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

Abstract

Background 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. Objective We aimed to investigate the impact of diagnostic delay on overall survival (OS) and transplant-free survival (TS) in AATD patients. Methods We analysed 268 AATD patients from the prospective multi-centre Austrian Alpha-1 Lung (AAL) Registry, employing descriptive statistics, Chi-square-test as well as univariable (Kaplan–Meier plots, log-rank test) and multivariable survival analysis (Cox regression). Results The predominant phenotype was Pi*ZZ (82.1%). At diagnosis, 90.2% had an AAT level below 0.6 g/L. At inclusion, 28.2% had never smoked, 68.0% had quit smoking and 3.8% continued to smoke. Lung disease was diagnosed in 98.5%, thereof most patients were diagnosed with emphysema (63.8%) and/or chronic obstructive pulmonary disease (44.0%). Median diagnostic delay was 5.3 years (inter-quartile range [IQR] 2.2–11.5 years). In multivariable analysis (n = 229), a longer diagnostic delay was significantly associated with worse OS (hazard ratio [HR] 1.61; 95% CI 1.09–2.38; p = 0.016) and TS (HR 1.43; 95% CI 1.08–1.89; p = 0.011), independent from age, smoking status, body mass index (BMI), forced expiratory volume in one second (FEV1) and long-term oxygen treatment. Furthermore, BMI, age and active smoking were significantly associated with worse OS as well as BMI, active smoking and FEV1 were with worse TS. Conclusions A delayed diagnosis was associated with significantly worse OS and TS. Screening should be improved and efforts to ensure early AATD diagnosis should be intensified.

Estimating the Prevalence of AATD Patients in the UK to Identify Underdiagnosis and Determine the Eligibility for Potential Augmentation Therapy

“…The median diagnostic delay in our cohort was 5 years, which is similar to previous studies and as this has been associated with worse AATD outcomes, it further reiterates the health impact of underdiagnosis. 1 , 3 …”

“…The median diagnostic delay in our cohort was 5 years, which is similar to previous studies and as this has been associated with worse AATD outcomes, it further reiterates the health impact of underdiagnosis. 1,3 Obstacles to early diagnosis of AATD, and indeed other rare diseases, are well recognized and have been reviewed elsewhere. 11 The state of readiness of health systems for screening or case finding to be conducted, the availability of easily conducted tests, level of knowledge of patients and healthcare practitioners all play a part.…”

“… 2 The diagnostic delay between symptom onset and diagnosis of AATD is generally reported as over 5 years and can result in worse clinical outcomes. 3 To decrease the number of un- or misdiagnosed patients, guidelines recommend testing every COPD patient for AATD, 4 although in practice low awareness and the cost of testing can result in low uptake. 1 Nevertheless, even if prevalence is known, it will remain unclear how many individuals with severe AATD will develop severe lung disease during their life, which is the main indication for the only currently licensed specific treatment for PiZZ patients, namely intravenous AAT replacement, known as augmentation therapy.…”

Development of a risk score to increase detection of severe alpha-1 antitrypsin deficiency

“…[6] People ultimately diagnosed with AATD see multiple physicians and experience long delays from symptom onset to diagnosis, which is associated with worsened clinical symptoms and overall survival, underscoring the importance of identifying persons with AATD earlier. [7,8] While the World Health Organization (WHO), American Thoracic Society (ATS), and European Respiratory Society (ERS) recommend testing all individuals with COPD for AATD, there is low uptake of this recommendation in clinical practice. [9][10][11][12] Failure to fully implement these guidelines is due to inadequate awareness of AATD, unclear test results, cost, testing taking too much time, and the belief that testing will not impact clinical care.…”