BackgroundThe clinical and prognostic characteristics of mild-to-moderate chronic obstructive pulmonary disease (COPD) with and without emphysema remain inadequately investigated. Research QuestionDo the clinical and prognostic characteristics differ between mild- to-moderate COPD with and without emphysema? Study Design and MethodsWe obtained clinical data of 989 participants with mild-to-moderate COPD from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). They were categorized into two groups based on their baseline %LAA-950 of less than 5% on CT scans: those with emphysema (EC group) and those without emphysema (NEC group). Linear mixed-effects models were utilized to assess the differences in the decline of lung function, health-related quality of life, and quantitative CT indices between these two groups. Zero-inflated negative binomial regressions were employed to evaluate the rates of acute respiratory exacerbations between the groups. ResultsAmong participants with mild-to-moderate COPD, 428 (43.3%) exhibited emphysema on CT scans. The annual decline in FEV1 was -56.1 mL/year for the EC group and -46.9 mL/year for the NEC group, with a non-significant between-group difference of 9.1 mL/year (95% CI, -24.0 to 5.7 mL/year). The rate of emphysema progression in the EC group was significantly lower than in the NEC group (-0.173%; 95% CI, -0.252 to -0.094). The EC group also showed a more pronounced annual increase in the SGRQ score (0.9 points) compared to the NEC group. The EC group had a higher rate of acute respiratory exacerbations (0.36 per person-year) than the NEC group (0.25 per person-year), with a rate ratio of 1.42 (95% CI, 1.27 to 1.54). InterpretationMild-to-moderate COPD with emphysema did not have accelerated rates of decline in FEV1, but they experienced significantly worsen health-related quality of life and a higher rate of acute respiratory exacerbations. The non-emphysema subtype demonstrated increased emphysema progression.