Significance of FEV3/FEV6 in Recognition of Early Airway Disease in Smokers at Risk of Development of COPD: Analysis of the SPIROMICS Cohort

Abstract

Background: Small airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease.

Research question: Can forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV₃/FEV₆) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD?

Study design and methods: The study included 832 current and former smokers with post-bronchodilator FEV₁/FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV₃/FEV₆ based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV₃ and FEV₆. Regression modeling was used to evaluate the relationship between baseline FEV₃/FEV₆ and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD.

Results: FEV₃/FEV₆ less than the LLN at baseline, defined as reduced compared with FEV₃/FEV₆ at or above the LLN, was associated with lower FEV₁, poorer health status (St. George's Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV₃ and FEV₆ showed excellent agreement between repeat measurements. A reduced FEV₃/FEV₆ was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV₃/FEV₆ was also associated with development of COPD according to spirometry results (post-bronchodilator FEV₁/FVC < 0.7) during study follow-up.

Interpretation: FEV₃/FEV₆ is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV₃/FEV₆ can identify those at risk for future development of COPD and respiratory exacerbations.

Clinical trial registration: ClinicalTrials.gov; No.: NCT01969344; URL: www.

Clinicaltrials: gov: ClinicalTrials.gov.

Keywords: COPD; FEV(3); FEV(3)/FEV(6); FEV(6); early airflow obstruction; small airways disease; spirometry.