Isolated abnormal FEF75% detects unsuspected bronchiolar obstruction in CF children.

BACKGROUND: Physiologic detection of bronchiolar obstruction in children with cystic fibrosis (CF) may be clinically unsuspected because of normal routine spirometry despite bronchiectasis on lung CT. METHODS: Children from two accredited CF facilities had spirometry obtained every 3 months when clinically stable. Pre-bronchodilator maximum expiratory flow volume curves were retrospectively analyzed over 16 years to detect an isolated abnormal FEF75%, despite normal routine spirometry. RESULTS: At Miller Children's and Women's Hospital (MCWH), an abnormal FEF75% was initially detected in 26 CF children at age 7.5 ± 4 (SD) years despite normal routine spirometry initially. FEF75% remained an isolated abnormality for 2.5 ± 1.5 years after it was initially detected in these 26 CF children. At Cohen Children's Medical Center (CCMC), despite normal routine spirometry initially, abnormal FEF75% occurred in 13 children at age 11.7 ± 4.5 years, and abnormal FEF25-75% in 10 children at age 11.8 ± 5.3 years. CONCLUSIONS: FEF75% was most sensitive spirometric test for diagnosing both early and isolated progressive bronchiolar obstruction. Data from CCMC in older children demonstrated the simultaneous detection of abnormal FEF75% and FEF25-75% values consistent with greater bronchiolar obstruction when serial spirometry was initiated at an older age. IMPACT: There is very little published spirometric data regarding diagnosis of isolated small airways obstruction in CF children. FEF75% can easily detect unsuspected small airways obstruction in CF children with normal routine spirometry and bronchiectasis on lung CT and optimize targeted modulatory therapies.

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.

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.

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 ß2-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.

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.

Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD.

BACKGROUND: Aclidinium is a novel, long-acting muscarinic antagonist indicated for maintenance treatment of COPD. METHODS: In this 52-week, parallel-group, double-blind study, patients with moderate-to-severe COPD were randomized (1:1) to receive aclidinium twice-daily (BID) 200 µg or 400 µg via a novel, dry powder inhaler (Genuair(®)/Pressair(®)) [Registered trademarks of Almirall, SA, Barcelona, Spain for use within the European Union, Iceland, Norway, and Switzerland as Genuair(®) and within the United States as Pressair(®)]. Safety, the primary objective, was assessed via adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead electrocardiograms. Efficacy was evaluated using spirometry, SGRQ, and rescue medication use. RESULTS: A total of 605 patients were randomized in the study. The percentage of patients reporting any treatment-emergent AE (TEAE) was comparable between groups; most TEAEs were mild or moderate. Anticholinergic TEAEs were reported by low percentages of patients in either treatment group (dry mouth: 200 µg, 1.3%; 400 µg, 2.7%; constipation: 200 µg, 2.9%; 400 µg, 1.7%). Cardiac TEAEs were also reported by a low percentage of patients (<2% for any event in any group) and did not appear to be dose dependent. There were no clinically relevant abnormalities in other safety outcomes. Both aclidinium 200 µg and 400 µg resulted in improvements from baseline to Week 52 in FEV1, with numerically greater increases observed with the higher dose. Clinically important improvements in SGRQ scores and a reduction in rescue medication use were observed throughout the study for both doses. CONCLUSIONS: Long-term treatment with aclidinium 200 µg or 400 µg BID was well tolerated, with sustained benefits in lung function and health status in patients with COPD throughout the 1-year study.

Airway dimensions in fatal asthma and fatal COPD: overlap in older patients.

In some patients with chronic asthma clinical and physiological similarities with COPD may exist, such as partial reversibility to bronchodilators and persistent expiratory airflow obstruction. However, pathological data comparing both diseases in patients of similar age and disease severity are scarce. We compared large and small airway dimensions in 12 younger (mean age 32 yrs) and 15 older (mean age 65 yrs) non-smoker adult fatal asthma patients with 14 chronic smokers with severe, fatal COPD (mean age 71 yrs). Using H&E, Movat pentachrome staining and image analysis, we quantified large airway basement membrane (BM) thickness (µm), submucosal gland area and large and small airway inner wall, smooth muscle and outer wall areas. Areas were normalized by BM perimeter (µm(2)/µm). Younger adult fatal asthma patients had thicker BM, smooth muscle, and outer wall areas in both small and large airways when compared to COPD patients. In older asthmatics there was an overlap in BM thickness and airway structure in small airways. Inner wall layer in large and small airway level and submucosal gland areas were similar among groups. In conclusion, there are airway histological structural similarities between fatal asthma and fatal COPD. Older fatal asthmatics present overlapping airway structural features with younger adult fatal asthmatics and severe COPD patients. Our data contributes to a better understanding of asthma pathology in the elderly.

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.

In moderate-to-severe asthma patients monitoring exhaled nitric oxide during exacerbation is not a good predictor of spirometric response to oral corticosteroid.

