The impact of diagnostic delay on survival in alpha-1-antitrypsin deficiency - results from the Austrian Alpha-1 Lung Registry

Abstract

<b>Background:</b> Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disorder that can manifest as lung disease. A delay between onset of symptoms and diagnosis of AATD is common and associated with worse clinical status and more advanced disease stage but the influence on survival is unclear. <b>Objective:</b> We aimed to investigate the impact of diagnostic delay on overall survival (OS) and transplant-free survival (TS) in AATD patients. <b>Methods:</b> We analysed 373 AATD patients from the Austrian Alpha-1 Lung (AAL) Registry. The AAL Registry is a&nbsp;prospective registry which includes AATD patients from nine specialized centres in Austria. <b>Results:</b> The predominant phenotype was Pi*ZZ (79%). At diagnosis, 84% had an AAT level below 0.6g/L. At inclusion into the registry, 34% had never smoked, 60% had quit smoking and 6 % continued to smoke. Any lung disease was diagnosed in 75%, thereof most patients were diagnosed with emphysema (49%) and/or chronic obstructive pulmonary disease (33%). Median diagnostic delay was 5.4 years. In multivariable analysis, a longer diagnostic delay was significantly associated with worse OS (hazard ratio [HR] 1.50; 95 % confidence interval [CI] 1.04 - 2.17; p = 0.030) and TS (HR 1.47; 95 % CI 1.11 - 1.94; p = 0.008). Furthermore, body mass index (BMI), age and active smoking were significantly associated with worse OS as well as BMI and forced expiratory volume in 1 second (FEV₁) were with worse TS. <b>Conclusions:</b> A delayed diagnosis was associated with significantly worse OS and TS, independent from age, smoking status, BMI and pulmonary function. Screening should be improved and efforts to ensure early AATD diagnosis should be intensified.