fifth visit that took place ∼3 years after visit 4. They were included for this substudy if they had ⩾20 pack-years of cumulative tobacco exposure and did not have COPD by GOLD criteria at time of entry to the study, defined as a post-BD FEV1-to-FVC ratio of 0.70. Participants were excluded from longitudinal analyses if they did not complete at least two visits in the study with both pre- and post-BD spirometry in each of these visits. A consolidated standards of reporting trials diagram illustrating flow of eligible participants into the analysis is found in Figure 1.
Figure 1. Consolidated standards of reporting trials flow diagram for study inclusion and exclusion. BD = bronchodilator; V = visit.
[More] [Minimize]Participants were classified as having “no obstruction” if their pre- and post-BD spirometry both had FEV1/FVC ⩾ 0.70, whereas those who had a pre-BD spirometry with FEV1/FVC < 0.70 and a post-BD FEV1/FVC ⩾ 0.70 were classified as having “variable obstruction”. Those with post-BD FEV1/FVC < 0.7 were classified as having “fixed obstruction”, meeting the definition for COPD under GOLD criteria (1). Participants were excluded from analysis if fixed obstruction was present at baseline. For modeling, we stratified VO versus no obstruction using baseline spirometry at study entry.
Progression to COPD was defined by those who developed fixed obstruction during the study, defined as post-BD FEV1/FVC < 0.70. Information about exacerbations was collected by participant self-report using questionnaires at quarterly intervals and summed by year of participation, classified by total number, and further defined as “healthcare utilization” if the exacerbation necessitated intervention with systemic corticosteroids and/or antibiotics, and as “severe” if the participant had an emergency department visit or hospitalization.
The no-obstruction and VO subgroups were compared using Student’s t test for continuous and chi-square tests for categorical variables. A Sankey diagram was plotted to illustrate transitions between outcome states using SankeyMatic. All analyses were conducted in SAS version 9.4.
A prespecified set of covariates was chosen based on prior literature for items with known association with our outcomes of interest. Physiologic, radiographic and outcome models were adjusted for age, self-reported sex, race (recategorized to binary as White versus non-White owing to low numbers for other racial identities), body mass index at the time of study entry, self-reported current tobacco use, cumulative tobacco exposure in pack-years, and history of diagnosis of asthma. Longitudinal models included an interaction term between VO and years of follow up. Exacerbation models included post-BD FEV1 percent predicted at study entry owing to known association of FEV1 with exacerbation risk (10).
Emphysema and functional small airway disease were quantified by parametric response mapping (PRM) (11, 12) on chest CT, which were available only at the baseline visit at the time of this analysis. A linear regression model was fit to determine and quantify the effect size of VO on the degree of radiographic emphysema (PRMemph) and small airways disease (PRMfsad) at the time of study entry, controlling for other factors felt to potentially affect these radiographic outcomes (e.g., tobacco exposure and history of asthma).
In longitudinal analyses, mixed effects models were used with observations nested within participants, with random intercepts and slopes at the participant level to account for repeated measures. Change in physiologic and functional measurements (i.e., spirometry and 6-minute-walk distance) as well as change in COPD Assessment Test (CAT) (13) and St. George’s Respiratory Questionnaire (SGRQ) (14) were fit using mixed-effects generalized linear models. Change in dyspnea over time by modified Medical Research Council (mMRC) questionnaire (15) was dichotomized to mMRC < 2 and ⩾2 and modeled using generalized estimating equations for odds of moving to the higher degree of dyspnea over time. Covariates were modeled as time invariant at baseline value.
Hazard for development of COPD was estimated using an interval censored nonparametric time-to-event model (16, 17), akin to the Cox proportional hazards model, but with discrete events rather than continuous time, with event-free curves compared using the log rank test of equality. This model was used in order to reduce SEs of parameter estimates due to the unknown time the participant’s physiology changed relative to when it was measured, given that participants had prespecified intervals between visits where spirometry was conducted (18).
An a priori designated sensitivity analysis was performed comparing those diagnosed with asthma in childhood versus those diagnosed with asthma at any point in their lives. The model fit between the original and sensitivity models was compared using Akaike information criteria (19, 20).
