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Background: Health-related quality of life (HRQoL) assessments such as St. George's Respiratory Questionnaire (SGRQ) are often used as outcome measures to evaluate patient-perceived changes in health status among individuals with lung disease. Several factors have been linked to deterioration in SGRQ, including symptoms (dyspnea, wheezing) and exercise intolerance. Whether these findings apply to individuals with alpha-1 antitrypsin deficiency (AATD) remains incompletely studied. This longitudinal study examines the trajectory of SGRQ scores in a cohort of United States individuals with AATD-associated lung disease and defines factors associated with longitudinal change., Methods: Individuals with AATD-associated lung disease enrolled in AlphaNet, a disease management program, who had ≥3 SGRQ measurements collected between 2009 and 2019, and baseline data for clinically important variables were included in these analyses. Data collected after lung transplants were excluded. Mixed-effects model analyses were used to evaluate the changes in SGRQ total and subscale scores over time and by modified Medical Research Council (mMRC) Scale, use of oxygen, age, sex, productive cough, and exacerbation frequency at baseline. Sensitivity analyses were conducted to examine the potential effect of survivor bias., Results: Participants (n=2456, mean age 57.1±9.9 years, 47% female) had a mean SGRQ total score of 44.7±18.9 at baseline, 48% used oxygen regularly, and 55% had ≥2 exacerbations per year. The median length of follow-up was 6 (IQR 3-9) years. The SGRQ total score and subscales remained stable throughout the observation period. Age, mMRC categories, presence or absence of productive cough, frequency of exacerbations, and use of oxygen at baseline were significantly associated with the rate of change of SGRQ total (p<0.0001)., Conclusion: We observed long-term stability in HRQoL and an association between the rate of change in SGRQ and baseline mMRC, exacerbation frequency, productive cough, and use of oxygen in this cohort of individuals with AATD-associated lung disease., Competing Interests: Dr Radmila Choate reports research support for AlphaNet. Dr Kristen Holm is affiliated with AlphaNet and reports personal fees from AlphaNet, outside the submitted work. Dr Robert Sandhaus is affiliated with AlphaNet and reports contract payments to AlphaNet, Inc. for Disease Management Services from Grifols and CSL Behring; grants to AlphaNet for Disease Management Services from Takeda, grants from Vertex for investigations in multicenter clinical trial at National Jewish Health and Inhibrx. In addition, he is also the data monitoring committee member for Takeda Alpha-1 liver therapy trial, advisory committee member for Grifols, CSL Behring, Beam, Kooro Bio, Intellia, ADARx, ARespo, Evolve, and Vertex. Some of these companies paid travel expenses. Dr David Mannino reports personal fees from AstraZeneca, GlaxoSmithKline, Regeneron, and Genentech, outside the submitted work. Dr Charlie Strange is a medical director of AlphaNet and reports personal fees and/or non-financial support from AlphaNet and Inhibrx. He also reports grants/personal fees from Grifols, Takeda, CSL Behring, Dicerna, from Inhibrx, and Vertex, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2024 Choate et al.)

Aim: Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD., Methods: Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE., Results: Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001)., Conclusion: In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking., Competing Interests: PE has received speaker fees from Chiesi, GSK, and AstraZeneca. AT has had grants and/or honoraria from AstraZeneca, GSK, Chiesi, CSLBehring, Vertex, and Grifols. KEH has received consulting income from AlphaNet. RS is employed by AlphaNet, reports personal fees from Grifols and CSL Behring, non-financial support from Inhibrx and Arrowhead, and grants from Matrx, outside the submitted work. EB, RC, and MN have no conflicts of interest., (© 2024 Ellis 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.)

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., Competing Interests: Dr Robert A Sandhaus and Dr Charlie Strange are medical directors of AlphaNet, a not-for profit disease management company for AATD. Dr Robert A Sandhaus reports participation in advisory boards for Grifols, CSL Behring, AstraZeneca, Mereo BioPharma, and Inhibrx for which he receives reimbursement of travel expenses. Dr Charlie Strange consults on AATD and/or asthma and COPD with AstraZeneca, CSL Behring, Dicerna, Grifols, and Vertex. He has grants paid to MUSC from Adverum, CSA Medical, CSL Behring, Grifols, MatRx, Novartis, Nuvaira, Pulmonx, Takeda, and Vertex. Dr Andrea Zanichelli has received meeting sponsorship from and performed clinical trial research funded by BioCryst, CSL Behring, Shire, Pharming Dyax Corporation, and acts as a consultant for CSL Behring and Shire. Karen Skålvoll reports personal fees from CSL Behring which was paid to Team Alpha-1 Athlete. Dr A Rembert Koczulla reports personal fees from CSL Behring, outside the submitted work. Dr Robert A Stockley serves on the advisory boards for several pharmaceutical companies with an interest in AATD, including CSL Behring, Mereo BioPharma, Vertex, Z Factor and Kamada, and has received non-commercial funding from CSL Behring, Grifols, Takeda and Mereo BioPharma. The authors report no other conflicts of interest in this work., (© 2020 Sandhaus 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.)

Background: 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., Competing Interests: Dr Robert A Sandhaus served in Advisory Board for Grifols, CSL Behring, and Shire, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2019 Attaway et al.)

Background: In an early study of highly symptomatic patients with PI*Z alpha-1 antitrypsin deficiency (AAT), tobacco smoking was identified as a risk factor by comparing the age of symptom onset in smokers and nonsmokers. Age of symptom onset has not been well studied in relationship to other environmental exposures., Methods: Environmental exposures were assessed in 313 PI*Z adults through retrospective self-administered questionnaire. Age of onset of symptoms with and without these exposures were analyzed through survival analysis., Results: Personal smoking was the most important risk factor, associated with earlier onset of cough and wheeze, and showed a dose-dependent relationship with the onset of dyspnea. Childhood environmental tobacco smoke (ETS) exposure was independently associated with younger age of onset of cough. Earlier onset of wheeze was also associated with childhood respiratory infections and family history of emphysema. The report of childhood respiratory infections was associated with childhood ETS exposure, but no statistically significant interactions were noted., Conclusions: We conclude that both personal and secondhand exposure to tobacco smoke in childhood are likely to accelerate the onset of symptoms in AAT deficient patients. Respiratory infections in childhood may also contribute to this risk.