Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry

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.

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.

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.

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.