Abstract
BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) with variable phenotypic expression among different genotypes. While the PiZZ genotype is well characterized, the clinical and structural progression of PiSZ individuals remains less defined. This study evaluates genotype-specific disease trajectories and the impact of augmentation therapy over a two-year follow-up. METHODS: A prospective observational cohort study was conducted, including 74 AATD patients (41 PiSZ, 33 PiZZ), stratified by augmentation therapy status. Disease progression was assessed through lung function decline (forced expiratory volume in one second [FEV1], diffusing capacity for carbon monoxide [DLCO], carbon monoxide transfer coefficient [KCO]) and densitometric changes (15th percentile lung density [PD-15], percentage of lung voxels below -950 Hounsfield units [HU-950]). Mixed-effects models and multivariable regression analyses were performed to evaluate genotype-specific progression patterns and treatment effects. RESULTS: Results: PiZZ individuals exhibited significantly greater annual decline in lung function and densitometric parameters compared to PiSZ individuals, with more pronounced loss in basal lung regions and with greater decline in advanced stages, in contrast to the PiSZ genotype, which showed greater progression in earlier stages. Augmentation therapy was associated with a significant reduction in PD-15 decline in both genotypes, with the greatest benefit observed in PiZZ patients and in those diagnosed within five years of disease onset. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression. CONCLUSIONS: PiZZ individuals experience a more aggressive disease trajectory than PiSZ individuals in the absence of treatment. Augmentation therapy effectively mitigates disease progression in both genotypes, with greater efficacy when initiated early. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression. These findings underscore the importance of genotype-specific monitoring and personalized therapeutic strategies in AATD to optimize clinical outcomes.