Effects of a Disease Management Program in Individuals with Alpha-1 Antitrypsin Deficiency

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

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

Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency

Background: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2). We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. Methods The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. Fev$_1$ percent of predicted and Fev$_1$/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. Results: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator Fev$_1$ percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator Fev$_1$ percent of predicted and pre-bronchodilator Fev$_1$/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. Conclusions: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact

Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results

Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for \u3e1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT \u3e20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations

Circulating polymers in α1-antitrypsin deficiency.

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Alpha-1 Antitrypsin Role in Health and Disease

This book offers a comprehensive overview of alpha-1 antitrypsin deficiency, an inherited condition that leads to lung disease in adults and liver disease in adults and children. While it is a rare condition, the mechanisms underlying its clinical manifestations have been largely clarified. Specific treatment, however, is available only for the lung disease that arises from the condition, thus necessitating continued research into new and alternative therapeutic solutions. The book discusses the biology of alpha-1 antitrypsin, protein misfolding and polymerization, and diagnosis and treatment of alpha-1 antitrypsin deficiency and its associated diseases.  It concludes with a discussion of  alpha-1 antitrypsin therapy in diseases not associated with alpha-1 antitrypsin deficiency, and the role of healthcare organizations in the rare disease space. Written for pulmonary clinicians and scientists, Alpha-1 Antitrypsin: Role in Health and Disease is a valuable resource that sheds light on this rare disease. 

Trends in the Diagnosis of Symptomatic Patients With α1-Antitrypsin Deficiency Between 1968 and 2003

α1-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. 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. 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), and years with symptoms before diagnosis (p > 0.05), while the proportion of cases diagnosed by the first or second physician decreased (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). 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

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.info:eu-repo/semantics/publishedVersio

Influenza Vaccination in Subjects With α1-Antitrypsin Deficiency

Influenza vaccination is recommended for all subjects with COPD, including α1-antitrypsin deficiency (AATD), but immunization practices are below US national goals. Influenza vaccination practices and their relation to respiratory outcomes in AATD are unknown. 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. 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. 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