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Background: The Short Form 36-Item Health Survey (SF-36) is a health-related quality of life (HRQoL) measure validated in people with chronic obstructive pulmonary disease (COPD). While physical health is often more impaired than mental health in people with COPD, research on alpha-1 antitrypsin deficiency (AATD)-associated COPD is limited. This longitudinal study examines changes in physical and mental health in individuals with AATD and associated factors., Methods: Analyses included participants of AlphaNet, a disease management program for individuals with AATD-associated lung disease who are prescribed augmentation therapy. Norm-based SF-36 scores for mental and physical component summaries (MCS and PCS) and 8 scales were analyzed. Linear mixed models evaluated mean changes in SF-36 scores over time., Results: The study included 2165 participants (mean age 56.9 ± 10.0 years, 47.0 % female). At enrollment, mean PCS score was 37.5 ± 9.6, and mean MCS score was 51.9 ± 10.5. Mean mMRC dyspnea score was 2.3 ± 1.3; 54.6 % had ≥2 exacerbations annually, and 46.5 % used oxygen regularly. Average follow-up was 6.6 ± 3.2 years. The HRQoL remained stable; MCS improved by 0.16 points/year (p < 0.0001), while the PCS score declined by 0.49 points/year (p < 0.0001). Subscales followed similar trends., Conclusions: At baseline, mental HRQoL scores were higher than physical HRQoL scores, indicating better mental health than physical health in this cohort with AATD-associated lung disease. Stable HRQoL with a slight improvement in mental scores over time and a small decrease in physical scores may be a unique feature of this cohort. Further studies are needed to correlate these findings with disease-specific instruments and patient physiology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RC has received research support from AlphaNet. KEH has received consulting income from AlphaNet. RAS is an employee of AlphaNet. DMM is a consultant to GlaxoSmithKline, AstraZeneca, Regeneron, Genentech, Up to Date, and the COPD Foundation. CS has grants in alpha-1 antitrypsin deficiency paid to the Medical University of South Carolina from Adverum, Arrowhead, Grifols, Krystal, Mereo, NIH, Takeda, and Vertex within the past 3 years. He is a salaried medical director at AlphaNet. He has consulted for CSL Behring, Dicerna, Grifols, Roche, and Vertex for Alpha-1. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alpha-1-antitrypsin (AAT) plays a homeostatic role in attenuating excessive inflammation and augmenting host defense against microbes. We demonstrated previously that AAT binds to the glucocorticoid receptor (GR) resulting in significant anti-inflammatory and antimycobacterial consequences in macrophages. Our current investigation aims to uncover AAT-regulated genes that rely on GR in macrophages. We incubated control THP-1 cells (THP-1 control ) and THP-1 cells knocked down for GR (THP-1 GR-KD ) with AAT, performed bulk RNA sequencing, and analyzed the findings. In THP-1 control cells, AAT significantly upregulated 408 genes and downregulated 376 genes. Comparing THP-1 control and THP-1 GR-KD cells, 125 (30.6%) of the AAT-upregulated genes and 154 (41.0%) of the AAT-downregulated genes were significantly dependent on GR. Among the AAT-upregulated, GR-dependent genes, CSF-2 that encodes for granulocyte-monocyte colony-stimulating factor (GM-CSF), known to be host-protective against nontuberculous mycobacteria, was strongly upregulated by AAT and dependent on GR. We further quantified the mRNA and protein of several AAT-upregulated, GR-dependent genes in macrophages and the mRNA of several AAT-downregulated, GR-dependent genes. We also discussed the function(s) of selected AAT-regulated, GR-dependent gene products largely in the context of mycobacterial infections. In conclusion, AAT regulated several genes that are dependent on GR and play roles in host immunity against mycobacteria., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Purpose: This study examined characteristics of clinical trials that influence interest in participation among individuals with alpha-1 antitrypsin deficiency (AATD)., Procedures: A cross-sectional survey was completed by individuals with AATD. Thirty-four items described characteristics of clinical trials, which were rated from 1 (would not participate) to 5 (highly interested in participating). Logistic regression was used to compare participants with high interest in trials (defined as scores of 4 or 5 on ≥50 % of responses) to all remaining participants., Results: Data were provided by 1664 participants (91.6 % with lung disease, 16.3 % with liver disease, 14.9 % with lung and liver disease). Nearly one-third (31.8 %) indicated that they would not participate in a trial if there was a chance of getting a placebo. If the trial included three liver biopsies, 53.3 % would not participate. More than two-thirds (69.8 %) of participants who were using augmentation therapy would not participate in a trial that required twelve months off therapy. Individuals with two or more exacerbations in the prior year were more likely to have high interest in trials (OR = 1.4, 95 % CI = 1.1-1.7, p = 0.009). In addition, individuals with a score of 10 or higher on the COPD Assessment Test were more likely to have high interest (OR = 1.4, 95 % CI = 1.1-1.8, p = 0.010)., Conclusions: A sizeable percentage of participants indicated that they would not participate in clinical trials that include a placebo, involve multiple liver biopsies, or involve discontinuing augmentation therapy. Individuals who are more affected by AATD have more interest in trial participation than individuals who are less affected., Competing Interests: Declaration of competing interest KEH receives consulting income from AlphaNet. RAS is a paid medical director for AlphaNet. He has grants in alpha-1 antitrypsin deficiency paid to National Jewish Health from Inhibrx, the Alpha-1 Foundation, and Mereo. He has consulted for Astra Zeneca, CSL Berhing, Vertex, Grifols, Takeda, Dicerna, Inhibrx, Peak Bio, and Beam Therapeutics. SA has no competing interests to declare. CS is a paid medical director for AlphaNet. He has grants in alpha-1 antitrypsin deficiency or COPD paid to the Medical University of South Carolina from Arrowhead, AstraZeneca, CSA Medical, Dicerna, Grifols, Krystal, Nuvaira,OCI, Pandorum, Renovion, Takeda and Vertex. CS has consulted for Astra Zeneca, CSL Behring, Morair, Pulmanage, UpToDate, and Vertex for Alpha-1 and/or COPD., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Background: Generic measures of health-related quality of life (HRQoL), such as the 36-Item Short Form Survey (SF-36), are widely used in assessing chronic conditions. These tools have an advantage over disease-specific instruments, as they allow comparisons across different health conditions and with the general population. In alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD), HRQoL research remains scarce. This cross-sectional study evaluates the factors associated with HRQoL in a cohort of patients with AATD-associated COPD., Methods: Our study included participants of AlphaNet (2008-2019), a health management organization for people with AATD in the US who are prescribed augmentation therapy. Norm-based SF-36 scores for the mental and physical component summary scores (MCS and PCS, mean of 50 ± 10 in the general US population) and 8 individual scales were evaluated. Individuals with lung disease and data available on ≥1 measurement on any SF-36 scale and clinically relevant characteristics such as modified Medical Research Council (mMRC) scale, exacerbation frequency, productive cough, and use of oxygen were included in these analyses. Generalized linear regression models were fit to examine the association of baseline characteristics with MCS and PCS scores. Age, sex, regular use of oxygen, exacerbation frequency, mMRC, and productive cough were included in these models., Results: Participants (n=4398, mean age 57.6 [SD=10.6] years, 45.4% female) had a mean MCS score of 51.2 ± 10.8 and PCS of 36.3 ± 9.8. The average mMRC score was 2.4 ± 1.3, and 56.4% had 2 or more exacerbations per year. Overall, the physical component of SF-36 was more severely impacted compared to the mental component. In multivariable regression analyses, PCS scores were significantly associated with exacerbation frequency, mMRC, regular use of oxygen, and productive cough; MCS was associated with age, sex, exacerbation frequency, mMRC, and productive cough., Conclusions: These findings demonstrate that patient-perceived physical health is significantly impaired in this cohort of people with AATD-associated COPD compared to mental health. Longitudinal studies are needed to evaluate the change in physical and mental health status over time in this population., (© 2024. The Author(s).)

