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Background: Currently approved therapies for individuals with alpha-1 antitrypsin deficiency (AATD) are intravenously infused products. The burdens and demographics of infusion practices in the United States are not well-characterized., Research Question: What is the prevalence of different infusion practices in the United States?, Study Design and Methods: AlphaNet disease management participants completed a survey that captured current and past infusion practices. Data regarding the reasons for choosing their current infusion practice, problems with past infusion practices, resources required, and support services utilized were collected from February 8, 2022 through July 1, 2022., Results: Among 5266 individuals, infusions happened at home by health care providers (60.2%), at infusion clinics (30.6%), and by self-infusion (8.1%). Self-infusion prevalence increased with time on therapy and was more prevalent in younger individuals (61.2 ± 10.5 years) compared to users of other infusion practices (64.1 ± 11.0 years), ( p <0.001). The perceived benefits of self-infusion included: (1) freedom and flexibility (77.9%), (2) ability to travel (44.5%), (3) avoidance of infusion clinics (41.8%), (4) time-savings (35.9%), (5) less absence from work (26.6%), (6) less exposure to infections (22.1%), and (7) less cost (16.4%). Self-infusion was done through permanent intravenous catheters in 41.2% and peripheral intravenous catheters in 58.3%. Self-infusers were more satisfied (93.1% "very satisfied") than other groups. Among individuals currently infusing with home nurses or in clinics, 21.4% would consider self-infusing in the future., Interpretation: Self-infusion of alpha-1 antitrypsin is feasible and associated with high satisfaction scores. Recommendations for catheter care, infusion support, and cost management are informed by survey results., (JCOPDF © 2023.)

Background: Individuals with alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD) may be at increased risk of coronavirus disease 2019 (COVID-19) pneumonia since COPD is associated with an increased risk of severe COVID-19 infection., Research Question: We hypothesized that the AlphaNet disease management program would lower COVID-19 burdens. We evaluated the prevalence of COVID-19 infection, severe COVID-19, interruptions in augmentation therapy, and intention to vaccinate., Study Design and Methods: Data regarding COVID-19 were collected monthly from March 2020 through February 2022. Responses from 8019 individuals were analyzed to evaluate the prevalence and severity of COVID-19 infections, interruptions in AATD care, and the likelihood of vaccination., Results: By the end of 2020, 4% of patients reported a positive COVID-19 test. Of those, 35.3% were hospitalized, with 8.6% admitted to the intensive care unit (ICU). By February 2022, the prevalence of COVID-19 infections had increased to 18.6%, with hospitalization rates of 22.1% and ICU admissions at 4.7%. Attitudes about COVID-19 vaccination assessed in December 2020 before the vaccine was widely available suggested 10.3% of patients would definitely not get the vaccine. Notably, 38.2% of those subsequently self-reported receipt of a COVID-19 vaccine., Interpretation: The prevalence of COVID-19 infections in patients with AATD was lower than the prevalence in the general U.S. population during 2020, although with a higher hospitalization rate. This health-managed population has a high vaccination intent. Those with an initially low vaccination intent changed their minds over time. We interpret these results as showing that most AlphaNet individuals with AATD had success at navigating the COVID-19 pandemic with lower case rates than the general U.S. population., (JCOPDF © 2023.)

Background: Intravenous alpha-1 antitrypsin (AAT) augmentation therapy is the only specific treatment available for alpha-1 antitrypsin deficiency (AATD)-related lung disease. It is widely used worldwide but remains unavailable to patients with AATD in the United Kingdom. While randomized trials of augmentation therapy have demonstrated biochemical efficacy and lung tissue preservation using computed tomography (CT) densitometry, these studies were not adequately powered to demonstrate effectiveness in well-accepted clinical endpoints such as quality of life (QOL) or survival. We used large, prospectively followed AATD patient populations in the United States and United Kingdom to explore these important clinical endpoints., Methods: Our inclusion criterion was adults with severe AATD and associated lung disease. The treatment group was U.S. AATD patients receiving augmentation therapy for lung disease. The control group was augmentation therapy naïve AATD patients. Multivariable regression and survival analyses were used to assess QOL and mortality outcomes respectively., Results: Mean annual deterioration of the St George's Respiratory Questionnaire total score was 1.43 points greater/year in the control group compared to those receiving augmentation therapy (95% confidence interval [CI] 0.47 to 2.39, p =0.003). At 7 years, median survival was 82.7% (95% CI 75.3 to 90.7) for the control group versus 87.8% (95% CI 82.8 to 93.2) in the augmentation group, p =0.66. There was significant heterogeneity between cohorts., Conclusions: A comparison of 2 highly characterized AATD cohorts was not able to reliably determine if AAT augmentation therapy improves QOL or mortality in patients with severe AATD-related lung disease. Alternative surrogate biomarkers of disease progression, such as CT lung density, may be a more pragmatic option., (JCOPDF © 2023.)

