Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema.

This review covers protease-antiprotease imbalance in the development of emphysema in smokers. This imbalance is likely to play a major pathogenic role in the development of emphysema in subjects with severe alpha1-antitrypsin deficiency who smoke because of a deficient antiprotease protection against neutrophil elastase release in the lung. Neutrophil elastase is a potent elastolytic enzyme, and its instillation in the lungs of animals results in emphysema. Smoking attracts neutrophils to the lungs and there is an additional accumulation of neutrophils, because the abnormal antitrypsin polymerizes in the lungs and acts as a chemo-attractant to neutrophils. In subjects who do not have antitrypsin deficiency, the case for elastolytic injury by neutrophils causing emphysema is less definite, because of the lack of a severe deficiency of active alpha1-ntitrypsin leading to unopposed elastolysis by neutrophil elastase. It is likely that alveolar macrophages play a pathogenic role in emphysema; they express potent elastolytic enzymes, cathepsins and matrix metalloproteases (MMPs), which are induced by smoking. The numbers of macrophages are increased in the region of the respiratory bronchiole, where centrilobular emphysema develops in smokers. Macrophage cathepsins are inhibited by an antiprotease cystatin C, while the MMPs are inhibited by the tissue inhibitors of metalloproteases (TIMPs). Some pro-inflammatory mediators induce release of MMPs from macrophages without inducing increase in TIMPs, leading to possible protease-antiprotease imbalance. Studies of proteases in alveolar macrophages obtained by bronchoalveolar lavage and studies on lung tissue indicate increased protease expression in subjects with chronic obstructive pulmonary disease (COPD) compared to subjects without COPD.

Goodpasture's syndrome: recurrence after a five-year remission. Case report and review of the literature.

Herein is reported the case of a man who has had a recurrence of Goodpasture's syndrome following a five-year remission. The patient presented initially in 1977 at the age of 28 with Goodpasture's syndrome manifested by pulmonary hemorrhage without clinical evidence of renal disease, and positive antiglomerular basement membrane antibody. Following treatment with corticosteroids, remission occurred and the serum antiglomerular basement membrane antibody became negative. In 1983, he experienced a relapse with the reappearance of serum antiglomerular basement membrane antibody, the development of severe life-threatening intrapulmonary hemorrhage, and hematuria. This case illustrates that life-threatening relapse may occur in Goodpasture's syndrome despite a prolonged remission and the disappearance of detectable antiglomerular basement membrane antibody in the circulation.

Impaired exercise performance after successful liver transplantation.

BACKGROUND: Recipients of heart, lung, and kidney transplants have impaired peak exercise performance (peak Vo2 40% to 60% predicted, reduced anaerobic threshold [AT]) without evidence of ventilatory or cardiac limitations. The aim of this study was to determine whether similar exercise impairment occurs in liver transplant recipients. METHODS: We studied eight healthy liver transplant recipients (age 42+/-9 [SD] years, 6 male, 31+/-13 months posttransplant). Immunosuppression included FK506 or cyclosporine, azathioprine or mycophenolate mofetil, and prednisone. Subjects underwent lung function testing and cardiopulmonary exercise testing on a cycle ergometer. RESULTS: Peak exercise oxygen consumption (Vo2) was 22+/-8 ml/min/kg (66+/-20% predicted maximum). No subject demonstrated exercise desaturation or ventilatory limitation (peak minute ventilation 55+/-8% predicted maximum voluntary ventilation). Peak heart rate was 87+/-8% of predicted maximum. Early AT was evident (1.2+/-0.34 L/min, 48+/-11% predicted Vo2max). CONCLUSIONS: Liver transplant recipients exhibit impaired peak exercise performance similar to that observed after other solid organ transplants, possibly as a result of chronic deconditioning or myopathy related to immunosuppressive medications.

Interlaboratory and intralaboratory variability in pulmonary function testing. A 13-year study using a normal biologic control.