Serine proteases are members of a large family of hydrolytic enzymes in which a particular serine residue in the active site performs an essential role as a nucleophile, which is required for their proteolytic cleavage function. The array of functions performed by serine proteases is vast and includes, among others, the following: (i) the ability to fight infections; (ii) the activation of blood coagulation or blood clot lysis systems; (iii) the activation of digestive enzymes; and (iv) reproduction. Serine protease activity is highly regulated by multiple families of protease inhibitors, known collectively as the SERine Protease INhibitor (SERPIN). The serpins use a conformational change mechanism to inhibit proteases in an irreversible way. The unusual conformational change required for serpin function provides an elegant opportunity for allosteric regulation by the binding of cofactors, of which the most well-studied is heparin. The goal of this review is to discuss some of the clinically relevant serine protease-serpin interactions that may be enhanced by heparin or other negatively charged polysaccharides. The paired serine protease-serpin in the framework of heparin that we review includes the following: thrombin-antithrombin III, plasmin-anti-plasmin, C1 esterase/kallikrein-C1 esterase inhibitor, and furin/TMPRSS2 (serine protease Transmembrane Protease 2)-alpha-1-antitrypsin, with the latter in the context of COVID-19 and prostate cancer.

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.)

Chronic obstructive pulmonary disease (COPD) is characterized by nonresolving inflammation fueled by breach in the endothelial barrier and leukocyte recruitment into the airspaces. Among the ligand-receptor axes that control leukocyte recruitment, the full-length fractalkine ligand (CX3CL1)-receptor (CX3CR1) ensures homeostatic endothelial-leukocyte interactions. Cigarette smoke (CS) exposure and respiratory pathogens increase expression of endothelial sheddases, such as a-disintegrin-and-metalloproteinase-domain 17 (ADAM17, TACE), inhibited by the anti-protease α-1 antitrypsin (AAT). In the systemic endothelium, TACE cleaves CX3CL1 to release soluble CX3CL1 (sCX3CL1). During CS exposure, it is not known whether AAT inhibits sCX3CL1 shedding and CX3CR1 + leukocyte transendothelial migration across lung microvasculature. We investigated the mechanism of sCX3CL1 shedding, its role in endothelial-monocyte interactions, and AAT effect on these interactions during acute inflammation. We used two, CS and lipopolysaccharide (LPS) models of acute inflammation in transgenic Cx3cr1 gfp/gfp mice and primary human endothelial cells and monocytes to study sCX3CL1-mediated CX3CR1 + monocyte adhesion and migration. We measured sCX3CL1 levels in plasma and bronchoalveolar lavage (BALF) of individuals with COPD. Both sCX3CL1 shedding and CX3CR1 + monocytes transendothelial migration were triggered by LPS and CS exposure in mice, and were significantly attenuated by AAT. The inhibition of monocyte-endothelial adhesion and migration by AAT was TACE-dependent. Compared with healthy controls, sCX3CL1 levels were increased in plasma and BALF of individuals with COPD, and were associated with clinical parameters of emphysema. Our results indicate that inhibition of sCX3CL1 as well as AAT augmentation may be effective approaches to decrease excessive monocyte lung recruitment during acute and chronic inflammatory states. NEW & NOTEWORTHY Our novel findings that AAT and other inhibitors of TACE, the sheddase that controls full-length fractalkine (CX3CL1) endothelial expression, may provide fine-tuning of the CX3CL1-CX3CR1 axis specifically involved in endothelial-monocyte cross talk and leukocyte recruitment to the alveolar space, suggests that AAT and inhibitors of sCX3CL1 signaling may be harnessed to reduce lung inflammation.

Rationale: Interventions to promote adherence to long-term oxygen therapy (LTOT) in chronic obstructive pulmonary disease (COPD) are needed. Objectives: To examine the real-world effectiveness of phone-based peer coaching on LTOT adherence and other outcomes in a pragmatic trial of patients with COPD. Methods: In a hybrid effectiveness/implementation pragmatic trial, patients were randomized to receive phone-based proactive coaching (educational materials, five phone-based peer coaching sessions over 60 d), reactive coaching (educational materials, peer coaching when requested), or usual care. Study staff members collected baseline and outcome data via phone at 30, 60, and 90 days after randomization. Adherence to LTOT over 60 days, the primary effectiveness outcome, was defined as mean LTOT use ⩾17.7 h/d. LTOT use was calculated using information about home oxygen equipment use in worksheets completed by study participants. Comparisons of adherence to LTOT between each coaching group and the usual care group using multivariable logistic regression models were prespecified as the primary analyses. Secondary effectiveness outcomes included Patient Reported Outcome Management Information System measures for physical, emotional, and social health. We assessed early implementation domains in the reach, adoption, and implementation framework. Results: In 444 participants, the proportions who were adherent to LTOT at 60 days were 74% in usual care, 84% in reactive coaching, and 70% in proactive coaching groups. Although reach, adoption by stakeholder partners, and intervention fidelity were acceptable, complete LTOT adherence data were available in only 73% of participants. Reactive coaching (adjusted odds ratio, 1.77; 97.5% confidence interval, 0.80-3.90) and proactive coaching (adjusted odds ratio, 0.70; 97.5% confidence interval, 0.34-1.46) did not improve adherence to LTOT compared with usual care. However, proactive coaching significantly reduced depressive symptoms and sleep disturbance compared with usual care and reduced depressive symptoms compared with reactive coaching. Unexpectedly, LTOT adherence was significantly lower in the proactive compared with the reactive coaching group. Conclusions: The results were inconclusive about whether a phone-based peer coaching strategy changed LTOT adherence compared with usual care. Further studies are needed to confirm the potential benefits of proactive peer coaching on secondary effectiveness outcomes and differences in LTOT adherence between proactive and reactive peer coaching. Clinical trial registered with ClinicalTrials.gov (NCT02098369).

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.)

Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution. We next underscored that measures to prevent severe COVID-19 currently exists but teeters on a balance and that current treatment for severe COVID-19 remains grossly suboptimal. We then reviewed the epidemiologic and clinical evidence that AAT deficiency increases risk of COVID-19 infection and of more severe disease, and the experimental evidence that AAT inhibits cell surface transmembrane protease 2 (TMPRSS2) - a host serine protease required for SARS-CoV-2 entry into cells - and that this inhibition may be augmented by heparin. We also elaborated on the panoply of other activities of AAT (and heparin) that could mitigate severity of COVID-19. Finally, we evaluated the available clinical evidence for AAT treatment of COVID-19., (© 2023 The Author(s).)

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.)

α1-Antitrypsin (AAT), a serine protease inhibitor, is the third most abundant protein in plasma. Although the best-known function of AAT is irreversible inhibition of elastase, AAT is an acute-phase reactant and is increasingly recognized to have a panoply of other functions, including as an anti-inflammatory mediator and a host-protective molecule against various pathogens. Although a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Because AAT has anti-inflammatory properties, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in human macrophages. We report the finding that AAT binds to GR using several approaches, including coimmunoprecipitation, mass spectrometry, and microscale thermophoresis. We also performed in silico molecular modeling and found that binding between AAT and GR has a plausible stereochemical basis. The significance of this interaction in macrophages is evinced by AAT inhibition of LPS-induced NF-κB activation and IL-8 production as well as AAT induction of angiopoietin-like 4 protein, which are, in part, dependent on GR. Furthermore, this AAT-GR interaction contributes to a host-protective role against mycobacteria in macrophages. In summary, this study identifies a new mechanism for the gene regulation, anti-inflammatory, and host-defense properties of AAT., (Copyright © 2022 by The American Association of Immunologists, Inc.)

