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Timm Greulich,1 Sina Mager,1 Tanja Lucke,2 Andreas Rembert Koczulla,1 Robert Bals,3 Sebastian Fähndrich,3 Rudolf A Jörres,2 Peter Alter,1 Anne Kirsten,4 Claus Franz Vogelmeier,1 Henrik Watz4 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine Ludwig-Maximilians-Universität München, Munich, Germany; 3Department of Internal Medicine V, Pulmonology, Allergology, Respiratory and Intensive Care Medicine, Saarland Hospital, Homburg/Saar, Germany; 4Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Centre for Lung Research (DZL), Grosshansdorf, GermanyIt has been increasingly recognized that the numbers of blood eosinophils (eos) might be an important biomarker in patients with COPD to identify patients at risk for exacerbations and for treatment to inhaled corticosteroid (ICS) treatment or anti-interleukin-5 therapy.1–3 However, data about the stability of blood eos counts over time are rare. We used data from the multicenter COSYCONET study to analyze the variability of eos by strata over a period of 18 months.4

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. The respiratory symptoms were recorded as well.Results: Regarding the distribution of the wild type allele M and the most frequent mutations S (E264V) and Z (E342K), no significant differences could be found between COPD/emphysema [Pi*MM (58.24%); Pi*SZ (2.49%); Pi*ZZ (9.12%)] and bronchiectasis [Pi*MM (59.30%) Pi*SZ (2.81%); Pi*ZZ (7.02%)]. When COPD/emphysema and bronchiectasis were recorded in the same patient, the rate of Pi* ZZ (14.78%) mutations was even higher. Asthma patients exhibited significantly less deficient genotypes [Pi*MM (54.81%); Pi*SZ (2%); Pi*ZZ (2.77%)] than two other groups. Associated respiratory symptoms confirmed the diagnosis.Conclusion: COPD/emphysema and bronchiectasis, but not asthma patients, exhibit higher frequency of AATD genotypes. Our data suggest that AATD testing should be offered to patients with COPD/emphysema and bronchiectasis.Keywords: SERPINA1, alpha-1-antitrypsin deficiency, bronchiectasis, asthma, diagnosis

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 phase, 1133 samples were analyzed with the Luminex xMAP only.Results: By introducing a Luminex xMAP based algorithm, we were able to simultaneously identify 14 mutations in SERPINA1 gene (instead of two- S and Z-by using our old algorithm). Although the quantity of IEF assays remained unchanged, the nephelometric measurements and sequencing were reduced by 79% and 63.4%, respectively.Conclusion: The new method is convenient, fast and user-friendly. The application of the Luminex xMAP technology can simplify and shorten the diagnostic workup of patients with suspected AATD.Keywords: SERPINA1, diagnosis, Luminex xMAP technology, mutations

Felix JF Herth,1 Robert A Sandhaus,2 Alice M Turner,3 Maria Sucena,4 Tobias Welte,5 Timm Greulich6 1Department of Pneumology and Critical Care Medicine, University of Heidelberg, Heidelberg, Germany; 2Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA; 3Institute of Applied Health Research, University of Birmingham, Birmingham, England; 4Pulmonology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal; 5Department of Pulmonary and Infectious Diseases, Hannover Medical School, Hannover, Germany; 6Department of Internal Medicine and Pneumology, University Hospital Marburg, Marburg, GermanyCorrespondence: Alice M Turner Email a.m.turner@bham.ac.ukAbstract: Alpha 1 Antitrypsin deficiency (AATD) is a hereditary condition characterized by low serum Alpha 1 Antitrypsin (AAT) levels and a predisposition towards early-onset emphysema. Infusion of AAT is the only disease-modifying therapy that can sufficiently raise plasma AAT levels above the putative protective threshold and reduce the decline in lung density loss. Several randomized controlled trials (RCTs) and registry studies support the clinical efficacy of AAT therapy in slowing the progression of AATD-related emphysema and improving survival outcomes. The COVID-19 pandemic has prompted physicians to develop additional strategies for delivering AAT therapy, which are not only more convenient for the patient, but are “COVID-19 friendly”, thereby reducing the risk of exposing these vulnerable patients. Intravenous (IV) self-administration of AAT therapy is likely to be beneficial in certain subgroups of patients with AATD and can remove the need for weekly hospital visits, thereby improving independence and well-being. Increasing the awareness of self-administration in AATD through the development of formal guidelines and training programs is required among both physicians and patients and will play an essential role, especially post-COVID-19, in encouraging physicians to consider self-administration for AATD in suitable patients. This review summarizes the benefits of AAT therapy on the clinical endpoints of mortality and quality of life (QoL) and discusses the benefits of self-administration therapy compared with conventional therapy administered by a healthcare professional. In addition, this review highlights the challenges of providing AAT therapy during the COVID-19 pandemic and the potential considerations for its implementation thereafter.Keywords: Alpha 1 Antitrypsin, Alpha 1 Antitrypsin deficiency, COVID-19, efficacy, self-administration

