Key Points
Question
What is the natural history of people who currently smoke or previously smoked cigarettes and have respiratory symptoms without airflow obstruction based on spirometry?
Findings
In this prospective cohort study that included 1397 participants, those with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS) had a similar rate of decline in lung function and similar incidence of chronic obstructive pulmonary disease defined by spirometry as those with TEPS without symptoms (asymptomatic TEPS), but participants with symptomatic TEPS experienced significantly more respiratory exacerbations over 2 to 10 years of follow-up.
Meaning
Participants with symptomatic TEPS did not have an accelerated decline in lung function compared with those with asymptomatic TEPS, but did have persistent symptoms and a higher rate of respiratory exacerbations at a median follow-up of 5.8 years.
Abstract
Importance
People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies.
Objective
To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS).
Design, Setting, and Participants
SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021.
Exposures
Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls.
Main Outcomes and Measures
The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic–defined airway wall thickening or emphysema.
Results
Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was −31.3 mL/y for participants with symptomatic TEPS vs −38.8 mL/y for those with asymptomatic TEPS (between-group difference, −7.5 mL/y [95% CI, −16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001).
Conclusions and Relevance
Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.
This study defines the natural history of persons with tobacco exposure and preserved spirometry aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without chronic obstructive pulmonary disease compared with controls without tobacco exposure or airflow obstruction.
Introduction
The diagnosis of chronic obstructive pulmonary disease (COPD) requires both respiratory symptoms and evidence of airflow obstruction, which is defined by a postbronchodilator ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) of less than 0.70.1,2 Some individuals who smoke cigarettes or are exposed to other noxious particulates develop COPD.3 Other individuals develop respiratory symptoms, including chronic cough, sputum production, and dyspnea without evidence of airflow obstruction.4 These individuals have generally been excluded from clinical trials because they do not meet spirometric criteria for COPD. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS I) enrolled 2979 participants who (1) had current or prior tobacco exposure, (2) had a history of tobacco use for longer than 20 pack-years, (3) had COPD defined by spirometry or did not have COPD, or (4) never smoked (controls) from November 11, 2010, until March 30, 2015.
SPIROMICS I followed up participants for 3 years, obtained spirometry and computed tomographic (CT) scans at baseline and at years 1 and 2 after enrollment, and assessed symptoms and respiratory exacerbations by telephone every 3 to 4 months. SPIROMICS I5 reported that 50% of persons with current or previous tobacco exposure and preserved spirometry (TEPS) had respiratory symptoms; participants with TEPS and symptoms (symptomatic TEPS) experienced more respiratory exacerbations, limitation of activity, and evidence of airway disease than those with TEPS without symptoms (asymptomatic TEPS).
Although the number of people with symptomatic TEPS in the US is unknown, the US Centers for Disease Control and Prevention reported that more than 30 million currently smoke cigarettes,6 and millions more have a history of tobacco use of at least 20 pack-years. A recent randomized clinical trial reported that respiratory symptoms in persons with symptomatic TEPS did not decrease with use of dual-inhaled bronchodilators.7 Because the long-term clinical trajectory of persons with symptomatic TEPS is unknown, SPIROMICS II enrolled participants from SPIROMICS I who consented to undergo an additional 3 or more years of follow-up to determine whether persons with symptomatic TEPS experienced an accelerated rate of decline in FEV1, developed COPD defined by spirometry, experienced an increased pulmonary symptom burden and respiratory exacerbations, and experienced progression of CT-derived measures of disease associated with COPD vs those with asymptomatic TEPS.
Methods
Study Design and Population
SPIROMICS II is a longitudinal extension study of SPIROMICS I, which was a multicenter, longitudinal, observational study that enrolled participants aged 40 to 80 years who had current or former tobacco use for longer than 20 pack-years and control participants without a history of smoking or lung disease. Persons with restrictive lung or pleural diseases, unstable cardiovascular disease, or a body mass index (calculated as weight in kilograms divided by height in meters squared) greater than 40 were not enrolled. Participants with a history of asthma were included in this study. The trial protocol appears in Supplement 1 and the statistical analysis plan appears in Supplement 2.
In SPIROMICS I, participants underwent a baseline physical examination, completed an assessment of pulmonary symptoms with the COPD Assessment Test, and underwent spirometry and a high-resolution chest CT scan during the baseline visit (visit 1). During the spirometric assessment, participants received 4 puffs of albuterol and 4 puffs of ipratropium to assess for bronchodilator responsiveness. Every 3 months, patients underwent a telephone interview with a structured questionnaire about tobacco use, pulmonary symptoms (COPD Assessment Test score), respiratory exacerbations, use of oral corticosteroids and antibiotics, emergency department (ED) visits and hospitalizations. In-person visits were performed annually for up to 3 years (visits 2-4) at which time spirometry and COPD Assessment Test scores were obtained. High-resolution chest CT scans were performed at visits 1 and 2.
In SPIROMICS II, participants had 1 in-person visit (visit 5), occurring 5 to 10 years after their baseline visit in SPIROMICS I, and were contacted by phone every 4 months to determine tobacco use, pulmonary symptoms, respiratory exacerbations, use of oral corticosteroids and antibiotics, and ED visits and hospitalizations (the follow-up exacerbation questionnaire appears in Supplement 3). SPIROMICS II was approved by the institutional review boards at each participating site. Only participants from SPIROMICS I were eligible for SPIROMICS II. All participants provided written informed consent to participate in SPIROMICS II.
