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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.)

Rationale: Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven. Objectives: To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy. Methods: Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained. Measurements and Main Results: DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val 360 ), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers. Conclusions: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).

Alpha-1 antitrypsin deficiency (AATD) is characterized by low serum levels of or dysfunctional alpha-1 proteinase inhibitor. In the lung parenchyma, this results in a loss of protection against the activity of serine proteases, particularly neutrophil elastase. The resultant imbalance in protease and antiprotease activity leads to an increased risk for the development of early-onset emphysema and COPD. As in traditional smoke-related COPD, the assessment of the severity and disease progression of lung disease in AATD is conventionally based on lung function; however, pulmonary function tests are unable to discriminate between emphysema and airways disease, the two hallmark pathologic features of COPD. CT imaging has been used as a tool to further characterize lung structure and evaluate therapeutic interventions in AATD-related COPD. Moreover, recent advances in quantitative CT have significantly improved our assessment of the lung architecture, which has provided investigators and clinicians with a more detailed evaluation of the extent and severity of emphysema and airways disease in AATD. In addition, serial CT imaging measures are becoming increasingly important, as they provide a tool to monitor emphysema progression. This review describes the principles of CT technology and the role of CT imaging in assessing pulmonary disease progression in AATD, including the effect of therapeutic interventions., (Published by Elsevier Inc.)

Introduction: Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder which reduces serum alpha 1-antitrypsin (AAT or alpha1-proteinase inhibitor, A1PI) and increases the risk of chronic obstructive pulmonary disease (COPD). Management strategies include intravenous A1PI augmentation, and, in some cases, a health management program (Prolastin Direct ® ; PD)., Objectives: This study compared clinical and economic outcomes between patients with and without PD program participation., Methods: This retrospective study included commercial and Medicare Advantage health insurance plan members with ≥ 1 claim with diagnosis codes for COPD and ≥ 1 medical or pharmacy claim including A1PI (on index date). Outcomes were compared between patients receiving only Prolastin ® or Prolastin ® -C (PD cohort) and patients who received a different brand without PD (Comparator cohort). Demographic and clinical characteristics were captured during 6 months pre-index. Post-index exacerbation episodes and healthcare utilization and costs were compared between cohorts., Results: The study sample comprised 445 patients (n = 213 in PD cohort; n = 232 in Comparator cohort), with a mean age 55.5 years, 50.8% male, and 78.9% commercially insured. The average follow-up was 822 days (2.25 years), and the average time on A1PI was 747 days (2.04 years). Few differences were observed in demographic or clinical characteristics. Adjusting for differences in patient characteristics, the rate of severe exacerbation episodes was reduced by 36.1% in the PD cohort. Adjusted total annual all-cause costs were 11.4% lower, and adjusted mean respiratory-related costs were 10.6% lower in the PD cohort than the Comparator cohort. Annual savings in all-cause total costs in the PD cohort relative to the Comparator cohort was US$25,529 per patient, largely due to significantly fewer and shorter hospitalizations., Conclusions: These results suggest that comprehensive health management services may improve both clinical and economic outcomes among patients with COPD and AATD who receive augmentation therapy., Funding: Grifols Shared Services of North America, Inc.

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.

Objective: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder that can cause chronic obstructive pulmonary disease (COPD) and liver cirrhosis, two clinical conditions commonly seen by primary care physicians. AATD is estimated to affect 1/4000-1/5000 people in the United States and 1-2% of all COPD cases., Methods: PubMed was searched for relevant articles using AAT/AATD-related terms., Results: Unfortunately, <10% of symptomatic individuals have been properly diagnosed primarily due to the underdiagnosis of COPD and the lack of awareness of AATD as a possible underlying cause. Because primary care providers are most likely to be the first to encounter symptomatic individuals, their role in the identification and early diagnosis of AATD patients is instrumental, particularly since therapy to slow lung disease progression is available. The diagnosis of AATD is laboratory-based rather than clinical. Testing for AATD should be part of the reflex testing that follows any COPD diagnosis or unexplained liver disease and can be performed by determining the AAT phenotype or genotype along with serum AAT levels. Both nonpharmacological and pharmacological approaches are recommended for treatment of lung disease, including smoking cessation, bronchodilators or supplemental oxygen as needed. Specific augmentation of AAT levels with regular purified AAT infusions has been found to slow lung function decline and emphysema progression in patients with moderate airflow obstruction and severely low serum AAT levels., Conclusions: Improving primary care provider awareness and promoting regular reflex testing all COPD patients for AATD may significantly improve the care of COPD patients.