The purpose of this study was to document the precision with which measurements can be made on a normal subject as a "biologic control" when comparisons are made both on an intralaboratory and interlaboratory basis. One individual had a total of about 300 routine pulmonary function measurements in 22 laboratories during a 13-year period. In this study, significant variation was found in interlaboratory testing, while less variation was found in intralaboratory measurements. This technique of periodic testing of normal individuals as biologic controls is useful for documenting reproducibility and precision; evaluation of accuracy will require a check of the physical calibration of the equipment. The testing (on at least a monthly basis) of a normal nonsmoking subject as a biologic control is recommended as an integral component of quality assurance in the pulmonary function laboratory.

Effect of oral administration of delta-tetrahydrocannabinol on airway mechanics in normal and asthmatic subjects.

We performed a double-blind study on the effect of oral administration of 10 mg of delta9-tetrahydrocannabinol on specific airway conductance (Gaw/VL) and the maximal expiratory flow at 50% of vital capacity (Vmax 50%) in six control and six asthmatic subjects. In control subjects, there was a slight but statistically significant increase in Gaw/VL after oral administration of delta9-tetrahydrocannabinol; however, there was no significant increase in Vmax 50%. One of the asthmatic patients developed severe bronchoconstriction following administration of delta9-tetrahydrocannabinol; among the remaining five patients, there were variable changes in Gaw/VL and Vmax 50% after oral administration of delta9-tetrahydrocannabinol, but mean changes were not significant. Mild effects on the central nervous system (CNS) were observed in three subjects; six subjects, three of whom had unpleasant mood changes, had more prominent CNS effects. We concluded that oral administration of delta9-tetrahydrocannabinol is unlikely to be of therepeutic value in asthma, since its bronchodilator action was mild and inconstant and was associated with significant CNS effects. Moreover, one asthmatic patient developed severe bronchoconstriction following oral administration of delta 9-tetrahydrocannabinol.

Effect of smoking on functional activity of plasma alpha 1-protease inhibitor.

We determined the levels of alpha 1-protease inhibitor, the plasma trypsin-inhibiting capacity (TIC), and elastase-inhibiting capacity (EIC) in 29 nonsmokers and 30 smokers, who were healthy volunteers matched for age (mean age, 39 +/- 12 years [+/- SD]). The functional activity of plasma alpha 1-protease inhibitor (in micrograms of enzyme inhibited per microgram of alpha 1-protease inhibitor) was slightly but significantly lower in smokers, compared with nonsmokers, both for TIC and EIC (smokers' TIC and EIC were 88.0 +/- 16.2 percent (+/- SD) and 90.4 +/- 17.9 percent of the respective mean values in nonsmokers; p less than 0.05). Among smokers, there was a significant negative correlation (r = -0.37; p less than 0.05) between the average number of cigarettes smoked per day and the functional activity of plasma alpha 1-protease inhibitor; the seven subjects who smoked 40 or more cigarettes per day had significantly lower EIC and TIC than the remaining smokers. In 12 smokers tested before and after a two-hour period of intense smoking of eight cigarettes, there was a statistically significant decrease (p less than 0.05) in EIC one hour after smoking to 93.9 +/- 2.5 percent (+/- SE) of the initial value prior to smoking. It is concluded that there is a slight but significant decrease in the functional activity of plasma alpha 1-protease inhibitor in smokers, both for TIC and EIC.

"Density mask". An objective method to quantitate emphysema using computed tomography.

We used a computed tomography (CT) scanner program ("density mask") that highlights voxels within a given density range to quantitate emphysema by defining areas of abnormally low attenuation. We compared different density masks, mean lung attenuation, visual assessment of emphysema and the pathologic grade of emphysema in 28 patients undergoing lung resection for tumor. In each patient, a single representative CT image was compared with corresponding pathologic specimens of tissue. There was good correlation between the extent of emphysema as assessed by the density mask and the pathologic grade of emphysema. The optimal attenuation level to define areas of emphysema may vary in different scanners, but, once determined for a particular scanner, the density mask accurately assesses the extent of emphysema and eliminates interobserver and intraobserver variability. It has the added advantage of determining the exact percentage of lung parenchyma showing changes consistent with emphysema.

Quantitation of emphysema by computed tomography using a "density mask" program and correlation with pulmonary function tests.

