B Hargadon

Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial

Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.

Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease

Background: An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear. Methods: A randomised, double blind, crossover trial of placebo and mometasone furoate (800 μg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase. Results: Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV1), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV1 increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV1 with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count. Conclusions: An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV1 following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.

Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma.

Recent studies have suggested that alveolar nitric oxide (NO) concentration is a noninvasive test of distal lung inflammation. The current study determined whether alveolar NO concentration can be measured in patients with asthma of varying severity, tested the hypothesis that there is an association between alveolar NO and bronchoalveolar lavage (BAL) eosinophil count and determined whether refractory asthma is characterised by a raised alveolar NO concentration. Finally, the present authors assessed the effect of 2 weeks of prednisolone (30 mg q.d.) on alveolar NO concentration. Alveolar NO concentration was both measurable and repeatable in patients with refractory asthma. A positive correlation was found between alveolar NO concentration and BAL eosinophil count but not with bronchial wash or sputum eosinophil count. Alveolar NO concentration was increased in patients with refractory asthma (7.1 ppb) compared with mild-to-moderate asthma (3.4 ppb) and normal controls (3.4 ppb) and reduced by treatment with prednisolone. In conclusion, these findings support the hypothesis that alveolar nitric oxide is a measure of distal airway inflammation and suggest that distal lung inflammation is present in refractory asthma.

Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 μg b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 μg b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5–0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7–1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2–2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.

Airway function and markers of airway inflammation in patients with treated hypothyroidism

Background: There is increasing evidence of an association between organ specific autoimmune diseases, particularly autoimmune thyroid disease and respiratory morbidity. A study was undertaken to determine whether patients with autoimmune thyroid disease have objective evidence of airway inflammation and dysfunction. Methods: Twenty six non-smoking women with treated hypothyroidism and 19 non-smoking controls completed a symptom questionnaire and underwent full lung function tests, capsaicin cough reflex sensitivity measurement, methacholine challenge test, and sputum induction over two visits. Results: Symptoms of cough (p = 0.01), dyspnoea (p = 0.01), sputum production (p = 0.004), and wheeze (p = 0.04) were reported more commonly in patients than controls. Patients with hypothyroidism had heightened cough reflex sensitivity compared with controls (geometric mean concentration of capsaicin causing five coughs: 40 v 108 mmol/l; mean difference 1.4 doubling doses; 95% confidence interval of difference 0.4 to 2.5; p = 0.008) and a significantly higher proportion of patients had airway hyperresponsiveness (methacholine provocative concentration (PC20) <8 mg/ml: 38% v 0%; p = 0.016). Patients with hypothyroidism also had a significantly higher induced sputum total neutrophil cell count (p = 0.01), total lymphocyte count (p = 0.02), and sputum supernatant interleukin-8 concentrations (p = 0.048). Conclusion: Patients with treated hypothyroidism report more respiratory symptoms and have objective evidence of airway dysfunction and inflammation.

Temporal assessment of airway remodeling in severe asthma using quantitative computed tomography.

