Zoë Borrill

Airway inflammation in COPD can be measured using biomarkers such as induced sputum and Fe_NO. This study set out to explore the heterogeneity of COPD using biomarkers of airway and systemic inflammation and pulmonary function by principal components analysis (PCA). In 127 COPD patients (mean FEV₁ 61%), pulmonary function, Fe_NO, plasma CRP and TNF-α, sputum differential cell counts and sputum IL8 (pg/ml) were measured. Principal components analysis as well as multivariate analysis was performed. PCA identified four main components (% variance): (1) sputum neutrophil cell count and supernatant IL8 and plasma TNF-α (20.2%), (2) Sputum eosinophils % and Fe_NO (18.2%), (3) Bronchodilator reversibility, FEV₁ and IC (15.1%) and (4) CRP (11.4%). These results were confirmed by linear regression multivariate analyses which showed strong associations between the variables within components 1 and 2. COPD is a multi dimensional disease. Unrelated components of disease were identified, including neutrophilic airway inflammation which was associated with systemic inflammation, and sputum eosinophils which were related to increased Fe_NO. We confirm dissociation between airway inflammation and lung function in this cohort of patients.

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What is already known about this subject • Forced expiratory voume in 1 s (FEV₁) is the standard measurement used to measure drug effects in chronic obstructive pulmonary disease (COPD) clinical trials.• Having previously shown that specific airway conductance (sGaw) measured using body plethysmography and impulse oscillometry (IOS) are more sensitive than FEV₁ for assessing short‐acting bronchodilator effects in patients with COPD, we conducted the first randomized, placebo‐controlled study to compare long‐acting bronchodilators in COPD patients using these techniques. What this study adds • sGaw and IOS sensitively differentiated between the effects of tiotropium and salmeterol when FEV₁ measurements were similar.• sGaw and IOS measurements are better than FEV₁ for sensitively assessing bronchodilator pharmacology and differentiating between treatments in COPD clinical trials.Aims: Assessment of bronchodilator pharmacology in chronic obstructive pulmonary disease (COPD) may be improved by using more sensitive methods than spirometry, such as impulse oscillometry (IOS) and body plethysmography. We sought to compare salmeterol (S) and tiotropium (Tio) using these methods.Methods: In this double‐blind, randomized, four‐way crossover study, 32 COPD patients received single doses of Tio (18 µg), S (50 and 100 µg) or placebo. Specific airway conductance (sGaw), forced expiratory volume in 1 s (FEV₁) and IOS were measured pre‐ and up to 26 h postdose. Comparisons between treatments were analysed by weighted means (WM) between 0 and 12 (WM 0–12 h) and 12–24 h (WM 12–24 h) postdose. Data are expressed as mean difference (or geometric ratio for nonparametric data) with 95% confidence intervals.Results: Tio and S100 significantly improved FEV₁, sGaw and IOS parameters up to 26 h and S50 up to 16 h. WM analysis showed no difference between Tio and S100 in FEV₁ for 0–12 h or 12–24 h. Maximum mid‐expiratory flow (−0.06; −0.11, −0.01) and R35 (0.02; 0.01, 0.03) demonstrated superiority of S100 compared with Tio for WM 0–12 h sGaw (1.12; 1.02, 1.23), R5 (−0.06; −0.09, −0.02), R15 (−0.03; −0.05, −0.01), and resonant frequency (RF) (−2.30; −3.83, −0.77) showed superiority of Tio compared with S100 for WM 12–24 h. At 26 h, sGaw, R5, R15, X5 and RF also showed superiority of Tio compared with S100.Conclusions: sGaw and IOS parameters sensitively differentiated between the effects of Tio and S when FEV₁ measurements were similar. Clinical trials in patients with COPD should use IOS and sGaw to assess comprehensively bronchodilator pharmacology.

This study compared the effect of inhaled fluticasone propionate (FP) with the combination of salmeterol/fluticasone propionate (SFC) on lung function parameters in patients with mild asthma. Adult patients with mild persistent asthma (≥ 80% predicted FEV₁) receiving 200–500 μg of BDP or equivalent were randomised to receive either FP 100 μg or SFC 50/100 μg twice daily from a Diskus^® inhaler for four weeks. The primary outcome was the change from baseline in airway resistance (sRaw) at 12 hrs post dose measured by whole body plethysmography. Impulse oscillometry and spirometry were also performed. A comparison of the geometric mean sRaw at 12 hrs post dose in the SFC group to the FP group gave a ratio of 0.76 (0.66 – 0.89, p < 0.001) at week 2 and 0.81 (0.71 – 0.94, p = 0.006) at week 4. Similarly, significant results in favour of SFC for oscillometry measurements of resistance and reactance were observed. FEV₁ was also significantly superior at week 2 in the SFC group (mean difference 0.16L, 95% CI; 0.03 – 0.28, p = 0.015), but not at week 4 (mean difference 0.17L, 95% CI -0.01 – 0.34, p = 0.060). SFC is superior to FP in reducing airway resistance in mild asthmatics with near normal FEV₁ values. This study provides evidence that changes in pulmonary function in patients with mild asthma are detected more sensitively by plethysmography compared to spirometry NCT00370591.