Of the 2,982 participants in SPIROMICS, we identified an analytic cohort of 778 participants eligible for analysis, of whom 603 had normal FEV1/FVC both before and after BD administration and 175 of whom had VO on baseline visit spirometry (Figure 1). Participants with variable obstruction were 2.5 years older on average and more commonly male, both statistically significant. Those with variable obstruction reported significantly more childhood asthma and a non–statistically significant trend toward ever being diagnosed with asthma, with cohort prevalence similar to population estimates (21). There was not a significant difference in the prevalence of chronic bronchitis between the two groups (Table 1). No significant racial or ethnic difference in distribution of VO was observed, nor was there a significant difference in active tobacco use with a trend toward more cumulative tobacco exposure in the VO group. Those with VO exhibited significantly lower mean pre-BD FEV1 at the time of enrollment, but mean post-BD values did not differ significantly. They also exhibited significantly higher pre- and post-BD FVC and lower pre- and post-BD FEV1/FVC values.
| Variable | Never Obstructed (N = 603) | Variable Obstruction (N = 175) | P Value* |
|---|---|---|---|
| Age, mean ± SD | 60.7 ± 9.7 | 63.2 ± 9.4 | 0.003 |
| Male sex, n (%) | 264 (44%) | 98 (56%) | 0.005 |
| Body mass index, mean ± SD, kg/m2 | 29.2 ± 5.0 | 28.5 ± 5.1 | 0.125 |
| Hispanic/Latinx ethnicity, n (%) | 37 (6%) | 7 (4%) | 0.354 |
| Racial identity, n (%) | |||
| White | 417 (69%) | 124 (71%) | 0.992 |
| Black | 153 (25%) | 41 (23%) | |
| Other/mixed race | 29 (5%) | 9 (5%) | |
| Not reported | 4 (0.7%) | 1 (0.6%) | |
| Reported history of childhood asthma, n (%) | 33 (6%) | 18 (11%) | 0.026 |
| Reported history of any diagnosis of asthma, n (%) | 85 (15%) | 32 (19%) | 0.185 |
| Reported history of diagnosis of chronic bronchitis, n (%) | 76 (13%) | 23 (14%) | 0.897 |
| Current combusted tobacco use, n (%) | 291 (49%) | 74 (43%) | 0.195 |
| Tobacco exposure, mean ± SD, pack-years | 43 ± 27 | 46 ± 21 | 0.056 |
| Spirometric values, mean ± SD | |||
| Baseline FEV1 (pre-BD), L | 2.65 ± 0.68 | 2.47 ± 0.64 | 0.001 |
| Baseline FEV1 (pre-BD), % predicted | 94 ± 14 | 84 ± 12 | <0.001 |
| Baseline FVC (pre-BD) L | 3.49 ± 0.89 | 3.66 ± 0.94 | 0.032 |
| Baseline FVC (pre-BD), % predicted | 95 ± 13 | 95 ± 13 | 0.814 |
| Baseline FEV1/FVC (pre-BD) | 0.76 ± 0.04 | 0.68 ± 0.02 | <0.001 |
| Baseline FEV1 (post-BD), L | 2.78 ± 0.70 | 2.7 ± 0.67 | 0.201 |
| Baseline FEV1 (post-BD), % predicted | 98 ± 13 | 92 ± 11 | <0.001 |
| Baseline FVC (post-BD), L | 3.54 ± 0.89 | 3.72 ± 0.92 | 0.020 |
| Baseline FVC (post-BD), % predicted | 96 ± 13 | 97 ± 13 | 0.546 |
| Baseline FEV1/FVC (post-BD) | 0.79 ± 0.05 | 0.73 ± 0.02 | <.001 |
| Bronchodilator response | |||
| BD responsive by ATS/ERS criteria, n (%) | 40 (7%) | 55 (31%) | <0.001 |
| Δ FEV1 pre-/post-BD, mean ± SD, ml | 129 ± 130 | 238 ± 151 | <0.001 |
| Δ FVC pre-/post-BD, mean ± SD, ml | 48 ± 168 | 60 ± 189 | 0.460 |
| Δ FEV1 pre-/post-BD, mean ± SD | 4.6 ± 4.5% | 8.2 ± 5.2% | <0.001 |
| Δ FVC pre/post-BD, mean ± SD, % predicted | 1.3 ± 4.7% | 1.7 ± 5.2% | 0.352 |
| Radiographic % PRMemphysema, mean ± SD | 0.42 ± 1.12% | 0.82 ± 1.47% | 0.002 |
| Radiographic % PRMfsad, mean ± SD | 7.61 ± 9.25% | 11.07 ± 9.82% | <0.001 |
| Baseline CAT Score†, mean ± SD | 11.3 ± 8.5 | 10.7 ± 7.7 | 0.439 |
| Baseline SGRQ total score‡, mean ± SD | 23.7 ± 19.6 | 24.3 ± 19.0 | 0.705 |
| Baseline mMRC ⩾ 2, n (%) | 85 (14%) | 18 (10%) | 0.207 |
| Medications in use at enrollment, n (%) | |||
| Inhaled bronchodilators | 130 (21%) | 48 (28%) | 0.126 |
| Nebulized bronchodilators | 29 (5%) | 10 (6%) | 0.694 |
| Inhaled corticosteroids | 65 (11%) | 28 (16%) | 0.085 |
| Years of follow-up, mean ± SD | 7.0 ± 2.4 | 7.0 ± 2.3 | 0.927 |
Significantly more radiographic structural changes were observed among those with VO, with nearly twice the emphysema and 1.5 times more small airway disease, and nearly 5 times as frequent BD responsiveness by American Thoracic Society/European Respiratory Society criteria (22). In addition, the average magnitude of change in FEV1 after bronchodilator administration was significantly higher (1.8 times absolute volume and 1.7 times by percent predicted) among those with VO, whereas that for FVC demonstrated no significant differences.
