MEDLINE Abstracts: Alpha 1-Antitrypsin Deficiency in COPD
What's new in diagnostic techniques and therapeutic strategies for alpha1-antitrypsin deficiency in the setting of COPD? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pulmonary Medicine.
1-Antitrypsin Deficiency
Wilcke JT, Dirksen A
Respiratory Medicine 91(5):275-9, 1997 May
Despite the success of inhaled steroids in controlling asthma, the benefit in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Five subjects with moderate to severe emphysema due to alpha1-antitrypsin deficiency (phenotype PiZ) were followed with daily home spirometry in a 2 x 8 weeks, randomized double-blind, placebo-controlled, crossover study of inhaled budesonide 0.8 mg b.i.d. In three of the five patients, there was a statistically significant increase in the mean forced expiratory volume in 1 s (FEV1), and in two of these patients, there was also a statistically significant increase in the mean forced vital capacity (FVC) during budesonide treatment. A significant diurnal variation in FEV1 and FVC was found in three and two patients, respectively, but did not change significantly during treatment. These findings emphasize the need for renewed evaluation of inhaled steroids in the treatment of patients with emphysema, and indicate that individual patients may have significant clinical improvement.
1-Antitrypsin (Prolastin) Contains a Conformationally Inactive, Latent Component
Lomas DA, Elliott PR, Carrell RW
European Respiratory Journal 10(3):672-5, 1997 Mar
Fractionated plasma alpha1-antitrypsin is widely-used as replacement therapy in patients with Z alpha1-antitrypsin deficiency-related emphysema. We have recently shown that purified antitrypsin may be induced to adopt an inactive latent conformation by heating at high temperatures in stabilizing concentrations of sodium citrate. Such a conformation was predicted to be present in commercial preparations of antitrypsin, as these require heating under similar conditions for viral inactivation. Native antitrypsin was purified from plasma, and commercial antitrypsin (Prolastin) was obtained from Bayer Corporation. Western blot analysis of transverse urea gradient (TUG) gels showed that commercial antitrypsin migrated as two bands: one with an unfolding profile of native antitrypsin and the second with a profile of latent antitrypsin. A latent fraction, comprising approximately 8% of the total antitrypsin, was separated from the native antitrypsin in Prolastin by anion exchange chromatography. The specific activity of this latent form against bovine alpha-chymotrypsin increased from 1 to 2% to 50% over 3 h after refolding from 6 M guanidine hydrochloride. These data show that commercial antitrypsin contains a latent component. The significance of this conformation in vivo is unknown, although Prolastin has shown few adverse side-effects in prolonged clinical usage.
1-Antitrypsin Deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group
Stoller JK, Buist AS, Burrows B, Crystal RG, Fallat RJ, McCarthy K, Schluchter MD, Soskel NT, Zhang R
Chest 111(4):899-909, 1997 Apr
As part of the multicenter National Heart, Lung, and Blood Institute registry of patients with severe deficiency of alpha1-antitrypsin with 1,129 enrollees, this report describes measures undertaken to achieve high-quality FEV1 measurements, the rates of satisfying reproducibility and acceptability criteria, and clinical features of participants unable to achieve reproducible FEV1 values at baseline. Spirograms were performed both before and after an inhaled bronchodilator in enrollees followed up at 37 participating clinical centers. Using a reproducibility criterion of < 100 mL or 5% (whichever greater), high reproducibility rates for FEV1 measurements at baseline were observed for both prebronchodilator (95.0% of 1,090 sessions) and postbronchodilator measurements (95.7% of 1,077 sessions). Using the more recently published reproducibility criterion of < or = 200 mL, reproducibility rates were even higher. Eighty-four percent of clinical centers submitted FEV1 values that satisfied reproducibility criteria for at least 90% of spirograms. Also, the mean coefficient of variation for prebronchodilator FEV1 values measured over serial visits separated by up to 9 months was 5.6% for participants with baseline FEV1 55 to 90% predicted. This degree of reproducibility is similar to that observed in the Lung Health Study. Rates of satisfying acceptability criteria for prebronchodilator spirograms were lower, almost universally (98% of tests) due to failure to achieve end-of-test criteria (which usually required 15 s of expiration in this population with mean FEV1 = 42.6+/-29.6% [SD] predicted). Multivariate logistic regression models show that clinical correlates of failure to achieve reproducible prebronchodilator FEV1 efforts include symptoms of chronic wheeze, chronic cough, and chronic phlegm, and the degree of airflow obstruction. We conclude that highly reproducible FEV1 measurements are achievable in a population with severe airflow obstruction despite the additional challenges posed by testing in multiple centers on a variety of spirometers. Furthermore, the difficulty of satisfying end-of-test criteria in a large cohort with severe airflow obstruction did not preclude achieving high rates of reproducibility for FEV1 measurements. Finally, our study confirms prior observations that failure to achieve reproducible efforts is associated with the presence of pulmonary symptoms and the degree of airflow obstruction. Thus, excluding patients with nonreproducible FEV1 efforts from epidemiologic studies would bias results by including only healthier participants.