Rationale: Identifying pulmonary exacerbations in patients with alpha-1 antitrypsin deficiency (AATD) is critical as they are associated with disease progression and poor health-related quality of life. Not all changes in usual respiratory symptoms will be identified as exacerbations by patients with AATD., Methods: Data collected via regular monthly telephone calls during the first year of the AlphaNet Step Forward Study were analyzed. AlphaNet subscribers were asked about changes in their usual respiratory symptoms, whether they considered changes in symptoms to be pulmonary exacerbations, and their management. Participants who reported changes in their usual respiratory symptoms throughout the year were included in the study. Per-patient and per-event analyses were performed., Results: Participants (n=316, age 58±10 years, 53% female) reported 797 events of changes in their usual respiratory symptoms in 1 year. Almost half (48%) of these symptom events were identified as pulmonary exacerbations by the study participants. The average number of symptoms was higher in events recognized by participants as exacerbations than those not identified as exacerbations (3.3±1.5 versus 1.8±1.1, respectively). A greater proportion of the exacerbation events were managed by taking antibiotics or corticosteroids or both (81%, 53%, and 41% of the events, respectively). With exacerbations, participants mainly spoke to the pulmonary specialist (39%) or went to the doctor's office (37%). Symptom events not recognized as exacerbations were mostly self-treated (56%)., Conclusions: Changes in usual pulmonary symptoms are not universally recognized as exacerbations. Patients' perspectives in recognizing changes in pulmonary symptoms as exacerbation events are critical., (JCOPDF © 2022.)

Background: The Step Forward Study (SFS) was designed to increase exercise activity and improve body mass index (BMI) among individuals with alpha-1 antitrypsin deficiency (AATD)-associated lung disease., Methods: The SFS is a randomized trial of an intensive distance intervention that was delivered via a series of mailings and teleconferences versus no additional intervention. All participants (n=500) were also enrolled in a disease management program designed for individuals with AATD-associated lung disease who have been prescribed augmentation therapy. The primary outcome was self-reported number of exercise minutes per week. The secondary outcome was BMI. Linear mixed model analyses were used to assess the difference in average weekly exercise minutes between the intervention arms over time. T-tests, signed rank and Wilcoxon rank-sum tests were used to evaluate changes in BMI between the intervention arms and within each BMI category., Results: The study included 429 individuals with evaluable primary outcome data.There was a significant effect of intervention on exercise minutes over time (p =0.018). Participants in the intervention group reported an average of 167.14 minutes (standard deviation [SD]=10.68) of weekly exercise and those in the standard care group reported 148.31 minutes (SD=10.96). There was a significant difference in BMI change between the intervention (mean BMI decrease 0.74, SD=2.16) and the standard care group (mean BMI decrease 0.27, SD=1.63); p =0.0122., Conclusion: Individuals who were randomly assigned to the intervention group reported more exercise activity and improvements in BMI over the course of this multicomponent intervention compared to individuals assigned to standard care., Competing Interests: DMM is a former employee and current shareholder of GlaxoSmithKline. RAS has served on advisory boards and/or as a speaker for Grifols and CSL Behring. He is on the board of directors of AlphaNet and serves as the Medical Director of AlphaNet. KEH has received consulting income from AlphaNet. RC has received research support from AlphaNet. TB reports no conflicts., (JCOPDF © 2021.)