We evaluated transitions between states, represented graphically in a Sankey diagram (Figure 2). As in clinical practice, we carried forward previous observations until a new observation was made in cases where a complete pre- and post-BD spirometry test was not available for analysis, as without both phases of the spirometry test, it would be impossible to determine if VO were present. Among those with VO at baseline, 37% reverted to no obstruction at the subsequent visit, whereas 30% continued to have VO, and 33% progressed to fixed obstruction (COPD) at visit 2. Conversely, of those with no obstruction at baseline, 84% remained with no obstruction at visit 2 with very small proportions converting to VO (10%) or fixed obstruction (9%).
Figure 2. Sankey diagram illustrating transition states over time. Flows are shown color coded as the subsequent state, such that flows that are blue have no obstruction at next visit, flows that are green have variable obstruction at the next visit, and flows that are gold have fixed obstruction at the next visit. The nodes demonstrate the number in each state at each visit. Given unknown time of transition between visits, for missing (no spirometry performed or visit missed) or incomplete data (lacking both pre- and postbronchodilator results to be able to derive type of obstruction), last observation is carried forward until a new spirometry is available. V = visit.
[More] [Minimize]Interestingly, a small proportion who developed fixed obstruction at visit 2 reverted to VO (10%) or no obstruction (7%) by visit 3. Similar patterns were observed in the transitions between visits 3 and 5. A version of the Sankey diagram without last observation carried forward is found in Figure E1 in the online supplement to illustrate transitions inclusive of incomplete spirometry tests or missed visits. It should be noted that there were more missed visits for visits 3 and 4. This is in part owing to rolling recruitment in two time-limited phases of the study. As such, some participants did not have visit 1 until after others had completed visit 2 or even visit 3, and some participants did not complete all four visits before the end of the study time period for SPIROMICS I. Because visit 5 was conducted under a new funding mechanism (SPIROMICS II), participation again increased for visit 5, which influenced the temporal distribution of data.
Presence of variable obstruction at study entry portended an adjusted 6.2-fold hazard of developing COPD, defined by fixed obstruction noted on spirometry after BD administration (Table 2). The magnitude of difference in COPD hazard is more than 5.6 times greater than that observed for every 10 pack-years of tobacco exposure (Table E1). This corresponded to progression to COPD during the study that was significantly higher among those with VO than those without VO at study entry (61% vs. 14%, P < 0.001).
| Outcome | Unadjusted | Multivariable | ||||
|---|---|---|---|---|---|---|
| N | Effect Estimate for VO (95% CI) | P | N | Effect estimate for VO (95% CI) | P | |
| Progression to COPD*† | 778 | 6.26 (4.70 to 8.35) | <0.001 | 670 | 6.17 (4.57 to 8.32) | <0.001 |
| Exacerbation outcomes‡ | ||||||
| Exacerbation in next 365 days§ | 589 | 1.05 (0.59 to 1.87) | 0.877 | 579 | 1.08 (0.58 to 2.01) | 0.820 |
| Total exacerbations‖ | 772 | 0.93 (0.69 to 1.29) | 0.671 | 737 | 1.00 (0.72 to 1.38) | 0.975 |
| Exacerbations requiring health care‖ | 772 | 1.01 (0.73 to 1.41) | 0.960 | 737 | 1.067 (0.77 to 1.50) | 0.704 |
| Exacerbations requiring ED/hospitalization‖ | 772 | 1.21 (0.73 to 2.02) | 0.469 | 737 | 1.23 (0.74 to 2.09) | 0.432 |
| Radiographic outcomes* | ||||||
| Baseline PRM Emphysema | 692 | 0.40% (0.19% to 0.62%) | <0.001 | 661 | 0.30% (0.09% to 0.51%) | 0.006 |
| Baseline PRM Functional Small Airways Disease | 692 | 3.47% (1.79% to 5.15%) | <0.001 | 661 | 2.17% (0.56% to 3.78%) | 0.008 |
| HRQoL and functional outcomes* | ||||||
| Baseline effect for CAT score | 778 | 1.00 (0.88 to 1.14) | 0.953 | 743 | 1.02 (0.91 to 1.20) | 0.716 |
| Δ CAT score per year | 778 | 1.03 (1.01 to 1.05) | <0.001 | 743 | 1.04 (1.02 to 1.06) | <0.001 |
| Baseline effect for mMRC < 2 vs. ⩾2§ | 778 | 1.00 (0.92 to 1.10) | 0.948 | 743 | 1.05 (0.94 to 1.17) | 0.354 |
| Δ mMRC (odds of ⩾2) per year§ | 778 | 0.86 (0.57 to 1.31) | 0.477 | 743 | 0.97 (0.61 to 1.53) | 0.891 |
| Baseline effect for SGRQ score | 773 | 1.07 (0.92 to 1.25) | 0.369 | 736 | 1.10 (0.96 to 1.23) | 0.176 |
| Δ SGRQ per year | 773 | 1.00 (0.98 to 1.02) | 0.889 | 736 | 1.01 (0.99 to 1.03) | 0.305 |
| Baseline effect for 6MWD, m | 778 | −3.3 (−18.4 to 11.9) | 0.671 | 743 | −3.0 (−17.4 to 11.4) | 0.683 |
| Δ 6MWD per year, m | 778 | 0.9 (−2.0 to 3.9) | 0.534 | 743 | 0.3 (−2.5 to 3.1) | 0.845 |
An interval censored time-to-event curve (Figure 3) further demonstrated the rapidity of development of COPD among those with VO. The median time to COPD development for those with VO was 1.95 years, whereas 75.3% of those without VO at study entry had not developed COPD by the end of follow-up (log rank P < 0.001).
Figure 3. Interval-censored time-to-event model for progression to chronic obstructive pulmonary disease by presence of variable obstruction, where the blue line is those without variable obstruction (data as observed), and the red line is those with variable obstruction at study entry. Data shown with 95% confidence intervals. BD = bronchodilator; VO = variable obstruction.
[More] [Minimize]Participants with VO at study entry had 0.3% more emphysema by PRM than those without obstruction at baseline (Table 2) even after adjusting for other factors. To put this effect into context, every 10 pack-years of cumulative tobacco exposure conferred only 0.04% more emphysema when controlling for other factors (Table E2). A parallel pattern was observed for small airway disease, where participants with VO had 2.17% greater PRMfsad than those without (Table 2), an effect size 20 times greater than that per 10 pack-years of tobacco exposure (Table E3).
Variable obstruction present at study entry was associated with 9.6% lower baseline pre-BD FEV1 (Table 3), corresponding to 225 ml less airflow (P < 0.001). Rate of decline of pre-BD FEV1, however, was not significantly different between these groups (Table 3). In post-BD models, the adjusted baseline difference in FEV1 was significantly lower for those with VO by 6.6%, with 0.6% more annual decline. This corresponded to a significantly lower baseline value of 135 ml with 17 ml greater annual decline.
