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

<b>Rationale:</b> Among tobacco-exposed persons with preserved spirometry (TEPSs), 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. <b>Objective:</b> We sought to determine differential disease characteristics and trajectories associated with lung volume indices among TEPSs in the SPIROMICS cohort. <b>Methods:</b> We categorized TEPSs (<i>n</i> = 814) by tertiles (low, intermediate, and high) of TLC or residual volume-to-TLC ratio (RV/TLC) derived from baseline computed tomography 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 computed tomography-measured emphysema (Hounsfield units [HU] ⩽-950; parametric response mapping [PRM] of emphysema), air trapping (HU⩽-856; PRM of functional small airway disease; a disease probability measure for non-emphysematous gas trapping), airway geometry (the mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), respiratory symptoms (on the modified Medical Research Council Dyspnea Scale; COPD Assessment Test [CAT]; St. George's Respiratory Questionnaire [SGRQ]; and Short Form-12 [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 vs. former smoker) and burden (pack-years). <b>Results:</b> In TEPSs, the pattern of spirometric disease progression differed between participants with [TLC]^high and those with [RV/TLC]^high: There was increased forced vital capacity with stable forced expiratory volume in 1 second in participants with [TLC]^high, versus unchanged forced vital capacity but nominally decreased forced expiratory volume in 1 second in those with [RV/TLC]^high. Compared with participants with [TLC]^high, TEPSs with [RV/TLC]^high had less emphysema (by HU ⩽-950) but more airway disease (by HU ⩽-856; PRM of functional small airway disease; disease probability measure for gas trapping, and mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), more respiratory symptoms (on the modified Medical Research Council Dyspnea Scale, CAT, SGRQ, and SF12), and more severe exacerbations at baseline. Over an average follow-up of 4.1 ± 2.4 years (range = 0.5-8.5 yr), TEPSs with [RV/TLC]^high also had a higher likelihood of developing more severe spirometric disease (preserved ratio impaired spirometry or Global Initiative for Chronic Obstructive Lung Disease Classification 2) and worsening of their respiratory symptoms (on the CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not significantly different between the two categories over the follow-up period, TEPSs with [RV/TLC]^high were more likely to have been prescribed a respiratory inhaler at their last follow-up visit. <b>Conclusions:</b> In these TEPSs from the 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 in the COPDGene cohort using TLC versus FRC/TLC stratification.