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: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity., Methods: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis., Findings: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes., Interpretation: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD., Funding: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion., Competing Interests: Declaration of interests KAS serves on Alpha-1 Foundation Grant Advisory Committee, Alpha-1 Foundation Medical Advisory and Scientific Committee, ATS - RCMB Website Committee, National Jewish Health IBC committee (all unpaid); KAP does not report any potential conflict of interest; CS reports grants or contracts from Adverum, Arrowhead, AstraZeneca, CSA Medical, Grifols, Nuvaira, Takeda, Vertex; consulting fees from AstraZenca, Dicerna, Glaxo Smith Kline, Inhibrx, Morair, UpToDate, Vertex; has received honoraria for presentations from the American Thoracic Society; has received support for travel from CSL Behring; serves as the Medical Director for AlphaNet; RAS reports grants or contracts from Vertex, NIH/NCATS, Alpha-1 Foundation, consulting fees from Grifols, CSL Behring, Vertex, Intellia, Inhibrx, Takeda, Evolve Biologics, has received travel support from CSL Behring; has served on the Advisory Board of Arrowhead Pharmaceuticals, and serves as the Medical Director for AlphaNet and on the board of directors for Global Implementation Solutions, Osteogenesis Imperfecta Foundation, Alpha-1 Foundation, and AlphaNet; AMT reports grants or contracts from Vertex, Grifols, and CSl Behring; has received consulting fees from CSL Behring, Inhibrix, Z-factor, and Takeda, has received honoraria for lectures from Glaxo Smith Kline and AstraZeneca; TB does not report any potential conflict of interest; DAS does not report any potential conflict of interest; LM does not report any potential conflict of interest; NH does not report any potential conflict of interest; EKS reports grants or contracts from Glaxo Smith Kline, Bayer; BDH does not report any potential conflict of interest; CPH reports grants or contracts from Alpha-1 Foundation, Bayer, Boehringer-Ingelheim, and Vertex, consulting fees from AstraZeneca and Takeda; DLD has received honoraria for lectures from Novartis and financial support from Bayer towards the institution; MHC reports grants or contracts from Glaxo Smith Kline, Bayer, consulting fees from AstraZeneca and Genentech, honoraria for presentations from Illumina, RPB does not report any potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The cell surface serine protease Transmembrane Protease 2 (TMPRSS2) is required to cleave the spike protein of SARS-CoV-2 for viral entry into cells. We determined whether negatively-charged heparin enhanced TMPRSS2 inhibition by alpha-1-antitrypsin (AAT). TMPRSS2 activity was determined in HEK293T cells overexpressing TMPRSS2. We quantified infection of primary human airway epithelial cells (hAEc) with human coronavirus 229E (HCoV-229E) by immunostaining for the nucleocapsid protein and by the plaque assay. Detailed molecular modeling was undertaken with the heparin-TMPRSS2-AAT ternary complex. Enoxaparin enhanced AAT inhibition of both TMPRSS2 activity and infection of hAEc with HCoV-229E. Underlying these findings, detailed molecular modeling revealed that: (i) the reactive center loop of AAT adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to an exogenous (nafamostat) or endogenous (HAI-2) TMPRSS2 inhibitor and (ii) negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2-AAT interface, neutralizing otherwise repulsive forces. In conclusion, enoxaparin enhances AAT inhibition of both TMPRSS2 and coronavirus infection. Such host-directed therapy is less likely to be affected by SARS-CoV-2 mutations. Furthermore, given the known anti-inflammatory activities of both AAT and heparin, this form of treatment may target both the virus and the excessive inflammatory consequences of severe COVID-19., (© 2022. The Author(s).)

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.)

Introduction: A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD., Methods: The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry., Results: Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group., Conclusions: The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.)

No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.)

