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Timm Greulich, 1,* Anna Albert, 1,* Werner Cassel, 2 Tobias Boeselt, 1 Erika Peychev, 1 Andreas Klemmer, 1 Francini Ferreira, 3 Christian Clarenbach, 4 Maria L Torres-Duran, 5, 6 Alice M Turner, 7 Marc Miravitlles 8 1University Medical Centre Giessen and Marburg, Philipps-University, Department of Medicine, Pulmonary and Critical Care Medicine, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 2University Medical Centre Giessen and Marburg, Philipps-University, Department of Medicine, Pulmonary and Critical Care Medicine, Sleep Disorders Centre, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 3Bioclever, Barcelona, Spain; 4Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland; 5Pneumology Department, Hospital Álvaro Cunqueiro, AS Vigo, Spain; 6Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain; 7Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 8Pneumology Department, Hospital Universitari Vall d´Hebron/Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain*These authors contributed equally to this workCorrespondence: Marc MiravitllesPneumology Department, Vall d´Hebron Barcelona Hospital Campus, P. Vall d’Hebron 119-129, Barcelona, 08035, SpainTel/Fax +34 932746083Email marcm@separ.esBackground: Augmentation therapy (AT) is the only specific treatment licensed for patients with alpha-1 antitrypsin deficiency (AATD) associated lung disease. Since patients with severe AATD may have a very different prognosis and AT requires intravenous infusions for life, the decision to initiate AT may be challenging.Methods: This survey was conducted on 63 experts in AATD from 13 European countries about their opinions and attitudes reg

Background: Augmentation therapy (AT) is the only specific treatment licensed for patients with alpha-1 antitrypsin deficiency (AATD) associated lung disease. Since patients with severe AATD may have a very different prognosis and AT requires intravenous infusions for life, the decision to initiate AT may be challenging. Methods: This survey was conducted on 63 experts in AATD from 13 European countries about their opinions and attitudes regarding AT. Participants were asked to rank the importance of 11 identified factors related with the prescription of AT. In addition, each participant was asked to respond to the indication of AT for 30 out of 500 hypothetical cases developed with the combinations of the 11 factors. Each case was evaluated by 3 experts to check the concordance. Results: The variables that scored higher on preferences for initiating AT were AAT genotype (score 8.6 from a Likert scale 0-10 (SD: 1.7)), AATD serum level (8.2 (SD:2.4)) and FEV1 (%) decline (7.9 (SD:2.4)). Among the 500 different cases, there was an agreement in indication of AT among the 3 experts in 291 (58.2%). Regarding the variables associated with AT, it was indicated to 81.9% of Pi*ZZ, 52.4% of Pi*SZ and 9.8% of Pi*MZ (p < 0.0001). For Pi*ZZ patients, multivariate analysis identified younger age, reduced FEV1 (%), higher FEV1 decline and worse emphysema as significantly associated with prescription (AUC = 0.8114); for Pi*SZ variables were younger age, worse FEV1 (%) and worse emphysema (AUC = 0.7414); and for Pi*MZ younger age, worse DLCO (%), higher DLCO decline and dyspnea (AUC = 0.8387). Conclusion: There is a high variability in the criteria for prescription of AT among European experts. Most cases were recommended AT according to guidelines, but a significant number of patients with genotype Pi*SZ and almost 10% Pi*MZ were recommended to initiate AT despite the lack of evidence of efficacy in these genotypes. Keywords: EARCO; Europe; augmentation therapy; survey.

