Central and peripheral airway/alveolar sites of exhaled nitric oxide in acute asthma.

INTRODUCTION: Central airway nitric oxide flux (J'(awNO)) and peripheral airway/alveolar nitric oxide concentration (C(ANO)) during asthma exacerbation has not been investigated after correction for axial NO back-diffusion. METHODS: After measuring exhaled NO (fraction of exhaled nitric oxide (F(E)NO); ppb) at 50, 100, 150 and 200 ml/s, J'(awNO) (nl/s) and C(ANO) (ppb) were calculated using the two-compartment model and corrected for axial NO back-diffusion. Fifteen (8 males), non-smoking, patients with moderate-to-severe treated (inhaled corticosteroid (ICS) and inhaled long-acting beta(2)-agonist (LABA)) asthma, age 57+/-13 years (mean+/-SD), were studied at baseline, during exacerbation prior to oral corticosteroid, and during recovery after an 8 day tapering prednisone course. Based on earlier asthma studies without correction, it was hypothesised that with correction for NO axial back-diffusion, the incidence of abnormal J'(awNO) and C(ANO) at baseline and after exacerbation would be > or = 30% in 15 patients with asthma with 80% power. RESULTS: At baseline when clinically stable, after 180 microg of albuterol, forced expiratory volume in 1 s (FEV(1); litres) was 78+/-26% predicted (p=0.009) with increased F(E)NO at 50 ml/s (p=0.01) and J'(awNO) (p=0.02), but C(ANO) was normal compared with the controls. During exacerbation FEV(1) (litres) was 57+/-20% predicted (p=0.02), with increased F(E)NO at 50 ml/s (p=0.01) and J'(awNO) (p=0.004), but C(ANO) was normal. Recovery results were similar to baseline. Two of 15 patients with asthma always had normal exhaled NO gas exchange. CONCLUSIONS: The central airways were the major site of abnormal NO flux in 13 of 15 patients with moderate-severe asthma when stable and during exacerbation and could be easily detected with abnormal F(E)NO at 50 ml/s. C(ANO) was normal.

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.

Role of add-on zileuton on total exhaled, large airway, and small airway/alveolar nitric oxide in moderate-severe persistent adult asthmatics on fluticasone 250 microg/Salmeterol 50 microg.

BACKGROUND: Measuring non-invasive exhaled biomarkers of inflammation may be important in monitoring asthma therapy. OBJECTIVE: Evaluate exhaled nitric oxide with add-on leukotriene synthesis inhibitor in moderate-severe persistent asthmatics on combination controllers. METHODS: In a non-randomized, non-placebo, single-blind, fixed sequence, pilot study, we evaluated 22 non-smoking, stable, moderate-severe adult asthmatics on maintenance inhaled fluticasone 250 microg/salmeterol 50 microg (F/S) via MDI bid> or =1 yr, with add-on oral zileuton 600 mg qid. Exhaled fractional nitric oxide (FENO) gas exchange, large airway NO, small airway/alveolar NO concentration (CANO), Juniper score and lung function were measured. Asthmatics were studied at baseline only on F/S bid (visit 1), on F/S bid pre and 2 h post first dose zileuton 600 mg (visit 2), and post 4 weeks (visit 3) F/S bid plus zileuton 600 mg qid. Values were compared at each visit and to healthy non-smoking age matched healthy controls with normal lung function. RESULTS: Three asthmatics stopped zileuton prematurely (headache and/or nausea) and 19 (12F) age 55+/-17 yr (mean+/-SD) completed the 4-week study. Baseline forced expiratory lung volume in 1 sec (FEV(1)) was 1.6+/-0.7L (53+/-19% pred) (mean+/-SD), FEV(1) over FVC ratio was 64+/-11% and post 180 microg albuterol FEV(1) was 1.8+/-0.7L (56+/-21% pred), and FEV(1) over FVC ratio was 67+/-12%. Baseline Juniper scores were mild (10+/-10) and similar (p=ns) at all visits. Baseline FENO@50 mL/s was 48+/-27 ppb (mean+/-SD), and FENO@100 mL/s was 29+/-16ppb, and were similar (p=ns) at all visits. Large airway NO flux was 2.0+/-1.3 nL/s (52% asthmatics abnormal) and small airway/alveolar NO was 8.0+/-4.0 ppb (79% asthmatics abnormal) and were similar (p=ns) at all visits. Compared to baseline, post 26+/-6 days Zileuton, mean FEV(1) (L)% predicted increased 3.3% predicted (p=0.03), and FEV(1) over FVC ratio increased 2.2% (p=0.03). CONCLUSION: In stable, moderate-severe persistent adult asthmatics, large airway NO flux, small airway/alveolar CANO, and Juniper airway scores, were not significantly different on F/S bid vs F/S bid plus Zileuton for 4 weeks, despite significant small increase in FEV(1) over FVC ratio and FEV(1)% predicted.

