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Long-term Smokers Have Symptomatic Lung Disease that is Not COPD, Has No Treatment


A new study found that approximately half of participants with extensive cigarette smoking histories did not exhibit airflow obstruction as assessed by spirometry despite experiencing a persistently high level of respiratory symptoms including frequent exacerbations and activity-limiting dyspnea.


The study results, published recently in JAMA, are based on long-term follow-up of participants in the original and an extension of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS I and SPIROMICS II, respectively). The findings suggest “a persistent, symptomatic non-obstructive chronic airway disease that is distinct from COPD,” said Prescott Woodruff, MD, MPH, UCSF division chief of Pulmonology and principal investigator for SPIROMICS, in a university news release.

“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,” Woodruff said.

Because these individuals do not meet spirometric criteria for COPD, they have generally been excluded from clinical trials, according to Woodruff and colleagues, leaving a large population without evidence-based therapies specifically targeting an undefined tobacco-related lung disease.

“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.”

Given the unknown nature of the long-term trajectory of people with symptomatic tobacco exposure and preserved spirometry (TEPS), Woodruff’s research team compared outcomes of participants enrolled in SPIROMICs II who had a 20-pack year history of tobacco exposure and TEPS vs participants with asymptomatic TEPS. A control group was comprised of SPIROMICS participants with a 1 pack-year or less smoking history and normal findings on spirometry. The primary outcome of interest was assessment for accelerated decline in lung function (FEV1) inthe former vs the latter group.

Participants were enrolled in SPIROMICS I from November 2010 to July 2015 and followed through July 2021 in the extended SPIROMICS II. These adults had attended yearly visits that involved spirometry, 6-minute walk distance testing, the COPD Assessment Test (CAT) and chest CT as part of the SPIROMICS I cohort study for 3 to 4 years, with follow-up testing occurring 5 to 7 years following enrollment as part of SPIROMICS II. Every 4 months, researchers called patients to record any respiratory symptoms and exacerbations.


Symptom prevalence, lung function decline

Woodruff et al analyzed 1397 participants of which 226 (mean age, 60.1 years; 59% women; 38% Black) had symptomatic TEPS, represented by a CAT ≥10, and 269 participants (mean age, 63.1 years; 50% women; 15% Black) had asymptomatic TEPS, defined as a CAT score of <10. More participants reported current smoking in the symptomatic group vs the asymptomatic group (58% vs. 34%); participants in the symptomatic TEPS group also reported more respiratory exacerbations during the 12 months before study enrollment as well as greater use of respiratory medications. The investigators reported that both groups had a normal postbronchodilator FEV1/FVC ratio of >0.7.

At a median follow up of 5.76 years, evaluation of lung function in the 2 groups found participants with symptomatic TEPS had a lower yearly rate of decline in FEV1 compared with adults with asymptomatic TEPS (–31.3 mL/year vs –38.8 mL/year; between group difference, -7.5 mL/y [95% CI, −16.6 to 1.6 mL/y]), according to the study. Investigators also observed that compared with participants currently not smoking, current smokers in both symptomatic and asymptomatic TEPS groups experienced greater declines in FEV1.

Further, yearly FEV1 decline was significantly greater among adults with symptomatic mild to moderate COPD (n = 459) vs adults with symptomatic TEPS (42.3 mL/year vs. 31.3 mL/year; between-group difference, 11.1 mL/y [95% CI, 2.8 to 19.3 mL/y]; P = .009]).

COPD cumulative incidence, respiratory exacerbations

Notably, Woodruff’s group found that the cumulative incidence of COPD was similar among those with symptomatic (33%) and with asymptomatic TEPS (31%) for a hazard ratio (HR) of 1.05 (95% CI, 0.76 to 1.46). They found, too, that the HR for airflow obstruction was not significantly different between the 2 groups after adjustment for age, sex, race, body mass index, pack-years of smoking, and current smoking status (HR, 1.02; 95% CI, 0.7 to 1.48).

Risk for development of COPD among participants in both TEPS groups who were current smokers was higher compared with participants who were not smoking (HR, 1.95; 95% CI, 1.27 to 2.98). Participants who were self-identified as Black also experienced greater risk for COPD compared with White participants (HR, 2.15; 95% CI, 1.39 to 3.35).

When the investigators evaluated change in 6MWD there was no difference in actual decrease between those with symptomatic and with asymptomatic TEPS (both decreased by 7m/year) or in rate of decline between the groups. They point out, however, that lower walk distance persisted among those with symptomatic TEPS.

Respiratory exacerbations

Exacerbations of respiratory symptoms were more frequent in the group with symptomatic vs asymptomatic TEPS (0.23 vs 0.08 per person-year; RR, 2.38; 95% CI, 1.71 to 3.31; P<.001), which translated to more ED visits or hospitalizations for severe exacerbations (31.4% vs 6.3%). Approximately half (51.3%) of participants with symptomatic TEPS and 29.7% of those with asymptomatic disease required medication for their exacerbations, according to the findings.

Examining CT-derived measures of lung disease, researchers observed no significant differences between either group in Pi10 (marker of proximal airway disease), emphysema, and parametric response mapping of functional small airway disease.


“Future studies should include symptomatic TEPS in clinical trials or dedicate clinical trials specifically to symptomatic TEPS,” Woodruff added. “They are currently excluded from most clinical trials because they do not meet the definition of COPD.”

1. McKleroy W, Shing T, Anderson WH, et al. Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry. JAMA. 2023;330(5):442-453. doi:10.1001/jama.2023.11676
2. Millions of long-term smokers have lung disease that defies diagnosis. University of California San Francisco. News release. August 1, 2023. Accessed August 16, 2023. https://www.ucsf.edu/news/2023/08/425896/millions-long-term-smokers-have-lung-disease-defies-diagnosis

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