α1 Antitrypsin deficiency (AATD) increases the risk of chronic obstructive pulmonary disease (COPD), liver disease and other conditions. Although it is not a rare disease, it is a condition rarely diagnosed because of unawareness by most healthcare providers who manage subjects at risk. Testing recommendations have been published and strongly suggest testing all subjects with confirmed COPD, cryptogenic liver cirrhosis, subjects with incompletely reversible airflow obstruction and siblings of affected individuals. Testing strategies usually imply a combination of measures of α1 antitrypsin (AAT) levels, phenotyping and genotyping, techniques that have been facilitated for in-office use by development of testing kits using dried blood spots. Early detection of subjects is crucial to apply effective preventive measures and early institution of therapy. The only specific Food and Drug Administration - approved therapy for this condition is lifelong weekly intravenous AAT replacement (augmentation therapy). Observational studies strongly suggest a beneficial effect of augmentation therapy in slowing lung function decline and randomized trials suggest a beneficial effect in slowing the progression of emphysema over time as measured by computed tomography. In addition, augmentation therapy has been shown to modulate systemic inflammatory responses and affect markers of elastin degradation. As new markers of disease progression are discovered, new doses of AAT replacement are tested and sub-phenotypes of disease are described, treatment recommendations are likely to change towards a more individualized therapeutic approach., (© The Author(s), 2014.)

Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 μM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.

Introduction: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease that may be manifested by chronic obstructive pulmonary disease. Despite professional society guidelines that recommend broad testing of at-risk individuals, fewer than 10% of affected individuals have been identified. The goals of this study were to estimate the frequency of abnormal AAT genotypes among patients found to have fixed airflow obstruction and to assess the feasibility of having Pulmonary Function Laboratory personnel administer the study., Methods: Nineteen medical centers in the United States participated in the study. Eligible patients (> GOLD II, FEV(1)/FVC ratio < 0.7, with post-bronchodilator FEV(1)<80% predicted) were offered testing for AATD by the Pulmonary Function Laboratory personnel at the time of pulmonary function testing., Results: A total of 3,457 patients were tested, of whom 3152 were eligible. Deficient patients (ZZ, SZ) constituted 0.63% of subjects, while 10.88% were carriers (MS, MZ). Neither demographic (except African-American race) nor post-bronchodilator pulmonary function variables (FEV(1), FVC, FEV(1)/FVC ratio, TLC, and FEV(1)/FVC) allowed us to predict AAT heterozygote or deficiency status., Conclusions: The prevalence of AATD among patients undergoing pulmonary function tests with fixed airflow obstruction was 0.63%. Pulmonary Function Laboratory personnel effectively conducted the study.

Background: Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha₁-PI) and may lead to emphysema. Alpha₁-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha₁-Proteinase Inhibitor [Human]) to increase the levels of alpha₁-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha₁-PI product, designated Prolastin®-C (Alpha₁-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency., Methods: In total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC₀₋₇ (days)) of alpha₁-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only., Results: Mean AUC₀₋₇ (days) was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC₀₋₇ (days) for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study., Conclusion: Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin., Trial Registration: ClinicalTrials.gov Identifier: NCT00295061.

Background: The frequency, characteristics and impact of acute exacerbations in patients with alpha-1 antitrypsin deficiency (AATD) and COPD who are on intravenous alpha-1 antitrypsin augmentation therapy have not been described., Methods: 922 subjects with AATD and COPD on augmentation therapy (mean age 54.5 years) were followed with monthly telephone surveys to record exacerbation characteristics, as well as healthcare resource utilization and health-related quality of life (HRQoL). Exacerbations were defined by symptom-based and healthcare resource utilization (HRU) criteria., Results: During the 1-year follow-up, 91.5% of participants experienced at least one exacerbation (mean 2.4 exacerbations per subject, median 2, and mean duration 17 days per episode, regardless of the definition used). Most exacerbations were categorized as severe by symptoms and moderate by HRU criteria. Subjects who had 3 or more exacerbations (48.6%) were younger, had higher medication use and had higher tobacco consumption compared with subjects with less exacerbations. Subjects with frequent exacerbations had the worst baseline HRQoL scores, as well as more physician visits, emergency room visits, and hospitalizations. Although most subjects received augmentation therapy on a weekly basis, other infusion schedules were more commonly observed in subjects with fewer exacerbations., Conclusion: COPD exacerbations occur frequently and are associated with significant disease burden in subjects with AATD receiving augmentation therapy.

Background: The clinical characteristics of elderly subjects with alpha(1)-antitrypsin deficiency (AATD)-associated COPD have not been described., Methods: The clinical, demographic, health-related quality of life (HRQoL) characteristics and 1-year exacerbation rates of 275 subjects with AATD and COPD receiving augmentation therapy aged > 59 years (mean [+/- SD] age, 66.3 +/- 5.7 years) were compared to those of 354 subjects aged 50 to 59 years (mean age, 54.3 +/- 2.8 years) and 293 subjects < 50 years (mean age, 43.9 +/- 3.8 years)., Results: Older subjects received diagnoses later in life (mean age at diagnosis, 55.0 +/- 8.5 years) and had a longer diagnostic delay (mean age at diagnosis, 12.9 +/- 14.3 years) than subjects in the other two age groups. Although the proportion of lifetime nonsmokers was higher in the older group, the majority (64%) had significant tobacco exposure but with a longer interval of tobacco abstinence. The mean FEV(1) values (n = 641) were similar between the three age groups, suggesting a slower disease progression in the oldest group. Subjects in the older group were less symptomatic, had less concomitant asthma, and had significantly better scores in most domains of two HRQoL instruments. During follow-up, older subjects had fewer acute exacerbations., Conclusions: Subjects with AATD-associated COPD who reach an older age exhibit a more indolent clinical course than younger affected individuals, possibly related in part to differences in tobacco exposure. This finding supports current guidelines that recommend screening of all patients with COPD for AATD, regardless of their age and prior smoking history.