To the Editor: Heterogeneity in asthma is evident in every aspect of the disease process (1–3). Quantitative computed tomography (QCT) has emerged as a reliable, noninvasive tool for assessment of proximal airway remodeling and air trapping in asthma (4). We have identified three asthma clusters based on QCT indices, using factor and cluster analysis (3). Subjects in clusters 1 and 3, with more severe asthma, had distinct patterns of proximal airway remodeling: cluster 1 showing a dilated right upper lobe apical segmental bronchus (RB1) lumen with wall thickening and cluster 3 had no wall thickening and markedly narrowed lumen. Subjects in cluster 2 had milder asthma, and there was a lack of proximal airway remodeling. It remains elusive whether airway structural changes reflect cause or effect; namely, are they a consequence of asthma and represent different stages of disease progression or the distinct remodeling changes that are fundamental to the pathogenesis of asthma, representing distinct asthma endotypes (5)? Our aim was to assess the temporal pattern of proximal airway remodeling in QCT-derived asthma clusters. Some of the results of this study have been previously reported in the form of an abstract (6). Twenty-two patients with severe asthma of mean (SEM) disease duration 28.6 (4) years, who were in the placebo arm of a previous study (7), were included in the analysis. All 22 patients had undergone two inspiratory thoracic CT scans to image RB1 and further inspiratory and expiratory full thoracic CT scans as part of research studies at our institute (3, 7). All CT scans were performed after administration of long-acting β2-agonist. The mean (range) duration between the first (baseline) and second CT scan was 1.6 (0.9–2.7) years and between the second and third was 2.6 (1.9–3.7) years. QCT-derived asthma clusters were determined on the basis of full thoracic paired inspiratory and expiratory CT scans obtained at time point 3 (3). Only inspiratory scans were used for the current analysis. Informed consent was obtained from all subjects and the studies were approved by the Leicestershire, Northamptonshire, and Rutland Research Ethics Committees. Fully automated software (VIDA Pulmonary Workstation, version 2.0; VIDA Diagnostics, Coralville, IA) was used for quantitative airway morphometry as described previously (3). RB1 wall area (WA)/body surface area (BSA) demonstrated a significant increase over time (mean [SEM]: first CT, 14.3 [0.9]; second CT, 14.7 [0.9]; third CT, 16.5 [1.3] mm2/m2; repeated measure analysis of variance [ANOVA], P = 0.008). No significant change was seen in RB1 lumen area (LA)/BSA (mean [SEM]: first CT, 9.1 [1.0]; second CT, 9.6 [1.0]; third CT, 9.9 [0.9]; repeated measure ANOVA, P = 0.4). There was an increase in RB1 length at the time of the third CT (mean [SEM]: first CT, 11.3 [0.8]; second CT, 11.0 [0.7]; third CT, 13.1 [0.6] mm; repeated measure ANOVA, P < 0.01). The change in RB1 WA/BSA (ΔRB1 WA/BSA = RB1 WA/BSA third CT − RB1 WA/BSA first CT) negatively correlated with change in RB1 length (Pearson correlation, −0.5; P = 0.03). When the subjects with severe asthma were split into previously described QCT-derived clusters (3), the mean (SEM) change in interval normalized RB1 WA/BSA and LA/BSA, respectively, was as follows: cluster 1 (n = 3), 3.6 (0.8) mm2/m2/year, 1.7 (1.1) mm2/m2/year; cluster 2 (n = 9), 1.0 (0.5) mm2/m2/year, −0.02 (0.4) mm2/m2/year; cluster 3 (n = 10), −0.1 (0.3) mm2/m2/year, 0.1 (0.4) mm2/m2/year (Figure 1). A one-way between-groups analysis of covariance (ANCOVA) was performed to compare the differences between clusters (independent variable), of airway mophometry at the time of the second and third CT (dependent variables) after controlling for airway morphometry at the time of first CT (covariate). After adjusting for airway morphometry (first CT), there were significant differences between the three clusters for RB1 WA/BSA (third CT) [F(2, 18) = 21, P < 0.001, partial η2 = 0.70] and for RB1 LA/BSA (third CT) [F(2, 18) = 32, P < 0.001, partial η2 = 0.78]. No significant difference was seen between the three clusters for RB1 WA/BSA (second CT) and RB1 LA/BSA (second CT) (data not shown). A comparison of airway morphometry in healthy control subjects at time point 3 with airway morphometry in severe asthma clusters at time points 1, 2, and 3 is presented in Table 1. Figure 1. Temporal assessment of airway remodeling in asthma clusters. Asthma clusters were determined on the basis of data from the third computed tomography (CT). Retrospective scans were available for temporal assessment of RB1 (right upper lobe apical segmental ... Table 1. RB1 Dimensions of Subjects with Severe Asthma and Healthy Subjects The subjects did not show any significant change in postbronchodilator FEV1% predicted (mean [SEM] change from baseline, −1.8 [2.7]; paired sample t test, P = 0.5), postbronchodilator FEV1/FVC (%) (mean [SEM] change from baseline, −0.7 [1.3]; paired sample t test, P = 0.6), asthma quality of life questionnaire (AQLQ) score (mean [SEM] change from baseline, 0.07 [1.3]; paired sample t test, P = 0.7), and sputum neutrophils (mean [SEM] change from baseline, 5.4 [7.1]; paired sample t test, P = 0.5) at the time of third CT scan compared with baseline. There was a statistically significant increase in the asthma control questionnaire (ACQ) (mean [SEM] change from baseline, 0.4 [0.2]; paired sample t test, P = 0.03). The change in RB1 QCT indices (LA/BSA, WA/BSA, and length) between third and first CT did not show any significant correlation with change in postbronchodilator FEV1% predicted, postbronchodilator FEV1/FVC%, ACQ, and AQLQ. Previous longitudinal studies have demonstrated a significant decrease in proximal airway wall dimensions after use of inhaled corticosteroids (ICS) (8, 9), an ICS/long-acting β2 agonist (LABA) combination (10), and anti-IgE treatment (11). In contrast, Brillet and colleagues found no change in CT-assessed airway dimensions in subjects with poorly controlled asthma treated for 12 weeks with inhaled LABA and ICS despite improvement in physiological measures of airway obstruction and air trapping (12). A follow-up of subjects with asthma on ICS from a previous study (8) for a mean duration of 4.2 years did not show any significant change in airway dimensions, with a reported mean (SEM) change in interval-normalized RB1 WA/BSA of −0.27 (0.59) mm2/m2/year (13). We have previously shown a decrease in RB1 WA/BSA in subjects with severe asthma after 1 year of treatment with anti–IL-5 compared with placebo, with an approximately 10% between-group change (7). In the current analysis subjects with severe asthma demonstrate a small, albeit significant temporal increase in RB1 WA/BSA but no change in RB1 LA/BSA. These varied patterns of airway remodeling exhibited by subjects with asthma may be explained by the heterogeneous nature of the disease, and differences in patient selection and duration of treatment and/or follow-up. A longitudinal study in subjects with severe asthma has demonstrated that in a multivariate regression model baseline %WA was a predictor of subsequent airway remodeling (14). In our analysis after adjusting for the RB1dimensions at time of first CT, significant differences were found in RB1 dimensions between severe asthma QCT-derived clusters at the time of third CT but not at the time of second CT. Patients with severe asthma, when grouped on the basis of QCT-derived clusters, show a differential temporal pattern of airway remodeling, particularly patients in cluster 3, where no significant change in airway wall or lumen dimensions was demonstrated over a period of 2.6 years. This suggests that the mechanism of lumen narrowing in this asthma phenotype may be due to decreased compliance of the airway wall or alteration between intrinsic and extrinsic airway wall properties (15), rather than thickened airway wall encroaching on the lumen. Mathematical modeling studies (16, 17) have also shown that thickening of the adventitia can uncouple the airway smooth muscle (ASM) from the lung’s elastic recoil forces, abating the airway–parenchymal interdependence. QCT based phenotyping could thus help us unravel novel asthma subtypes which may have distinct pathophysiological mechanisms. The inverse correlation between the change in RB1 WA/BSA and RB1 length suggests that despite bronchodilation, ASM shortening resulting in shortening of airway length may contribute to QCT-assessed airway wall thickening. We acknowledge that QCT-derived clusters were determined on the basis of full thoracic paired inspiratory (third CT in the current analysis) and expiratory CT scans as part of a recent study (3) and that temporal CT (first and second CT in the current analysis) data were obtained from retrospective scans. We therefore are unable to assess the stability of CT-derived phenotypes. Moreover, data are lacking in the current literature on the temporal stability of airway morphometry in healthy subjects. Temporal assessment was possible only in a small number of subjects in each cluster, with only three subjects in cluster 1, and therefore further verification of these findings is required by large longitudinal studies. Despite this limitation, temporal analysis may provide useful insight into the natural history of airway remodeling.