Background: Osteogenesis imperfecta (OI) is a heterogeneous group of collagen-related disorders characterized by osteopenia, bone fractures, spine deformities, and nonskeletal complications. Cardiopulmonary complications are the major cause of morbidity and mortality in adults with OI. The cause of such problems was often attributed solely to the presence of large scoliosis curves affecting pulmonary function and, indirectly, cardiovascular health. However, recent studies suggest this may not be the case. Therefore, determining the relationships and causative agents of cardiopulmonary problems in patients with OI, specifically pulmonary impairment, is important to improving the overall wellbeing, quality of life, and survival of these patients., Questions/purposes: (1) Is cardiopulmonary fitness in OI solely related to the presence of scoliosis? (2) What is the prevalence of heart and lung complications in this adult population? (3) Does the presence of pulmonary impairment impact quality of life in adults with OI?, Methods: This is a prospective observational cross-sectional study. Within 1 year, each participant (n = 30) completed pulmonary function testing, echocardiogram, ECG, chest CT, AP spine radiography, and quality-of-life assessments (SF-36, St. George's Respiratory Questionnaire, Functional Outcomes of Sleep Questionnaire, and Pittsburgh Sleep Quality Index). In terms of pulmonary function, we differentiated restrictive and obstructive physiology using the ratio of forced expiratory volume over one second to forced vital capacity (FEV1/FVC), with restrictive lung physiology defined as FEV1/FVC > 0.8 and obstructive lung physiology as FEV1/FVC < 0.7. Spine radiographs were evaluated for scoliosis. Chest CT images were reviewed to qualitatively assess the lungs. The statistical analysis involved a Kruskall-Wallis test with Bonferroni's correction and a bivariate correlation analysis using Spearman's rho correlation coefficient (p < 0.05)., Results: Sixteen of 23 participants with restrictive lung physiology had scoliosis; their ages ranged from 19 years to 67 years. There was no correlation between the magnitude of the scoliosis curve and deficient pulmonary function (R = 0.08; p = 0.68). Seven participants had normal pulmonary function. The average scoliosis curve was 44 ± 29°. Thirteen participants had abnormal ECG findings while 10 had abnormal echocardiogram results. All but two individuals with abnormal chest CT results were found to have bronchial wall thickening. There were no differences in pulmonary or cardiac findings between OI types, except for FVC and total lung capacity, which were lower in individuals with Type III OI than in those with other types of OI. FEV1/FVC correlated with St. George's Respiratory Questionnaire (R = 0.429; p = 0.02) but not with Functional Outcomes of Sleep Questionnaire (R = -0.26; p = 0.19) or SF-36 scores (physical component summary: R = -0.037, p = 0.85; mental component summary: R = -0.204, p = 0.29)., Conclusions: The lack of a relationship between decreased pulmonary function and the severity of scoliosis suggests that restrictive lung physiology in this population is likely because of factors intrinsic to OI and not entirely because of thoracic cage deformities. The fact that pulmonary impairment influences self-perceived quality of life exemplifies how detrimental such complications may be to everyday functioning. This also reinforces the importance of determining the underlying cause of cardiopulmonary impairment in this population to set clear clinical guidelines of care., Level of Evidence: Level II, prognostic study.

Objectives: There are challenges in conducting a budget impact analysis (BIA) for rare disorders. Through this case study, we present some challenges and limitations of a BIA of managing patients affected with alpha-1 antitrypsin deficiency (AATD). We explored a conceptual basis and barriers for health services researchers interested in quantifying budget impacts of rare disease management program (DMP)., Methods: We developed a static budget impact cost calculator model in Microsoft Excel, obtaining the clinical impact of a DMP from the literature and translating it into costs using OLDW. Cost inputs and resource use was obtained from 2010 to 2015 claims data using the OLDW. Insurers' payments were calculated and categorized into the following cost buckets: physician visits, emergency room visits, inpatients stays, augmentation therapy, other prescription drugs costs, and other costs., Results: Data were based on 6832 patients with alpha-1 antitrypsin deficiency identified among over 21 million OLDW enrollees observed between January 1, 2010, and December 31, 2015. The introduction of a DMP was estimated to decrease costs of the management of patients with alpha-1 antitrypsin deficiency by $13.5 million over 5 years. The savings attributed to the program over the 5-year time horizon are due to 2555 exacerbations, 5180 emergency room visits, 9342 specialist visits, and 105 358 general practitioner visits avoided., Conclusions: A comprehensive DMP for a rare condition might provide cost savings to a health plan. BIAs for rare disease may be more informative if they focus on DMPs rather than on individual drugs., (Copyright © 2020 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Respiratory insufficiency is the leading cause death in people with osteogenesis imperfecta (OI). Adults with OI reported that respiratory symptoms negatively impacted psychosocial wellbeing and limited daily physical activities, irrespective of OI type, age, stature, or scoliosis. The impact of respiratory status on quality of life in this population warrants further investigation., Purpose: Respiratory insufficiency is the leading cause of mortality in osteogenesis imperfecta (OI), a heterogeneous group of heritable connective tissue disorders characterized by fractures, bone fragility, and scoliosis. There is little research on how respiratory health influences daily life in this population. This study explores the relationship between respiratory function and quality of life in adults with OI., Methods: One hundred fifty-seven adults with OI completed the St. George's Respiratory Questionnaire (SGRQ) and provided demographic and health information through REDCap. SGRQ scores were compared to reference scores for the general population, and comparisons were made between OI type, presence of scoliosis, stature, and other factors such as age or comorbidities., Results: Average age was 45.87 years (range 19-81). Respondents scored worse on average (32 ± 23) than the normative data (6 ± 1). Those with type I OI scored better than those with type IV (p = 0.002) or type III (p = 0.024). Total scores correlated with age, activity level, assistive device use, and presence of pulmonary or cardiac comorbidities but did not correlate with stature or degree of scoliosis., Conclusion: Respiratory symptoms negatively impact both psychosocial wellbeing in the OI population and limit daily physical activity. These limitations occur irrespective of their OI type, age, stature, or scoliosis and reflect the dramatic impact of respiratory status on quality of life for people with OI. Future studies should examine the etiology of respiratory insufficiency in this population so guidelines for management can be established.

