In patients with alpha-1 antitrypsin deficiency (AATD), delayed diagnosis is associated with significantly worse overall survival (OS) and transplant-free survival (TFS), according to the results of the prospective, multicenter Austrian Alpha-1 Lung (AAL) Registry study published in the journal Respiratory Research.

Recognizing that delays between symptom onset and AATD diagnosis are common among individuals with the disorder, and are linked to worse clinical status and more advanced disease, the researchers sought to examine the impact of diagnostic delay on OS and TFS in patients with AATD.

A total of 268 patients with AATD, a genetic disorder, were analyzed in the AAL Registry. The predominant genotype was Pi*ZZ, which was reported in 82.1% of participants. Diagnostic delay was defined as “the time from the first onset of respiratory tract-related symptoms until AATD diagnosis.” At diagnosis with AATD, 90.2% of patients had an AAT level of less than 0.6 g/L. At study inclusion, 28.2% of individuals were never-smokers, 68.0% were former smokers, and 3.8% were current smokers.

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Lung disease was diagnosed in 98.5% of participants, with 63.8% diagnosed with emphysema and 44.0% with chronic obstructive pulmonary disease (COPD). The median diagnostic delay was 5.3 years (range, 2.2 to 11.5 years).

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Per multivariable analysis in 229 participants, a longer delay in diagnosis was significantly associated with worse OS (hazard ratio [HR],1.61; 95% CI, 1.09-2.38; P =.016) and TFS (HR, 1.43; 95% CI, 1.08-1.89; P =.011), regardless of age, body mass index (BMI), smoking status, forced expiratory volume in 1 second (FEV1), and use of long-term oxygen therapy. Age, BMI, and active smoking status were significantly associated with worse OS, whereas BMI, active smoking status, and FEV1 were significantly associated with worse TFS.

The authors concluded that the results from this study suggest that “efforts to ensure early AATD diagnosis should be intensified. Particularly, in accordance with the relevant guidelines, all patients with COPD, emphysema, poorly responsive or late-onset asthma, and relatives of [patients with AATD] should be tested.”

AATD is caused by mutations in the SERPINA1 gene, which encodes the proteinase inhibitor (Pi) alpha-1 antitrypsin (AAT). Patients with AATD can present with pulmonary and hepatic symptoms. Most of the severe cases of AATD result from the homozygous amino acid replacement Glu342Lys (known as the Z allele), the Pi*ZZ genotype, which can be associated with both lung and liver manifestations and is typically characterized by a low serum level of AAT.

A more common variant observed in patients with AATD is the S allele (ie, amino acid substitution Glu264Val), which when combined heterogeneously with the Z allele (Pi*SZ) can cause hepatic fibrosis, as well as an elevated risk for COPD and emphysema among smokers. In addition, recent evidence suggests that individuals with the heterogeneous combination of the Z allele and the wild-type M allele (Pi*MZ) may also have an increased risk for the development of liver cirrhosis or COPD, although the link has been shown to be weaker than in those with the Pi*SZ genotype.


Meischl T, Schmid-Scherzer K, Vafai-Tabrizi F, et al. The impact of diagnostic delay on survival in alpha-1-antitrypsin deficiency: results from the Austrian Alpha-1 Lung Registry. Respir Res. 2023;24(1):34. doi:10.1186/s12931-023-02338-0