The reproducibility of exhaled breath condensate (EBC) mediators is not well documented in chronic obstructive pulmonary disease (COPD). This study assessed within assay (WA), within (WD) and between day (BD) reproducibility of EBC leukotriene B4 (LTB4) and 8-isoprostane. Three EBC samples were collected from 24 COPD patients separated by 1 h and 1 wk, to assess WD and BD reproducibility. WA reproducibility was assessed by sample analysis by enzyme immunoassay in triplicate. WA coefficient of variation for LTB4 and 8-isoprostane (18.2% and 29.2%, respectively) was lower than corresponding values for WD (47.7% and 65.3%, respectively) and BD (75.7% and 79.1%, respectively). Repeatability coefficient for 8-isoprostane and LTB4 assays were 18.6 pg/ml and 13.2 pg/ml, respectively. Group mean differences for WD and BD were small and statistically nonsignificant. Using the Bland Altman method, there were wide limits of agreement for WD (−51.6 to 47.2 for 8-isoprostane and −31.8 to 31.4 for LTB4) and BD reproducibility (−61.4 to 75.7 for 8-isoprostane and −29.3 to 38.6 for LTB4). This is the first study to fully report the variability of EBC 8-isoprostane and LTB4 in COPD. WA variability and group mean changes were small. However, we observed considerable WD and BD variability for these biomarkers.

Increasingly, exhaled breath condensate (EBC) is being used to sample airway fluid from the lower respiratory tract. EBC pH may be a biomarker of airway inflammation in chronic obstructive pulmonary disease (COPD). In this study, the reproducibility of EBC pH in COPD was investigated.A total of 36 COPD patients and 12 healthy nonsmoking subjects participated in several investigations: duration of argon deaeration, within-sample variability, effect of freezing, leaving samples at room temperature, nose-peg use, within- (WD) and between-day (BD) variability. Analysis of repeated measurements was performed using the Bland–Altman method with limits of agreement (LOA; mean difference±2sd). Wider LOA indicate greater variability.EBC pH became significantly higher with argon deaeration for ≤5 min. Variability during sample analysis was minimal; LOA of within-sample variability, freezing for 3 months and leaving at room temperature for 3 h were −0.29–0.45, −0.37–0.42 and −0.13–0.09, respectively. In contrast, variability due to nose-peg use (LOA −1.46–1.99), WD (LOA −1.50–2.48) and BD variability (LOA −2.52–3.02) were higher in COPD. In healthy nonsmoking subjects, nose-peg use (LOA −0.27–0.23), WD (LOA −0.33–0.40) and BD variability (LOA −0.46–0.44) were more reproducible.In conclusion, the variability of exhaled breath condensate pH in chronic obstructive pulmonary disease patients is mainly due to changes in airway pH over time, which are not seen in healthy nonsmoking subjects. Reasons for these fluctuations in exhaled breath condensate pH are unclear and require further investigation.

Aims: The aim of this study was to compare the variability and sensitivity of impulse oscillometry (R5, X5 and RF), plethysmography (Raw and sGaw) and spirometry (FEV₁, FVC and MMEF) in order to determine the most powerful technique for assessing bronchodilation in COPD clinical trials.Methods: Twenty‐four patients with COPD had impulse oscillometry, plethysmography and spirometry measured twice 30 mins apart, to determine variability. Then ascending doses of salbutamol (20, 50, 100, 200, 400 and 800 µg) were given and the same measurements made after each dose. Significant changes greater than variability were determined for each performed measurement (expressed as mean percentage improvement with 95% CI).Results: Significant effects (P < 0.05) were detected after 20 µg by X5 (18.5% CI 9.8–27.2) RF (11.1% CI 7.2–15.0) and sGaw (21.5% CI 10.1–32.9), and after 50 µg by R5 (16.7% CI 10.8–22.5) and Raw (19.7% CI 13.0–26.4). FEV₁ was less sensitive, detecting significant bronchodilation at 100 µg (10.2% CI 7.4–12.9).Conclusions: We conclude that impulse oscillometry and plethysmography should be considered the preferred techniques for measuring bronchodilation in COPD clinical trials.