| Model Type | Unadjusted N = 778 | Multivariable N = 743 | ||
|---|---|---|---|---|
| Outcome | Effect Estimate for VO (95% CI) | P Value | Effect Estimate for VO (95% CI) | P Value |
| Baseline effect pre-BD FEV1 % predicted | −8.79% (−10.97% to −6.61%) | <0.001 | −9.61% (−11.79% to −7.43%) | <0.001 |
| Annualized Δ pre-BD FEV1 % predicted | −0.05% (−0.004% to 0.003%) | 0.785 | −0.13% (−0.51% to 0.25%) | 0.489 |
| Baseline effect post-BD FEV1 % predicted | −5.91% (−8.02% to −3.79%) | <0.001 | −6.60% (−8.73% to −4.48%) | <0.001 |
| Annualized Δ post-BD FEV1 % predicted | −0.53% (−0.90% to −0.15%) | 0.006 | −0.61% (−0.99% to −0.23%) | 0.002 |
| Baseline effect pre-BD FEV1, ml | −162.70 (−274.34 to −51.06) | 0.004 | −225.00 (−298.99 to −0.15) | <0.001 |
| Annualized Δ pre-BD FEV1, ml | −1.64 (−11.52 to 8.24) | 0.745 | −3.86 (−13.44 to 5.72) | 0.430 |
| Baseline effect post-BD FEV1, mL | −75.08 (−190.19 to 40.03) | 0.201 | −135.30 (−208.80 to −61.80) | <0.001 |
| Annualized Δ post-BD FEV1, ml | −14.11 (−23.68 to −4.54) | 0.004 | −16.89 (−26.35 to −7.43) | 0.001 |
| Baseline effect pre-BD FVC % predicted | 0.21% (−2.03% to 3.38%) | 0.857 | −0.11% (−2.33% to 2.12%) | 0.925 |
| Annualized Δ pre-BD FVC % predicted | −0.54% (−0.92% to 0.58%) | 0.006 | −0.65% (−2.33% to −0.27%) | 0.001 |
| Baseline effect post-BD FVC % predicted | 1.05% (−1.09% to 3.19%) | 0.337 | 0.74% (−0.14% to 2.88%) | 0.497 |
| Annualized Δ post-BD FVC % predicted | −0.30% (−0.69% to 0.09%) | 0.131 | −0.36% (−0.75% to 0.04%) | 0.080 |
| Baseline effect pre-BD FVC, ml | 164.60 (13.29 to 315.91) | 0.033 | 69.83 (−29.01 to 168.67) | 0.166 |
| Annualized Δ pre-BD FVC, ml | −24.05 (−37.62 to 0.01) | 0.001 | −27.91 (−41.26 to −14.56) | <0.001 |
| Baseline effect post-BD FVC, ml | 196.20 (46.08 to 346.32) | 0.011 | 100.90 (5.27 to 196.53) | 0.039 |
| Annualized Δ post-BD FVC, ml | −13.69 (−27.02 to −0.36) | 0.045 | −16.22 (−29.57 to −2.87) | 0.017 |
When we evaluated FVC using the same models, we found that participants with VO did not have significantly different baseline pre-BD FVC (70 ml greater; P = 0.166), but they did experience a greater rate of pre-BD FVC decline (−28 ml/yr; P < 0.001) than those never obstructed at baseline. In post-BD assessments, those with VO had a 100.9-ml significantly lower baseline post-BD FVC with 16 ml more loss of post-BD FVC per year than those without VO (P = 0.017). The relative magnitude of differences in FEV1 and FVC among those with VO, where post-BD FEV1 fell more over time relative to FVC, likely explains the conversion from variable to fixed obstruction observed. These differences are also shown graphically in Figure E2.
Functional capacity by 6-minute-walk distance was not significantly different between those with and without VO (Table 2). The mean adjusted effect of VO was 3 m lower average walk distance with 0.3 m less decline in distance per year for those with VO.
Participants with variable obstruction were observed to have an adjusted CAT score that was 1.02 points higher on average than those without VO, a value that was not statistically significant (Table 2). Those with VO, however, accrued an average of 1.04 more points per year (P < 0.001), which would meet the minimum clinically important difference threshold of 2 points for the test after 1 year of follow-up (23). Similarly, those with VO at study entry had a 1.1-point higher SGRQ score at baseline and an increase of 1.01 points per year higher than those with nonobstructed baseline spirometry, which, while not statistically significant, would meet the established MCID of 4 points for the battery after 3 years of follow-up (24). Lastly, there was no significant difference in increase of dyspnea by mMRC over the study between the two groups.
We operationalized exacerbations after study entry in two ways. We first compared the odds of having an exacerbation within 1 year of study entry on the basis of variable obstruction status, adjusting for the factors noted above. Among those with VO, the odds of an exacerbation within 1 year of study entry were 7.5% higher than those with no obstruction (Table 2), but this was not significant. We also compared incidence rate ratios for subsequent exacerbations after study entry using a zero-inflated negative binomial model. Although adjusted models demonstrated lower rates of annual exacerbations among those with VO, none of these differences were statistically significant.