Sample and Definitions
The COPD Assessment Test is an 8-item questionnaire that assesses cough, mucus, chest tightness, dyspnea on exertion, limitation on activities at home and outside the home, sleep, and energy. Scores from the COPD Assessment Test range from 0 to 40 and higher scores indicate more severe symptoms.8,9 An acute COPD exacerbation was recorded if participants reported an episode of breathing problems for which they were treated with oral corticosteroids, antibiotics, or both. A COPD exacerbation was defined as severe if patients reported visiting an ED or being admitted to a hospital during the exacerbation.
Participants with symptomatic TEPS were defined as those who currently or previously smoked cigarettes and had a history of smoking for longer than 20 pack-years, had a normal postbronchodilator spirometry ratio (FEV1:FVC >0.70) at their baseline visit in SPIROMICS I, and had a COPD Assessment Test score of 10 or greater. A score of 10 or greater on the COPD Assessment Test was selected based on current recommendations from the Global Initiative for Chronic Obstructive Lung Disease for clinicians to use a cutoff of 10 to distinguish between more symptomatic vs less or asymptomatic individuals with COPD.1,10 Participants with asymptomatic TEPS were defined as those who had normal postbronchodilator spirometry and a COPD Assessment Test score of less than 10 at their baseline visit in SPIROMICS I. Participants with a postbronchodilator FEV1:FVC less than 0.70 were classified as having mild to moderate COPD if their FEV1 was 50% or greater. These participants were further classified as having (1) symptomatic mild to moderate COPD if their COPD Assessment Test score was 10 or greater or (2) asymptomatic mild to moderate COPD if their COPD Assessment Test score was less than 10. The control participants had a history of smoking for 1 pack-year or less and normal spirometry. To effectively model the trajectory of lung function, the analyses were limited to participants who underwent spirometry at 3 or more study visits during SPIROMICS I and SPIROMICS II (Figure 1).
Figure 1. Study Enrollment and Attendance at Each Visit in SPIROMICS I and II.
This flowchart demonstrates selection of participants from the total SPIROMICS enrollment and attendance at baseline and follow-up visits by symptoms and presence of COPD (control participants and participants with symptomatic TEPS, asymptomatic TEPS, symptomatic mild to moderate COPD, or asymptomatic mild to moderate COPD). The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies the degree of airflow obstruction in patients with COPD into 4 stages of increasing severity. Control participants never smoked.
aStage 3 includes those with a forced expiratory volume in the first second (FEV1) of 30% or greater but less than 50% of predicted. Stage 4 includes those with an FEV1 of less than 30% of predicted.
bStage 1 includes those with an FEV1 of 80% or greater than predicted. Stage 2 includes those with an FEV1 of 50% or greater but less than 80% of predicted.
Outcome Measures
Spirometry was assessed using criteria from the American Thoracic Society and the European Respiratory Society11 and appropriate reference equations.12 Race and ethnicity, sex, and age were self-reported using fixed categories. Race is reported as multiple if participants selected more than 1 race. Information about race was collected because it was a variable used in the standard lung function prediction equations. Race and ethnicity also were included to address specific knowledge gaps about individuals in historically marginalized or underserved populations in research studies about people with tobacco exposure. High-resolution chest CT scans13 were evaluated for 3 radiographic markers associated with COPD: (1) Pi10 in mm, which is the square root of the airway wall area for a hypothetical airway with an internal lumen perimeter of 10 mm14; (2) the percentage of emphysema, which is calculated as the total area of low-attenuation lung voxels as a percentage of total lung voxels15; and (3) parametric response mapping of functional small airway disease, which quantifies nonemphysematous air trapping.16
Statistical Analyses
In SPIROMICS I, a sample size of 313 individuals with asymptomatic TEPS and 313 with symptomatic TEPS was estimated to provide 90% power to detect a difference in the rate of change of FEV1 of 18.3 mL/y or greater, assuming an SD of 70 mL/y. Restricting the sample to participants with 3 or more spirometry visits decreased the final sample size relative to the original estimate.
A linear mixed-effects model was used to determine the relationship between baseline symptoms and presence of COPD (control participants and participants with symptomatic TEPS, asymptomatic TEPS, symptomatic mild to moderate COPD, or asymptomatic mild to moderate COPD) and temporal change in FEV1, symptom scores, 6-minute walk distance, and CT-derived measures. The symptom and obstruction category, time, and the interaction between symptom and obstruction category and time were considered fixed effects. Random effects included random intercepts and slopes for participants (to account for potential autocorrelation from repeated measures) and study site. Model 1 was adjusted for baseline demographic, anthropometric, and smoking-related factors (including age, body mass index, height, self-reported sex, self-identified race, self-reported smoking history in pack-years) and time-varying current smoking status to best account for whether participants quit smoking during follow-up. Model 2 was additionally adjusted for CT-derived airway to lung ratio, which is a measure of lung dysanapsis.17 To approximate normal distributions, percent emphysema was log-transformed and parametric response mapping of functional small airway disease was square root–transformed prior to fitting models.
The McNemar test was used to examine the change in the proportion of participants with symptomatic or asymptomatic TEPS at both the baseline visit and visit 5. The risk of incident COPD and the factors that contributed to incident COPD during follow-up were analyzed using the Kaplan-Meier survival function and interval-censored Cox proportional hazards modeling. For the Kaplan-Meier analysis, the results were censored when 15% of the original participants remained. Zero-inflated negative binomial regressions were used to evaluate the rates and rate ratios (RRs) of respiratory exacerbations.18 The RRs were calculated by dividing the exacerbation rates. Missing data were addressed using available case methods. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc) and Stata version 17 (StataCorp). The Sankey diagrams were generated using open-source software (Sankeymatic.com).
