α1-Antitrypsin Binds to the Glucocorticoid Receptor with Anti-Inflammatory and Antimycobacterial Significance in Macrophages.

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.

Characteristics associated with SF-36 in alpha-1 antitrypsin deficiency-associated COPD: a cross-sectional analysis.

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.

The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions.

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.

Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions.

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 Cx3cr1gfp/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.

Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence.

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.

Gene coexpression networks reveal novel molecular endotypes in alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals. METHODS: We performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects' clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay. RESULT: We observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns. CONCLUSIONS: We successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals' genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.

Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype.

α1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α1-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.

Cardiopulmonary Status in Adults with Osteogenesis Imperfecta: Intrinsic Lung Disease May Contribute More Than Scoliosis.

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.

A multicenter study to evaluate pulmonary function in osteogenesis imperfecta.

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 (FEV1 ), 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 FEV1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV1 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 FEV1 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.

Quantitative disease progression model of α-1 proteinase inhibitor therapy on computed tomography lung density in patients with α-1 antitrypsin deficiency.

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 (A1 -PI; 60 mg kg-1  week-1 ) therapy completed to date, demonstrated for the first time that A1 -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 A1 -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 A1 -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 A1 -PI, forced expiratory volume in 1 s and body weight. The exposure-response model relates A1 -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 A1 -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 A1 -PI: 63 vs. 12%. CONCLUSION: Weight-based A1 -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 A1 -PI therapy in AATD. The model suggested higher doses of A1 -PI would yield greater clinical effects.

Bioequivalence of a Liquid Formulation of Alpha1-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha1-PI) in Alpha1-Antitrypsin Deficiency.

This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha1-proteinase inhibitor, Liquid Alpha1-PI, compared with the Lyophilized Alpha1-PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha1-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 Alpha1-PI or Lyophilized Alpha1-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 (AUC0-7 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 AUC0-7 days for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha1-PI concentration versus time curves for both formulations were superimposable. Mean AUC0-7 days was 20 320 versus 19 838 mg × h/dl for Liquid Alpha1-PI and Lyophilized Alpha1-PI, respectively. The LS mean ratio of AUC0-7 days (90% CI) for Liquid Alpha1-PI versus Lyophilized Alpha1-PI was 1.05 (1.03-1.08), indicating bioequivalence. Liquid Alpha1-PI was well tolerated and adverse events were consistent with Lyophilized Alpha1-PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha1-PI is bioequivalent to Lyophilized Alpha1-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.

Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. METHODS: The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 µM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS: Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). INTERPRETATION: Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. FUNDING: CSL Behring.

The social environment and illness uncertainty in chronic obstructive pulmonary disease.

PURPOSE: Illness uncertainty is associated with worse outcomes in patients with chronic health conditions. Research on social factors associated with uncertainty has focused on the beneficial role of social support. The goal of this study was to develop a more nuanced understanding of the social factors that are associated with uncertainty. METHODS: Four hundred sixty-two individuals with alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD) completed a mailed questionnaire. Measures of the social environment included general family functioning, perceived criticism from family members, whether the participant had family members with AATD or COPD, and participation in support groups. Uncertainty was measured using the Mishel Uncertainty in Illness Scale including subscales for ambiguity (uncertainty about physical cues and symptoms) and complexity (uncertainty about treatment and the medical system). Hierarchical regression was used to identify social correlates of ambiguity and complexity while adjusting for demographic and medical characteristics and psychological distress. RESULTS: Perceived criticism was associated with more complexity (b = 0.21, SE = 0.09, p = 0.015) and ambiguity (b = 0.40, SE = 0.12, p = 0.001). Having a family member with AATD or COPD was associated with more ambiguity (b = 3.28, SE = 1.00, p = 0.001). Participation in support groups was associated with less ambiguity. Individuals who attended three or more support groups in the prior year reported less ambiguity than individuals who had not attended any (b = -3.31, SE = 1.29, p = 0.010). CONCLUSIONS: The social environment is complex and encompasses more than social support. Multiple aspects of the social environment are associated with uncertainty, including perceived criticism, having a family member with a similar illness, and participation in support groups.

The impact of age on outcomes in chronic obstructive pulmonary disease differs by relationship status.

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that can lead to early-onset chronic obstructive pulmonary disease (COPD). The objective of this study was to examine the impact of age on psychological and clinical outcomes among individuals with AATD-associated COPD. 468 individuals with AATD-associated COPD (age 32-84 at baseline) completed questionnaires at baseline, 1- and 2-year follow-up. Age was examined as a predictor of depression, anxiety, health-related quality of life, and breathlessness at all three time points using linear mixed models. Age was associated with anxiety (b = -0.09, SE = 0.02, p < 0.001) and health-related quality of life (b = -0.29, SE = 0.09, p < 0.001). Age also had a statistically significant interaction with relationship status when predicting depression, health-related quality of life, and breathlessness. Among individuals who were single, younger age was associated with more symptoms of depression (b = -0.08, SE = 0.03, p < 0.01), worse health-related quality of life (b = -0.61, SE = 0.16, p < 0.001), and more breathlessness (b = -0.023, SE = 0.009, p < 0.01) throughout the 2-year study. Age was not associated with these three outcomes among individuals who were married/part of an unmarried couple. Results suggest that individuals who develop a chronic illness at a young age, particularly those who are single, may be more likely to have worse psychological and clinical outcomes.

Biochemical efficacy and safety of a new, ready-to-use, liquid alpha-1-proteinase inhibitor, GLASSIA (alpha1-proteinase inhibitor (human), intravenous).

Maintaining serum levels of alpha-1-proteinase inhibitor (A1PI) >11 µM by augmentation with plasma-derived human A1PI is currently the only specific therapy available to treat patients with the genetic deficiency of A1PI. In this study, a new, high-purity (≥90% A1PI in monomeric form), ready-to-use, liquid formulation of A1PI-GLASSIA (Kamada, Ness Ziona, Israel) was compared to PROLASTINÆ (Talecris, Research Triangle Park, NC, now Grifols), both commercially available, FDA-approved products. This multicenter, double-blind, randomized controlled trial with partial cross-over was designed to test the non-inferiority and safety of GLASSIA compared to PROLASTIN, assessing both antigenic and functional A1PI trough levels in subject serum. Non-inferiority of GLASSIA to PROLASTIN was demonstrated by remaining within the lower bounds of the confidence intervals (≤3 µM) for both antigenic and functional A1PI. The study concluded that GLASSIA, a new liquid, ready to use, formulation of A1PI, was not inferior to PROLASTIN and it was well tolerated with a safety profile comparable to PROLASTIN.

Clinical trial attitudes among individuals with Alpha-1 antitrypsin deficiency.

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.

Long-Term SGRQ Stability in a Cohort of Individuals with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease.

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.

Prevalence of Cardiovascular Disease and Rate of Major Adverse Cardiovascular Events in Severe Alpha-1 Antitrypsin Deficiency COPD.

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.