Densitometric and Functional Progression in Patients with Alpha-1 Antitrypsin Deficiency Genotype SZ

Smoking is a key determinant of chronic obstructive pulmonary disease (COPD) development in patients with the SZ genotype. Few studies have evaluated the impact of other factors associated with emphysema progression. Objectives: To evaluate the progression of lung function and densitometric parameters in PiSZ alpha-1 antitrypsin deficiency (AATD) patients, and to assess the impact of smoking, exacerbation frequency, severity and time since diagnosis. The study also explores correlations between functional and densitometric measures, as well as regional emphysema patterns. Methods: This two-year observational study included 31 PiSZ AATD patients stratified by time since diagnosis (<5 vs. ≥5 years), smoking status (current, former, and never smokers), and exacerbation frequency (<2 vs. ≥2 exacerbations/year). Functional [forced expiratory volume in 1 s (FEV1), carbon monoxide diffusion (DLCO), and carbon monoxide transfer coefficient (KCO)] and densitometric [15th percentile lung density (PD-15) and lung volume with density less than -950 Hounsfield Units (HU-950)] parameters were assessed at baseline and follow-up. Mixed-effects models evaluated disease progression, while correlation and regional analyses highlighted structural-functional relationships and spatial emphysema patterns. Results: Patients diagnosed <5 years previously exhibited faster PD-15 decline (-6.0 ± 1.4 HU/year) than those diagnosed ≥5 years previously (-5.1 ± 1.3 HU/year; p < 0.05). Current smokers showed the most pronounced deterioration in PD-15 (-7.1 ± 1.6 HU/year) and HU-950 (+0.8 ± 0.3% volume/year) versus never smokers (-4.6 ± 1.3 HU/year and +0.4 ± 0.2% volume/year; p < 0.05). Frequent and severe exacerbations, along with pulmonary-related hospitalizations, worsened structural decline, particularly in basal regions. Strong correlations between both PD-15 and HU-950 with FEV1, DLCO, and KCO were observed in advanced stages (≥5 years since diagnosis). Conclusions: This study underscores the pivotal role of densitometry in PiSZ AATD, highlighting its ability to detect early structural changes often missed by functional measures. These findings support integrating densitometry into clinical practice to guide personalized interventions and improve outcomes.