Results
Baseline Participant Characteristics
The baseline characteristics of the 1397 participants in SPIROMICS II, which were similar to those reported in SPIROMICS I,5 appear in Table 1. Of all individuals with TEPS, 46% had symptomatic TEPS. Compared with participants with asymptomatic TEPS, those with symptomatic TEPS were more likely to be female, Black, currently smoking, and have a longer pack-year history (Table 1). Participants with symptomatic TEPS reported more respiratory exacerbations during the 12 months prior to enrollment and more frequent use of inhaled corticosteroids, short-acting β-agonist medications, and long-acting antimuscarinic antagonist medications in the prior 3 months compared with those with asymptomatic TEPS. Baseline FEV1 was lower among participants with symptomatic TEPS compared with those with asymptomatic TEPS and the control participants. The participants with symptomatic TEPS had a lower 6-minute walk distance than any group except those with symptomatic mild to moderate COPD (Table 1).
Table 1. Baseline Characteristics of the Study Population.
| Characteristic | Tobacco exposure and preserved spirometrya | Mild to moderate COPDa | Never smoked (n = 164)a | ||
|---|---|---|---|---|---|
| Symptomatic (n = 226) | Asymptomatic (n = 269) | Symptomatic (n = 459) | Asymptomatic (n = 279) | ||
| Age, mean (SD), y | 60.1 (9.8) | 63.1 (9.1) | 65.2 (8.0) | 67.8 (6.8) | 56.8 (10.2) |
| Sex | |||||
| Female | 134 (59) | 134 (50) | 218 (47) | 89 (32) | 101 (62) |
| Male | 92 (41) | 135 (50) | 241 (53) | 190 (68) | 63 (38) |
| Self-reported raceb | (n = 224) | (n = 268) | (n = 455) | (n = 278) | (n = 162) |
| American Indian | 1 (<1) | 1 (<1) | 5 (1) | 0 | 2 (1) |
| Asian | 3 (1) | 1 (<1) | 7 (2) | 5 (2) | 4 (2) |
| Black | 84 (38) | 40 (15) | 71 (16) | 26 (9) | 37 (23) |
| Multiple | 9 (4) | 7 (3) | 3 (1) | 4 (1) | 6 (4) |
| White | 127 (57) | 219 (82) | 369 (81) | 243 (87) | 113 (70) |
| Hispanic ethnicity | 19 (8) | 8 (3) | 19 (4) | 10 (4) | 22 (13) |
| Body mass indexc | 30.0 (5.4) | 28.3 (4.8) | 28.6 (5.4) | 26.9 (4.3) | 28.5 (5.2) |
| Currently smoking | 130 (58) | 92 (34) | 186 (41) | 67 (24) | 0 |
| Smoking duration, median (IQR), pack-years | 40 (30-56) | 38 (30-50) | 46 (38-69) | 45 (35-60) | 0 |
| Medical history | |||||
| Wheezing | 155 (69) | 83 (31) | 342 (75) | 120 (43) | 24 (15) |
| COPD | 88 (39) | 26 (10) | 351 (76) | 124 (44) | 0 |
| Gastroesophageal reflux disease | 79 (35) | 68 (25) | 166 (36) | 79 (28) | 30 (18) |
| Asthma | 58 (26) | 19 (7) | 113 (25) | 43 (15) | 10 (6) |
| Congestive heart failure | 3 (1) | 1 (<1) | 13 (3) | 3 (1) | 1 (1) |
| Medication use within prior 3 mo | |||||
| Any inhaled bronchodilatord | 88 (39) | 16 (6) | 282 (61) | 82 (29) | 9 (5) |
| Short-acting β-agonist | 65 (29) | 8 (3) | 193 (42) | 43 (15) | 9 (5) |
| Inhaled steroid | 52 (23) | 5 (2) | 192 (42) | 46 (16) | 5 (3) |
| Long-acting muscarinic antagonist | 30 (13) | 4 (1) | 145 (32) | 48 (17) | 0 |
| Antibiotic use within prior year | 33 (15) | 15 (6) | 97 (21) | 25 (9) | 8 (5) |
| Spirometrye | |||||
| FEV1, mean (SD), L | 2.60 (0.59) | 2.85 (0.70) | 2.03 (0.60) | 2.32 (0.69) | 2.95 (0.71) |
| FEV1, mean (SD), % predicted | 96 (12) | 99 (12) | 72 (15) | 79 (15) | 102 (11) |
| FVC, mean (SD), L | 3.38 (0.80) | 3.69 (0.90) | 3.52 (0.96) | 3.89 (0.99) | 3.67 (0.92) |
| FVC, mean (SD), % predicted | 96 (12) | 98 (11) | 95 (16) | 99 (16) | 99 (11) |
| Bronchodilator responsivenessf | 74 (33) | 91 (34) | 316 (69) | 184 (66) | 36 (22) |
| Variable obstructiong | 63 (28) | 67 (25) | |||
| Computed tomographic measures | |||||
| Airway to lung ratio, mean (SD) | 0.035 (0.003) | 0.035 (0.003) | 0.032 (0.003) | 0.032 (0.003) | 0.035 (0.003) |
| Pi10, median (IQR), mmh | 3.71 (3.66-3.76) | 3.69 (3.64-3.75) | 3.70 (3.65-3.75) | 3.69 (3.64-3.75) | 3.66 (3.62-3.72) |
| Emphysema, median (IQR), %i | 0.9 (0.4-1.8) | 1.2 (0.6-2.5) | 3.8 (1.6-9.7) | 4.5 (2.2-8.0) | 1.0 (0.6-2.0) |
| Parametric response mapping of functional small airway disease, median (IQR), %j | 4.2 (1.8-10.3) | 6.9 (2.8-11.3) | 18.5 (11.1-27.4) | 18.4 (10.8-27.6) | 3.5 (1.6-9.0) |
| Quality of life and respiratory symptom scores | |||||
| COPD Assessment Test score, median (IQR)k | 16.0 (12.0-21.0) | 5.0 (3.0-7.0) | 16.0 (13.0-21.0) | 6.0 (4.0-8.0) | 3.0 (1.0-7.0) |
