Ruth Hartley

Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial

BACKGROUND Eosinophilic airway inflammation is often present in asthma, and reduction of such inflammation results in improved clinical outcomes. We hypothesised that fevipiprant (QAW039), an antagonist of prostaglandin D2 receptor 2, might reduce eosinophilic airway inflammation in patients with moderate-to-severe eosinophilic asthma. METHODS We performed a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial at Glenfield Hospital (Leicester, UK). We recruited patients with persistent, moderate-to-severe asthma and an elevated sputum eosinophil count (≥2%). After a 2-week single-blind placebo run-in period, patients were randomly assigned (1:1) by the trial pharmacist, using previously generated treatment allocation cards, to receive fevipiprant (225 mg twice per day orally) or placebo, stratified by the use of oral corticosteroid treatment and bronchoscopy. The 12-week treatment period was followed by a 6-week single-blind placebo washout period. The primary outcome was the change in sputum eosinophil percentage from baseline to 12 weeks after treatment, analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01545726, and with EudraCT, number 2011-004966-13. FINDINGS Between Feb 10, 2012, and Jan 30, 2013, 61 patients were randomly assigned to receive fevipiprant (n=30) or placebo (n=31). Three patients in the fevipiprant group and four patients in the placebo group withdrew because of asthma exacerbations. Two patients in the fevipiprant group were incorrectly given placebo (one at the mid-treatment visit and one throughout the course of the study). They were both included in the fevipiprant group for the primary analysis, but the patient who was incorrectly given placebo throughout was included in the placebo group for the safety analyses. Between baseline and 12 weeks after treatment, sputum eosinophil percentage decreased from a geometric mean of 5·4% (95% CI 3·1-9·6) to 1·1% (0·7-1·9) in the fevipiprant group and from 4·6% (2·5-8·7) to 3·9% (CI 2·3-6·7) in the placebo group. Compared with baseline, mean sputum eosinophil percentage was reduced by 4·5 times in the fevipiprant group and by 1·3 times in the placebo group (difference between groups 3·5 times, 95% CI 1·7-7·0; p=0·0014). Fevipiprant had a favourable safety profile, with no deaths or serious adverse events reported. No patient withdrawals were judged by the investigator to be related to the study drug. INTERPRETATION Fevipiprant reduces eosinophilic airway inflammation and is well tolerated in patients with persistent moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment. FUNDING Novartis Pharmaceuticals, AirPROM project, and the UK National Institute for Health Research.

Relationship between lung function and quantitative computed tomographic parameters of airway remodeling, air trapping, and emphysema in patients with asthma and chronic obstructive pulmonary disease: A single-center study

Background There is a paucity of studies comparing asthma and chronic obstructive pulmonary disease (COPD) based on thoracic quantitative computed tomographic (QCT) parameters. Objectives We sought to compare QCT parameters of airway remodeling, air trapping, and emphysema between asthmatic patients and patients with COPD and explore their relationship with airflow limitation. Methods Asthmatic patients (n = 171), patients with COPD (n = 81), and healthy subjects (n = 49) recruited from a single center underwent QCT and clinical characterization. Results Proximal airway percentage wall area (%WA) was significantly increased in asthmatic patients (62.5% [SD, 2.2]) and patients with COPD (62.7% [SD, 2.3]) compared with that in healthy control subjects (60.3% [SD, 2.2], P < .001). Air trapping measured based on mean lung density expiratory/inspiratory ratio was significantly increased in patients with COPD (mean, 0.922 [SD, 0.037]) and asthmatic patients (mean, 0.852 [SD, 0.061]) compared with that in healthy subjects (mean, 0.816 [SD, 0.066], P < .001). Emphysema assessed based on lung density measured by using Hounsfield units below which 15% of the voxels lie (Perc15) was a feature of COPD only (patients with COPD: mean, −964 [SD, 19.62] vs asthmatic patients: mean, −937 [SD, 22.7] and healthy subjects: mean, −937 [SD, 17.1], P < .001). Multiple regression analyses showed that the strongest predictor of lung function impairment in asthmatic patients was %WA, whereas in the COPD and asthma subgrouped with postbronchodilator FEV1 percent predicted value of less than 80%, it was air trapping. Factor analysis of QCT parameters in asthmatic patients and patients with COPD combined determined 3 components, with %WA, air trapping, and Perc15 values being the highest loading factors. Cluster analysis identified 3 clusters with mild, moderate, or severe lung function impairment with corresponding decreased lung density (Perc15 values) and increased air trapping. Conclusions In asthmatic patients and patients with COPD, lung function impairment is strongly associated with air trapping, with a contribution from proximal airway narrowing in asthmatic patients.