P20 The eligibility of patients with difficult asthma for omalizumab since the change to the treatment criteria

Omalizumab is a humanised monoclonal anti-IgE agent which is useful as an add-on therapy for severe atopic asthma. We have previously shown that 13.5% of patients attending our adult difficult asthma clinic were eligible for treatment with omalizumab. There has recently been a change to its prescribing licence with a widening of the eligible range of IgE from 30–700 iu/ml to 30–1500 iu/ml. Other prescribing criteria are (1) weight between 20 and 150 kg, (2) FEV1 <80% predicted, (3) positive skin prick tests or specific IgE to perennial aeroallergens and (4) ongoing symptoms despite a high-dose combination inhaler. In addition NICE guidance now recommends that its use is confined to patients who, within the past year, have had two or more hospital admissions or one admission plus two A&E attendances for asthma exacerbations. We aimed to determine how the new licensing criteria and the NICE guidelines have affected the proportion of patients attending our difficult asthma clinic eligible for treatment with omalizumab. We assessed 510 patients recording body weight (kg), FEV1 (% predicted), symptoms, total IgE (iU/ml) and skin prick tests. Our data demonstrate that 240 had an IgE outside the eligible range, 242 patients had an FEV1>80%, 46 patients had negative skin prick tests and a further 2 patients′ weight was outside the range for dosing. 67/510 (13.1%) patients met all the licensing criteria for omalizumab. There has therefore not been any increase in the proportion of eligible patients since the widening of the IgE range. Of these 67, 27 patients had two or more admissions with asthma exacerbations in the previous year. A further 16 patients had one admission but less than 2 A&E attendances. 12 patients required maintenance oral prednisolone but did not have sufficient admissions to meet the NICE prescribing guidelines. In total, 27/510 (5.3%) of patients with difficult-to-treat asthma were eligible for treatment with omalizumab according to NICE guidance. Although omalizumab is a helpful additional therapy for allergy-mediated asthma, its licensing criteria and current NICE guidelines limits its use in the UK to a small proportion of patients with difficult asthma.