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.

Effect of fluticasone 250 microg/salmeterol 50 microg and montelukast on exhaled nitric oxide in asthmatic patients.

BACKGROUND: Monitoring noninvasive biomarkers of inflammation is an important adjunct in asthma therapy. OBJECTIVE: The goal of the present study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in asthmatic patients, and to evaluate the NO response to maintenance fluticasone 250 microg/salmeterol 50 microg (F/S) and add-on montelukast 10 mg (M). METHODS: Thirty (24 women) nonsmoking, mild to moderate asthmatic patients were studied, mean age (+/- SD) 43+/-9 years, treated with F/S for more than one year. All were clinically stable for longer than eight weeks and had not taken oral corticosteroids and/or leukotriene antagonists for eight weeks before the present study. Spirometry, Juniper asthma symptom score, fractional exhaled NO (FENO) 100 mL/s, bronchial NO and alveolar NO concentration (CANO) were measured in a single-blind, nonrandomized crossover study. PROTOCOL: Visit 1: baseline F/S; visit 2: after four weeks of F/S plus M; visit 3: after four weeks of S plus M; and visit 4: after four weeks of S only. Values in asthmatic patients were also compared with 34 nonsmoking age-matched healthy controls with normal lung function. RESULTS: After 180 microg aerosolized metered dose inhaler albuterol, the forced expiratory volume in 1 s at baseline was 2.6+/-0.8 L (86%+/-16% of the predicted value) and the forced expiratory volume in 1 s over the forced vital capacity was 77%+/-9% (mean +/- SD), and was similar at visits 2 to 4. Juniper scores were mildly abnormal at visits 1 to 3, but significantly worse (P=0.03) at visit 4 versus visits 1 to 3. FENO values at visits 1 to 3 were similar but significantly increased (P=0.007) at visit 4. Bronchial NO was higher (P=0.03) at visit 4, versus visits 1 and 2, and was no different at visit 3. Compared with the healthy subjects, FENO and bronchial NO values were abnormal (greater than the normal mean plus 2 SD) in 33% of asthmatic patients at visits 1 to 3. CANO was similar for visits 1 to 4. CANO was abnormal (greater than the normal mean + 2 SD) in 20% of asthmatic patients. CONCLUSION: In clinically stable asthmatic patients, despite controller treatment including moderate-dose inhaled corticosteroids and add-on M, 33% of mild to moderate asthmatic patients have ongoing nonsuppressed bronchial sites of increased NO production, compared with healthy control subjects. These controllers have no effect on CANO, which was abnormal in 20% of the asthmatic patients studied. The addition of add-on M to baseline moderate-dose inhaled corticosteroid did not further reduce total exhaled, bronchial and/or alveolar NO production.

Tiotropium and simplified detection of dynamic hyperinflation.

STUDY OBJECTIVE: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium. METHODS: IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH. RESULTS: At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003). CONCLUSION: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.

Role of spirometry and exhaled nitric oxide to predict exacerbations in treated asthmatics.

