Phenotypes and Trajectories of Tobacco-exposed Persons with Preserved Spirometry: Insights from Lung Volumes.

Background-Among tobacco-exposed persons with preserved spirometry (TEPS), we previously demonstrated that different lung volume indices, specifically elevated total lung capacity (TLC) versus elevated ratio of functional residual capacity-to-TLC (FRC/TLC), identify different lung disease characteristics in the COPDGene cohort. Objective-Determine differential disease characteristics and trajectories associated with the lung volume indices among TEPS in the SPIROMICS cohort. Methods-We categorized TEPS (n=814) by tertiles (low, intermediate, high) of TLC or residual volume-to-TLC (RV/TLC) derived from baseline CT images, and then examined clinical and spirometric disease trajectories in mutually exclusive categories of participants with high TLC without high RV/TLC ([TLC]^high) versus high RV/TLC without high TLC ([RV/TLC]^high). We examined differences in CT-measured emphysema (HU≤-950; PRM^EMPH), airway trapping (HU≤-856; PRM^fSAD; DPM_GasTrap), and airway geometry (Pi10), respiratory symptoms (mMRC; CAT; SGRQ; SF12), and outcomes (annualized exacerbation rate) between the two categories at baseline and over follow-up time up to 8.5 years, using regression modeling adjusted for age, sex, height, weight, and smoking status (current versus former) and burden (pack-years). Results-In TEPS participants, the pattern of spirometric disease progression differed between [TLC]high and [RV/TLC]^high: increased FVC with stable FEV₁ in [TLC]^high versus unchanged FVC but nominally decreased FEV₁ in [RV/TLC]^high. Compared to [TLC]^high, TEPS with [RV/TLC]^high had less emphysema (by HU≤-950) but more airway disease (by HU≤-856; PRM^fSAD; DPM_GasTrap, and Pi10), more respiratory symptoms (by mMRC; CAT; SGRQ; SF12), and more severe exacerbations at baseline. Over an average follow-up time of 4.1±2.4 years (range: 0.5 to 8.5 years), [RV/TLC]^high TEPS also had higher likelihood of developing more severe spirometric disease (PRISm or GOLD-2) and worsening of their respiratory symptoms (by CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not different between the two categories over the follow-up time, [RV/TLC]^high TEPS were more likely to have been placed on a respiratory inhaler at their last follow-up visit. Conclusions-In these TEPS from SPIROMICS cohort, lung volume stratification by TLC versus RV/TLC identifies two pre-COPD phenotypes with distinct respiratory symptoms, radiographic features, and clinical trajectories. The characteristics of these pre-COPD phenotypes match those previously described from COPDGene cohort using TLC versus FRC/TLC stratification.