Alpha-1 Antitrypsin Augmentation Therapy Improves Survival in Severely Deficient Patients with Predicted FEV1 Between 10% and 60%: A Retrospective Analysis of the NHLBI Alpha-1 Antitrypsin Deficiency Registry.

Purpose: The extent of the survival benefit of augmentation therapy for alpha-1 antitrypsin deficiency (AATD) in individuals with advanced COPD is difficult to define. We performed a retrospective analysis using all available data from the observational registry of individuals with severe deficiency of alpha-1 antitrypsin (AAT) conducted by the NHLBI investigators. Patients and Methods: Individuals (N=1129) with severe deficiency of AAT were evaluated for mortality using all data sources and stratified by 10% increments of baseline forced expiratory volume in 1 second (FEV1) percent predicted and by augmentation therapy status (ever receiving versus never receiving). Kaplan-Meier survival curves were constructed for each of the deciles comparing survival in treated vs non-treated groups. A multivariable model was performed to define the correlates of survival in individuals with FEV1 <30% predicted. Results: Amongst all subjects, augmentation was associated with improved survival (p<0.0001). Among the individuals ever receiving augmentation therapy, survival was better than for those not receiving augmentation at all 10% increments of FEV1% predicted from 10% to 60% (P values <0.05 in all deciles). In subgroups of participants with hyperinflation defined as residual volume (RV)>120% predicted and in subgroups of participants with reduced diffusing capacity for carbon monoxide (DLCO) <70% predicted, there was significantly better survival for those ever receiving augmentation therapy than for those who never received augmentation (p<0.001). A multivariable analysis showed that mortality benefit is influenced by age, DLCO % predicted, and augmentation therapy. Conclusion: There is a survival benefit from augmentation therapy in AATD between FEV1 values in the 10-60% predicted range. Screening and treatment of AATD patients should therefore not be limited by the severity of illness as defined by FEV1.

The United States Alpha-1 Foundation Research Registry: Genesis, Impact and Future.

The Alpha-1 Foundation Research Registry has a long history of facilitating research studies in the United States. The current contact registry is used to invite participants to research studies. However, the next generation of individuals diagnosed with alpha-1 antitrypsin deficiency may look quite different from historical cohorts. This paper uses data from the Alpha Coded Testing (ACT) study, a home genetic testing program in which deficient individuals are invited to participate in the Registry, to demonstrate the impact that selection bias can introduce into registry data. Environmental tobacco smoke (ETS) exposure is rapidly declining in the United States. We queried whether consecutive non-smokers with or without childhood ETS in ACT (N = 801) had been diagnosed with COPD more often if deficiency genes were defined in subsequent testing. The prevalence of COPD was not different between cohorts with or without ETS exposure between normal (PiMM and PiMS), moderately deficient (PiMZ, PiMNull, and PiSS), and severely deficient (PiSZ, PiZZ, PiSNull, and PiZNull) genotypes. Surprisingly, age adjusted COPD Severity Scores in this cohort were higher for individuals with normal genotypes compared to moderately (P<0.001) and severely (P = 0.04) deficient genotypes. Ascertainment bias of testing within families (which yields the highest incidence of deficiency genotypes) also finds many family members without symptoms, even over the age of 40. We conclude that the future utility of registries will depend on accurate determination of testing mechanics. Larger database initiatives using the COPD Patient Powered Research Network are described.

Inhaled alpha 1-antitrypsin: gauging patient interest in a new treatment.

BACKGROUND: Given the high cost of plasma derived intravenous alpha 1-antitrypsin (AAT), a more efficient method of delivery to the lungs is desirable. Inhaled AAT has been shown feasible for the treatment of alpha 1-antitrypsin deficiency (AATD) and is currently in clinical trials. To better understand patient preferences about possible inhaled AAT therapy, a survey was conducted to explore patient attitudes. METHODS: We conducted an email based survey of patients in the Alpha-1 Foundation Research Registry with AATD on intravenous AAT replacement. Respondents were asked to rate their interest in hypothetical nebulized or dry powder inhaled AAT. RESULTS: Respondents reported high levels of interest in both dried powder inhaler and nebulizer delivered inhaled AAT. The interest in dried powder inhaled was higher than interest in nebulized AAT (71% vs 64%, p = 0.0001). The interest in dried powder inhaled AAT was particularly high in respondents currently on bronchodilator therapy (p = 0.0053). Patients were just as likely to use or not use the product if it required 20% more out of pocket cost. CONCLUSIONS: There is a high level of patient interest in the development of a commercially available inhaled AAT replacement product.

Hydration changes in the association of Hoechst 33258 with DNA.

The role of water in the interaction of Hoechst 33258 with the minor groove binding site of the (AATT)2 sequence was investigated using calorimetric and equilibrium constant measurements. Using isothermal titration calorimetry measurements, the heat capacity change for the reaction is -256 +/- 10 cal/(K mol of Hoechst). Comparison with the heat capacity changes based on area models supports the expulsion of water from the interface of the Hoechst-DNA complex. To further consider the role of water, the osmotic stress method was used to determine if the Hoechst association with DNA was coupled with hydration changes. Using four osmolytes with varying molecular weights and chemical properties, the Hoechst affinity for DNA decreases with increasing osmolyte concentration. From the dependence of the equilibrium constant on the solution osmolality, 60 +/- 13 waters are acquired in the complex relative to the reactants. It is proposed that the osmotic stress technique is measuring weakly bound waters that are not measured via the heat capacity changes.