OBJECTIVE: To evaluate the complementary roles of exhaled nitric oxide (NO) and spirometry to predict asthma exacerbations requiring one or more tapering courses of systemic corticosteroids. METHODS: We prospectively studied 44 nonsmoking asthmatics (24 women) aged 51 +/- 21 years (mean +/- SD) who were clinically stable for 6 weeks and receiving 250 mug of fluticasone/50 mug of salmeterol or equivalent for 3 years. Total exhaled NO (FENO), small airway/alveolar NO (CANO), large airway NO flux (J'awNO), and spirometry were measured. RESULTS: Baseline FEV(1) was 2.1 +/- 0.7 L, 70 +/- 20% of predicted after 180 mug of albuterol. Twenty-two of 44 asthmatics had one or more exacerbations over 18 months, 16 of 22 asthmatics had two exacerbations, and 6 of 22 asthmatics were hospitalized, including 1 asthmatic with near-fatal asthma. When baseline FEV(1) was 76% of predicted, exacerbations occurred only in 2 of 13 asthmatics (15%) [p = 0.003, chi(2)]. Using a receiver operating characteristic (ROC) curve for first exacerbation, the area under the curve was 0.67 with cutoff FEV(1) of 76% of predicted (sensitivity, 0.91; specificity, 0.50; positive predictive value, 0.65; negative predictive value, 0.85; positive likelihood ratio [LR(+)], 1.8; negative likelihood ratio [LR(-)], 0.18). When baseline FENO was >/= 28 parts per billion (ppb), exacerbations occurred in 13 of 17 asthmatics (76%); if baseline FENO was < 28 ppb, exacerbations occurred in only 9 of 27 asthmatics (33%) [p = 0.005, chi(2)]. Using the ROC curve for first exacerbation, the area under the curve was 0.71 with FENO cutoff point of 28 ppb (sensitivity, 0.59; specificity, 0.82; positive predictive value, 0.77; negative predictive value, 0.87; LR(+), 3.3; LR(-), 0.5). Independent of baseline FEV(1), FENO >/= 28 ppb increased the relative risk (RR) for exacerbation by 3.4 (95% confidence interval [CI], 1.3 to 9.1; Mantel-Haenszel, p = 0.007). An abnormal increase in CANO increased RR by 3.0 (95% CI, 0.9 to 9.9; p = 0.04), and abnormal J'awNO increased RR by 2.4 (95% CI, 1.0 to 5.6; p = 0.04). Independent of baseline FENO, FEV(1) /= 28 ppb and FEV(1) 76% of predicted had a 0% probability of exacerbation. CONCLUSION: Combining FENO and FEV(1) percentage of predicted can stratify risk for asthma exacerbation.

Risk factors for near-fatal asthma.

