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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

Robert A Sandhaus,1 Charlie Strange,2 Andrea Zanichelli,3 Karen Skålvoll,4 Andreas Rembert Koczulla,5,6 Robert A Stockley7 1Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA; 2Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA; 3Department of Internal Medicine, Luigi Sacco Hospital, University of Milan, AAST Fatebenefratelli Sacco, Milan, Italy; 4Team Alpha-1 Athlete, Olsvik, Norway; 5Department of Medicine, Pulmonary and Critical Care Medicine and Pulmonary Rehabilitation, and Head of Teaching Hospital Schoen Klinik BGL, Philipps-University Marburg, Marburg, Germany; 6German Center for Lung Research (DZL), Germany Teaching Hospital, Paracelsus Medical University, Salzburg, Austria; 7University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UKCorrespondence: Robert A StockleyQueen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham, UKTel +44 121 371 6808Email rob.stockley@uhb.nhs.ukAbstract: Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition that predisposes patients to lung and liver disease and is often underdiagnosed due to incomplete diagnosis of chronic obstructive pulmonary disease (COPD) and asthma. Improvements in physician awareness have been made, but better strategies for both diagnosis and management are still required. The only current disease-modifying therapy for AATD is the infusion of the missing Alpha-1 Antitrypsin (AAT) protein, which can slow progression of emphysema. However, AAT treatment can impact patient freedom and quality of life due to the need for weekly intravenous infusions. A symposium was held to discuss patient-centric aspects of care that have impact on the lives of patients with AATD, including exacerbations of their lung disease, self-administration of intravenous AAT therapy and pulmonary rehabilitation. Intravenous self-infusion of drugs is an established treatment strategy for patients with a variety of conditions and can improve patient quality of life, freedom and mental well-being. Experience from these areas show that patients typically manage their treatment well and without complications. When applied to AATD, training patients to self-infuse therapy can be successful, but formal guidelines would be beneficial. In addition to pharmacological intervention, individualized pulmonary rehabilitation, exercise and educational programs can encourage health-enhancing patient behavior and further improve patient quality of life. However, differences in skeletal muscle adaptations to pulmonary rehabilitation exercise regimens have been observed between patients with AATD and non-AATD COPD, highlighting the need to develop training programs specifically designed for patients with AATD.Keywords: alpha-1 antitrypsin, chronic obstructive pulmonary disease, exacerbations, quality of life, pulmonary rehabilitation, self-administration

Robert Sandhaus,1 Charlie Strange,2 Glenda Stone,3 M Chris Runken,3 Christopher M Blanchette,4 Reuben Howden5 1Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA; 2Department of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA; 3Global Health Economics & Outcomes Research, Grifols Shared Services of North America, Inc, Research Triangle Park, NC, USA; 4Department of Public Health Sciences, College of Health and Human Services, University of North Carolina at Charlotte, Charlotte, NC, USA; 5Department of Kinesiology, College of Health and Human Services, University of North Carolina at Charlotte, Charlotte, NC, USACorrespondence: Glenda StoneGlobal Health Economics & Outcomes Research, Grifols Shared Services of North America, Inc, 79 T.W. Alexander Dr, 4101 Research Commons, Research Triangle Park, NC 27709, USATel +1 (919)316-6415Email glenda.stone@grifols.comIntroduction: Alpha-1 antitrypsin deficiency (AATD) is often not identified in patients with chronic obstructive pulmonary disease (COPD) until advanced stages of disease, despite the availability of genetic testing. While clinical practice guidelines provide recommendations on patients who should be tested, more refined algorithms are needed to identify COPD patients who are likely candidates for AATD testing and to prevent delays in diagnosis and treatment. The objective of this study was to identify comorbid associations with AATD among patients diagnosed with COPD in the United States.Methods: Using data from the 2012– 2017 PharMetrics Plus Administrative Claims Database and 2011– 2014 Medicare Fee for Service 5% Sample, patients with COPD (ICD-9-CM: 491.xx, 492.xx, or 496, ICD-10-CM J41, J42, J43, J44) and AATD (ICD-9-CM: 273.4, ICD-10-CM: E88.01) were identified. Patient demographic and diagnostic characteristics were assessed. Logistic regression models were developed to identify significant predictors of AATD.Results: A cohort of 344,528 Medicare beneficiaries with COPD (of which 302 (0.09%) also had two diagnoses of AATD) and a cohort of 340,259 commercially insured patients with COPD (of which 1076 (0.3%) also had a diagnosis of AATD) were constructed. Associations with AATD identified in both models included ICD-9-CM and ICD-10-CM codes for chronic pulmonary heart disease, chronic liver disease and cirrhosis, and liver transplant.Discussion: Significant associations with a diagnosis of AATD among patients with COPD were consistently represented in each of the datasets evaluated, which suggests meaningful comorbidity implications in AATD patients. These findings reinforce the need to test individuals with COPD for AATD as early as possible to help reduce the development of associated comorbid conditions.Keywords: chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, comorbid, genetic

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

Amy Attaway,1,2Uddalak Majumdar,1,3Robert A Sandhaus,4,5Amy S Nowacki,6James K Stoller2,7 1Cleveland Clinic Lerner School of Medicine, Cleveland, OH, USA; 2Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA; 3Department of Hospital Medicine, Cleveland Clinic, Cleveland, OH, USA; 4Alpha-1 Antitrypsin Deficiency Program, National Jewish Health, Denver, CO, USA; 5Alpha-1 Foundation, Coral Gables, FL, USA; 6Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; 7Education Institute, Cleveland Clinic, Cleveland, OH, USACorrespondence: Amy AttawayRespiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USATel +1 216 445 2807Email attawaa@cc.orgBackground: Practice guidelines (PGs) attempt to standardize practice to optimize care. For uncommon lung diseases like alpha-1 antitrypsin deficiency (AATD), a paucity of definitive studies and geographic variation in prevalence may hamper guideline generation. The current study assembled and assesses the degree of concordance among available PGs regarding AATD.Methods: To assess concordance, 15 eligible guidelines focused on AATD were evaluated regarding recommendations surrounding 24 key clinical issues. A Delphi process achieved consensus on ratings for each statement among 3 reviewers. Agreement was quantified as the proportion of guideline comparisons with a matching rating.Results: The overall level of agreement was 47% (1190/2520 comparisons). The overall “affirmative agreement percentage” (ie, when guidelines agreed in endorsing a practice), was 42% (501/1190 comparisons). The agreement for individual clinical statements ranged from 26% to 75%. A broad consensus was seen in the recommendation to test all patients with a history of fixed obstruction on pulmonary function testing (either from asthma or COPD). Given that AATD is an under-recognized disease and that diagnosis often occurs at a late stage, the authors are encouraged by this consensus. Where overall the guidelines were less explicit was when to refer to a specialist or AATD center. Deciding on a treatment strategy requires a thorough understanding of the alpha 1 serum level, genotype, pulmonary function testing, and imaging, and therefore the authors feel that all patients would benefit from a specialty referral if the diagnosis of AATD is being considered.Conclusion: Available guidelines regarding AATD frequently disagreed in management recommendations. Possible explanations for discordance include differences in regional prevalence, availability of augmentation therapy, and insurance environments. Attempts to harmonize the various guidelines by empaneling a broadly representative international group of disease experts should be considered for AATD. Similar comparisons among guidelines for other diseases are recommended.Keywords: alpha-1 antitrypsin deficiency, practice guidelines, chronic obstructive pulmonary disease, clinical management

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.