Normal Routine Spirometry Can Mask COPD/Emphysema in Symptomatic Smokers.

BACKGROUND: Recent studies have emphasized the difficulty of early detection of chronic obstructive pulmonary disease (COPD) in symptomatic smokers with normal routine spirometry. This includes post-bronchodilator normal forced expiratory volume in 1 second (FEV1)(L)≥80% predicted, forced vital capacity (FVC)(L)≥80% predicted, and FEV1/FVC ≥70% or greater than age corrected lower limit of normal (LLN). However, in COPD the pathologic site of small airway obstruction and emphysema begins in the small peripheral airways ≤2 mm id which normally contribute <20% of total airway resistance. METHODS: Expiratory airflow at high and low lung volumes post-bronchodilator were measured and correlated with lung computed tomography (CT) and lung pathology (6 patients) in 16 symptomatic, treated smokers, and all with normal routine spirometry. RESULTS: Despite normal routine spirometry, all16 patients had isolated, abnormal forced expiratory flow at 75% of FVC (FEF75) using data from Knudson et al, Hankinson et al NHAMES III, and Quanjer et al and the Global Lung Function Initiative. This reflects isolated detection of small airways obstruction and/or emphysema. Measuring airflow at FEF50 detected only 8 of 16 patients, maximal expiratory flow at 25%-75% of FVC (MEF25-75) only 4 of 16, residual volume (RV) 4 of 16, and RV to total lung capacity ratio only 2 of 16. There was excellent correlation between limited lung pathology and lung CT for absence of emphysema. CONCLUSION: This study confirms our earlier observations that detection of small airways obstruction and/or emphysema, in symptomatic smokers with normal routine spirometry, requires analysis of expiratory airflow at low lung volumes, including FEF75. Dependence upon normal routine spirometry may result in clinical and physiologic delay in the diagnosis and treatment in symptomatic smokers with emphysema and small airways obstruction.

Tiotropium induced bronchodilation and protection from dynamic hyperinflation is independent of extent of emphysema in COPD.

BACKGROUND: The magnitude of tiotropium (1) induced bronchodilation and (2) protection against dynamic hyperinflation in COPD phenotypes has not been studied. METHODS: We studied moderate to severe COPD patients with varying extent of emphysema as evaluated by high-resolution thin-section lung CT. Spirometry including inspiratory capacity (IC) was measured before and immediately after metronome paced hyperventilation (MPH) at 2 times resting respiratory rate for 20s to induce dynamic hyperinflation. Spirometry was obtained at baseline and pre- and 1.5h post-18 microg tiotropium via HandiHaler after 30 day tiotropium treatment period in a single blind, open label intervention. RESULTS: In 29 COPD patients (15M), age 70+/-9 years (mean+/-SD) with smoking history of 53+/-37 pack years, baseline forced expiratory volume in 1s (FEV(1)) post-180 microg albuterol MDI was 1.6+/-0.4 L (61+/-8% predicted) and FEV(1)/FVC 59+/-6%. Lung CT emphysema score (LCTES) was 23+/-20 (mean+/-SD) on a scale of 0-100 (none to most severe emphysema). After 30-day tiotropium, FEV(1) increased 101+/-124 mL (mean+/-SD) (p<0.001) and Spearman correlation (r)=-0.04, p=0.8 with LCTES; IC increased 163+/-232 mL (p<0.001), and r=-0.2, p=0.3 with LCTES. Results following MPH induced DH before and after 30-day tiotropium were significant (p<0.001) and similar: IC decreased 340+/-280 mL before and 337+/-270 mL after tiotropium, and r=-0.3, p=0.9 with LCTES. CONCLUSION: Tiotropium significantly increased FEV(1) (L) and inspiratory capacity in moderate-severe COPD, independent of extent of lung CT emphysema score. Despite bronchodilation and lower resting lung volume, tiotropium did not abbreviate induced dynamic hyperinflation, which was also independent of underlying emphysema.

Further Studies of Unsuspected Emphysema in Nonsmoking Patients With Asthma With Persistent Expiratory Airflow Obstruction.