Computed tomography scans in severe asthma: utility and clinical implications.

Purpose of review Asthma is a global burden, affecting 5% of the general adult population, of whom approximately 5–10% suffer from severe asthma. Severe asthma is a complex heterogeneous disease entity, with high morbidity and mortality. Increasingly novel techniques in computed tomography (CT) are being used to understand the pathophysiology of severe asthma. The utility and clinical implications of these CT techniques are the focus of this review. Recent findings Novel qualitative and quantitative CT imaging techniques have enabled us to study the large airway architecture in detail, assess the small airway structure, and perform functional analysis of regional ventilation. Summary Despite advances in CT imaging techniques, there is an urgent need for both proof-of-concept studies and large cross-sectional and longitudinal clinical trials in severe asthma to validate and clinically correlate imaging derived measures. This will extend our current understanding of the pathophysiology of severe asthma, and unravel the structure–function relationship, with the potential to discover novel severe asthma phenotypes and predict mortality, morbidity, and response to existing and novel pharmacological and nonpharmacological therapies.

A method for quantitative analysis of regional lung ventilation using deformable image registration of CT and hybrid hyperpolarized gas/1H MRI

Hyperpolarized gas magnetic resonance imaging (MRI) generates highly detailed maps of lung ventilation and physiological function while CT provides corresponding anatomical and structural information. Fusion of such complementary images enables quantitative analysis of pulmonary structure-function. However, direct image registration of hyperpolarized gas MRI to CT is problematic, particularly in lungs whose boundaries are difficult to delineate due to ventilation heterogeneity. This study presents a novel indirect method of registering hyperpolarized gas MRI to CT utilizing (1)H-structural MR images that are acquired in the same breath-hold as the gas MRI. The feasibility of using this technique for regional quantification of ventilation of specific pulmonary structures is demonstrated for the lobes.The direct and indirect methods of hyperpolarized gas MRI to CT image registration were compared using lung images from 15 asthma patients. Both affine and diffeomorphic image transformations were implemented. Registration accuracy was evaluated using the target registration error (TRE) of anatomical landmarks identified on (1)H MRI and CT. The Wilcoxon signed-rank test was used to test statistical significance.For the affine transformation, the indirect method of image registration was significantly more accurate than the direct method (TRE = 14.7 ± 3.2 versus 19.6 ± 12.7 mm, p = 0.036). Using a deformable transformation, the indirect method was also more accurate than the direct method (TRE = 13.5 ± 3.3 versus 20.4 ± 12.8 mm, p = 0.006).Accurate image registration is critical for quantification of regional lung ventilation with hyperpolarized gas MRI within the anatomy delineated by CT. Automatic deformable image registration of hyperpolarized gas MRI to CT via same breath-hold (1)H MRI is more accurate than direct registration. Potential applications include improved multi-modality image fusion, functionally weighted radiotherapy planning, and quantification of lobar ventilation in obstructive airways disease.

Dynamic flow characteristics in normal and asthmatic lungs

Complex flow patterns exist within the asymmetric branching airway network in the lungs. These flow patterns are known to become increasingly heterogeneous during disease as a result of various mechanisms such as bronchoconstriction or alterations in lung tissue compliance. Here, we present a coupled model of tissue deformation and network airflow enabling predictions of dynamic flow properties, including temporal flow rate, pressure distribution, and the occurrence of reverse flows. We created two patient-specific airway geometries, one for a healthy subject and one for a severe asthmatic subject, derived using a combination of high-resolution CT data and a volume-filling branching algorithm. In addition, we created virtually constricted airway geometry by reducing the airway radii of the healthy subject model. The flow model was applied to these three different geometries to solve the pressure and flow distribution over a breathing cycle. The differences in wave phase of the flows in parallel airways induced by asymmetric airway geometry and bidirectional interaction between intra-acinar and airway network pressures were small in central airways but were more evident in peripheral airways. The asthmatic model showed elevated ventilation heterogeneity and significant flow disturbance. The reverse flows in the asthmatic model not only altered the local flow characteristics but also affected total lung resistance. The clinical significance of temporal flow disturbance on lung ventilation in normal airway model is obscure. However, increased flow disturbance and ventilation heterogeneity observed in the asthmatic model suggests that reverse flow may be an important factor for asthmatic lung function.