| St George’s Respiratory Questionnaire score, median (IQR)l | 35.6 (22.0-48.7) | 9.0 (5.3-15.2) | 37.0 (28.1-50.3) | 13.1 (7.5-20.3) | 5.4 (3.9-9.4) |
| Modified Medical Research Council dyspnea questionnaire score, median (IQR)m | 1.0 (1.0-1.0) | 0 (0-1.0) | 1.0 (1.0-2.0) | 0 (0-1.0) | 0 (0-1.0) |
| 6-min Walk distance, mean (SD), mn | 406 (85) | 470 (87) | 395 (103) | 450 (85) | 471 (104) |
| History within prior 12 moo | |||||
| ≥1 Exacerbations | 53 (23) | 15 (6) | 127 (28) | 30 (11) | 7 (4) |
| ≥1 Acute COPD exacerbationsp | 40 (18) | 12 (4) | 108 (24) | 22 (8) | 6 (4) |
| ≥1 Severe acute COPD exacerbationsq | 25 (11) | 1 (<1) | 52 (11) | 13 (5) | 3 (2) |
Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity.
Data are expressed as No. (%) unless otherwise indicated.
Could select 1 or more options in a structured questionnaire.
Calculated as weight in kilograms divided by height in meters squared.
Short- or long-acting bronchodilator either used alone or in combination with other inhaled medications.
Measurements obtained after administration of 4 puffs of albuterol and 4 puffs of ipratropium.
Defined as 12% and a 200-mL increase in either FEV1 or FVC after bronchodilation.
Defined as having a prebronchodilator ratio of FEV1 to FVC of less than 0.70 that improves to 0.70 or greater after administration of a bronchodilator.
Square root of the airway wall area for a hypothetical airway with an internal lumen perimeter of 10 mm. Abnormal values suggest proximal airway disease.
Calculated as the total area of low-attenuation lung voxels as a percentage of total lung voxels. Higher values denote increased lung unit destruction and air trapping.
Quantifies nonemphysematous air trapping thought to be caused by abnormal small airway function rather than lung destruction as seen with emphysema.
Validated 8-domain symptom questionnaire with a range of 0 to 40; higher scores indicate greater severity of symptoms.
A 50-item symptom questionnaire with a range of 0 to 100; higher scores indicate greater severity of symptoms.
Ranges from 0 to 4; higher scores indicate greater severity of dyspnea.
Assesses exercise capacity by measuring the distance walked on flat ground in 6 minutes. The normal distance ranges between 400 m and 700 m and depends on age, weight, and height.
Recorded using a structured questionnaire.
Answered “yes” to having experienced an “episode of breathing problems” for which they were treated with oral corticosteroids, antibiotics, or both.
Visited an emergency department or were admitted to a hospital during the episode.
On baseline CT scans, Pi10 in participants with symptomatic TEPS was mildly increased compared with those with asymptomatic TEPS and the control group, and was similar to participants with mild to moderate COPD (Table 1). Functional small airway disease (measured by parametric response mapping of functional small airway disease), percentage of emphysema, and mean airway to lung ratio did not differ at baseline among those with symptomatic TEPS, asymptomatic TEPS, and the control group, but were increased in both the asymptomatic and the symptomatic mild to moderate COPD groups (Table 1 and eFigures 1-2 in Supplement 3). The majority of participants in the 2 TEPS groups returned for visit 5: 71% with asymptomatic TEPS and 75% with symptomatic TEPS (eTable 1 in Supplement 3). Participants who completed 1 or 2 visits and those who completed 3, 4, or 5 visits had similar baseline characteristics (eTable 2 in Supplement 3).
Rate of FEV1 Decline
At a median follow-up of 5.76 years, the decline in FEV1 was −31.3 mL/y for participants with symptomatic TEPS vs −38.8 mL/y for those with asymptomatic TEPS (between-group difference, −7.5 mL/y [95% CI, −16.6 to 1.6 mL/y]) (Table 2 and eTable 3 and eFigure 3 in Supplement 3). In both TEPS groups, participants with current smoking had a higher rate of FEV1 decline vs those not currently smoking (eTable 3 in Supplement 3). The rate of FEV1 decline was highest in the participants with mild to moderate COPD and lowest in the control group (never exposed to tobacco smoke). Participants with symptomatic mild to moderate COPD had a rate of FEV1 decline of 42.3 that was significantly higher compared with the rate of 31.3 in those with symptomatic TEPS (between-group difference, 11.1 mL/y [95% CI, 2.8 to 19.3 mL/y]; P = .009) (model 1 in Table 2 and eTable 3 and eFigure 3B in Supplement 3).