S133 Eosinophilic airway inflammation is associated with FEV1 decline in severe asthma

Background Severe asthma is a multidimensional disease, with recent evidence supporting the notion that eosinophilic airway inflammation (EAI) is an important driver for exacerbations. In addition EAI has been shown to be associated with airflow limitation in cross sectional studies. However, it remains to be established whether EAI may drive FEV1 decline. Methods The severe asthma registry at Glenfield hospital, Leicester, was screened for patients with a physician diagnosis of asthma and at least 5 years of longitudinal data recording sputum eosinophils, pre- and post-bronchodilator spirometry, inhaled corticosteroid usage as well as standard demographic indices during stable scheduled follow-up visits. Linear mixed effects models were used to investigate the effect of log sputum eosinophils as a time varying covariate on decline of post bronchodilator FEV1. Models were iteratively compared and refined using standard information criteria. Other fixed effects in the final model were, time and the interaction terms for time * log sputum eosinophils and time *daily dose of inhaled corticosteroids and pack years smoked. Individual variations in the slopes and intercepts of time and time*log sputum eosinophils were considered by adding them iteratively as random effects. A first-order autoregressive correlation structure was used to model covariance of random effects. Results 92 patients, 46% male with severe asthma were identified from a registry cohort of 686 between 2000 and 2009. The mean (sem) age was 54(12.9) years and age of onset 23 (2.1) years. The mean (range) duration of follow-up and number of visits were 6 years (4.6–10.5), 2.7/year. We found a significant interaction between sputum eosinophils, time and post bronchodilator FEV1. Indicating a net decline (95% CI) of −16.8 mls(25.8–7.8 mls) /annum/log unit increase in sputum eosinophils (F(1, 43.4); p<0.0001). In contrast there was a net decline 95%CI of −0.015 mls (0.029 to 0.0014 mls)/annum/mcg of inhaled beclamethasonediproprionate daily (F(1,726); p=0.031). Conclusion Eosinophilic airway inflammation is associated with a significant decline in FEV1 in severe asthma.

P17 Self-reported physical activity levels and attitudes towards a structured exercise programme in adults with difficult asthma

Background Patients with difficult-to-treat asthma often have dyspnoea which limits their physical activity. This may lead to progressive deconditioning which may further hamper exercise capacity. We aimed to assess current levels of activity, perceptions of current fitness and interest in a structured exercise programme in patients attending the Glenfield Hospital Difficult Asthma Clinic. Method Patients completed the General Practice Physical Activity Questionnaire which provides a simple Physical Activity Index (PAI) and answered structured questions about their satisfaction with current fitness and their interest in participating in an exercise programme. They were also asked to rate their current fitness compared to peers of the same age on a 100 mm visual analogue score. Responses were compared to demographic details and markers of asthma severity and control. Results Sixty patients participated (37 female, mean (SD) age 53(13)). Only 15/60 (25%) was classified as ‘active’ by the PAI. There were no significant differences in age, gender, body mass index or Juniper asthma control scores between those patients who were active compared to the remaining group but active patients had less severe airflow obstruction (post-bronchodilator FEV1 83.7(16.5)% predicted vs 68.7(21.8), p=0.04) and better self-reported fitness scores (55.3(27.4) vs 36.7(23.0), p=0.013). There was a statistically significant inverse correlation between fitness scores and Juniper asthma control scores (r = −0.5, p<0.0001) and Hospital Anxiety (r=−0.4, p=0.004) and Depression scores (r=−0.4,p=0.001) but no association with age, BMI or FEV1. 65% of patients reported that they had stopped exercising due to their asthma symptoms and 86.7% of patients wanted to be fitter. 71.7% were interested in participating in an exercise programme. Of these 13 (30%) preferred a hospital setting with the remainder preferring a community scheme or an independent programme with support from healthcare professionals. Conclusion Many patients with difficult asthma reported concerns about their current fitness and most were not exercising at the recommended level. There appears to be a demand for the development of a community-based structured exercise programme and further work is needed to determine whether this would improve asthma related outcomes for this group of patients.

A randomised comparison of the effects of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and airway responsiveness

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 μg b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 μg b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5–0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7–1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2–2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.