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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., Competing Interests: Timm Greulich reports grants from CSL-Behring, grants from Grifols, grants from Kamada, during the conduct of the study; personal fees from Astra Zeneca, personal fees from Berlin-Chemie, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from CSL-Behring, grants and personal fees from Grifols, personal fees from GSK, personal fees from Novartis, grants from German Centre for Lung Research (DZL), Marburg, Germany (Deutsches Zentrum für Lungenforschung), outside the submitted work. Christian Clarenbach received advisory fees from Roche, Novartis, Boehringer, GSK, Astra Zeneca, Sanofi, Vifor, OM Pharma, Grifols and Mundipharma. María L Torres-Duran has received speaker and consulting fees from CSL Behring and Grifols. Alice M Turner has received either grants or speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, CSL Behring, Takeda, Vertex and Grifols Biotherapeutics. Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, pH Pharma, Palobiofarma SL, Takeda, Novartis, Sanofi and Grifols and research grants from Grifols. The authors report no other conflicts of interest in this work., (© 2022 Greulich et al.)

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., Competing Interests: RA Sandhaus has received honoraria, research funding, and/or travel reimbursement from CSL Behring, Grifols, Vertex, AstraZeneca, Takeda, Dicerna, Arrowhead, Inhibrx and the US National Institutes of Health. AM Turner has received grant funding and/or honoraria from CSL Behring, Grifols and Vertex within the last 5 years. M Sucena has received consulting fees for lectures and participation in advisory boards from Bial, Boehringer Ingelheim, CSL Behring, Grifols and Novartis. FJF Herth reports personal fees from CSL, during the conduct of the study. T Greulich reports personal fees from CSL-Behring, grants from Grifols, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Herth et al.)

Background: Despite hospitalization for exacerbation being a high-risk event for morbidity and mortality, there is little consensus globally regarding the assessment and management of hospitalised exacerbations of COPD. We aimed to establish a consensus list of symptoms, physiological measures, clinical scores, patient questionnaires and investigations to be obtained at time of hospitalised COPD exacerbation and follow-up., Methods: A modified Delphi online survey with pre-defined consensus of importance, feasibility and frequency of measures at hospitalisation and follow-up of a COPD exacerbation was undertaken., Findings: A total of 25 COPD experts from 18 countries contributed to all 3 rounds of the survey. Experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein and cardiac blood biomarkers (BNP and troponin) should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale (mMRC) and COPD assessment test (CAT) should be performed at time of exacerbation and follow-up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation., Interpretation: This Europe-wide consensus document is the first attempt to standardise the assessment and care of patients hospitalised for COPD exacerbations. This should be regarded as the starting point to build knowledge and evidence on patients hospitalised for COPD exacerbations., Competing Interests: Dr. Ramakrishnan reports non-financial support from AstraZeneca, PhD scholarship from Australian Government Research Training Program (RTP) and junior researcher salary support from National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), during the conduct of the study and outside the submitted work. Dr. Janssens reports grants from Chiesi, AstraZeneca and GSK, advisory board membership for Boerhinger Ingelheim, AstraZeneca, Chiesi, GSK outside the submitted work; and W. Janssens is cofounder of ARTIQ, a spinoff company of KULEUVEN. Dr. Burgel reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Pfizer, Insmed and Zambon, and grants and personal fees from GSK and Vertex, outside the submitted work. Dr. Contoli reports grants and personal fees from Chiesi, AstraZeneca and GlaxoSmithKline, personal fees from Boehringer Ingelheim, Alk-Abello, Novartis and Zambon and grants from University of Ferrara, Italy, outside the submitted work. Dr. Franssen reports grants and personal fees from AstraZeneca and Novartis, and personal fees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline and TEVA, outside the submitted work. Dr. Greening reports grants and personal fees from GSK, personal fees and non-financial support from Chiesi, and Boehringer Ingelheim outside the submitted work. Dr. Greulich reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, Novartis, grants from German Centre for Lung Research (DZL), Marburg, Germany (Deutsches Zentrum für Lungenforschung), grants and personal fees from Grifols and CSL-Behring and lectures and advisory boards for GSK, Novartis and Roche, outside the submitted work. Dr. Gyselinck reports other non financial support from KU-Leuven, outside the submitted work. Dr. Quint reports grants from MRC, during the conduct of the study; personal fees from GSK, grants from Asthma UK, Chiesi, MRC and The Health Foundation, grants and personal fees from AZ and BI, Bayer outside the submitted work. Dr. Vanfleteren reports grants and personal fees from AstraZeneca, personal fees from Novartis, GSK, Chiesi, Menarini, Pulmonx, Resmed, Boehringer, Verona Pharma and AGA Linde outside the submitted work. Dr. Bafadhel reports grants and personal fees from AstraZeneca, personal fees from Chiesi and GSK, grants and non-financial support from AZ, non-financial support from Chiesi and GSK and advisory board membership for Albus Health and ProAxsis, outside the submitted work. The authors report no other potential conflicts of interest for this work., (© 2021 Ramakrishnan et al.)