Background : The aim of this study was to examine differences in demographic, health, and behavioral characteristics in individuals with ZZ and SZ genotypes of alpha-1 antitrypsin deficiency (AATD) within AlphaNet's Disease Management and Prevention Program (ADMAPP). Methods : Self-reported data from 3535 patients with AATD, including 3031 (85.7%) patients with ZZ, ZNull, and NullNull genotypes (referred to here as ZZ), and 504 (14.3%) with the SZ genotype were analyzed using t-tests, ANOVAs, and Chi-squared tests. Results: The average age of the cohort was 56.3±10.6 years. The majority of respondents were male (51.2%), white (98.2%) and married (65.2%). SZs reported having more frequent exacerbations ( p <0.001) and hospitalizations ( p =0.012) than ZZs. A higher proportion of SZs than ZZs had been diagnosed with high blood pressure, diabetes, congestive heart failure, and other comorbid conditions. SZs were more likely than ZZs to report "poor" health ( p =0.005). Over a third (38.4%) of SZs do not exercise compared to 27.1% of ZZs ( p <0.001). A greater proportion of SZs compared to ZZs view themselves as being overweight ( p <0.001) or "out of shape" ( p =0.001). A higher proportion of SZs than ZZs reported any history of smoking and current smoking ( p <0.001). Conclusions: In patients with AATD and lung disease participating in a disease management program, a higher proportion of SZs than ZZs report exacerbations, comorbidities, and overall poor health, as well as unhealthy behaviors such as lack of exercise and current smoking. Future work should consider the extent to which genotype-specific health promotion interventions would be useful., Competing Interests: David Mannino is a full-time employee of GlaxoSmithKline plc and owns stock of GlaxoSmithKline plc. Furthermore, he has received royalties from Up-to-Date, and has been compensated as a medical expert in legal cases. Robert Sandhaus has served on advisory boards and/or as a speaker for Grifols, CSL Behring, Shire, and AstraZeneca. He is on the board of directors of AlphaNet and the Alpha-1 Project, is on the Medical Advisory Committee of the COPD Foundation and serves as the Medical Director of AlphaNet. Kristen Holm has received consulting income from AlphaNet. Radmila Choate has received research support from AlphaNet.

Background : This study is the first to utilize a large claims database to estimate medical costs of patients with alpha-1 antitrypsin deficiency (AATD) in the United States. Methods: Adult AATD patients were identified from the OptumLabs™ Data Warehouse. Insurer and patient out-of-pocket costs were categorized into the following cost buckets, stratified by augmentation therapy use: physician visits (PV), emergency department visits (ED), inpatient stays (IP), augmentation therapy (AUG), other prescription drug costs (RX), and other costs (OTH). Costs were weighted and adjusted to 2017 U.S. dollars using the medical care component of the consumer price index. Results: The study cohort consisted of9117 AATD patients followed for 53,872 person years observed between 1993 and 2015. The annual costs among AATD patients totaled $127,537 among augmentation therapy users and $15,874 among non-users. The major drivers of annual costs to the insurer among the 7975 patients not on augmentation therapy were: PV: $5352 (37.7%) and IP: $4506 (31.8%). Among the 1142 augmentation users, major annual cost drivers to the insurer were PV: $15,064 (12.3%) and AUG: $82,002 (66.7%). Annual patient out-of-pocket costs were $4601 (AUG: $2084 [45.3%]; RX: $940 [20.4%]) and $1689 (PV: $727 [43.0%]; RX: $589 [34.9%]) among augmentation therapy users and non-users, respectively. Averaged across the entire cohort, the average annual costs per AATD patient were $22,975, paid by insurers ($21,100) and patients ($1875). Conclusions: Annual medical costs among patients with AATD are $127,537 and $15,874 among augmentation therapy users and non-users, respectively, with 75.3% of the cost difference attributable to AUG., Competing Interests: Jan Sieluk: Research funding from Bayer HealthCare (recipient: University of Maryland, Baltimore), research funding from AlphaNet (recipient: University of Maryland, Baltimore), research funding from Alpha-1 Foundation (recipient: University of Maryland, Baltimore); Joseph Levy receives postdoctoral fellowship support from Merck & Co., Inc.; Robert Sandhaus: Medical Director of AlphaNet; medical advisor to Grifols, CSL Behring, Shire, Octapharma, Inhibrx, AstraZeneca; grants from the National Institutes of Health, CSL Behring, Grifols, Matrx; Henry Silverman: nothing to declare; Kristen Holm:consulting income from AlphaNet; C. Daniel Mullins: Research funding from Amgen, Bayer, Merck, Novartis, Pfizer (recipient: University of Maryland, Baltimore), consulting income from Amgen, Bayer, Janssen/Johnson & Johnson, MundiPharma, Novartis, Pfizer, Regeneron/Sanofi-Aventis.