BACKGROUND: The importance of monitoring exhaled nitric oxide (NO) in asthma remains controversial. OBJECTIVE: To measure exhaled NO, postnebulized albuterol/ipratropium spirometry, and Asthma Control Test (ACT) during asthma exacerbation requiring 8- to 10-day tapering oral corticosteroid in nonsmoking patients with moderate-to-severe asthma on moderate-dose inhaled corticosteroid and long-acting ß(2)-agonist but not maintenance oral corticosteroid. METHODS: After measuring the fraction of exhaled NO (Feno [ppb]) at 50, 100, 150, and 200 mL/s, the total Feno at 50 mL/s (ppb), large central airway NO flux (J'(awNO) [nL/s]), and peripheral small airway/alveolar NO concentration (C(ANO) [ppb]) were calculated and corrected for NO axial back-diffusion. Outpatient exacerbation required the patient with asthma to be afebrile with normal chest x-ray and white blood cell count. RESULTS: Group 1 included 17 patients (6 men) with asthma, age 52 ± 12 years, studied at baseline, during 18 exacerbations with abnormal Feno at 50 mL/s, J'(awNO), and/or C(ANO), and post 8- to 10-day tapering 40 mg prednisone (recovery). Baseline: IgE, 332 ± 243 Kµ; total blood eosinophils, 304 ± 266 cells/µL; body mass index, 28 ± 6; ACT, 16 to 19; and FEV(1), 2.5 ± 0.7 L (86% ± 20% predicted); exacerbation: FEV(1), 1.7 ± 0.4 L (60% ± 17%) (P < .001); recovery: FEV(1), 2.5 ± 0.7 L (85% ± 13%) (P < .001). Group 2 included 11 (7 men) similarly treated patients with asthma, age 49 ± 14 years, studied at baseline, during 15 exacerbations with normal Feno at 50 mL/s, J'(awNO), and C(ANO). Baseline: IgE, 307 ± 133 Kµ; total blood eosinophils, 296 ± 149 cells/µL; body mass index, 28 ± 6; ACT, 16 to 19; and FEV(1), 2.7 ± 0.9 L (71% ± 12% predicted); exacerbation: FEV(1), 1.7 ± 0.6 L (54% ± 19%) (P< .006); recovery: FEV(1), 2.7 ± 0.9 L (70% ± 14%) (P= .002). On comparing group 1 versus group 2, there was no significant difference for baseline IgE, eosinophils, body mass index, and ACT and similar significant (≤.006) decrease from baseline in FEV(1) (L) during exacerbation and similar increase (≤.006) at recovery. CONCLUSIONS: Increased versus normal exhaled NO during outpatient exacerbation in patients with moderate-to-severe asthma on inhaled corticosteroid and long-acting ß(2)-agonist but not maintenance oral corticosteroid does not preclude a robust clinical and spirometric response to tapering oral prednisone.

Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I).

BACKGROUND: This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 µg and 400 µg versus placebo in the treatment of moderate-to-severe COPD. METHODS: In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 µg, aclidinium 400 µg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12, respectively. Health status (St. George's Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed. RESULTS: A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV1 of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 µg and 400 µg showed significant improvements from baseline in mean (95% CI) trough FEV1 compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV1 by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%-1.6%; constipation: 0%-1.1%). CONCLUSIONS: Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 µg and 400 µg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo. TRIAL REGISTRATION: This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as "Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)".

Increased nitric oxide concentrations in the small airway of older normal subjects.

BACKGROUND: There is a paucity of normal-age stratified data for fraction of exhaled nitric oxide (Feno). Our goal was to obtain normal data for large-airway nitric oxide flux (J'awno) and small-airway and/or alveolar nitric oxide concentration (Cano) in nonsmoking, healthy, adult subjects of various ages. METHODS: In 106 normal volunteer subjects (60 women) aged 55 ± 20 years (mean ± SD), Feno (parts per billion [ppb]) was measured at 50, 100, 150, and 200 mL/s and J'awno (nL/s) and Cano (ppb) were calculated using a two-compartment model with correction for axial nitric oxide (NO) back diffusion. Fourteen older normal subjects were also treated with inhaled corticosteroid (540 µg budesonide bid) for 14 days. RESULTS: We studied 34 younger normal subjects (17 women) aged 18 to 39 years (younger), 26 middle-aged normal subjects (22 women) aged 40 to 59 years (middle-aged), and 46 older normal subjects (21 women) aged 60 to 86 years (older). Feno at 50 mL/s in the younger group was 21 (14-28) ppb (median, 1-3 interquartile); in the middle-aged group it was 22 (18-30) ppb, and in the older group it was 27 (21-33) ppb, (analysis of variance [ANOVA]) P = .02. For Feno, the younger vs older groups was (Mann-Whitney) P = .03, and Feno in the combined younger and middle-aged groups was 21 (15-29) ppb vs 27 (21-33) ppb, P = .006 for the older group. Corrected J'awno in the younger group was 1.5 (1.0-2.1) nL/s; in the middle-aged group it was 1.4 (1.0-2.0) nL/s, and in the older group it was 1.8 (1.2-2.4) nL/s, (ANOVA) P = .3. Corrected Cano in the younger group was 1.9 (0.8-3.0) ppb; in the middle-aged group it was 2.8 (0.8-5.1) ppb, and in the older group it was 3.9 (1.4-6.6) ppb, (ANOVA) P = .02. Cano in the younger vs older groups was P = .003, and the combined younger and middle-aged group result was 2.0 (0.8-3.8) vs 3.9 (1.4-6.6), P = .01 in the older group. There was no change in NO gas exchange with inhaled corticosteroids. CONCLUSIONS: In nonsmoking healthy subjects with normal spirometry, Feno at 50 mL/s and Cano increased significantly with age ≥ 60 years, whereas J'awno did not. We suspect the increase in Cano was due to a decrease in capillary blood volume with reduced NO diffusion, which is also reflected in increased Feno. Inhaled budesonide had no anti-NO-mediated inflammatory effect. Age-matched control subjects will be needed in NO comparative studies. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00576069 and NCT00568347; URL: www.clinicaltrials.gov.