Matthys H
Versicherungsmedizin 47(6):201-3, 1995 Dec 1
The most frequent form of lung emphysema leading to respiratory failure is the tobacco bronchitis-induced type of emphysema the so called chronic obstructive pulmonary (lung) disease (COPD). Histologically the centrilobular or centriacinar emphysema is believed to develop due to elastase and oxidant overload with concomitant antiprotease deficiency. The alpha1-antitrypsin deficiency is a rare genetic defect leading also in non-smoking patients to early death due to panlobular or panacinar emphysema. The functional pattern of both emphysema types shows irreversible lung overinflation with severe mainly expiratory bronchial obstruction with various degrees of pulmonary hypertension alpha1-proteinaseNinhibitor deficiency emphysema is prophylactically treated with prolastine and if hypoxia (PaO2 > 55 mm/Hg) is present with long term oxygen therapy. If hypercapnia develops O2 Therapy is combined with non invasive pressure supported ventilation. Volume reducing surgery may precede. In nonsmoking emphysema patients long term oxygen therapy and later unilateral lung transplantation improves quality of life as well as life expectancy.
1-Antitrypsin Deficiency. A Program for Long-Term Administration
Barker AF, Siemsen F, Pasley D, D'Silva R, Buist AS
Chest 105(5):1406-10, 1994 May
This retrospective chart review describes the efficacy and safety of long-term administration of intravenous alpha1-antitrypsin (AAT) in 14 patients with hereditary AAT deficiency and COPD. During the 12- to 48-month observation period, 12 to 14 patients had stabilization of functional status; 4 patients had reductions in hospitalizations. Thirteen of 14 patients had no decline in pulmonary function. Three patients had self-limited adverse reactions to the AAT with one patient requiring a brief hospitalization.
What's new in diagnostic techniques and therapeutic strategies for alpha1-antitrypsin deficiency in the setting of COPD? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Pulmonary Medicine.
1-Antitrypsin Deficiency
Wilcke JT, Dirksen A
Respiratory Medicine 91(5):275-9, 1997 May
Despite the success of inhaled steroids in controlling asthma, the benefit in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Five subjects with moderate to severe emphysema due to alpha1-antitrypsin deficiency (phenotype PiZ) were followed with daily home spirometry in a 2 x 8 weeks, randomized double-blind, placebo-controlled, crossover study of inhaled budesonide 0.8 mg b.i.d. In three of the five patients, there was a statistically significant increase in the mean forced expiratory volume in 1 s (FEV1), and in two of these patients, there was also a statistically significant increase in the mean forced vital capacity (FVC) during budesonide treatment. A significant diurnal variation in FEV1 and FVC was found in three and two patients, respectively, but did not change significantly during treatment. These findings emphasize the need for renewed evaluation of inhaled steroids in the treatment of patients with emphysema, and indicate that individual patients may have significant clinical improvement.
1-Antitrypsin (Prolastin) Contains a Conformationally Inactive, Latent Component
Lomas DA, Elliott PR, Carrell RW
European Respiratory Journal 10(3):672-5, 1997 Mar
Fractionated plasma alpha1-antitrypsin is widely-used as replacement therapy in patients with Z alpha1-antitrypsin deficiency-related emphysema. We have recently shown that purified antitrypsin may be induced to adopt an inactive latent conformation by heating at high temperatures in stabilizing concentrations of sodium citrate. Such a conformation was predicted to be present in commercial preparations of antitrypsin, as these require heating under similar conditions for viral inactivation. Native antitrypsin was purified from plasma, and commercial antitrypsin (Prolastin) was obtained from Bayer Corporation. Western blot analysis of transverse urea gradient (TUG) gels showed that commercial antitrypsin migrated as two bands: one with an unfolding profile of native antitrypsin and the second with a profile of latent antitrypsin. A latent fraction, comprising approximately 8% of the total antitrypsin, was separated from the native antitrypsin in Prolastin by anion exchange chromatography. The specific activity of this latent form against bovine alpha-chymotrypsin increased from 1 to 2% to 50% over 3 h after refolding from 6 M guanidine hydrochloride. These data show that commercial antitrypsin contains a latent component. The significance of this conformation in vivo is unknown, although Prolastin has shown few adverse side-effects in prolonged clinical usage.