The systematic review on patient-related outcome measures (PROM) for assessing quality of life (QoL) in patients with alpha-1-antitrypsin deficiency (AATD) was registered at PROSPERO (CRD 42021265360).

Joanna Chorostowska-Wynimko,1 Miriam Barrecheguren,2 Ilaria Ferrarotti,3 Timm Greulich,4 Robert A Sandhaus,5 Michael Campos6 1Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; 2Department of Pneumology, University Hospital Vall d’Hebron, Barcelona, Spain; 3Department of Internal Medicine and Therapeutics, Pneumology Unit IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy; 4Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 5Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA; 6Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami School of Medicine, Miami, FL, USACorrespondence: Joanna Chorostowska-WynimkoDepartment of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, ul. Płocka 26, 01-138, Warsaw, PolandTel +48 22 43 12 158Fax +48 22 43 12 358Email j.chorostowska@gmail.comAbstract: Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed genetic predisposition for COPD and emphysema and other conditions, including liver disease. Although there have been improvements in terms of awareness of AATD and understanding of its treatment in recent years, current challenges center on optimizing detection and management of patients with AATD, and improving access to intravenous (IV) AAT therapy – the only available pharmacological intervention that can slow disease progression. However, as an orphan disease with geographically dispersed patients, international cooperation is essential to address these issues. To achieve this, new European initiatives in the form of the European Reference Network for Rare Lung Diseases (ERN-LUNG) and the European Alpha-1 Research Collaboration (EARCO) have been established. These organizations are striving to address the current challenges in AATD, and provide a new platform for future research efforts in AATD. The first objectives of ERN-LUNG are to establish a quality control program for European AATD laboratories and create a disease management program for AATD, following the success of such programs in the United States. The main purpose of EARCO is to create a pan-European registry, with the aim of understanding the natural history of the disease and supporting the development of new treatment modalities in AATD and access to AAT therapy. Going further, other patient-centric initiatives involve improving the convenience of intravenous AAT therapy infusions through extended-interval dosing and self-administration. The present review will discuss the implementation of these initiatives and their potential contribution to the optimization of patient care in AATD.Keywords: Alpha-1 antitrypsin deficiency, registries, testing, self-administration, alternative dosing

Additional file 1: Table S1 displays the baseline characteristics according to the blood eosinophils of patients in whom systemic steroids were administered only after the blood samples had been taken. Continuous parameters are displayed as Median and (IQR). Chi-Square test was performed to compare gender between the groups. For continuous parameters: Mann-Whitney test was calculated for two groups comparisons, Kruskal-Wallis test with Dunn’s test for three groups comparisons. * significant between 300; $ significant between 100 and 300 and > 300; § significant between 300; $ significant between 100 and 300 and > 300; § significant between 300; $ significant between 100 and 300 and > 300; § significant between 300; $ significant between 100 and 300 and > 300; § significant between