Martina Veith,1 Julia Tüffers,1 Erika Peychev,1 Andreas Klemmer,1 Viktor Kotke,1 Sabina Janciauskiene,2 Susanne Wilhelm,1 Robert Bals,3 Andreas Rembert Koczulla,4 Claus Franz Vogelmeier,1 Timm Greulich1 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Member of the German Center for Lung Research, Marburg, Germany; 2Clinic for Pneumology, German Center for Lung Research (DZL), Medical University Hannover, Hannover, Germany; 3Department of Internal Medicine V, Pulmonology, Allergology, Respiratory and Intensive Care Medicine, Saarland Hospital, Homburg/Saar, Germany; 4Institute for Pulmonary Rehabilitation Research, Schoen Klinik Berchtesgadener Land, Teaching Hospital of Philipps-University of Marburg, Marburg, GermanyCorrespondence: Martina VeithDepartment of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Member of the German Center for Lung Research, Marburg, GermanyTel +4964215864723Fax +496421586370Email veithm@staff.uni-marburg.dePurpose: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary condition characterized by low circulating levels of alpha-1antitrypsin (AAT). While the association between AATD and COPD/emphysema is undisputed, the association between AATD and asthma or bronchiectasis is still a matter of debate.Aims and Objectives: Our study aimed to investigate the distribution of AAT genotypes between patients with COPD/emphysema, asthma and bronchiectasis. To back up the diagnostic labels, we described symptoms associated with the diagnosis.Methods: Between September 2003 and March 2020, 29,465 testing kits (AlphaKit®) were analyzed in the AAT laboratory, University of Marburg, Germany. The diagnosis of AATD has been made based on the measurements of AAT serum levels, followed by genotyping, phenotyping or whole gene sequencing depending on the availability and/or the need for more detailed interpretation of the results

Martina Veith,1 Andreas Klemmer,1 Iker Anton,2 Rachid El Hamss,2 Noelia Rapun,2 Sabina Janciauskiene,3 Viktor Kotke,1 Christian Herr,4 Robert Bals,4 Claus Franz Vogelmeier,1 Timm Greulich1 1Department of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Research Marburg, University Medical Center Giessen And Marburg, Germany; 2Progenika Biopharma, S.A. A Grifols Company, Derio, Bizkaia, Spain; 3Department of Respiratory Medicine, Member of the German Center for Lung Research (DZL), Hannover Medical School, Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), Hannover 30625, Germany; 4Department of Internal Medicine V, Pulmonology, Allergology, Respiratory and Intensive Care Medicine, Saarland Hospital, Homburg/Saar, GermanyCorrespondence: Martina VeithDepartment of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Research Marburg, University Medical Center Giessen and Marburg, Germany Tel +49 642 1586 4723Fax +49 642 158 6370Email veithm@staff.uni-marburg.dePurpose: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary condition resulting from the mutations in the SERPINA1 (serine protease inhibitor) gene and is characterized by low circulating levels of the alpha-1 antitrypsin (AAT) protein. The traditional algorithm for laboratory testing of AATD involves the analysis of AAT concentrations (nephelometry), phenotyping (isoelectric focusing, IEF), and genotyping (polymerase chain reaction, PCR); in selected cases, full sequencing of the SERPINA1 gene can be undertaken. New technologies arise that may make diagnosis easier and faster.Methods: We developed and evaluated a new diagnostic algorithm based on Luminex xMAP (multi-analyte profiling) technology using Progenika A1AT Genotyping Test. In an initial learning phase, 1979 samples from individuals suspected of having AATD were examined by both, a traditional and a “new” algorithm. In a second

Alpha-1-Antitrypsin (AAT) deficiency (AATD) is a hereditary disorder that manifests primarily as pulmonary emphysema and liver cirrhosis. The clinically most relevant mutation causing AATD is a single nucleotide polymorphism Glu342Lys (Z-mutation). Despite the recommendation to test every COPD patient, the condition remains severely underdiagnosed with a delay of several years between first symptoms and diagnosis. The Grifols' AlphaKit® QuickScreen is a novel qualitative point-of-care (POC) in vitro screening test developed for the detection of the Z AAT protein in capillary whole blood. The objective of this prospective, international, multi-center, diagnostic, interventional real-world study was to assess the performance of this device for the detection of AATD in test-naïve COPD patients. 1044 test-naïve COPD patients were recruited from 9 centers in Spain and 10 centers in Germany, ranging from primary to tertiary care. To evaluate the performance of the test, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated compared with the gold standard (genotyping). Genotyping and phenotyping of all 1019 evaluable samples revealed 4.12% of patients as carriers of at least one Z-allele, while 0.29% carried the homozygous genotype Pi*ZZ. The evaluation of the test's ability to detect the PiZ protein yielded the following results: specificity 97.8%, sensitivity 73.8%, negative predictive value 98.9%, and positive predictive value 58.5%. All false negatives (n = 11) were heterozygote Pi*MZ samples. The tested device can be used as an appropriate tool to exclude AATD in primary care and in the overall COPD population, except in patients with a high a-priori- probability of AATD