Table 2. Estimated Rates of Decline for Forced Expiratory Volume in the First Second (FEV1)a.
| Tobacco exposure and preserved spirometry | Mild to moderate COPD | Never smoked | |||
|---|---|---|---|---|---|
| Symptomatic | Asymptomatic | Symptomatic | Asymptomatic | ||
| No. of participants at baseline | 226 | 269 | 459 | 279 | 164 |
| No. of participants at visit 5 | 169 | 190 | 297 | 186 | 103 |
| Observation time, median (IQR), y | 5.76 (3.86 to 6.81) | 5.76 (3.24 to 6.89) | 5.35 (3.07 to 6.82) | 5.83 (3.10 to 6.97) | 5.72 (3.10 to 7.20) |
| FEV1, mean (SD), mL | |||||
| At baseline | 2.60 (0.59) | 2.85 (0.70) | 2.03 (0.60) | 2.32 (0.69) | 2.95 (0.71) |
| At visit 5 | 2.45 (0.61) | 2.63 (0.73) | 1.81 (0.58) | 2.11 (0.71) | 2.86 (0.72) |
| Unadjusted FEV1 rate of decline (95% CI), mL/y (n = 1397)b | −32.2 (−38.8 to −25.6) | −35.1 (−41.2 to −29.0) | −39.0 (−43.7 to −34.2) | −41.7 (−47.7 to −35.8) | −21.6 (−29.5 to −13.8) |
| Model 1 (n = 1395)c | −31.3 (−37.9 to −24.7) | −38.8 (−45.0 to −32.6) | −42.3 (−47.2 to −37.4) | −46.7 (−52.9 to −40.4) | −27.8 (−36.3 to −19.3) |
| Model 2 (n = 1381)d | −31.0 (−37.6 to −24.3) | −39.3 (−45.5 to −33.0) | −42.1 (−47.1 to −37.2) | −46.4 (−52.7 to −40.1) | −27.8 (−36.3 to −19.2) |
| FEV1 rate of decline among those currently smoking (95% CI), mL/yb | |||||
| Model 1 (n = 1395)c | −38.6 (−45.9 to −31.4) | −46.1 (−53.7 to −38.6) | −49.7 (−56.0 to −43.4) | −54.0 (−61.7 to −46.3) | |
| Model 2 (n = 1381)d | −38.6 (−45.9 to −31.4) | −46.9 (−54.5 to −39.3) | −49.8 (−56.1 to −43.4) | −54.1 (−61.8 to −46.3) | |
| FEV1 rate of decline among those not currently smoking (95% CI), mL/yb | |||||
| Model 1 (n = 1395)c | −23.9 (−31.3 to −16.6) | −31.5 (−37.7 to −25.2) | −35.0 (−40.2 to −29.8) | −39.3 (−45.5 to −33.2) | −20.5 (−28.4 to −12.6) |
| Model 2 (n = 1381)d | −23.3 (−30.7 to −16.0) | −31.6 (−37.9 to −25.3) | −34.5 (−39.8 to −29.3) | −38.8 (−45.0 to −32.6) | −20.1 (−28.1 to −12.2) |
| Acute COPD exacerbationse,f | |||||
| Per person-year | 0.23 | 0.08 | 0.39 | 0.15 | 0.03 |
| Total No. | 397 | 170 | 1337 | 320 | 43 |
| Severe acute COPD exacerbationse,g | |||||
| Per person-year | 0.10 | 0.02 | 0.15 | 0.05 | 0.01 |
| Total No. | 167 | 39 | 504 | 105 | 10 |
Abbreviation: COPD, chronic obstructive pulmonary disease.
The between-group difference-in-difference calculations appear in eTable 3 in Supplement 3. The details on observation time for each group appear in eTable 9 in Supplement 3.
All models included symptom and obstruction group, time (in years since visit 1), and the symptom and obstruction group × time interaction.
Includes covariates for mean centered age, body mass index, height (cm), and pack-years of smoking at the baseline visit (visit 1), sex (reference group = male), race (reference group = White), and time-varying current smoking status (reference group = not currently smoking).
Includes all model 1 covariates and mean centered airway to lung ratio at visit 1.
Recorded using a structured questionnaire.
Answered “yes” to having experienced an “episode of breathing problems” for which they were treated with oral corticosteroids, antibiotics, or both.
Visited an emergency department or were admitted to a hospital during the episode.
Incidence of COPD Defined by Spirometry
The cumulative incidence of COPD (postbronchodilator FEV1:FVC <0.70) was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio [HR], 1.05 [95% CI, 0.76 to 1.46]) (Figure 2). In the unadjusted, interval-censored Cox proportional hazards model, the HR of developing COPD was significantly higher in participants with symptomatic TEPS (HR, 3.76 [95% CI, 2.02 to 7.00], P < .001) and asymptomatic TEPS (HR, 3.58 [95% CI, 1.93 to 6.63], P < .001) compared with the control group (eFigure 4A in Supplement 3). The HR for airflow obstruction did not differ significantly between the symptomatic TEPS group and the asymptomatic TEPS group (HR, 1.02 [95% CI, 0.7 to 1.48]) when adjusted for age, sex, race, body mass index, pack-years of smoking, current smoking status, and Pi10 (eFigure 4B in Supplement 3).
Figure 2. Development of Chronic Obstructive Pulmonary Disease (COPD) Defined by Spirometry.