Computed tomography (CT) lung density is an accepted biomarker for emphysema in alpha-1 antitrypsin deficiency (AATD), although concerns for radiation exposure limit its longitudinal use. Serum proteins associated with emphysema, particularly in early disease, may provide additional pathogenic insights. We investigated whether distinct proteomic signatures characterize the presence and progression of emphysema in individuals with severe AATD and normal forced expiratory volume in 1 second (FEV 1 ). QUANT itative lung CT U n M asking emphysema progression in AATD (QUANTUM-1) is a multicenter, prospective 3-year study of 49 adults with severe AATD and FEV 1 post-bronchodilator values (Post-BD) ≥ 80% predicted. All participants received chest CT, serial spirometry, and contributed to the serum biobank. Volumetric imaging display and analysis (VIDA) software defined the baseline 15 th percentile density (PD15) which was indexed to CT-derived total lung capacity (TLC). We measured 317 proteins using a multiplexed immunoassay (Myriad Discovery MAP ® panel) in 31 individuals with a complete dataset. We analyzed associations between initial PD15/TLC, PD15/TLC annual decline, body mass index (BMI), and protein levels using Pearson's product moment correlation. C-reactive protein (CRP), adipocyte fatty acid-binding protein (AFBP), leptin, and tissue plasminogen activator (tPA) were found to be associated with baseline emphysema and all but leptin were associated with emphysema progression after adjustments were made for age and sex. All 4 proteins were associated with BMI after further adjustment for multiple comparisons was made. The relationship between these proteins and BMI, and further validation of these findings in replicative cohorts require additional studies., Competing Interests: TB has received grants from the CHEST Foundation and the Alpha-1 Foundation. MGJ, AVA and CA have nothing to declare. HOC reports grants from Spiration Inc., and personal fees from Samsung, outside of the submitted work. JLB, SES, CLW, LMS, AB, MB, RAS and EKS have nothing to declare. JKS is a consultant to: Grifols, Shire, CSL Behring, Arrowhead Pharmaceuticals and reports research funding from the National Institutes of Health, the Alpha-1 Foundation, and CSL Behring. He is also a member of the Board of Directors of the Alpha-1 Foundation and a member of the Medical and Scientific Advisory Committees of the Alpha-1 Foundation and the COPD Foundation. BT has nothing to declare. CS has grants with Adverum, the Alpha-1 Foundation, CSL Behring, Grifols, and Baxalta/Shire and has consulted for Grifols, Adverum and CSL Behring in alpha-1 antitrypsin deficiency and has an equity interest in Abeona. Computed tomography (CT) lung density is an accepted biomarker for emphysema in alpha-1 antitrypsin deficiency (AATD), although concerns for radiation exposure limit its longitudinal use. Serum proteins associated with emphysema, particularly in early disease, may provide additional pathogenic insights. We investigated whether distinct proteomic signatures characterize the presence and progression of emphysema in individuals with severe AATD and normal forced expiratory volume in 1 second (FEV1). QUANTitative lung CT UnMasking emphysema progression in AATD (QUANTUM-1) is a multicenter, prospective 3-year study of 49 adults with severe AATD and FEV1 post-bronchodilator values (Post-BD) ≥ 80% predicted. All participants received chest CT, serial spirometry, and contributed to the serum biobank. Volumetric imaging display and analysis (VIDA) software defined the baseline 15th percentile density (PD15) which was indexed to CT-derived total lung capacity (TLC). We measured 317 proteins using a multiplexed immunoassay (Myriad Discovery MAP® panel) in 31 individuals with a complete dataset. We analyzed associations between initial PD15/TLC, PD15/TLC annual decline, body mass index (BMI), and protein levels using Pearson’s product moment correlation. C-reactive protein (CRP), adipocyte fatty acid-binding protein (AFBP), leptin, and tissue plasminogen activator (tPA) were found to be associated with baseline emphysema and all but leptin were associated with emphysema progression after adjustments were made for age and sex. All 4 proteins were associated with BMI after further adjustment for multiple comparisons was made. The relationship between these proteins and BMI, and further validation of these findings in replicative cohorts require additional studies.

