The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency.
ABSTRACT alpha1-Antitrypsin (AAT) deficiency predisposes to bronchitis and emphysema associated with neutrophilic airway inflammation. The efficacy of augmentation therapy has not been proven clinically or by demonstrating an effect on airway inflammation. We treated 12 patients with four infusions of Prolastin (60 mg/kg) at weekly intervals and monitored both the serum and secretion concentrations of AAT as well as markers of neutrophilic inflammation, including myeloperoxidase, elastase, and the neutrophil chemoattractants interleukin-8 and leukotriene B(4). Serum AAT rose and was maintained above the protective threshold. In addition, AAT concentrations in the sputum rose from a mean of 0.17 microM (SEM +/- 0.04) before therapy to concentrations similar to nondeficient subjects (0.43 +/- 0.12) 1 week after the first infusion (p < 0.01). This was associated with a reduction in elastase activity (p < 0.002) and the chemoattractant leukotriene B(4) (p < 0.02), which fell from a median baseline value of 13.46 nM (range, 4.17-55.00) to 8.62 nM (4.23-21.59) the day following the last infusion. Although median values for myeloperoxidase and interleukin-8 also fell, the changes failed to achieve statistical significance. In summary, short-term therapy with AAT increased lung secretion concentrations and was associated with a fall in leukotriene B(4), which is thought to be central to the airway inflammation of AAT deficiency.
Article: Factors associated with the evolution of lung function in patients with alpha-1 antitrypsin deficiency in the Spanish registry.[show abstract] [hide abstract]
ABSTRACT: The present study intends to describe the characteristics of patients diagnosed with severe alpha-1 antitrypsin deficiency (AATD) in Spain, to observe the rate of decline in forced expiratory volume in 1 second (FEV1) with and without substitutive therapy, and to identify factors associated with a rapid rate of decline in FEV1. A retrospective study of the evolution of individuals with AATD was carried out based on data collected from the Spanish registry. The primary response variable was the annual rate of decline in FEV1, calculated using the baseline and last postbronchodilator FEV1 values in an endpoint analysis. 303 patients with severe AATD and Pi ZZ phenotype were identified. Follow-up spirometric data were collected for 117 subjects. Being a smoker or ex-smoker versus never smoker (odds ratio [OR]=10.31; 95% confidence interval (CI)=1.8-58.8; p=0.008) and having a higher baseline postbronchodilator FEV1 (% predicted) (OR=1.03; 95% CI=1.005-1.06; p=0.018) were independently associated with a more rapid rate of decline in FEV1. There was also a trend towards a relationship between low body mass index (BMI) and a greater rate of deterioration in lung function (OR=1.14; 95% CI=0.98-1.33; p=0.085). Being a smoker or ex-smoker, greater baseline lung function, and low BMI were the main risk factors associated with an accelerated rate of decline in FEV1. This finding warrants the close observation of younger patients with a better-preserved FEV1.Archivos de Bronconeumología 07/2011; 47(10):495-503. · 2.17 Impact Factor
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ABSTRACT: α(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage (e.g., from neutrophil elastase). Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (∼ 3-7 μM with normal serum levels of 20-53 μM). A serum AAT level of 11 μM represents the protective threshold value below which the risk of emphysema is believed to increase. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protective threshold. Although definitive evidence from randomized controlled trials of augmentation therapy is lacking and therapy is expensive, the available evidence suggests that this approach is safe and can slow the decline of lung function and emphysema progression. Promising novel therapies are under active investigation.American Journal of Respiratory and Critical Care Medicine 09/2011; 185(3):246-59. · 11.08 Impact Factor
Article: Why has it been so difficult to prove the efficacy of alpha-1-antitrypsin replacement therapy? Insights from the study of disease pathogenesis.[show abstract] [hide abstract]
ABSTRACT: Alpha-1-antitrypsin is the most abundant circulating protease inhibitor. It is mainly produced by the liver and secreted into the circulation where it acts to prevent excessive proteolytic damage in the lungs by the enzyme neutrophil elastase. The most common severe deficiency allele is the Z mutation, which causes the protein to self-associate into ordered polymers. These polymers accumulate within hepatocytes to cause liver damage. The resulting lack of circulating α(1)-antitrypsin predisposes the Z homozygote to proteolytic lung damage and emphysema. Other pathways may also contribute to the development of lung disease. In particular, polymers of Z α(1)-antitrypsin can form within the lung where they act as a pro-inflammatory stimulus that may exacerbate protease-mediated lung damage. Researchers recognized in the 1980s that plasma α(1)-antitrypsin levels could be restored by intravenous infusions of purified human protein. Alpha-1-antitrypsin replacement therapy was introduced in 1987 but subsequent clinical trials have produced conflicting results, and to date there remains no widely accepted clinical evidence of the efficacy of α(1)-antitrypsin replacement therapy. This review addresses our current understanding of disease pathogenesis in α(1)-antitrypsin deficiency and questions why this treatment in isolation may not be effective. In particular it discusses the possible role of α(1)-antitrypsin polymers in exacerbating intrapulmonary inflammation and attenuating the efficacy of α(1)-antitrypsin replacement therapy.Drug Design, Development and Therapy 01/2011; 5:391-405. · 2.88 Impact Factor