1-Antitrypsin Deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group
Stoller JK, Buist AS, Burrows B, Crystal RG, Fallat RJ, McCarthy K, Schluchter MD, Soskel NT, Zhang R
Chest 111(4):899-909, 1997 Apr
As part of the multicenter National Heart, Lung, and Blood Institute registry of patients with severe deficiency of alpha1-antitrypsin with 1,129 enrollees, this report describes measures undertaken to achieve high-quality FEV1 measurements, the rates of satisfying reproducibility and acceptability criteria, and clinical features of participants unable to achieve reproducible FEV1 values at baseline. Spirograms were performed both before and after an inhaled bronchodilator in enrollees followed up at 37 participating clinical centers. Using a reproducibility criterion of < 100 mL or 5% (whichever greater), high reproducibility rates for FEV1 measurements at baseline were observed for both prebronchodilator (95.0% of 1,090 sessions) and postbronchodilator measurements (95.7% of 1,077 sessions). Using the more recently published reproducibility criterion of < or = 200 mL, reproducibility rates were even higher. Eighty-four percent of clinical centers submitted FEV1 values that satisfied reproducibility criteria for at least 90% of spirograms. Also, the mean coefficient of variation for prebronchodilator FEV1 values measured over serial visits separated by up to 9 months was 5.6% for participants with baseline FEV1 55 to 90% predicted. This degree of reproducibility is similar to that observed in the Lung Health Study. Rates of satisfying acceptability criteria for prebronchodilator spirograms were lower, almost universally (98% of tests) due to failure to achieve end-of-test criteria (which usually required 15 s of expiration in this population with mean FEV1 = 42.6+/-29.6% [SD] predicted). Multivariate logistic regression models show that clinical correlates of failure to achieve reproducible prebronchodilator FEV1 efforts include symptoms of chronic wheeze, chronic cough, and chronic phlegm, and the degree of airflow obstruction. We conclude that highly reproducible FEV1 measurements are achievable in a population with severe airflow obstruction despite the additional challenges posed by testing in multiple centers on a variety of spirometers. Furthermore, the difficulty of satisfying end-of-test criteria in a large cohort with severe airflow obstruction did not preclude achieving high rates of reproducibility for FEV1 measurements. Finally, our study confirms prior observations that failure to achieve reproducible efforts is associated with the presence of pulmonary symptoms and the degree of airflow obstruction. Thus, excluding patients with nonreproducible FEV1 efforts from epidemiologic studies would bias results by including only healthier participants.
Matthys H
Versicherungsmedizin 47(6):201-3, 1995 Dec 1
The most frequent form of lung emphysema leading to respiratory failure is the tobacco bronchitis-induced type of emphysema the so called chronic obstructive pulmonary (lung) disease (COPD). Histologically the centrilobular or centriacinar emphysema is believed to develop due to elastase and oxidant overload with concomitant antiprotease deficiency. The alpha1-antitrypsin deficiency is a rare genetic defect leading also in non-smoking patients to early death due to panlobular or panacinar emphysema. The functional pattern of both emphysema types shows irreversible lung overinflation with severe mainly expiratory bronchial obstruction with various degrees of pulmonary hypertension alpha1-proteinaseNinhibitor deficiency emphysema is prophylactically treated with prolastine and if hypoxia (PaO2 > 55 mm/Hg) is present with long term oxygen therapy. If hypercapnia develops O2 Therapy is combined with non invasive pressure supported ventilation. Volume reducing surgery may precede. In nonsmoking emphysema patients long term oxygen therapy and later unilateral lung transplantation improves quality of life as well as life expectancy.
1-Antitrypsin Deficiency. A Program for Long-Term Administration
Barker AF, Siemsen F, Pasley D, D'Silva R, Buist AS
Chest 105(5):1406-10, 1994 May
This retrospective chart review describes the efficacy and safety of long-term administration of intravenous alpha1-antitrypsin (AAT) in 14 patients with hereditary AAT deficiency and COPD. During the 12- to 48-month observation period, 12 to 14 patients had stabilization of functional status; 4 patients had reductions in hospitalizations. Thirteen of 14 patients had no decline in pulmonary function. Three patients had self-limited adverse reactions to the AAT with one patient requiring a brief hospitalization.
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