When we specified models using history of childhood asthma rather than any personal history of asthma, we found very minor variations in effect sizes for variable obstruction on lung function outcomes after this change of covariate with no sign changes nor any variables that changed degree of significance (Tables E4 and E5). Those with childhood asthma did not have greater worsening of CAT score over time, whereas those with any diagnosis of asthma did. There was no difference in model fit by Akaike information criteria with this change, defined a priori as a change in AIC by 25 points or more.
In this analysis of participants with current or former tobacco exposure but without COPD at study entry, we found that presence of VO, defined by pre-BD FEV1/FVC < 0.70 with post-BD FEV1/FVC ⩾ 0.70, portended a significant hazard for future development of COPD. We also saw more emphysema and more functional small airway disease among those with VO and significantly more annual decline in FEV1. These findings raise a question as to whether this represents a unique phenotype of lung disease, another point on the asthma–COPD overlap (ACO) continuum, or a proverbial stop along the way to development of progressive, irreversible lung obstruction.
The designation of COPD as an entity is principally made by aggregated phenotypic characteristics, hallmarked by chronic cough or wheezing, progressive dyspnea, airflow obstruction, and emphysema. However, there is increasing interest in describing endotypes using biomarkers that could be deployed in a precision medicine approach to diagnosis and treatment of the underlying pathology (25, 26). Our findings indicate that current spirometric definition for COPD is inadequate and probably identifies patients too late in the course of their disease (8, 27).
Because the hazard of future fixed airflow obstruction among those with VO is high, we may be detecting respiratory changes compatible with a pre-COPD state. This is further supported by findings in other published work from this cohort that BD responsiveness by FEV1 was very common in earlier stages of COPD (5). This is an interesting contrast to the Lung Health Study 1, where a large proportion of participants had only mild COPD (i.e., FEV1 ⩾ 80% of predicted), and only a small proportion had bronchodilator responsiveness by ATS/ERS criteria (28), and to the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, where the majority of BD responsiveness was observed among those with moderate airflow obstruction (29). This raises the question as to whether VO’s relationship with BD responsiveness may represent a signal that future progression to fixed obstruction is coming in at-risk patients, and whether early interventions could change the trajectory of disease.
Our findings also bring into question the requirement for post-BD FEV1/FVC < 0.70 for the diagnosis of COPD as recommended by GOLD (1) and raise questions about the appropriateness of this criterion and the potential delay in the diagnosis of COPD. Most patients with respiratory complaints consistent with COPD are assessed in primary care offices (30, 31). This is coupled with the fact that access to pulmonary function testing creates a potential barrier to the diagnosis of COPD (32–34). Use of pre-BD spirometry alone in the assessment of COPD could potentially improve diagnosis by office spirometry, which could be more easily deployed in a primary care setting than laboratory-based pulmonary function tests as part of routine evaluation of respiratory complaints in at-risk patients. Furthermore, VO as a marker could be used in addition to other spirometric indices to enhance earlier COPD diagnosis (35–37).
We observed an increased hazard of future fixed obstruction among participants with a clinical diagnosis of asthma. This raises questions as to whether the reversibility of obstruction described by this analysis represents a phenotype of hyperreactive airway disease. ACO is associated with increased respiratory symptoms, poorer health status, as well as exacerbations (38, 39) and emphysema (40). The clinical guidance on management of ACO as a separate entity from COPD or asthma is lacking, at least in part owing to inconsistent definitions for diagnosis. The VO phenotype may represent some point on the continuum of ACO and may provide a venue for further study in the harmonization of asthma and COPD treatments, which could differ from either diagnosis alone (41, 42).
Because we only document lung function at and following entry to the study, participants may have had variable or fixed obstruction before study entry, as would also be the case in clinical practice where previous records are not available. We account for this in our evaluation of transition states by carrying the last known observation forward until a new one occurs. The study design did not allow for us to make additional adjustments for early-life risk factors for COPD, such as low birth weight or home environment in childhood. In addition, data on death were incomplete at the time of our analyses, and our analyses are therefore agnostic to vital status.