BACKGROUND: There is a paucity of lung function data in patients, both before and after episodes of near-fatal asthma (NFA), requiring transient endotracheal intubation and mechanical ventilation. METHODS: Lung function was initially measured in 43 asthmatic patients (age range, 16 to 49 years), who were observed and treated in a tertiary referral asthma clinic and were clinically stable at the time of study. Subsequently, clinical and physiologic follow-up studies were obtained over > 5 years. The primary outcomes were to determine (1) the integrity of lung elastic recoil and (2) the severity of expiratory airflow limitation, and (3) to correlate these outcomes with adverse clinical complications. RESULTS: Fourteen of 26 asthmatic patients (54%) [age range, 30 to 49 years] had significantly reduced lung elastic recoil pressures at all lung volumes compared to 3 of 17 asthmatic patients (18%); p = 0.02 [chi(2) test and Fisher exact test] [age range, 16 to 26 years]. In asthmatic patients between the ages of 30 and 49 years, significant loss of lung elastic recoil was noted in 4 of 10 patients with mild reduction in FEV(1) (FEV(1), > 79% predicted), 6 of 12 patients with moderate reduction in FEV(1) (FEV(1), 61 to 79% predicted), and all 4 patients with severe reduction in FEV(1) (FEV(1), < 61% predicted). In asthmatic patients between the ages of 16 and 26 years, significant loss of lung elastic recoil was noted in 0 of 11 patients with mild reduction in FEV(1), 2 of 5 patients with moderate reduction in FEV(1), and 1 of 1 patient with severe reduction in FEV(1). A subgroup of 10 asthmatic patients (7 men) [mean (+/- SD) age, 37 +/- 11 years] were studied when clinically stable, both before and after an episode of NFA in 8 cases and only after an episode of NFA in 2 additional cases. In 1 of 10 cases, the FEV(1) was mildly reduced, in 4 cases it was moderately reduced, and in 5 cases it was severely reduced, both before and after an episode of NFA. The sensitivity was 90%, the specificity was 61%, the positive predictive value was 41%, and the negative predictive value was 95% for NFA with an FEV(1) < or = 79% predicted or FEV(1)/FVC ratio of < 75%. Prior to an episode of NFA, all 8 asthmatic patients had significant loss of lung elastic recoil pressure, and afterward all 10 had significant loss of lung elastic recoil pressure (ie, less than the predicted normal mean minus 1.64 SD at a total lung capacity [TLC] of 100 to 70% predicted). The sensitivity was 100%, the specificity was 79%, the positive predictive value was 59%, and the negative predictive value was 100% for NFA with the loss of lung elastic recoil. The mean TLC measured with a plethysmograph in 10 patients with NFA was 7.2 +/- 1.41 (124 +/- 16% predicted). The sensitivity for TLC of > 115% predicted was 70%, the specificity was 70%, the positive predictive value was 88%, and the negative predictive value was 41% for NFA. CONCLUSION: A persistent reduction in FEV(1) of < or = 79% predicted or an FEV(1)/FVC ratio of < 75%, and, especially, the loss of lung elastic recoil and hyperinflation at TLC are risk factors for NFA. The loss of lung elastic recoil in asthmatic patients was associated with increased age, duration of disease, and progressive expiratory airflow limitation.

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.

Unsuspected loss of lung elastic recoil in chronic persistent asthma.

STUDY OBJECTIVES: To investigate the progression and mechanism(s) for fixed maximum expiratory airflow (max) limitation in patients with chronic persistent asthma. METHODS: When optimally treated and in clinically stable condition, we studied 21 asthmatic patients and classified them into three groups based on the severity of expiratory airflow limitation: (1) group A included 5 asthmatic patients (four women; mean +/- SD age, 51 +/- 17 years) with mild persistent asthma (FEV(1) > 80% predicted) with serial FEV(1) measurements obtained prior to the present study for 16 +/- 4 years; (2) group B included 11 asthmatic patients (three women; mean age, 64 +/- 11 years) with moderate persistent asthma (FEV(1) of 60 to 80% predicted) with serial FEV(1) measurements for 12 +/- 4 years; and (3) group C included 5 asthmatic patients (three women; mean age, 55 +/- 16 years) with severe persistent asthma (FEV(1) < 60% predicted) with serial FEV(1) measurements for 11 plus minus 5 years. RESULTS: Lung CT indicated no or trivial emphysema, and diffusion was normal in all asthmatics. There was a marked loss of lung elastic recoil at total lung capacity (TLC) in all asthmatic patients in group B (16 +/- 4 cm H(2)O) and group C (15 +/- 5 cm H(2)O), but none or minimal in group A (22 +/- 1 cm H(2)O) [p < 0.01], and loss of elastic recoil accounted for 34% and 50% of decreased maximal expiratory airflow (max) at 80% and 70% TLC, respectively. Comparison with previous longitudinal data indicated individual asthmatics when in clinically stable condition remained predominantly in the same FEV(1) percent predicted classification group as in the current study. CONCLUSION: Patients with chronic moderate and severe persistent asthma, despite optimal therapy, have reduced max for many years in part due to (early?) loss of lung elastic recoil from unknown mechanism(s). This challenges current concept of airway remodeling.