α 1 -Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α 1 -antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals., Competing Interests: Conflict of interest: G.N. McElvaney reports personal fees for advisory board work from CSL Behring and Vertex, grants and personal fees for advisory board work from Grifols, outside the submitted work. Conflict of interest: R.A. Sandhaus reports personal fees for advisory board work and reimbursement for travel from CSL Behring, during the conduct of the study; personal fees for advisory work from AstraZeneca, and is an unpaid advisory for Grifols, outside the submitted work. Conflict of interest: M. Miravitlles reports personal fees for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Zambon, CSL Behring, Grifols and Novartis, personal fees for consultancy from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis and Grifols, grants from GlaxoSmithKline and Grifols, outside the submitted work. Conflict of interest: G.M. Turino has nothing to disclose. Conflict of interest: N. Seersholm has nothing to disclose. Conflict of interest: M. Wencker reports personal fees for consultancy from CSL Behring, during the conduct of the study. Conflict of interest: R.A. Stockley reports personal fees for advisory board work and lectures from AstraZeneca, personal fees for lectures from Nycomed, personal fees for advisory board work, lectures and meeting attendance from Boehringer Ingelheim and CSL Behring, personal fees for advisory board work from Shire, Chiesi, Polyphor, GlaxoSmithKline, Mereo BioPharma, Vertex Pharmaceuticals Inc. and Akari Therapeutics plc, outside the submitted work., (Copyright ©ERS 2020.)

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.)

Alpha-1 Antitrypsin Deficiency (AATD) is a progressive pulmonary disease under-recognized or misdiagnosed by clinicians. Patients with AATD can develop a variety of organ-specific complications and as a result, often require hospitalization and treatment within critical care and ICU settings. Due to the complexity of AATD there are minimal guidelines in place to address the specific and highly variable needs of these patients in the critical care setting. This review presents clinical considerations with respect to the management of patients with AATD and provides treatment recommendations for these patients in the critical care setting. In addition, we have outlined certain aspects of the care of this patient population that may be of interest to critical care practitioners. With greater disease awareness and earlier diagnosis the onset of symptoms can be delayed, which will ultimately reduce the frequency of deleterious health consequences., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Study Design: Retrospective clinical study of individuals with osteogenesis imperfecta (OI)., Objective: To assess the relationship between severity of scoliosis and pulmonary function, and to assess the relationship between restrictive lung disease and self-reported quality of life in individuals with OI., Summary of Background Data: OI is a heritable connective tissue disorder characterized by osteopenia and a predisposition to fracture. Respiratory insufficiency is a leading cause of mortality. Literature on pulmonary function in this population has shown a negative correlation between percent-predicted vital capacity and severity of scoliosis. However, it has been suggested that decreased pulmonary function in OI may be due to intrinsic pulmonary disease, in addition to the impact of vertebral compression fractures and scoliosis., Methods: Anterior-posterior spine radiographs and pulmonary function tests from 30 individuals with OI were reviewed. Radiographs were evaluated for scoliosis, defined as a curve ≥ 10°. If more than one curve was present, the largest curve was used. Pulmonary function was defined as the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio. Restrictive pulmonary disease was defined as FEV1/FVC > 80%, while obstructive disease was defined as FEV1/FVC < 70%. Bivariate correlation analysis was performed, using Spearman rho correlation coefficient (P < 0.05). Quality of life was assessed by SF-36., Results: The mean age was 27.6 years (range: 12-42 yrs). 57.6% were female. OI type IV was the most common (46.7%), followed by OI type III (33.3%), OI type I (10%), OI type IX (6.67% each), and OI type VIII (3.33%). Pulmonary comorbidity was present in 40% of individuals, while 6.67% had a cardiac comorbidity. The correlation between scoliosis and pulmonary function was weak and not significant (R = -0.059, P = 0.747)., Conclusion: Pulmonary function is not significantly correlated with scoliosis, supporting the hypothesis that decreased pulmonary function is intrinsic to OI and/or chest wall deformities, rather than secondary to scoliosis., Level of Evidence: 4.

Rationale: The association between non-tuberculous mycobacterial lung disease and alpha-1-antitrypsin (AAT) deficiency is likely due, in part, to underlying emphysema or bronchiectasis. But there is increasing evidence that AAT itself enhances host immunity against microbial pathogens and thus deficiency could compromise host protection. Objectives: The goal of this project is to determine if AAT could augment macrophage activity against non-tuberculous mycobacteria. Methods: We compared the ability of monocyte-derived macrophages cultured in autologous plasma that were obtained immediately before and soon after AAT infusion-given to individuals with AAT deficiency-to control an ex vivo Mycobacterium intracellulare infection. Measurements and Main Results: We found that compared to pre-AAT infused monocyte-derived macrophages plus plasma, macrophages, and contemporaneous plasma obtained after a session of AAT infusion were significantly better able to control M. intracellulare infection; the reduced bacterial burden was linked with greater phagosome-lysosome fusion and increased autophagosome formation/maturation, the latter due to AAT inhibition of both M. intracellulare -induced nuclear factor-kappa B activation and A20 expression. While there was a modest increase in apoptosis in the M. intracellulare -infected post-AAT infused macrophages and plasma, inhibiting caspase-3 in THP-1 cells, monocyte-derived macrophages, and alveolar macrophages unexpectedly reduced the M. intracellulare burden, indicating that apoptosis impairs macrophage control of M. intracellulare and that the host protective effects of AAT occurred despite inducing apoptosis. Conclusion: AAT augments macrophage control of M. intracellulare infection through enhancing phagosome-lysosome fusion and autophagy.

Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV 1 ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV 1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV 1 using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV 1 and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

Objective: To examine the association of genotype with smoking and other key health behaviors among individuals with alpha-1 antitrypsin deficiency (AATD) associated lung disease., Methods: Self-reported data were analyzed from 3506 individuals with AATD-associated lung disease. All data were collected upon enrollment in a disease management program designed for individuals who have been prescribed augmentation therapy. Multivariate logistic regression was utilized to examine the extent to which genotype was associated with smoking and other key health behaviors (i.e., getting a pneumonia vaccine, getting a flu vaccine, exercising, and maintaining a healthy weight). We hypothesized that MZs and SZs are more likely than ZZs to be current smokers, and that genotype is associated with additional health behaviors., Results: MZs and SZs had higher odds of being a current smoker than ZZs (MZ versus ZZ OR = 2.73, p < .001; SZ versus ZZ OR = 4.34, p < .001). For every additional health behavior examined, MZs had higher odds of unhealthy behavior than ZZs (ORs ranged from 1.35 to 1.98, p < .05). SZs had higher odds of unhealthy behavior than ZZs with regard to lack of exercise (OR = 1.52, p = .003) and failure to maintain a healthy weight (underweight OR = 1.93, p = .028; overweight OR = 1.43, p = .015)., Conclusions: Among individuals who have been prescribed augmentation therapy for lung disease due to AATD, genotype is associated with smoking and additional health behaviors that are central to managing lung disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha 1 -proteinase inhibitor, Liquid Alpha 1 -PI, compared with the Lyophilized Alpha 1 -PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha 1 -antitrypsin deficiency (AATD). In this double-blind, randomized, 20-week crossover study, 32 subjects with AATD were randomized to receive 8 weekly infusions of 60 mg/kg of Liquid Alpha 1 -PI or Lyophilized Alpha 1 -PI. Serial blood samples were drawn for 7 days after the last dose followed by 8 weeks of the alternative treatment. The primary endpoint was bioequivalence at steady state, as measured by area under the concentration versus time curve from 0 to 7 days (AUC 0-7 days ) postdose using an antigenic content assay. Bioequivalence was defined as 90% confidence interval (CI) for the ratio of the geometric least squares (LS) mean of AUC 0-7 days for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha 1 -PI concentration versus time curves for both formulations were superimposable. Mean AUC 0-7 days was 20 320 versus 19 838 mg × h/dl for Liquid Alpha 1 -PI and Lyophilized Alpha 1 -PI, respectively. The LS mean ratio of AUC 0-7 days (90% CI) for Liquid Alpha 1 -PI versus Lyophilized Alpha 1 -PI was 1.05 (1.03-1.08), indicating bioequivalence. Liquid Alpha 1 -PI was well tolerated and adverse events were consistent with Lyophilized Alpha 1 -PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha 1 -PI is bioequivalent to Lyophilized Alpha 1 -PI, with a similar safety profile. The liquid formulation would eliminate the need for reconstitution and shorten preparation time for patients receiving augmentation therapy for AATD.

Aims: Early-onset emphysema attributed to α-1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID-RCT/RAPID-OLE, the largest clinical trials of purified human α-1 proteinase inhibitor (A 1 -PI; 60 mg kg -1  week -1 ) therapy completed to date, demonstrated for the first time that A 1 -PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response., Methods: A disease progression model was constructed, utilizing observed A 1 -PI exposure and lung density decline rates (measured by computed tomography) from RAPID-RCT/RAPID-OLE, to predict effects of population variability and higher doses on A 1 -PI exposure and clinical response. Dose-exposure and exposure-response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose-exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A 1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A 1 -PI exposure to lung density decline rate at varying exposure levels., Results: A dose of 60 mg kg -1  week -1 achieved trough serum levels >11 μmol l -1 (putative 'protective threshold') in ≥98% patients. Dose-exposure-response simulations revealed increasing separation between A 1 -PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l -1  year -1 occurred more often in patients receiving A 1 -PI: 63 vs. 12%., Conclusion: Weight-based A 1 -PI dosing reliably raises serum levels above the 11 μmol l -1 threshold. However, our exposure-response simulations question whether this is the maximal, clinically effective threshold for A 1 -PI therapy in AATD. The model suggested higher doses of A 1 -PI would yield greater clinical effects., (© 2017 CSL Behring. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Rationale: Alpha-1 antitrypsin deficiency, caused primarily by homozygosity for the Z allele of the SERPINA1 gene, is a well-established genetic cause of chronic obstructive pulmonary disease (COPD). Whether the heterozygous PiMZ genotype for alpha-1 antitrypsin confers increased risk for COPD has been debated., Objectives: We analyzed 8,271 subjects in the Genetic Epidemiology of COPD (COPDGene) Study, hypothesizing that PiMZ would independently associate with COPD and COPD-related phenotypes., Methods: The COPDGene Study comprises a multiethnic, cross-sectional, observational cohort of non-Hispanic white and African American current and former smokers with at least 10 pack-years of smoking who were enrolled for detailed clinical and genetic studies of COPD and COPD-related traits. We performed multivariate logistic regression analysis for moderate to severe COPD and assessed Pi genotype with other relevant covariates in models stratified by race. We analyzed quantitative characteristics on the basis of volumetric computed tomography with generalized linear models controlling for genotype, scanner type, and similar covariates., Results: White PiMZ COPDGene subjects had significantly lower lung function, FEV 1 percent predicted (68 ± 28 vs. 75 ± 27; P = 0.0005), and FEV 1 /FVC ratio (0.59 ± 0.18 vs. 0.63 ± 0.17; P = 0.0008), as well as more radiographic emphysema (P = 0.001), than subjects without alpha-1 antitrypsin Z risk alleles. Similarly, African American PiMZ subjects had lower lung function, FEV 1 percent predicted (65 ± 33 vs. 84 ± 25; P = 0.009) and FEV 1 /FVC (0.61 ± 0.21 vs. 0.71 ± 0.15; P = 0.03)., Conclusions: In the COPDGene Study, we demonstrate that PiMZ heterozygous individuals who smoke are at increased risk for COPD and obstructive lung function impairment compared with Z-allele noncarriers, regardless of race. Although severe alpha-1 antitrypsin deficiency is uncommon in African Americans, our study adds further support for initial targeted detection of all subjects with COPD for alpha-1 antitrypsin deficiency, including African Americans. Clinical trial registered with www.clinicaltrials.gov (NCT00608784).