Purpose: 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., Competing Interests: Martina Veith reports grants from Grifols. Prof. Dr. Robert Bals reports grants from BMBF, during the conduct of the study; grants from Schwiete Stiftung, Novartis, and Mukoviszidose e.V. and personal fees from AstraZeneca and CSL Behring, outside the submitted work. Prof. Dr. Claus Franz Vogelmeier reports grants, personal fees from AstraZeneca, Boehringer Ingelheim, Grifols, GlaxoSmithKline, and Novartis; personal fees from CSL Behring, Chiesi, Menarini, Nuvaira, MedUpdate, outside the submitted work. Dr Timm Greulich reports grants from Grifols, during the conduct of the study; personal fees from AstraZeneca, serves as a lecturer and part of the advisory board for Berlin Chemie, Boehringer Ingelheim, Chiesi, CSL Behring, Grifols, GSK, Novartis, received grants from German Centre for Lung Research, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Veith et al.)

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., Competing Interests: Professor Joanna Chorostowska-Wynimko reports grants, personal fees, non-financial support from Grifols, Boehringer Ingelheim, and CSL Behring, personal fees, non-financial support from Novartis, and personal fees from GSK, outside the submitted work. Dr Miriam Barrecheguren reports personal fees from Grifols, Menarini, CSL Behring, GSK, Novartis, and Gebro Pharma, outside the submitted work. Dr Ilaria Ferrarotti reports personal fees from Grifols and grants from CSL Behring, outside the submitted work. Dr Timm Greulich reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer-Ingelheim, Chiesi, CSL-Behring, Grifols, GSK, and Novartis, outside the submitted work. Professor Robert A Sandhaus reports participation in advisory boards for Grifols, CSL Behring, AstraZeneca, Mereo, and Inhibrx for which he receives reimbursement of travel expenses. Dr Michael Campos reports grants, non-financial support, and personal fees from CSL Behring, and grants and personal fees from Grifols, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Chorostowska-Wynimko et al.)

Purpose: 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., Competing Interests: Martina Veith reports grants from Grifols, during the conduct of the study; grants from Grifols, outside the submitted work. Iker Anton, Rachid El Hamss, and Noelia Rapun are employees of Progenika Biopharma-Grifols. Viktor Kotke reports grants from Grifols, outside the submitted work. Dr. Robert Bals reports grants, personal fees from CSL Behring and Grifols, grants from Boehinger Ingelheim and Novartis, during the conduct of the study. Claus Franz Vogelmeier reports grants, personal fees from AstraZeneca, GlaxoSmithKline, Grifols, Novartis, and Boehringer Ingelheim, personal fees from CSL Behring, Menarini, Mundipharma, Teva, Cipla, Nuvaira, and Chiesi, grants from Bayer Schering Pharma AG, MSD, and Pfizer, outside the submitted work. Timm Greulich reports grants from Grifols, during the conduct of the study; personal fees from AstraZeneca, Berlin-Chemie, Boehringer-Ingelheim, Chiesi, CSL-Behring, Grifols, GSK, and Novartis, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2019 Veith et al.)

Purpose: COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function. Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy. This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting β 2 -agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID., Methods: CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings. Three definitions of CID (D1-D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV 1 ), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD). In D1 and D2, either TDI or CCQ was evaluated along with FEV 1 and AECOPD, whereas in D3, all 4 parameters were included. ClinicalTrials.gov number: NCT01985334., Results: Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments. The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]). Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89])., Conclusion: In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice., Competing Interests: Disclosure TG has received compensation from Novartis during the conduct of the study. He has also received lecture fees from AstraZeneca, Chiesi, CSL-Behring, GlaxoSmithKline, Grifols, Mundipharma, and Novartis, and received compensation for organizing or participating in advisory boards from AstraZeneca, CSL-Behring, Novartis, Boehringer Ingelheim and Grifols, and received a grant to support an AATD-Lab from Grifols. KK has previously received honoraria for speeches and consulting services from AstraZeneca, Chiesi, ELPEN, and Takeda, and received honoraria for speeches from Boehringer Ingelheim outside the submitted work. MG has received a grant and personal fees from Novartis, Pharmaten and Menarini, outside the sub mitted work. She has also received personal fees from Chiesi, Boehringer Ingelheim and Teva, and received compensation for organizing or participating in advisory boards from GlaxoSmithKline, and received a grant from AstraZeneca. XN and VAP were statisticians for this subgroup analysis of the CRYSTAL study and work at a Novartis contracted CRO. CFV has received personal fees from Novartis during the conduct of the study. Outside the submitted work, he has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Menarini, Mundipharma and Teva, and grants from GlaxoSmithKline and Grifols. KK is an employee and shareholder of Novartis Pharma AG. MA-M and NL are employees of Novartis Pharma AG. AC and FP are employees and shareholders of Novartis Pharma AG. RF is an employee and shareholder of Novartis Pharmaceutical Corporation. The authors report no other conflicts of interest in this work.

Background: The major concept behind augmentation therapy with human α(1)-antitrypsin (AAT) is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys)-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema., Objective: To evaluate the short-term effects of augmentation therapy (Prolastin) on plasma levels of AAT, C-reactive protein, and chemokines/cytokines., Materials and Methods: Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12) on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8), monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL)., Results: There were significant fluctuations in serum (but not in exhaled breath condensate) levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor within a week of augmentation therapy. In general, augmented individuals had higher AAT and lower serum levels of IL-8 than nonaugmented subjects. Prolastin added for 3 hours to neutrophils from protease inhibitor phenotype ZZ individuals in vitro reduced IL-8 release but showed no effect on cytokine/chemokine release from human bronchial epithelial cells., Conclusion: Within a week, augmentation with Prolastin induced fluctuations in serum levels of AAT polymers and cytokine/chemokines but specifically lowered IL-8 levels. It remains to be determined whether these effects are related to the Prolastin preparation per se or to the therapeutic efficacy of augmentation with AAT.