We used a CT program "density mask" outlining areas with attenuation values less than -910 HU, to indicate areas of emphysema on a chest CT and to provide an overall percentage of lung involvement by emphysema. The "density mask" quantitation of emphysema was previously shown to correlate well with the pathologic assessment of emphysema in patients undergoing lung resection. We compared the CT quantitation of emphysema with mean lung density, overall lung volume on CT and pulmonary function tests in 85 patients. There was a significant correlation between the extent of emphysema on CT and FEV/FVC percent of predicted, functional residual capacity percent predicted and Dsb percent predicted. Determination of the percentage of lung with areas of low attenuation by CT provides a useful method for quantitating emphysema in life and correlates significantly with pulmonary function tests.

Relationship of alveolar macrophage plasminogen activator and elastase activities to lung function and CT evidence of emphysema.

OBJECTIVE: To evaluate the relationship between alveolar macrophage (AM) elastase and plasminogen activator (PA) activities (considered to be potential pathogenetic factors in emphysema) and the development of emphysema in smokers. PARTICIPANTS: Thirty-four healthy smokers >35 years of age (mean+/-SD, 46+/-7 years), with a mean+/-SD of 33+/-10 pack-years of smoking, who were recruited as volunteers. METHODS: Subjects had lung function testing and BAL to obtain AMs; limited high-resolution CT scans of the chest were obtained in 32 subjects to assess the presence of emphysema. Macrophage PA and elastase were determined using AM cultured on (131)I-fibrin-coated plates and 3H-elastin-coated plates, respectively. RESULTS: The number of AMs recovered per milliliter of BAL was significantly greater in the 16 subjects with CT evidence of mild emphysema than the 16 subjects without evidence of emphysema (669+/-301 x 10(3)/mL vs 414+/-268x 10(3)/mL; p=0.01). There was no significant difference between AM elastase or PA activities in the 16 subjects with CT evidence of mild emphysema, when compared with the 16 subjects who had no CT evidence of emphysema (elastase, 2.72+/-1.35 microg vs 2.49+/-0.91 microg elastin per 10(6) AMs per first 24 h; PA, 0.375+/-0.126 vs 0.344+/-0.096 urokinase units/10(6) AMs). There was no significant correlation between levels of PA or elastase activities and FEV1, FEV1/FVC, forced expiratory flow rate between 25% and 75% of the FVC; PA activity but not elastase activity had a significant negative correlation (r=-0.47, p<0.01) with diffusion of carbon monoxide (DCO). The macrophage count in BAL had a significant negative correlation with DCO percent predicted (r=-0.61, p<0.001). CONCLUSIONS: The findings suggest that the number of AMs recovered per milliliter of BAL (presumably indicating the number in the alveolar spaces) is related to the development of emphysema in smokers as indicated by CT scan of the chest and DCO. The results also suggest that the level of PA enzyme activity in AMs may be a pathogenetic factor in the decrease in DCO in smokers.

Bronchial leukocyte proteinase inhibitor levels in bronchial washings in asthma patients.

To evaluate whether epithelial damage of airways in asthma could be related to diminished levels of the low molecular weight bronchial leukocyte proteinase inhibitor (BLPI) in airways, we determined BLPI in bronchial washings of 13 asthma patients and 13 healthy subjects, using a sensitive enzyme-linked immunoassay. The patients had asthma due to western red cedar and had bronchial washings done 24 to 48 hours after a mild to moderate asthmatic reaction induced by inhalation challenge. We did not find significant differences in BLPI concentrations in lavage fluid of asthma patients and healthy control subjects. The ratios of BLPI to albumin levels in bronchial washings appeared to be lower among asthmatic patients, but this difference was mainly due to an increase in albumin levels in lavage fluid in asthma. In addition, there were no significant differences in BLPI levels in washings obtained from main and segmental bronchi in both control subjects and asthma patients.

Effect of exposure of guinea pigs to cigarette smoke on elastolytic activity of pulmonary macrophages.

