Dataset Information

Comparing Patients with ZZ Versus SZ Alpha-1 Antitrypsin Deficiency: Findings from AlphaNet's Disease Management Program.

ABSTRACT: Background: The aim of this study was to examine differences in demographic, health, and behavioral characteristics in individuals with ZZ and SZ genotypes of alpha-1 antitrypsin deficiency (AATD) within AlphaNet's Disease Management and Prevention Program (ADMAPP). Methods: Self-reported data from 3535 patients with AATD, including 3031 (85.7%) patients with ZZ, ZNull, and NullNull genotypes (referred to here as ZZ), and 504 (14.3%) with the SZ genotype were analyzed using t-tests, ANOVAs, and Chi-squared tests. Results: The average age of the cohort was 56.3±10.6 years. The majority of respondents were male (51.2%), white (98.2%) and married (65.2%). SZs reported having more frequent exacerbations (p<0.001) and hospitalizations (p=0.012) than ZZs. A higher proportion of SZs than ZZs had been diagnosed with high blood pressure, diabetes, congestive heart failure, and other comorbid conditions. SZs were more likely than ZZs to report "poor" health (p=0.005). Over a third (38.4%) of SZs do not exercise compared to 27.1% of ZZs (p<0.001). A greater proportion of SZs compared to ZZs view themselves as being overweight (p<0.001) or "out of shape" (p=0.001). A higher proportion of SZs than ZZs reported any history of smoking and current smoking (p<0.001). Conclusions: In patients with AATD and lung disease participating in a disease management program, a higher proportion of SZs than ZZs report exacerbations, comorbidities, and overall poor health, as well as unhealthy behaviors such as lack of exercise and current smoking. Future work should consider the extent to which genotype-specific health promotion interventions would be useful.

SUBMITTER: Choate R

PROVIDER: S-EPMC6373591 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Comparing Patients with ZZ Versus SZ Alpha-1 Antitrypsin Deficiency: Findings from AlphaNet's Disease Management Program.

Choate Radmila R Mannino David M DM Holm Kristen E KE Sandhaus Robert A RA

Chronic obstructive pulmonary diseases (Miami, Fla.) 20181130 1

<b>Background</b>: The aim of this study was to examine differences in demographic, health, and behavioral characteristics in individuals with ZZ and SZ genotypes of alpha-1 antitrypsin deficiency (AATD) within AlphaNet's Disease Management and Prevention Program (ADMAPP). <b>Methods</b>: Self-reported data from 3535 patients with AATD, including 3031 (85.7%) patients with ZZ, ZNull, and NullNull genotypes (referred to here as ZZ), and 504 (14.3%) with the SZ genotype were analyzed using t-tests ...[more]

PMID: 30775422

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Project description:Rationale: The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is associated with chronic obstructive pulmonary disease (COPD), even among never-smokers. The SZ genotype is also considered severe; yet, its effect on lung health remains unclear.Objectives: To determine the effect of SZ-AATD on spirometry compared with a normal-risk population and to determine the effect of smoking cessation in this genotype.Methods: We prospectively enrolled 166 related individuals, removing lung index cases to reduce bias, and compared spirometry between 70 SZ and 46 MM/MS individuals (control subjects). The effect of AAT concentrations on outcomes was assessed in 82 SZ individuals (including lung index cases). Subsequently, we analyzed retrospective SZ registry data to determine the effect of smoking cessation on spirometry decline (n = 60) and plasma anti-neutrophil elastase capacity (n = 20).Measurements and Main Results: No difference between SZ and control never-smokers was seen. Ever smoking was associated with a lower FEV1% predicted (-14.3%; P = 0.0092) and a lower FEV1/FVC ratio (-0.075; P = 0.0041) in SZ-AATD. No association was found between AAT concentration and outcomes for SZ-AATD. Longitudinal analysis of 60 SZ individuals demonstrated that COPD at baseline, but not former smoking or AAT concentrations, predicted greater spirometry decline. Finally, anti-neutrophil elastase capacity did not differ between former smokers and never-smokers (P = 0.67).Conclusions: SZ never-smokers demonstrated no increased risk of COPD, regardless of AAT concentration. Smoking interacts with SZ-AATD to significantly increase airflow obstruction. Former smoking alone is not associated with greater spirometry decline in SZ-AATD, suggesting that cessation attenuates the obstructive process. We found no evidence that the putative protective threshold or AAT concentrations predict risk within the SZ genotype, raising further doubts over the need for intravenous AAT augmentation in this cohort.

