Lung disease in never-smokers with severe α1 -antitrypsin deficiency: the EARCO Registry

Background: Although the role of smoking as a risk factor for emphysema in α1-antitrypsin deficiency (AATD) is well known, never-smokers with severe AATD may also develop lung disease, ranging from mild asymptomatic disease to severe emphysema. Methods: We performed a cross-sectional and observational study to analyse the characteristics of the population of never-smoker severe AATD (genotype) individuals of the international EARCO Registry. Results: 914 PI*ZZ individuals were analysed, of whom 472 (51.7%) were active or former smokers and 442 (48.3%) were never-smokers. Never-smokers were older (p<0.001), more frequently females (58.8% versus 43.9%; p<0.001) and had better forced expiratory volume in 1 s (FEV1) (81.3±26.5% versus 48.4±23% predicted; p<0.001). Lung disease was more frequent in smokers compared to never-smokers (98.5% versus 75%; p<0.001), but bronchiectasis was more frequent in never-smokers (28.6% versus 17.7%; p<0.001). A total of 319 (34.9%) patients were receiving augmentation therapy, of whom 235 (49.9%) were former smokers and 84 (19.2%) never-smokers. Among never-smokers, 320 (72.7%) were index cases, were older (61.8±11.2 versus 55.3±10.9 years; p<0.001) and had lower FEV1 (77.2±27.5% versus 92.7±19.3% predicted; p<0.001) compared to non-index cases, but there were no differences in sex distribution. Of the 84 never-smokers on augmentation, 11 (9.4%) were non-index cases. Conclusions: Among PI*ZZ never-smokers lung disease remains prevalent, even if milder. Nonetheless, some never-smokers develop severe lung impairment requiring augmentation therapy. Non-index cases are healthier with a higher quality of life. Among never-smokers, lower body mass index, male sex, comorbidities and pulmonary exacerbations are associated with fixed airflow obstruction.