STUDY OBJECTIVE: To determine the effect of exposure to cigarette smoke on the elastolytic activity of guinea pigs' alveolar macrophages (AMs), and to compare elastolytic activity of AMs obtained by BAL with that of lung macrophages (LMs) obtained from minced lung tissue. METHODS: AMs were obtained by BAL from seven adult guinea pigs exposed to cigarette smoke for 5 d/wk during 6 weeks, as well as from age-matched control guinea pigs. From each animal, one lung was used to obtain LMs by mincing and teasing the lung, followed by enzymatic digestion and isolation of mononuclear cells by Hypaque-Ficoll separation. The other lung was inflated and fixed to quantitate emphysema by the destructive index (DI). Elastolytic activity (microgram of elastin degraded by 10(6) macrophages) was determined at 24, 48, and 72 h, by culturing AMs and LMs (1 x 10(6) cells in 1 mL of medium) in 3H-elastin-coated wells. RESULTS: In animals exposed to cigarette smoke, the total number of BAL cells (8.6+/-2.1 x 10(6)) and DI (21.8+/-8.1) were significantly higher than in nonexposed animals (6.4+/-1.8 x 10(6), p<0.05 for cells, and 12.1+/-4.1, p<0.01 for DI). Elastolytic activity of AMs from smoke-exposed guinea pigs was significantly higher at 24, 48, and 72 h than elastolytic activity of AMs from control animals (19.0+/-9.4 vs 10.0+/-5.3, p<0.05 at 72 h). Likewise, elastolytic activity of LMs was significantly higher in exposed than nonexposed guinea pigs (11.8+/-7.7 vs 7.4+/-5.0 at 72 h, p<0.05). Elastolytic activity of LMs was not significantly different from elastolytic activity of AMs, both in exposed guinea pigs (11.8+/-7.7 vs 19.0+/-9.4 at 72 h) and nonexposed animals (7.4+/-5.0 vs 10.0+/-5.3 at 72 h). CONCLUSIONS: These results indicate that elastolytic activity of both AMs and LMs of guinea pigs increases significantly after exposure to cigarette smoke and that AMs and LMs have similar elastolytic activities.

Cardiovascular safety of high doses of inhaled fenoterol and albuterol in acute severe asthma.

BACKGROUND: It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma. METHODS: Asthmatic patients presenting to the ED with acute severe asthma (FEV1 less than 50% of predicted) were enrolled in a multicenter, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determination of serum potassium and serum theophylline levels, oximetry, 12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol, 200 micrograms per puff, or albuterol, 100 micrograms per puff, 1 puff every 30 s via an MDI attached to a holding chamber. Additional doses of inhaled beta 2-agonist were administered by dose titration, 2 puffs every 10 min to a maximal cumulative dose of 16 puffs of albuterol or fenoterol, side effects were intolerable to the patient, or an FEV1 plateau (i.e., < 10% improvement for 2 consecutive doses) occurred. ECG was recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV1 were assessed after each dose. RESULTS: 128 patients were randomized to receive fenoterol and 129 to receive albuterol. Overall, fenoterol increased FEV1 160 mL more than albuterol. The mean (SEM) FEV1 increase from baseline was 0.75 +/- 0.06 L in the fenoterol group and 0.59 +/- 0.06 L in the albuterol group (p < 0.03). Both beta 2-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23 +/- 0.04 mmol/L) than in the salbutamol (0.06 +/- 0.03 mmol/L) group (p = 0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011 +/- 0.003 s compared with 0.003 +/- 0.003 s in the albuterol group (p < 0.05). Differences in hypokalemia and Q-Tc prolongation associated with fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol group. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycardia were detected in either group. CONCLUSIONS: In adequately oxygenated patients, using dose titration of fenoterol, in a formulation of 200 micrograms per puff by MDI valved holding chamber and mask, to a total dose of 3,200 micrograms and salbutamol (100 micrograms per puff) to a total dose of 1,600 micrograms over 90 min, showed cardiovascular safety in acute severe asthma. This was evidenced by absence of cardiovascular mortality or clinically significant arrhythmias in either group. The 100% greater dose of fenoterol improved FEV1 significantly more than salbutamol and was associated with a relatively small but significantly greater prolongation of the Q-Tc interval and decrease in serum potassium level. This study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia.

