Mark J. Schein

A randomized prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema

Two procedures (laser bullectomy and lung reduction surgery with staples) are currently available for the surgical treatment of patients with diffuse emphysema. We compared the efficacy of these two surgical approaches in 72 patients, aged 67 +/- 7 years (mean +/- standard deviation), who had diffuse emphysema scored as severe on computed tomography and severe fixed expiratory airflow obstruction. The patients were prospectively randomized to undergo either neodymium:yttrium aluminum garnet contact laser surgery (n = 33) or stapled lung reduction surgery (n = 39) by unilateral thoracoscopy. The operative mortalities were 0% and 2.5%, respectively. No significant differences were noted between the groups (p < 0.05) with respect to operating time, hospital days, or air leakage for more than 7 days. However, a delayed pneumothorax developed in six patients (18%) who had laser treatment (p = 0.005). The operations eliminated dependency on supplemental oxygen in 52% of the laser group and 87.5% of the stapled lung reduction group (p = 0.02). The mean postoperative improvement in the forced expiratory volume in 1 second at 6 months was significantly greater for the patients undergoing the staple technique (32.9% vs 13.4%, p = 0.01) than for the laser treatment group.

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.

Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction

responsible for this separation: levels of threonine (and/or lactate), alanine, carnitine, acetylcarnitine, and trimethylamineN-oxide were suggested to be increased in the exacerbated condition, whereas levels of acetate, citrate, malonate, hippurate, dimethylglycine, and phenylacetylglutamine seemed to be decreased compared with the stable condition (Fig 2, B). During exacerbations, urine revealed increased levels of aldehydes and alkanes, as well as alterations in a number of nonvolatile metabolites. As for limitations and strengths of this study, diet and current treatment might interfere with the urine metabolomic profile. No food restriction was made. Despite all patients having a similar initial dose of methylprednisolone (approximately 80 mg/d), this remains a confounding factor. Further studies with a larger population are necessary to confirm these findings. The use of 2 high-throughput techniques used in this study provides complementary information, enhancing the current understanding of themetabolic pathways affected (see the Results and discussion, Limitations and strengths section, in this article’s Online Repository at www.jacionline.org). Alkanes and aldehydes, end products of the peroxidation of unsaturated fats, can be formed during inflammation. Their levels were found to be increased during exacerbation, suggesting a high level of oxidative stress compared with the stable state (see the Results and discussion, Data interpretation section, in this article’s Online Repository at www.jacionline.org). Carnitine and acetylcarnitine can be linked to increased oxidative burden because they play an essential role in the transport of fatty acids into mitochondria for oxidation. These metabolites are critically altered in asthmatic patients. Moreover, changes in metabolites, such as citrate and alanine, suggest a disturbance of the tricarboxylic acid cycle, whereas altered levels of trimethylamine-N-oxide, hippurate, and phenylacetylglutamine might be related to diet. Urine is an easily accessible and information-rich biofluid. Our preliminary data show that urine metabolomics might provide important information on the patients’ oxidative stress status. They also show promise in asthma management. This would suggest that research on metabolomic signatures in a broader group of asthmatic patients, including different phenotypes and disease presentation, might be valuable. In conclusion, urinarymetabolic compositionwas highly altered during exacerbation comparedwith that seen in the stable state. GC 3 GC-TOFMS– and H-NMR–based methodologies allowed complementary information to be retrieved. In spite of the limited number of cases considered, the present results suggest that oxidative stress is a fundamental factor in asthma exacerbation.

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 &mgr;g 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.