The unadjusted Kaplan-Meier curves show COPD-free survival among control participants who never smoked, asymptomatic participants with tobacco exposure and preserved spirometry (asymptomatic TEPS), and symptomatic participants with TEPS (symptomatic TEPS). Participants with COPD at baseline were not included because they already had airflow obstruction. Data were censored when 15% of the original cohorts remained. The median observation time was 4.82 years (IQR, 3.01-6.85 years) for control participants who never smoked, 3.84 years (IQR, 2.09-6.18 years) for participants with asymptomatic TEPS, and 4.43 years (IQR, 2.14-6.17 years) for participants with symptomatic TEPS. P = .77 (using the log-rank test) for the comparison of asymptomatic participants vs symptomatic participants.
Among participants with symptomatic TEPS and those with asymptomatic TEPS, development of COPD defined by spirometry was higher among self-described Black participants vs White participants (HR, 2.15 [95% CI, 1.39 to 3.35]) and among those reporting current smoking vs not currently smoking (HR, 1.95 [95% CI, 1.27 to 2.98]) (eFigure 4B in Supplement 3). In contrast, a higher airway to lung ratio on chest CT scan was associated with a decreased risk of developing COPD.
Longitudinal Symptoms and Activity Limitations
The mean COPD Assessment Test score in the symptomatic TEPS group declined slightly but remained greater than 10 and increased in the asymptomatic TEPS group but remained less than 10 during follow-up (eFigure 5 and eTable 4 in Supplement 3). Among the subgroup of participants who attended a fifth study visit 5 years or longer after the baseline visit, spirometry and COPD Assessment Test score at visit 5 demonstrated that 107 participants (73%) with symptomatic TEPS continued to have symptomatic TEPS, 20 (14%) were reclassified as having asymptomatic TEPS, 14 (10%) had symptomatic mild to moderate COPD, and 5 (3%) had asymptomatic mild to moderate COPD. For participants in this subgroup with asymptomatic TEPS at their baseline visit, 94 (55%) continued to have asymptomatic TEPS, 47 (27%) were reclassified as having symptomatic TEPS, 10 (6%) had symptomatic mild to moderate COPD, and 21 (12%) had asymptomatic mild to moderate COPD (eFigure 6 and eTable 5 in Supplement 3).
The 6-minute walk distance decreased by 7 m per year in both the symptomatic and asymptomatic TEPS groups, by 4 m per year in the control (never smoking) group, and by 10 m per year in both the asymptomatic and symptomatic mild to moderate COPD groups (eTable 4 in Supplement 3). The rate of decline in 6-minute walk distance did not differ between the symptomatic TEPS group and the asymptomatic TEPS group (difference in rate of decline, 0 m per year [95% CI, −3 to 3 m per year]; P = .82) (eTable 6 in Supplement 3). However, the participants with symptomatic TEPS continued to have lower 6-minute walk distance19 than those with asymptomatic TEPS at visit 5 (Figure 3A).
Figure 3. Six-Minute Walk Distance and Exacerbation Rates According to Categorization at Baseline.
The boxes represent the IQR and contain the mean (dot or diamond) values and the median (line) values. The whiskers represent 1.5 times the IQR; the dots or diamonds that appear beyond the bounds of the whiskers are outliers. A, The median observation time was 6.52 years (IQR, 5.58-7.25 years). B, Exacerbations were recorded using a structured questionnaire. An exacerbation was defined as an episode of acutely worsening respiratory symptoms that was treated with corticosteroids, antibiotics, or both. The more extreme values (>1.5 events per year) not shown in this figure include 1.15 (lowest extreme value) and 1.83 (highest extreme value) for 4 symptomatic participants with tobacco exposure and preserved spirometry (TEPS) who were not currently smoking, 1.51 (lowest extreme value) and 2.81 (highest extreme value) for 11 symptomatic participants with mild to moderate chronic obstructive pulmonary disease (COPD) who were not currently smoking, 1.52 (lowest extreme value) and 7.63 (highest extreme value) for 14 symptomatic participants with mild to moderate COPD who were currently smoking, and 1.91 (extreme value) for 1 asymptomatic participant with mild to moderate COPD who was not currently smoking. Additional data on change in 6-minute walk distance and incidence of exacerbations appear in eTables 4, 6, and 7 in Supplement 3.
Respiratory Exacerbations
The number of acute and severe acute respiratory exacerbations was highest in participants with symptomatic mild to moderate COPD (0.39 per person-year) and participants with symptomatic TEPS (0.23 per person-year) (Table 2). Participants with symptomatic TEPS had a significantly higher rate of respiratory exacerbations than participants with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; RR, 2.38 [95% CI, 1.71 to 3.31], P < .001) and participants in the control group (0.03 exacerbations per person-year; RR, 6.77 [95% CI, 4.04 to 11.34], P < .001) (Figure 3B and eTable 7 in Supplement 3). During follow-up, respiratory exacerbations that were treated with medications were reported by 51.3% of participants with symptomatic TEPS, 29.7% of participants with asymptomatic TEPS, 51.3% of participants with asymptomatic mild to moderate COPD, and 68.6% of participants with symptomatic mild to moderate COPD. Severe exacerbations resulting in ED visits or hospitalizations were reported by 31.4% of participants with symptomatic TEPS, 6.3% of those with asymptomatic TEPS, 21.2% of participants with asymptomatic mild to moderate COPD, and 41.6% of participants with symptomatic mild to moderate COPD.
Longitudinal Analysis of CT-Derived Measures of Obstructive Lung Disease
A marker of proximal airway disease, Pi10 increased in all groups. The rate of change for Pi10 did not differ significantly between the symptomatic TEPS group and the control group, the symptomatic TEPS group and the asymptomatic TEPS group, or the symptomatic TEPS group and participants with mild to moderate COPD (eFigure 7 and eTable 8 in Supplement 3). The rate of change in percentage of emphysema and parametric response mapping of functional small airway disease did not differ significantly between those with symptomatic TEPS and those with asymptomatic TEPS, but were significantly lower in the symptomatic TEPS group compared with participants in the symptomatic and asymptomatic mild to moderate COPD groups (eTable 8 and eFigures 8-9 in Supplement 3).