Assessment of the antielastase activities in bronchoalveolar lavage fluid: effect of assay buffer ionic strength.

OBJECTIVE: To evaluate the effect of assay buffer ionic strength on assessment of the antielastase activities in bronchoalveolar lavage fluid. METHOD: An improved assay protocol in which elastase (in Tris-HCI buffer) is added to increasing volumes of test samples (made up to equal volume with phosphate-buffered saline) was used. RESULTS: The percent NE activity inhibited by BALF decreased with increasing NaCl concentration of the buffer. Inhibition of pancreatic elastase (PE) was not affected. One hundred percent inhibition of NE by pure AAT and SLPI standards occurred at molar ratios of 0.91 +/- 0.03 for AAT-to-NE and 0.83 +/- 0.02 for SLPI-to-NE when assayed in buffer with < or = 0.15 mol NaCl/L, compared to ratios of 0.99 +/- 0.02 and 1.06 +/- 0.02, respectively, for assays in buffers with 0.50-1.00 mol NaCl/L (p < 0.05 for AAT-to-NE; p < 0.02 for SLPI-to-NE). The AAT-to-PE molar ratio at 100% inhibition of PE was not affected. Assays in buffer with < or = 0.15 mol NaCl/L indicated that 86.9 +/- 4.1% of AAT and 100.9 +/- 4.9% of SLPI in BALF were active against NE, while assays in buffer with 0.50-1.00 mol NaCl/L showed that 84.4 +/- 3.5% of AAT and 81.6 +/- 5.9% of SLPI present were active. AAT inhibited NE and PE equally only in buffer with 0.50-1.00 mol NaCl/L. CONCLUSIONS: The results of assays of BALF antielastase activities depend on the assay buffer NaCl concentration, which may account for the conflicting reports in the literature. The buffer with 0.50-1.00 mol NaCl/L appear to be optimal for valid quantitation of anti-NE activities in BALF.

Effect of assay conditions on measurement of elastolytic activity of alveolar macrophages in culture and characterization with proteinase inhibitors.

We have investigated whether varied assay conditions account for the conflicting reports on measured elastolytic activity of alveolar macrophages (AM) cultured in direct contact with the 3H-elastin substrate coated onto 16-mm wells in serum-containing media. The data indicate that measured elastolytic activity in this assay system was dependent on the amount of 3H-elastin/culture well. 3H-elastin > 350 micrograms/well, in contrast to the < or = 200 micrograms/well commonly used in this assay system, resulted in optimal measurement of elastolytic activity that was linear with respect to culture time (up to 72 h examined) and was directly proportional to number of AM/well (up to 1.0 x 10(6) examined). The sensitivity of measured elastolytic activity to tissue inhibitor of metalloproteinases (TIMP) and to Z-phe-phe (a specific cysteine proteinase inhibitor) was not affected by amount of 3H-elastin/well, but appears to be dependent on the time period of AM culture. TIMP (at 5 microM, maximal dose examined) inhibited the measured elastolytic activity by 25% in 24-h cultures compared to 69% in 72-h cultures; Z-phe-phe (at 10 microM, dose at which maximal effect was obtained) inhibited the elastolytic activity by 45% in the 24-h cultures compared to 34% in the 72-h cultures. These findings indicate that differences in substrate levels and in culture time have a significant effect on the results obtained in measurement of AM-mediated elastolytic activity in culture, which may account for the conflicting reports in the literature. Thus standard optimal assay condition are required for valid interpretation of results of AM-mediated elastolytic activity measurements.

The effect of postural drainage positioning on ventilation homogeneity in healthy subjects.