Disease management programs improve outcomes in subjects with chronic obstructive pulmonary disease (COPD), but their effect in subjects with alpha-1 antitrypsin deficiency (AATD) has not been evaluated. To assess the impact of a disease management program, applicable to subjects with AATD-associated COPD throughout the United States, on exacerbations, healthcare resource utilization and health-related quality of life (HRQoL). The Alpha-1 Disease Management and Prevention Program (ADMAPP) consisted of comprehensive written educational patient-directed material for self-study and treatment plans. Program reinforcement was performed through monthly phone calls by specialized coordinators. Outcomes were collected prospectively for 12 months before, and 12 months after enrollment into the program. Exacerbations and healthcare resource utilization were recorded monthly. HRQoL was measured with the St George's Respiratory Questionnaire (SGRQ) every 6 months and the Short Form-36 (SF-36) every 12 months. A total of 878 subjects completed the 2-year study. During the intervention year, there was a significant increase in the use of long-acting bronchodilators, better compliance with oxygen therapy, and more use of steroid courses during exacerbations. Total exacerbation rates, unscheduled physician visits and emergency room visits significantly decreased. There was also a statistically significant slowing in the deterioration of the SGRQ's activity domain, while total SGRQ scores remained stable during the study. Significant improvements were observed in some of the SF-36 domains, particularly in the general health domain. The ADMAPP improved health outcomes in subjects with AATD-associated COPD.

Background: Influenza vaccination is recommended for all subjects with COPD, including alpha(1)-antitrypsin deficiency (AATD), but immunization practices are below US national goals. Influenza vaccination practices and their relation to respiratory outcomes in AATD are unknown., Methods: Nine hundred thirty-nine subjects with AATD were followed up prospectively by monthly telephone interviews during the 2003 to 2004 influenza season. Vaccination status, exacerbation rates, and health-care utilization were documented. Residence zip codes were used to group subjects as living in high or low influenza-like illness (ILI) prevalence areas according to published Centers for Disease Control and Prevention data for the same influenza season., Results: Overall, 81.6% of subjects received influenza vaccination, with no differences noted by gender, age (median age 52 years), Global Initiative for Chronic Obstructive Lung Disease stage, or ILI prevalence area. No significant differences were noted in the overall acute exacerbation rates using two different criteria between vaccinated and unvaccinated subjects (mean, 1.5 +/- 1 exacerbations per subject). Similarly, no differences were noted in either the severity of exacerbations or the monthly exacerbation rates between the two groups. Unvaccinated subjects had more unscheduled physician visits than vaccinated subjects, but there were no significant differences in scheduled visits, emergency department visits, or hospitalizations between the two groups. Older age (> 60 years) or residence in a high ILI prevalence area had no effect on outcomes., Conclusion: Subjects with AATD in the United States receive adequate influenza vaccination regardless of age. However, we did not observe a significant impact of the vaccination on disease exacerbations and other respiratory outcomes during the 2003 to 2004 influenza season.

Background: Alpha1-antitrypsin deficiency (AATD) is usually underrecognized, with only 5% of cases being diagnosed in the estimated 100,000 affected individuals in the United States. To support current guidelines recommending AATD testing of all individuals with COPD, we analyzed the diagnostic experience of a large cohort of symptomatic patients with AATD., Methods: A total of 1,020 members of AlphaNet, a not-for-profit health management company devoted to patients with AATD, provided information regarding their AATD diagnostic experience as part of a larger survey-based outcome study., Results: The average age at diagnosis was 45.5 +/- 9.5 years, and the average interval between the onset of symptoms and diagnosis was 8.3 +/- 6.9 years (+/- SD); 30.8% were diagnosed in patients > 50 years old. Two thirds of the diagnoses were made by the first or second physician, and 20% by the fourth or more physicians. From 1968 to 2003, there was a steady increase in age at diagnosis (p < 0.05), the number of physicians required for diagnosis (p > 0.05), and years with symptoms before diagnosis (p > 0.05), while the proportion of cases diagnosed by the first or second physician decreased (p < 0.001). Individuals with a diagnosis at < 35 years of age saw fewer physicians than other age groups (p < 0.05), and show a tendency toward a shorter diagnostic interval over time (p > 0.05). Diagnoses were made in men earlier than in women (p < 0.05), and the proportion of individuals in whom AATD was detected because of asthma or COPD has increased (p < 0.05)., Conclusion: There has not been a significant improvement in earlier disease diagnosis between 1968 and 2003. There has been improved AATD detection in older individuals. The diagnostic delay is still significant, and efforts should be directed to increase early AATD detection by health-care providers and patients.