Exploratory Analyses
In a sensitivity analysis that excluded participants who self-reported a history of childhood asthma (n = 169), the results did not differ substantially from the main analyses (eAppendix 1 in Supplement 4). An additional exploratory analysis categorized all participants with TEPS into 2 groups based on chronic bronchitis (defined as chronic cough with sputum production for 3 months per year for 2 consecutive years)20,21 or dyspnea (determined by self-reported modified Medical Research Council scores ≥2 vs <2). Only 67 participants (31.4%) with symptomatic TEPS met the criteria for chronic bronchitis (eAppendix 2 in Supplement 4).
The annual rate of FEV1 decline, change in 6-minute walk distance, or change in CT-derived measures of disease were not significantly different when examined by the presence vs absence of chronic bronchitis or dyspnea. However, there was a slightly higher rate of increase in percentage of emphysema among participants with TEPS and chronic bronchitis compared with those without chronic bronchitis. An additional exploratory analysis included subgroups of participants with symptomatic TEPS and asymptomatic TEPS who did not change from their respective categories for the duration of the study. This analysis found that comparisons of FEV1 decline, exacerbation frequency, decline in 6-minute walk distance, and CT measures of disease between consistently symptomatic TEPS and consistently asymptomatic TEPS subgroups yielded the same results as the analyses of the full populations (eAppendix 3 in Supplement 4).
Discussion
This extension study of SPIROMICS found that participants with symptomatic TEPS had similar rates of FEV1 decline and similar incidence of COPD diagnosed by spirometry as participants with asymptomatic TEPS over a median follow-up of 5.8 years. However, participants with symptomatic TEPS had increased pulmonary symptoms, higher rates of respiratory exacerbations, and increased activity limitation compared with those with asymptomatic TEPS.
These findings suggest that a large proportion of tobacco smoke-exposed persons without airflow obstruction have a persistent, symptomatic nonobstructive chronic airway disease that is distinct from COPD. Although tobacco-exposed persons with preserved spirometry are currently categorized as having pre-COPD by the Global Initiative for Chronic Obstructive Lung Disease guidelines,1 the data from the current study emphasize that the symptomatic subset (symptomatic TEPS) experience ongoing respiratory symptoms, activity limitations, and increased respiratory exacerbations that warrant further investigation into the cause and potential treatments even in the absence of progression to COPD.
Among the 318 tobacco-exposed persons with normal spirometry who completed visit 5 in SPIROMICS II, 48% had substantial and persistent respiratory symptoms (COPD Assessment Test scores ≥10) without evidence of COPD on spirometry at the final follow-up visit. Although spirometry remains an important tool in the diagnosis of airway disease, these results demonstrate the importance of patient-centered factors such as respiratory symptoms and exacerbations when evaluating patients with primary tobacco smoke exposure in the clinical setting.
The results from the current study diverge from prior studies that found an association of nonobstructive chronic bronchitis (defined by chronic cough and phlegm with preserved spirometry22) with accelerated lung function decline.22,23,24 This difference may result from the use of the COPD Assessment Test,4 a tool recommended by the Global Initiative for Chronic Obstructive Lung Disease because it captures 8 distinct domains of respiratory symptoms to distinguish more vs less symptomatic participants. In this study, only 31.4% of participants with symptomatic TEPS met criteria for chronic bronchitis (using the definition of chronic cough with sputum production for 3 months per year for 2 consecutive years). Disease-based vs population-based study designs and the older age of the current study population may also explain why recategorizing the symptomatic TEPS and asymptomatic TEPS groups according to the presence or absence of chronic bronchitis did not support the finding that chronic bronchitis itself may contribute to more rapid FEV1 decline.
It is unclear why only some tobacco-exposed individuals develop respiratory symptoms. Studies have reported an increased inflammatory state,25 and a higher airway mucin concentration and mucin subtype ratios26 in participants with symptomatic TEPS compared with participants with asymptomatic TEPS. Although individuals with symptomatic TEPS may experience chronic airway inflammation and mucus abnormalities in the airways, the anatomical location of these abnormalities and the physiological consequences remain uncertain. In the current study, although one measure of functional small airway disease (parametric response mapping of functional small airway disease) was similar between the asymptomatic TEPS group and the symptomatic TEPS group, Pi10 was slightly greater in participants with symptomatic TEPS at baseline and during follow-up, suggesting a proximal airway abnormality mediated by either thicker airway walls or smaller airway lumens in those with symptomatic TEPS. An evaluation of the contribution of occupational and environmental exposures,27 socioeconomic status,28 and structural racism29 to the development of these symptoms is indicated, given the increased proportion of Black individuals with symptomatic TEPS compared with those with asymptomatic TEPS, and the increased risk of progression to COPD in Black participants vs White participants in this study.
This study has several strengths, including a large and diverse group of participants, frequent assessment of COPD Assessment Test scores, 3 or more in-person visits, and completion of at least 3 spirometric assessments and 3 CT scans.
Limitations
This study has several limitations. First, this study included older participants (aged 40-80 years) so these results may not be applicable to a younger population. Second, there was potential for selection bias at enrollment because participants with pulmonary symptoms may have been more likely to enroll.
