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.

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.

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.

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.

A Hybrid Effectiveness/Implementation Clinical Trial of Adherence to Long-Term Oxygen Therapy for Chronic Obstructive Pulmonary Disease.

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).

Augmentation Therapy for Alpha-1 Antitrypsin Deficiency: Patient Experiences With Self-Infusion, Home Providers, and Clinics.

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.

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.

Impact of Coronavirus Disease 2019 and Vaccination Attitudes on Alpha-1 Antitrypsin Deficiency.

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.

Quality of Life and Mortality Outcomes for Augmentation Naïve and Augmented Patients with Severe Alpha-1 Antitrypsin Deficiency.

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.

Patient-Reported Pulmonary Symptoms, Exacerbations, and Management in a Cohort of Patients With Alpha-1 Antitrypsin Deficiency.

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.

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.

Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19.

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.

Alpha 1 Antitrypsin Therapy in Patients with Alpha 1 Antitrypsin Deficiency: Perspectives from a Registry Study and Practical Considerations for Self-Administration During the COVID-19 Pandemic.

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.

A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy.

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.

Home-Based Multicomponent Intervention Increases Exercise Activity and Improves Body Mass Index: Results of a 5-Year Randomized Trial Among Individuals with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease.

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.

Hypothesis: Alpha-1-antitrypsin is a promising treatment option for COVID-19.

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.