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.

Alpha-1 antitrypsin deficiency (AATD) is a condition caused by the inheritance of two mutated SERPINA1 gene alleles. Individuals with AATD are at increased risk of injury to the liver and lungs. The pulmonary manifestations include precocious onset of pulmonary emphysema and bronchiectasis. For nearly three decades, treatment has been available to individuals with emphysema caused by AATD, but this therapy-augmentation of plasma and tissue alpha-1 antitrypsin levels by intravenous administration of human plasma-derived protein-was approved by regulatory authorities based on its biochemical efficacy. This therapy appears to slow the progression of emphysema in patients with AATD. The medical, patient, and regulatory communities have sought assurance that this expensive therapy provides measurable clinical benefit. Documenting such benefit has been difficult because of the slow progression of the underlying lung disease in AATD, the rarity of this genetic condition, and the lack of direct quantitative measurements of emphysema progression. Over the past decade, quantitative computed tomography (CT) densitometry of the lungs has been found to correlate with severity and progression of emphysema. The recent publication of a well-powered, masked, placebo-controlled study using CT densitometry to evaluate the effectiveness of augmentation therapy at slowing the progression of emphysema has provided some assurance of the clinical efficacy of this therapy.

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.

Background: Patients are increasingly viewed as key stakeholders who can contribute in meaningful ways to clinical research and are emphasized in research funded by the Patient-Centered Outcomes Research Institute (PCORI). We are not aware of other peer-reviewed publications that report methods and outcomes of patient engagement to refine study design for a PCORI-sponsored clinical effectiveness trial., Objective: The aim of this report was to describe the process and outcomes of involving patients in the design of a clinical trial to promote adherence to supplemental oxygen therapy among patients with chronic obstructive pulmonary disease., Methods: In-person focus groups and individual discussions via telephone and email were used to elicit feedback to refine the intervention and clarify outcomes of highest importance to patients., Results: A total of 25 patients and five caregivers provided feedback. Their feedback has informed decisions regarding the length of intervention sessions (20 min and in some cases longer was acceptable), the importance of including caregivers, and discussion topics (e.g., social discomfort about using oxygen in public, identifying personally relevant reasons to use oxygen, pulmonary rehabilitation). Multiple outcomes were rated as highly important to patients (physical function, fatigue, sleep, anxiety, depression, and ability to participate in social roles and activities), and the outcome that was ranked as most important varied by individual. Therefore, multiple patient-reported outcomes will be used as endpoints for the clinical trial., Conclusions: Patient involvement led to refinements of the intervention and clinical trial endpoints to better address the expressed needs and concerns of patients and caregivers.

Severe deficiency of alpha-1 antitrypsin has a highly variable clinical presentation. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis α1 Study is a prospective, multicenter, cross-sectional study of adults older than age 35 years with PiZZ or PiMZ alpha-1 antitrypsin genotypes. It is designed to better understand if microbial factors influence this heterogeneity. Clinical symptoms, pulmonary function testing, computed chest tomography, exercise capacity, and bronchoalveolar lavage (BAL) will be used to define chronic obstructive pulmonary disease (COPD) phenotypes that can be studied with an integrated systems biology approach that includes plasma proteomics; mouth, BAL, and stool microbiome and virome analysis; and blood microRNA and blood mononuclear cell RNA and DNA profiling. We will rely on global genome, transcriptome, proteome, and metabolome datasets. Matched cohorts of PiZZ participants on or off alpha-1 antitrypsin augmentation therapy, PiMZ participants not on augmentation therapy, and control participants from the Subpopulations and Intermediate Outcome Measures in COPD Study who match on FEV1 and age will be compared. In the primary analysis, we will determine if the PiZZ individuals on augmentation therapy have a difference in lower respiratory tract microbes identified compared with matched PiZZ individuals who are not on augmentation therapy. By characterizing the microbiome in alpha-1 antitrypsin deficiency (AATD), we hope to define new phenotypes of COPD that explain some of the diversity of clinical presentations. As a unique genetic cause of COPD, AATD may inform typical COPD pathogenesis, and better understanding of it may illuminate the complex interplay between environment and genetics. Although the biologic approaches are hypothesis generating, the results may lead to development of novel biomarkers, better understanding of COPD phenotypes, and development of novel diagnostic and therapeutic trials in AATD and COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01832220).