Body position is known to have significant effects on oxygen transport. These effects, however, are seldom considered during postural drainage (PD). The purpose of this study was to examine the effect of modified PD positions on ventilation homogeneity (the evenness of the distribution of ventilation), which is a key component of oxygen transport. The single-breath nitrogen washout test was used to obtain an index of ventilation homogeneity (slope of phase 3 [SBN2/L%]). Seventeen healthy individuals, ranging from 22 to 40 years of age ( mean = 28.4, SD = 5.6), performed the single-breath nitrogen test while sitting, lying supine with the bed tipped head down, right side lying, and right side lying with the bed tipped head down. Within-subject one-way analyses of variance and Tukey's post hoc analyses were used to compare differences in SBN2/L% across the four positions. The distribution of ventilation was significantly less homogeneous in the side-lying positions compared with the supine and sitting positions. Although these results reflect a position-induced change in pleural pressure gradient, they also reflect the effect of gravity-independent, intraregional changes on ventilation distribution. Thus, modified PD positioning has a significant effect on ventilation homogeneity, which may predispose a patient to arterial desaturation. Given the complexity of the factors involved, patients considered for PD positioning should be monitored for arterial saturation.

Effects of side lying on lung function in older individuals.

BACKGROUND AND PURPOSE: Body positioning exerts a strong effect on pulmonary function, but its effect on other components of the oxygen transport pathway are less well understood, especially the effects of side-lying positions. This study investigated the interrelationships between side-lying positions and indexes of lung function such as spirometry, alveolar diffusing capacity, and inhomogeneity of ventilation in older individuals. SUBJECTS AND METHODS: Nineteen nonsmoking subjects (mean age=62.8 years, SD=6.8, range=50-74) with no history of cardiac or pulmonary disease were tested over 2 sessions. The test positions were sitting and left side lying in one session and sitting and right side lying in the other session. In each of the positions, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), single-breath pulmonary diffusing capacity (DLCO/VA), and the slope of phase III (DN2%/L) of the single-breath nitrogen washout test to determine inhomogeneity of ventilation were measured. RESULTS: Compared with measurements obtained in the sitting position, FVC and FEV1 were decreased equally in the side-lying positions, but no change was observed in DLCO/VA or DN2%/L. CONCLUSION AND DISCUSSION: Side-lying positions resulted in decreases in FVC and FEV1, which is consistent with the well-documented effects of the supine position. These findings further support the need for prescriptive rather than routine body positioning of patients with risks of cardiopulmonary compromise and the need to use upright positions in which lung volumes and capacities are maximized.

Alpha1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society.

OBJECTIVE: To prepare new guidelines for the Canadian Thoracic Society (CTS) regarding severe alpha1-antitrypsin (AAT) deficiency and AAT replacement therapy. MATERIALS AND METHODS: Previously published guidelines and the medical literature about AAT deficiency and AAT replacement were reviewed. The prepared statement was reviewed and approved by the CTS Standards and Executive Committees. RESULTS: Three studies evaluated AAT replacement. The National Heart, Lung and Blood Institute's AAT Registry was a nonrandomized comparison of patients receiving and not receiving AAT replacement, and evaluated the decline in forced expiratory volume in 1 s (FEV1) in 927 subjects. The rate of FEV1 decline was significantly less in those receiving AAT treatment (66 +/- SE 5 mL/year versus 93 +/- SE 11 mL/year; P=0.03) only in the subgroup with FEV1 35% to 49% predicted. In another study comparing 198 German patients receiving weekly AAT infusions and 97 untreated Danish patients, the mean annual decline in FEV1 was significantly less in treated patients only in the subgroup with FEV1 31% to 65% predicted (62 mL versus 83 mL, P=0.04). Neither of these studies was a randomized, controlled study and, thus, cannot be taken as proof of efficacy. A randomized, double-blind, placebo controlled trial of monthly replacement therapy over three years in 56 exsmokers with severe AAT deficiency and moderate emphysema showed a trend (P=0.07) favouring slower progression of emphysema by computed tomography scan in the group receiving AAT replacement. CONCLUSIONS: AAT replacement therapy has not been proven definitively to be clinically effective in reducing the progression of disease in AAT-deficient patients, but there is a possible benefit to selected patients. A placebo controlled, randomized clinical trial of AAT replacement therapy is required. The authors recommend reserving AAT replacement therapy for AAT-deficient patients with impaired FEV1 of 35% to 50% predicted who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV1, and participation of all AAT-deficient subjects in the Canadian AAT Registry.