Some participants were known to be taking respiratory medications, but there were no significant differences between the VO and nonobstructed groups (Table 1), and as such, we did not adjust for treatments in our models, which would have been more complex owing to time-varying use of medications and questions of validity given unknown treatment adherence. However, if some participants did not withhold their medication for a sufficient duration before spirometry, this may have skewed results somewhat, particularly among those without fully reversible obstruction (4, 5). In addition, the study protocol uses four metered dose inhalations each of albuterol and ipratropium, which represents a dose higher than in standard clinical practice, affecting generalizability. However, this goal of achieving “maximal bronchodilation” in SPIROMICS could have revealed a larger subpopulation of subjects whose airflow obstruction was still potential reversible. This would identify more patients likely to respond to novel treatments targeting airway inflammation and dilation.
This analysis demonstrates that among a well-phenotyped cohort of clinical research participants, airflow obstruction that corrects with inhaled BD is associated with a significantly increased hazard of the development of COPD, as well as higher burdens of emphysema and small airway disease. Were we to accept pre-BD obstruction as a diagnostic criterion for COPD, we could potentially diagnose more patients and intervene earlier using interventions like smoking cessation and novel therapies that target early airway inflammation (43). Data on early pharmacotherapy to reduce progression of obstructive lung disease offer conflicting results (28, 44, 45). Using presence of VO and/or respiratory symptoms as criteria to consider initiation of COPD-specific therapies in these patients who we know experience exacerbations and limitations in their health status (6) may offer benefit and should undergo further investigation. Prospective studies to assess the long-term changes in disease trajectory by early intervention with COPD therapies and smoking cessation assistance among those with this phenotype, as well as the health status and economic tradeoffs thereof, are needed to understand the utility of changes to clinical practice.
The authors thank the SPIROMICS participants and participating physicians, investigators, and staff for making this research possible. More information about the study and how to access SPIROMICS data is at www.spiromics.org. The project officers from the Lung Division of the NHLBI were Lisa Postow, Ph.D., and Lisa Viviano, B.S.N.
SPIROMICS Investigators: Neil E. Alexis; Wayne H. Anderson; Mehrdad Arjomandi; Igor Barjaktarevic; R. Graham Barr; Lori A. Bateman; Surya P. Bhatt; Eugene R. Bleecker; Richard C. Boucher; Russell P. Bowler; Stephanie A. Christenson; Alejandro P. Comellas; Christopher B. Cooper; David J. Couper; Gerard J. Criner; Ronald G. Crystal; Jeffrey L. Curtis; Claire M. Doerschuk; Mark T. Dransfield; Brad Drummond; Christine M. Freeman; Craig Galban; MeiLan K. Han; Nadia N. Hansel; Annette T. Hastie; Eric A. Hoffman; Yvonne Huang; Robert J. Kaner; Richard E. Kanner; Eric C. Kleerup; Jerry A. Krishnan; Lisa M. LaVange; Stephen C. Lazarus; Fernando J. Martinez; Deborah A. Meyers; Wendy C. Moore; John D. Newell, Jr.; Robert Paine III; Laura Paulin; Stephen P. Peters; Cheryl Pirozzi; Nirupama Putcha; Elizabeth C. Oelsner; Wanda K. O’Neal; Victor E. Ortega; Sanjeev Raman; Stephen I. Rennard; Donald P. Tashkin; J. Michael Wells; Robert A. Wise; and Prescott G. Woodruff.
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*Co–senior authors.
A complete list of SPIROMICS Investigators may be found before the beginning of the References.
Supported by the NIH NHLBI (contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C and grants U01HL137880, U24HL141762, and L30HL134025 [to R.G.B.]) and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. R.G.B. additionally received support from NIH National Center for Advanced Translational Sciences grant KL2TR001882. The findings and opinions in this manuscript do not necessarily represent those of the Department of Veterans Affairs.
Author Contributions: R.G.B., I.Z.B., L.A.B., E.R.B., J.L.C., B.A.D., M.K.H., N.N.H., J.A.K., F.J.M., W.M., R.P., S.I.R., D.P.T., P.G.W., R.E.K., and C.B.C. enrolled participants and collected data. R.G.B., I.Z.B., R.E.K., and C.B.C. conceived the design of the analysis. R.G.B., P.M.Q., and D.J.C. analyzed the data. R.G.B. and C.B.C. drafted the manuscript with critical editing from I.Z.B., D.J.C., B.A.D., N.N.H., J.A.K., R.P., D.P.T., and R.E.K. All authors reviewed and approved the final version of the manuscript for publication.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202201-0094OC May 12, 2022
Author disclosures are available with the text of this article at www.atsjournals.org.