Project description:Background: The diagnosis and clinical management of adults with alpha-1 antitrypsin deficiency (AATD) have been the subject of ongoing debate, ever since the publication of the first American Thoracic Society guideline statement in 1989.1 In 2003, the "American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency" made a series of evidence-based recommendations, including a strong recommendation for broad-based diagnostic testing of all symptomatic adults with chronic obstructive pulmonary disease (COPD).2 Even so, AATD remains widely under-recognized. To update the 2003 systematic review and clinical guidance, the Alpha-1 Foundation sponsored a committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD. Purpose: To provide recommendations for: (1) the performance and interpretation of diagnostic testing for AATD, and (2) the current management of adults with AATD and its associated medical conditions. Methods: A systematic review addressing the most pressing questions asked by clinicians (clinician-centric) was performed to identify citations related to AATD that were published since the 2003 comprehensive review, specifically evaluating publications between January 2002 and December 2014. Important, more recent publications were solicited from the writing committee members as well. The combined comprehensive literature reviews of the 2003 document and this current review comprise the evidence upon which the committee's conclusions and recommendations are based. Results: Recommendations for the diagnosis and management of AATD were formulated by the committee. Conclusions: The major recommendations continue to endorse and reinforce the importance of testing for AATD in all adults with symptomatic fixed airflow obstruction, whether clinically labeled as COPD or asthma. Individuals with unexplained bronchiectasis or liver disease also should be tested. Family testing of first-degree relatives is currently the most efficient detection technique. In general, individuals with AATD and emphysema, bronchiectasis, and/or liver disease should be managed according to usual guidelines for these clinical conditions. In countries where intravenous augmentation therapy with purified pooled human plasma-derived alpha-1 antitrypsin is available, recent evidence now provides strong support for its use in appropriate individuals with lung disease due to AATD.

Project description:BACKGROUND:Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton variant as on IEF profile it resembles the wild M2 subtype. METHODS:This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients. The review has been implemented by additional histological stains, electron microscopic observations and 3-D modeling studies of the sites of the mutations. RESULTS:Z, Mmalton and Siiyama liver specimen contained characteristic intrahepatocytic PAS-D globules. The globules differed in the three variants as only Mmalton cases showed dark basophilic precipitates within the AAT inclusions. The precipitates were visualized in haematoxylin-eosin (H.E.) stained preparations and corresponded to calcium precipitates as demonstrated by von Kossa staining. On immunohistochemistry, ZAAT inclusions were stained by polyclonal as well as monoclonal noncommercial anti-AAT antibody (AZT11), whilst Mmalton and Siiyama inclusion bodies remained negative with the monoclonal anti-Z antibody. 3-D protein analysis allowed to predict more severe misfolding of the Mmalton molecule as compared to Z and Siiyama that could trigger anomalous interaction with endoplasmic reticulum chaperon proteins, namely calcium binding proteins. CONCLUSIONS:Mmalton AAT inclusion bodies contain calcium precipitates inside them that allow the differential diagnosis with Siiyama and ZAAT inclusions in routine histological sections. The study has confirmed the specificity of the monoclonal AZT11 for the Z mutant. Thus, the combination of these two features is crucial for the distinction between the three variants and for predicting the genotype, whose confirmation would definitely require molecular analysis. Our study provides new data on the pathomorphogenesis of Mmalton inclusion bodies whose mineralization could play a central role in disease pathogenesis of Mmalton that is distinct from the Z and Siiyama variants. Calcium is known to be a major effector of cell death either via the increased intracellular concentration or the alteration of homeostasis.

Project description: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.

Dataset Information

Comparing Patients with ZZ Versus SZ Alpha-1 Antitrypsin Deficiency: Findings from AlphaNet's Disease Management Program.

Publications

Comparing Patients with ZZ Versus SZ Alpha-1 Antitrypsin Deficiency: Findings from AlphaNet's Disease Management Program.

Similar Datasets

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