BACKGROUND: Previously, we and other investigators have described reversible loss of lung elastic recoil in patients with acute and persistent, moderate-to-severe, chronic, treated asthma who never smoked, and its adverse effect on maximal expiratory airflow. In four consecutive autopsies, we reported the pathophysiologic mechanism(s) has been unsuspected mild, diffuse, middle and upper lobe centrilobular emphysema. METHODS: We performed prospective studies (5 to 22 years) in 25 patients (12 female) with chronic asthma, age 55 ± 15 years, who never smoked, with persistent moderate-to-severe expiratory obstruction. Studies included measuring blood eosinophils, IgE, total exhaled nitric oxide (NO), central airway NO flux, peripheral airway/alveolar NO concentration, impulse oscillometry, heliox curves, lung elastic recoil, and high-resolution thin-section (1 mm) lung CT imaging at full inspiration with voxel quantification. RESULTS: In 25 patients with stable asthma with varying type 2 phenotype, after 270 µg of aerosolized albuterol sulfate had been administered with a metered dose inhaler with space chamber, FVC was 3.1 ± 1.0 L (83% ± 13% predicted) (mean ± SD), FEV1 was 1.8 ± 0.6 L (59% ± 11%), the FEV1/FVC ratio was 59% ± 10%, and the ratio of single-breath diffusing capacity of the lung for carbon monoxide to alveolar volume was 4.8 ± 1.1 mL/min/mm Hg/L (120% ± 26%). All 25 patients with asthma had loss of static lung elastic recoil pressure, which contributed equally to decreased intrinsic airway conductance in limiting expiratory airflow. Lung CT scanning detected none or mild emphysema. In all four autopsied asthmatic lungs previously reported and one unreported explanted lung, microscopy revealed unsuspected mild, diffuse centrilobular emphysema in the upper and middle lung fields, and asthma-related remodeling in airways. In eight cases, during asthma remission, there were increases in measured static lung elastic recoil pressure-calculated intrinsic airway conductance, and measured maximal expiratory airflow at effort-independent lung volumes. CONCLUSIONS: As documented now in five cases, unsuspected microscopic mild centrilobular emphysema is the sentinel cause of loss of lung elastic recoil. This contributes significantly to expiratory airflow obstruction in never-smoking patients with asthma, with normal diffusing capacity and near-normal lung CT scan results. TRIAL REGISTRY: Protocol No. 20070934 and Study No. 1090472, Western Institutional Review Board, Olympia, WA; ClinicalTrials.gov; No. NCT00576069; URL: www.clinicaltrials.gov.

Central and peripheral airway sites of nitric oxide gas exchange in COPD.

BACKGROUND: This study investigated sites of nitric oxide (NO) gas exchange and response to inhaled corticosteroids (ICS) in patients with COPD and varying extents of emphysema. METHODS: This was a prospective, randomized, single-blind, crossover study in treated, stable, ex-smoking patients with COPD who were ICS and leukotriene receptor antagonists naive. Lung function, high-resolution thin-section CT scan of the lung, and exhaled NO were measured at 50, 100, 150, and 200 mL/s. Airway NO was adjusted for NO axial backdiffusion. RESULTS: In 39 (18 women), clinically stable ex-smokers with COPD aged 73 +/- 9 years (mean +/- SD) on salmeterol 50 microg (S50) bid, after 180 microg aerosolized albuterol, FEV(1) (L) was 52% +/- 12% predicted and FEV(1)/FVC was 55% +/- 6%. Compared with 20 (12 men) age-matched controls, 39 patients with COPD had normal large airway NO flux and small airway/alveolar NO. Subsequently, 19 patients with COPD (Group A) were randomized and continued on S50, and 20 (Group B) were randomized to fluticasone propionate 250 microg (F250)/S50 bid for 86 +/- 16 days. Group A (S50) patients were then switched to F250/S50, and 12 of 19 completed 77 +/- 15 days; there was significant (P < .001) reduction only in the exhaled fraction of NO (FENO) at 50 mL/s and large airway NO flux. In 20 patients with COPD initially randomized to F250/S50 (Group B), after 57 +/- 22 days of S50 in 16 of 20 patients there was a significant (P = .04) increase only in (FENO) at 50 mL/s and large airway NO flux, which was not reduced after 60 +/- 23 days of fluticasone propionate 100 microg (F100)/S50(P = .07). There was no correlation between NO gas exchange and CT-scored emphysema. CONCLUSIONS: In COPD, there was normal NO gas exchange in both large and small airways/alveoli and only large airway NO flux was suppressed with F250/S50 but not F100/S50, despite varying extents of emphysema. Peripheral NO must be corrected for axial NO backdiffusion to avoid spurious conclusions. TRIAL REGISTRATION: NCT #00568347.

Alveolar and airway sites of nitric oxide inflammation in treated asthma.

The goal of this study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in treated patients with asthma, including response to oral corticosteroids, and correlate these sites with expiratory airflow limitation. In 53 (24 male) patients with asthma, age 43 +/- 23 years (mean +/- SD) and all on inhaled corticosteroids, post 180 microg aerosolized albuterol, FEV(1) was 74 +/- 23% predicted and FEV(1)/FVC was 68 +/- 11%. Exhaled NO at 100 ml/second was 27 +/- 23 ppb (p < 0.001 compared with normal, 12 +/- 15 ppb). Bronchial NO maximal flux was 2.4 +/- 3.1 nl/second (p < 0.001 compared with normal, 0.85 +/- 0.55). Alveolar NO concentration was 7.0 +/- 7.4 ppb (p = 0.01 compared with the normal value, 3.2 +/- 2.0 ppb). There was no significant correlation between FEV(1) % predicted or lung elastic recoil and NO bronchial flux or alveolar concentration. However, there was a weak but significant correlation between NO bronchial flux and alveolar concentration (Spearman r = 0.50, p < 0.001). In 10 subjects with asthma on inhaled corticosteroids, 5 days of 30 mg prednisone resulted in isolated significant decreases in NO alveolar concentration, from 13 +/- 10 to 4 +/- 4 ppb (p = 0.002). Despite treatment, including inhaled corticosteroids, patients with asthma may have ongoing separate airway and alveolar sites of NO inflammation, the latter responsive to oral corticosteroids.