Novel imaging approaches in adult asthma and their clinical potential.

Currently, imaging in asthma is confined to chest radiography and CT. The emergence of new imaging techniques and tremendous improvement of existing imaging methods, primarily due to technological advancement, has completely changed its research and clinical prospects. In research, imaging in asthma is now being employed to provide quantitative assessment of morphology, function and pathogenic processes at the molecular level. The unique ability of imaging for non-invasive, repeated, quantitative, and in vivo assessment of structure and function in asthma could lead to identification of ‘imaging biomarkers’ with potential as outcome measures in future clinical trials. Emerging imaging techniques and their utility in the research and clinical setting is discussed in this review.

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.

Associations in asthma between quantitative computed tomography and bronchial biopsy-derived airway remodelling

Airway remodelling in asthma remains poorly understood. This study aimed to determine the association of airway remodelling measured on bronchial biopsies with 1) lung function impairment and 2) thoracic quantitative computed tomography (QCT)-derived morphometry and densitometry measures of proximal airway remodelling and air trapping. Subjects were recruited from a single centre. Bronchial biopsy remodelling features that were the strongest predictors of lung function impairment and QCT-derived proximal airway morphometry and air trapping markers were determined by stepwise multiple regression. The best predictor of air trapping was validated in an independent replication group. Airway smooth muscle % was the only predictor of post-bronchodilator forced expiratory volume in 1 s (FEV1) % pred, while both airway smooth muscle % and vascularity were predictors of FEV1/forced vital capacity. Epithelial thickness and airway smooth muscle % were predictors of mean segmental bronchial luminal area (R2=0.12; p=0.02 and R2=0.12; p=0.015), whereas epithelial thickness was the only predictor of wall area % (R2=0.13; p=0.018). Vascularity was the only significant predictor of air trapping (R2=0.24; p=0.001), which was validated in the replication group (R2=0.19; p=0.031). In asthma, airway smooth muscle content and vascularity were both associated with airflow obstruction. QCT-derived proximal airway morphometry was most strongly associated with epithelial thickness and airway smooth muscle content, whereas air trapping was related to vascularity. Airway remodelling in asthma biopsies is associated with proximal airway QCT-derived morphometry and air trapping http://ow.ly/ucoA308Jv9F

3D mapping of airway wall thickening in asthma with MSCT: a level set approach

Assessing the airway wall thickness in multi slice computed tomography (MSCT) as image marker for airway disease phenotyping such asthma and COPD is a current trend and challenge for the scientific community working in lung imaging. This paper addresses the same problem from a different point of view: considering the expected wall thickness-to-lumen-radius ratio for a normal subject as known and constant throughout the whole airway tree, the aim is to build up a 3D map of airway wall regions of larger thickness and to define an overall score able to highlight a pathological status. In this respect, the local dimension (caliber) of the previously segmented airway lumen is obtained on each point by exploiting the granulometry morphological operator. A level set function is defined based on this caliber information and on the expected wall thickness ratio, which allows obtaining a good estimate of the airway wall throughout all segmented lumen generations. Next, the vascular (or mediastinal dense tissue) contact regions are automatically detected and excluded from analysis. For the remaining airway wall border points, the real wall thickness is estimated based on the tissue density analysis in the airway radial direction; thick wall points are highlighted on a 3D representation of the airways and several quantification scores are defined. The proposed approach is fully automatic and was evaluated (proof of concept) on a patient selection coming from different databases including mild, severe asthmatics and normal cases. This preliminary evaluation confirms the discriminative power of the proposed approach regarding different phenotypes and is currently extending to larger cohorts.