Rationale: Alpha-1 antitrypsin deficiency (AATD) is characterized by decreased circulating levels or activity of the serum protein, alpha-1 antitrypsin, which increases risk for chronic lung or liver injury and may lead to diseases such as chronic obstructive pulmonary disease (COPD). Currently there is no cure for AATD, and it is largely controlled through disease management and augmentation therapy. This study was designed to describe characteristics of patients enrolled in a disease management and prevention program. Methods: Data from questionnaires administered by AlphaNet were obtained on 4747 AATD patients and included demographic information, medical history, lifestyle choices, and adherence to the Alpha-1 Disease Management and Prevention Program (ADMAPP). A total of 1221 participants (25.72%) had missing adherence information and were excluded, leaving a final study population of 3526. Questionnaire answer dates ranged from May 29, 2008 to February 14, 2015. Logistic regression was used to adjust for demographic factors and comorbidities, comparing the populations stratified by adherence to ADMAPP. Results: After adjustment for age, sex, race, Charlson Comorbidity Index, and income level, individuals who self-reported any adherence to ADMAPP were more likely to feel informed about their condition (odds ratio[OR] adj 4.95, 95% confidence interval[CI][3.24, 7.57]), and be taking preventive measures, such as smoking cessation (OR adj 0.47, 95% CI [0.31, 0.70]), appropriate immunizations, and self-reported exercise (OR adj 2.07, 95% CI [1.74, 2.47]). Conclusions: This study suggests that ADMAPP may be a useful tool for informing and improving preventive measures taken by individuals with AATD. Future studies are needed to clarify the observed associations and study additional outcomes., Competing Interests: DM has received honoraria/consulting fees and served on speaker bureaus for GlaxoSmithKline PLC, Novartis Pharmaceuticals, Pfizer Inc., Boehringer-Ingelheim, AstraZeneca PLC, Forest Laboratories Inc., Merck, Amgen, and Sunovion. Furthermore, he has received royalties from Up-to-Date, is on the Board of Directors of the COPD Foundation, and has been compensated as a medical expert in legal cases. JTP, RC, and SRB report no conflicts of interest. RAS has received research funding from Grifols, CSL Behring, AstraZeneca, and the National Institutes of Health/National Heart Lung and Blood Institute. He has served as an advisor or consultant for Grifols, CSL Behring, Baxter, AstraZeneca, and Alnylam. He is on the Board of Directors of AlphaNet and a member of the Medical and Scientific Advisory Committee of the COPD Foundation and is the medical director of the Alpha-1 Foundation and AlphaNet.

The RAPID (NCT00261833; N=180) and RAPID Extension (NCT00670007; N=140) trials demonstrated significantly reduced lung density decline in patients with alpha-1 antitrypsin deficiency (AATD) receiving alpha-1 proteinase inhibitor (A1PI) versus placebo. Desmosine and isodesmosine (DES/IDES) are unique crosslinkers of mature elastin fibers and are utilized as measures of elastin degradation. The aim of this post-hoc study was to determine the effect of A1PI therapy on DES/IDES levels in patients from RAPID/RAPID Extension. Plasma levels of DES/IDES were measured using high-performance liquid chromatography and tandem mass spectrometry. Correlation between changes in DES/IDES levels and computed tomography (CT) lung density decline was assessed. Analysis showed that DES/IDES levels were significantly reduced versus baseline in patients receiving A1PI at all time points, from month 3 through month 48. A significant increase from baseline in DES/IDES was observed with placebo at month 24 (n=54; 0.016; p =0.018). DES/IDES change from baseline was significantly different with A1PI versus placebo at months 3 (-0.021; 95% confidence interval [CI] -0.037, 0.004; p =0.026), 12 (-0.040; 95% CI -0.055, 0.025; p <0.001), and 24 (-0.052; 95% CI -0.070, 0.034; p <0.001). Placebo patients started A1PI therapy at month 24 and showed significant reductions in plasma DES/IDES at months 36 ( p <0.001) and 48 ( p <0.001). Reduced elastin degradation was associated with slower lung density decline ( p =0.005), correlating a chemical index of therapy with an anatomical index by CT. In conclusion, A1PI therapy reduced elastin degradation, including pulmonary elastin, in patients with AATD. These data support using DES/IDES levels as biomarkers to monitor emphysema progression and treatment response., Competing Interests: GMT reports grants from CSL Behring during the conduct of the study. JOC has a patent (USPTO 7166437) licensed to MatRx Pharm. KRC reports grants from CSL Behring during the conduct of the study, and grants for other work from AstraZeneca, GlaxoSmithKline, Novartis, Genentech, Grifols, Sanofi, Kamada, Merck, Amgen, Roche and Boehringer Ingelheim. RAS reports grants from CSL Behring during the conduct of the study, and is employed part-time by the Alpha-1 Foundation and AlphaNet, 2 not-for-profit entities that support research and health management in Alpha-1 and that receive part of their funding from pharmaceutical industry sources. NGM reports grants and personal fees from CSL Behring during the conduct of the study. MF is an employee of CSL Behring. JME was employed by CSL Behring at the time of the study. All other authors have nothing to disclose.

