Arthur F. Gelb

Exhaled nitric oxide in pulmonary diseases: a comprehensive review

The upregulation of nitric oxide (NO) by inflammatory cytokines and mediators in central and peripheral airway sites can be monitored easily in exhaled air. It is now possible to estimate the predominant site of increased fraction of exhaled NO (FeNO) and its potential pathologic and physiologic role in various pulmonary diseases. In asthma, increased FeNO reflects eosinophilic-mediated inflammatory pathways moderately well in central and/or peripheral airway sites and implies increased inhaled and systemic corticosteroid responsiveness. Recently, five randomized controlled algorithm asthma trials reported only equivocal benefits of adding measurements of FeNO to usual clinical guideline management including spirometry; however, significant design issues may exist. Overall, FeNO measurement at a single expiratory flow rate of 50 mL/s may be an important adjunct for diagnosis and management in selected cases of asthma. This may supplement standard clinical asthma care guidelines, including spirometry, providing a noninvasive window into predominantly large-airway-presumed eosinophilic inflammation. In COPD, large/central airway maximal NO flux and peripheral/small airway/alveolar NO concentration may be normal and the role of FeNO monitoring is less clear and therefore less established than in asthma. Furthermore, concurrent smoking reduces FeNO. Monitoring FeNO in pulmonary hypertension and cystic fibrosis has opened up a window to the role NO may play in their pathogenesis and possible clinical benefits in the management of these diseases.

Unraveling the Pathophysiology of the Asthma-COPD Overlap Syndrome: Unsuspected Mild Centrilobular Emphysema Is Responsible for Loss of Lung Elastic Recoil in Never Smokers With Asthma With Persistent Expiratory Airflow Limitation

Investigators believe most patients with asthma have reversible airflow obstruction with treatment, despite airway remodeling and hyperresponsiveness. There are smokers with chronic expiratory airflow obstruction despite treatment who have features of both asthma and COPD. Some investigators refer to this conundrum as the asthma-COPD overlap syndrome (ACOS). Furthermore, a subset of treated nonsmokers with moderate to severe asthma have persistent expiratory airflow limitation, despite partial reversibility. This residuum has been assumed to be due to large and especially small airway remodeling. Alternatively, we and others have described reversible loss of lung elastic recoil in acute and persistent loss in patients with moderate to severe chronic asthma who never smoked and its adverse effect on maximal expiratory airflow. The mechanism(s) responsible for loss of lung elastic recoil and persistent expiratory airflow limitation in nonsmokers with chronic asthma consistent with ACOS remain unknown in the absence of structure-function studies. Recently we reported a new pathophysiologic observation in 10 treated never smokers with asthma with persistent expiratory airflow obstruction, despite partial reversibility: All 10 patients with asthma had a significant decrease in lung elastic recoil, and unsuspected, microscopic mild centrilobular emphysema was noted in all three autopsies obtained although it was not easily identified on lung CT scan. These sentinel pathophysiologic observations need to be confirmed to further unravel the epiphenomenon of ACOS. The proinflammatory and proteolytic mechanism(s) leading to lung tissue breakdown need to be further investigated.

Review of exhaled nitric oxide in chronic obstructive pulmonary disease

The up-regulation of nitric oxide (NO) by inflammatory cytokines and mediators in central and peripheral airway sites can be easily monitored in exhaled air (F(E)NO). It is now possible to estimate the predominant airway site of increased F(E)NO i.e. large versus peripheral airway/alveoli, and its potential pathologic and physiologic role in obstructive lung disease. In asthma, six double-blind, randomized, controlled algorithm trials have reported only equivocal benefits of add-on measurements of F(E)NO to usual clinical guideline management including spirometry. Significant design issues, as emphasized by Gibson, may exist. However, meta-analysis of these six studies (Petsky et al 2012 Thorax 67 199-208) concluded that routine serial measurements of F(E)NO for clinical asthma management does not appear warranted. In COPD including chronic bronchitis and emphysema, despite significant expiratory airflow limitation, when clinically stable as well as during exacerbation, F(E)NO, j(awNO) and C(ANO) may all be normal or increased. Furthermore, the role of add-on monitoring of exhaled NO to GOLD management guidelines is less clear because of the absence of conclusive doubleblind, randomized, control trial studies concerning potential clinical benefits in the management of COPD.

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.

Understanding the pathophysiology of the asthma–chronic obstructive pulmonary disease overlap syndrome

Purpose of review The review will provide an update on the pathophysiology and studies of inflammation associated with the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) and the mechanism(s) responsible for persistent expiratory airflow limitation in never-smoked asthma patients who develop loss of lung elastic recoil consistent with an asthma–COPD clinical phenotype (ACOS in nonsmokers).

Understanding the pathophysiology of the asthma-chronic obstructive pulmonary disease overlap syndrome.

Purpose of review The review will provide an update on the pathophysiology and studies of inflammation associated with the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) and the mechanism(s) responsible for persistent expiratory airflow limitation in never-smoked asthma patients who develop loss of lung elastic recoil consistent with an asthma–COPD clinical phenotype (ACOS in nonsmokers). Recent findings Patients with a clinical diagnosis of ACOS have more frequent respiratory exacerbations and hospitalizations than COPD patients without ACOS. ACOS patients should be treated with inhaled corticosteroids, short and long-acting &bgr;2-agonist, and long-acting muscarinic receptor antagonist. Biomarker work suggests that a molecular phenotype of ACOS (e.g., elevated markers of eosinophilic or type 2 inflammation) incompletely corresponds to clinical phenotypes. Recently, we reported sentinel observation of unsuspected mild diffuse centrilobular emphysema in never-smoked asthma patients at autopsy, despite mild changes in lung computed tomography and normal diffusing capacity. Summary Recent studies have shown that subgroups of COPD and asthma patients may have overlapping immune responses. Never-smoked asthma patients may have persistent expiratory airflow limitation because of loss of lung elastic recoil. This may be because of unsuspected centrilobular emphysema detected at autopsy, and not easily diagnosed on lung computed tomography and diffusing capacity.

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.

Lack of protective effect of tiotropium vs induced dynamic hyperinflation in moderate COPD.

STUDY OBJECTIVEnNovel evaluation of protective effect of tiotropium against induced dynamic hyperinflation (DH) during metronome paced hyperventilation (MPH) in moderate COPD.nnnMETHODSnProspective, randomized, double-blind, placebo control, crossover study. Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 (18 M) COPD patients (GOLD Stage 2) age 70±9 yr (mean ± SD) before and after 30 days of 18 μg tiotropium bromide vs placebo. Lung CT scored for emphysema (ES).nnnRESULTSnAt baseline post 180 μg aerosolized albuterol sulfate, FEV(1): 1.8±0.6 L (69±6% pred) and ≥60% predicted in all, and 14 of 29 had FEV(1) (L) ≥70% predicted with FEV(1)/FVC 58±8%. After 29 days + 23 h post tiotropium (trough) there was significant decrease only in FRC/TLC% (p=0.04); after 30 days + 2 h post tiotropium (peak) significant increase only in FEV(1) (L) (p=0.03) compared to placebo. Results post MPH induced DH at baseline and after 30 days and 2 h post placebo or tiotropium were similar with decrease in IC 0.44±0.06 L (p<0.001). Correlation between ES and increased FEV(1) (L) at peak tiotropium: r=0.19, p=0.96 and decreased FRC/TLC% at trough tiotropium: r=-0.26, p=0.36.nnnCONCLUSIONnIn moderate COPD, tiotropium did not reduce MPH induced DH and reduction in IC. However, at peak tiotropium, there was significant bronchodilation in FEV(1) (L) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema.