Clarifying the Risk of Lung Disease in SZ α1-antitrypsin Deficiency

RATIONALE: The ZZ-genotype of alpha1-antitrypsin deficiency (AATD) is associated with COPD, even amongst never-smokers. The SZ-genotype is also considered severe, yet its effect on lung health remains unclear. OBJECTIVES: To determine the effect of SZ-AATD on spirometry compared to a normal-risk population and determine the effect of smoking cessation in this genotype. METHODS: We prospectively enrolled 166 related individuals, removing lung-index cases to reduce bias, and compared spirometry between 70 SZ and 46 MM/MS individuals (controls). The effect of AAT levels on outcomes was assessed in 82 SZs (including lung-indexes). Subsequently, we analyzed retrospective SZ registry data to determine the effect of smoking cessation on spirometry decline (n=60) and plasma anti-neutrophil-elastase (anti-NE) capacity (n=20). MEASUREMENTS AND MAIN RESULTS: No difference between SZ and control never-smokers was seen. Ever-smoking was associated with a lower FEV1pp (-14.3%, p=0.0092), and FEV1/FVC Ratio (-0.075, p=0.0041) in SZ-AATD. No association was found between AAT-level and outcomes for SZ-AATD. Longitudinal analysis of 60 SZs demonstrated that COPD at baseline, but not former-smoking or AAT levels, predicted greater spirometry decline. Finally, anti-NE capacity did not differ between former and never-smokers (p=0.67). CONCLUSIONS: SZ never-smokers demonstrated no increased risk of COPD regardless of AAT level. Smoking interacts with SZ-AATD to significantly increase airflow obstruction. Former-smoking alone is not associated with greater spirometry decline in SZ-AATD, suggesting cessation attenuates the obstructive process. We found no evidence that the putative-protective-threshold or AAT-levels predict risk within the SZ genotype, raising further doubts over the need for intravenous-AAT augmentation in this cohort.