Background: The diagnosis and clinical management of adults with alpha-1 antitrypsin deficiency (AATD) have been the subject of ongoing debate, ever since the publication of the first American Thoracic Society guideline statement in 1989. 1 In 2003, the "American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency" made a series of evidence-based recommendations, including a strong recommendation for broad-based diagnostic testing of all symptomatic adults with chronic obstructive pulmonary disease (COPD). 2 Even so, AATD remains widely under-recognized. To update the 2003 systematic review and clinical guidance, the Alpha-1 Foundation sponsored a committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD. Purpose: To provide recommendations for: (1) the performance and interpretation of diagnostic testing for AATD, and (2) the current management of adults with AATD and its associated medical conditions. Methods: A systematic review addressing the most pressing questions asked by clinicians (clinician-centric) was performed to identify citations related to AATD that were published since the 2003 comprehensive review, specifically evaluating publications between January 2002 and December 2014. Important, more recent publications were solicited from the writing committee members as well. The combined comprehensive literature reviews of the 2003 document and this current review comprise the evidence upon which the committee's conclusions and recommendations are based. Results: Recommendations for the diagnosis and management of AATD were formulated by the committee. Conclusions: The major recommendations continue to endorse and reinforce the importance of testing for AATD in all adults with symptomatic fixed airflow obstruction, whether clinically labeled as COPD or asthma. Individuals with unexplained bronchiectasis or liver disease also should be tested. Family testing of first-degree relatives is currently the most efficient detection technique. In general, individuals with AATD and emphysema, bronchiectasis, and/or liver disease should be managed according to usual guidelines for these clinical conditions. In countries where intravenous augmentation therapy with purified pooled human plasma-derived alpha-1 antitrypsin is available, recent evidence now provides strong support for its use in appropriate individuals with lung disease due to AATD., Competing Interests: The work of this writing committee was supported by the Alpha-1 Foundation through payment of travel and meeting expenses and payment of library searching and printing fees. No other assistance was provided. Specifically, there was not honoraria paid and there was not writing assistance of any sort provided. Ms. Knight and Drs. Turino, Brantly, and Goodman have nothing to disclose. Dr. Sandhaus reports grants from CSL Behring. He is employed part-time by the Alpha-1 Foundation and AlphaNet, 2 not-for-profit entities that support research and health management in alpha-1 antitrypsin deficiency and receive part of their funding from pharmaceutical industry sources. Dr. Sandhaus serves on the Medical and Scientific Advisory Committee of the COPD Foundation. Dr. Campos reports grants from Grifols and CSL Behring. Dr. Cross reports personal fees from CSL Behring and Baxter. Dr. Hogarth reports personal fees from Baxter, CSL Behring, and Grifols. Dr. Stocks reports grants to the University of Texas from Kamada, Grifols, and Talecris. Dr. Stoller has served as a scientific consultant to Grifols, CSL Behring, Baxalta, and Kamada regarding alpha-1 antitrypsin deficiency and serves on the Board of Directors of the Alpha-1 Foundation and on the Medical and Scientific Advisory Committees of the Alpha-1 Foundation and the COPD Foundation. Dr. Strange reports personal fees and stock options from Abeona, grants from Baxalta, grants and personal fees from CSL Behring, grants and personal fees from Grifols, and grants from Alpha-1 Foundation. Dr. Teckman reports he is a paid consultant for Isis Pharmaceuticals, Arrowhead Research, Alnylam Inc., Editas Inc., Proteostasis Inc., Genkyotix, Grifols, Intellia, Retrophin, RxCelerate, Velfene, and Vertex. He has received grants from the National Institutes of Health and the Alpha-1 Foundation.

