Whether they had respiratory symptoms or not, former and current smokers who didn’t meet criteria for chronic obstructive pulmonary disease (COPD) had similar declines in lung function and progression to COPD in subsequent years, the SPIROMICS II study found.

Participants with symptomatic tobacco exposure and preserved spirometry (TEPS) experienced no significant difference in annual declines in forced expiratory volume in the first second (FEV₁) compared with asymptomatic TEPS participants (-31.3 vs -38.8 mL per year, respectively).

Nor was there a difference in the two groups’ cumulative incidence of COPD over the average of 5.8 years of follow-up (33.0% vs 31.6%), reported Prescott Woodruff, MD, MPH, of the University of California San Francisco (UCSF), and coauthors.

However, participants with symptomatic TEPS experienced significantly more respiratory exacerbations per year (RR 2.38, 95% CI 1.71-3.31), had more pulmonary symptoms, and were more likely to have their condition limit activity, the multi-center study group reported in JAMA.

“These finding suggest that a large proportion of tobacco smoke-exposed persons without airflow obstruction have a persistent, symptomatic non-obstructive chronic airway disease that is distinct from COPD,” Woodruff said in a statement.

“Although tobacco-exposed persons with preserved spirometry are currently categorized as having pre-COPD by the COPD guidelines, the data from the current study emphasize that the definition of smoking-related lung disease needs to be broadened so new treatments can be developed,” he added.

Across the two TEPS groups, 48% of those who completed a final study visit had “substantial and persistent respiratory symptoms,” yet had no evidence of COPD on spirometry, the researchers found.

Recently, the randomized RETHINC trial showed that dual-inhaled bronchodilators failed to ease respiratory symptoms in individuals with symptomatic TEPS.

In this extension study of SPIROMICS I, the rate of FEV₁ decline was highest in people with mild-to-moderate COPD (-42.3 to -46.7 mL per year) and lowest in never-smoker controls (-27.8 mL per year). Participants with symptomatic or asymptomatic TEPS had a roughy threefold to fourfold higher risk of developing COPD versus the control group.

The researchers noted that while COPD can be caused by smoking, there are many former smokers who experience an array of respiratory symptoms but have normal spirometry results that preclude them from participating in COPD trials.

“We found that many people who have a lot of primary tobacco exposure have the same symptoms as people who have COPD, but can’t be diagnosed with COPD, because their FEV₁/FVC ratio is considered normal on spirometry,” said coauthor William McKleroy, MD, also of UCSF, in the press release. “This demonstrates a major gap in effective and compassionate care for tobacco-exposed persons and highlights the need for further study to find ways to help them.”

SPIROMICS II was an extension of the SPIROMICS I trial, which originally took place from November 2010 to July 2015 and had participants followed through July 2021. During the first trial, participants received yearly tests that included assessments of their respiratory symptoms, a CT scan of the chest, and a 6-minute walk distance test for 3 to 4 years.

A total of 1,395 participants from age 40 to 80 years were included in the trial, with 226 participants experiencing symptomatic TEPS and 269 experiencing asymptomatic TEPS. Participants had all smoked cigarettes for more than 20 pack-years.

Between symptomatic and asymptomatic groups, half or more were women, and the average participant age was over 60. The majority in both groups were white.

Participants with symptomatic TEPS experienced significantly more respiratory exacerbations compared to their asymptomatic counterparts (0.23 vs 0.08 exacerbations per person-year).

The investigators found that in symptomatic and asymptomatic TEPS alike, spirometry-defined COPD was more likely in Black patients compared with white patients (HR 2.15, 95% CI 1.39-3.35). A similar trend was seen in current versus former smokers (HR 1.95, 95% CI 1.27-2.98).

Woodruff and colleagues suggested that the differences between Black and white TEPS patients could be due to already-present disparities.

“An evaluation of the contribution of occupational and environmental exposures, socioeconomic status, and structural racism 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,” they wrote.

Among the study’s limitations are its relatively short follow-up and reliance on patient-reported respiratory symptoms and exacerbations. There was also possible selection bias at enrollment, the investigators acknowledged.

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