Third, COPD Assessment Test scores may have been affected by transient conditions such as upper respiratory tract infections; however, symptom scores were not recorded if a participant reported any respiratory infection within 6 weeks of contact. Fourth, because this study used patient-reported history of exacerbations, medication use, ED visits, and hospitalizations, there may have been recall bias.30
Fifth, although tobacco use was assessed at each visit, this study was not powered to subdivide participants into categories by quit status (eg, always quit, never quit, or current smoking at some but not all visits). Sixth, visit 5 data were missing for 25% of those with symptomatic TEPS and 29% of those with asymptomatic TEPS.
Seventh, it is possible that if there had been a longer follow-up, participants with TEPS may have experienced more FEV1 decline or increased incidence of COPD because airflow obstruction develops with increased smoking duration and pack-years of smoking.31 Eighth, our study was underpowered relative to the original power calculation. However, the difference in FEV1 decline between the symptomatic and asymptomatic TEPS groups is small, and the original power calculation was derived according to the hypothesis that FEV1 decline in participants with symptomatic TEPS would be greater than in those with asymptomatic TEPS, whereas the results show a small but nonsignificant difference in the opposite direction.
Conclusions
Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.
Trial protocol
Statistical analysis plan
Follow-up Exacerbation Questionnaire
eFigure 1. Airway-to-lung ratio at Visit 1 by symptom-obstruction group
eFigure 2. PRMfSAD (%) at Visit 1 by symptom-obstruction group
eFigure 3. Annual FEV1 Decline among Symptom-Obstruction Groups
eFigure 4. Hazard Ratio Estimates and Cox Proportional Hazard Models
eFigure 5. Average CAT score over time (units/year) by Symptom-Obstruction Group
eFigure 6. Re-categorization of Symptomatic and Non-Symptomatic TEPS among those with both Baseline and 5-year Follow-up Exams
eFigure 7. Estimated Pi10 over Time by Symptom-Obstruction Category
eFigure 8. Estimated Log-Transformed Percent Emphysema Over Time by Symptom-Obstruction Category
eFigure 9. Estimated Square-Root Transformed PRMfSAD Over Time by Symptom-Obstruction Category
eTable 1. Longitudinal Characteristics of Study Population by Visit
eTable 2. Characteristics of Study Population by Number of PFT Visits Completed
eTable 3. Estimated Differences in Rates of FEV1 (mL/year) Decline between Symptom-Obstruction Groups
eTable 4. Annual Change in COPD Symptom Scores and Six-Minute Walk Distance in Units Per Year
eTable 5. Frequency Distribution of Symptom-Obstruction Group at Visits 1 and 5 Among Those Who Were Re-Examined
eTable 6. Estimated Differences in Rates of Change in COPD Outcomes Between Selected Symptom-Obstruction Groups
eTable 7. Exacerbation Rate Ratios by Symptom-Obstruction Group
eTable 8. Estimated Differences in Rates of Change in Pi10, Log-Transformed %Emphysema, and Square Root-Transformed PRMfSAD (units/year) Between Selected Other Symptom-Obstruction Groups
eTable 9. Total Number of Participants and Person-Years included in each Model by Symptom-Obstruction Group
eAppendix 1. Asthma Sensitivity Analysis
eAppendix 2. Chronic Bronchitis and Dyspnea Exploratory Analysis
eAppendix 3. Constant TEPS Exploratory Analysis
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
Statistical analysis plan
Follow-up Exacerbation Questionnaire
eFigure 1. Airway-to-lung ratio at Visit 1 by symptom-obstruction group
eFigure 2. PRMfSAD (%) at Visit 1 by symptom-obstruction group
eFigure 3. Annual FEV1 Decline among Symptom-Obstruction Groups
eFigure 4. Hazard Ratio Estimates and Cox Proportional Hazard Models
eFigure 5. Average CAT score over time (units/year) by Symptom-Obstruction Group
eFigure 6. Re-categorization of Symptomatic and Non-Symptomatic TEPS among those with both Baseline and 5-year Follow-up Exams
eFigure 7. Estimated Pi10 over Time by Symptom-Obstruction Category
eFigure 8. Estimated Log-Transformed Percent Emphysema Over Time by Symptom-Obstruction Category
eFigure 9. Estimated Square-Root Transformed PRMfSAD Over Time by Symptom-Obstruction Category
eTable 1. Longitudinal Characteristics of Study Population by Visit
eTable 2. Characteristics of Study Population by Number of PFT Visits Completed
eTable 3. Estimated Differences in Rates of FEV1 (mL/year) Decline between Symptom-Obstruction Groups
eTable 4. Annual Change in COPD Symptom Scores and Six-Minute Walk Distance in Units Per Year
eTable 5. Frequency Distribution of Symptom-Obstruction Group at Visits 1 and 5 Among Those Who Were Re-Examined
eTable 6. Estimated Differences in Rates of Change in COPD Outcomes Between Selected Symptom-Obstruction Groups
eTable 7. Exacerbation Rate Ratios by Symptom-Obstruction Group
eTable 8. Estimated Differences in Rates of Change in Pi10, Log-Transformed %Emphysema, and Square Root-Transformed PRMfSAD (units/year) Between Selected Other Symptom-Obstruction Groups
eTable 9. Total Number of Participants and Person-Years included in each Model by Symptom-Obstruction Group
eAppendix 1. Asthma Sensitivity Analysis
eAppendix 2. Chronic Bronchitis and Dyspnea Exploratory Analysis
eAppendix 3. Constant TEPS Exploratory Analysis
Data sharing statement