Clinical research in rare diseases, including alpha-1 antitrypsin deficiency (AATD), faces challenges not shared by common disease research. These challenges may include the limited number of patient volunteers available for research, lack of natural history studies on which to base many clinical trial interventions, an urgency for the development of drug therapies given the often poor prognosis of rare diseases and uncertainties about appropriate biomarkers and clinical outcomes critical to clinical trial design. To address these challenges and initiate formal discussions among key stakeholders-patients, researchers, industry, federal regulators-the Alpha-1 Foundation hosted the Clinical Trial Design for Alpha-1 Antitrypsin Deficiency: A Model for Rare Diseases conference February 3-4, 2014 in Bethesda, Maryland. Discussions at the conference led to the conclusions that 1) adaptive designs should be considered for rare disease clinical trials yet more dialogue and study is needed to make these designs feasible for smaller trials and to address current limitations; 2) natural history studies, including the identification of appropriate biomarkers are critically needed and precompetitive collaborations may offer a means of creating these costly studies; and 3) patient registries and databases within the rare disease community need to be more publicly available and integrated, particularly for AATD. This report summarizes the discussions leading to these conclusions., Competing Interests: Dr. Brantley has received research funding from the Alpha-1 Foundatioin, Baxter Biologics, Grifols, Kamada Ltd, AGTC and CSL Behring. Dr. Edelman is an employee of CSL Behring Pharmaceuticals. Dr. McCaleb is an employee of Isis Pharmaceuticals. No other authors had any conflict of interests to declare.

Objectives: This study compared characteristics of chronic obstructive pulmonary disease (COPD) among patients with and without alpha-1 antitrypsin deficiency (A1AD). Methods: Data from WebMD's Lung Disease Health Check was analyzed for participants who self-reported a COPD diagnosis (N=177,865) and whether or not they had an A1AD diagnosis (based on a positive response to the question "Do you have alpha-1 antitrypsin deficiency?"). We used regression modeling to determine the relation between A1AD status and demographic characteristics, symptoms, lung function, quality of life, comorbidities, and smoking habits. Results: Out of 177,865 participants who reported a COPD diagnosis, 1,619 (0.92%) also reported an A1AD diagnosis. When compared to the total COPD population, those with A1AD were less likely to be female (odds ratio [OR]=0.68, 95% confidence interval [CI] 0.61, 0.75) or current smokers (OR 0.72, 95% CI 0.62, 0.83), and more likely to know their lung function value (OR=3.44, 95% CI 3.07, 3.87). With regard to symptoms, those with A1AD were less likely to report wheezing (OR=0.82, 95% CI 0.75, 0.91) and chronic cough (OR=0.81, 95% CI 0.73, 0.89) and more likely to report tightness in the chest (OR= 1.19, 95% CI 1.08, 1.32). Overall, A1AD participants had a lower quality of life with a higher proportion reporting severe impairment in work life (OR=1.55, 95% CI 1.39, 1.7), home life (OR=1.40, 95% CI 1.26, 1.56), and personal relationships (OR=1.48, 95% CI 1.32, 1.65). Conclusions: COPD patients with A1AD report significantly worse quality of life relative to the non-A1AD COPD population., Competing Interests: TM has no conflicts of interest. DMM has received research funding from GlaxoSmithKline, Novartis, Boehringer-Ingelheim, and Pfizer and has worked as a consultant or advisor for GlaxoSmithKline, Novartis, Boehringer-Ingelheim, Astra-Zeneca and Pfizer and is on the Board of Directors of the COPD Foundation and the Chair of the Medical and Scientific Advisory Committee for the Alpha-1 Foundation. EM is employed by the COPD Foundation. BMT has worked as an advisor or consultant for GlaxoSmithKline, Novartis, Boehringer-Ingelheim, Astra-Zeneca, Forest, and Intermune and is the Chairman of the Board of the COPD Foundation. JW is CEO of the COPD Foundation and the Alpha-1 Foundation. RAS has received research funding from Grifols, CSL Behring, AstraZeneca, and the NIH/NHLBI. He has served as an advisor or consultant for Grifols, CSL Behring, Baxter, AstraZeneca, and Alnylam. He is on the Board of Directors of AlphaNet and a member of the Medical and Scientific Advisory Committee of the COPD Foundation and is the medical director of the Alpha-1 Foundation and AlphaNet. JKS has served as a consultant or advisor for Boehringer-Ingelheim, Theravance, Grifols, CSL Behring, Pfizer, and Baxter, has received research funding from Astra Zeneca, and has served on the Board of Directors for the COPD Foundation, currently serves on the Board of Directors of the Alpha-1 Foundation, and is a member of the Medical and Scientific Advisory Committee of both organizations.