Sherif Gonem

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.

Lung damage and airway remodelling in severe asthma

Severe asthma is a heterogeneous disease with substantial unmet clinical need. Airway damage and remodelling is a consequence of complex host–environment interactions and is considered to be the cardinal feature leading onto the development and persistence of airflow obstruction. In this review, we shall bring together recent insights into the causes of airway damage and remodelling that propose key roles for pathogens and mechanical damage in addition to allergens, underlying genetic susceptibility, inflammatory and structural cell interactions, and impaired resolution of damage. We shall consider the consequences of airway remodelling in terms of airway geometry, mechanics and clinical expression of disease. Understanding the causes and consequences of airway damage and remodelling will shed light upon the structure–function relationships required to begin to unravel the complexity of severe asthma and will enable us to target current and novel therapies as we begin to move towards realizing personalized medicine.

Phenotyping airways disease: an A to E approach.

The airway diseases asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous conditions with overlapping pathophysiological and clinical features. It has previously been proposed that this heterogeneity may be characterized in terms of five relatively independent domains labelled from A to E, namely airway hyperresponsiveness (AHR), bronchitis, cough reflex hypersensitivity, damage to the airways and surrounding lung parenchyma, and extrapulmonary factors. Airway hyperresponsiveness occurs in both asthma and COPD, accounting for variable day to day symptoms, although the mechanisms most likely differ between the two conditions. Bronchitis, or airway inflammation, may be predominantly eosinophilic or neutrophilic, with different treatments required for each. Cough reflex hypersensitivity is thought to underlie the chronic dry cough out of proportion to other symptoms that can occur in association with airways disease. Structural changes associated with airway disease (damage) include bronchial wall thickening, airway smooth muscle hypertrophy, bronchiectasis and emphysema. Finally, a variety of extrapulmonary factors may impact upon airway disease, including rhinosinusitis, gastroesophageal reflux disease, obesity and dysfunctional breathing. This article discusses the A to E concept in detail and describes how this framework may be used to assess and treat patients with airway diseases in the clinic.

Lung clearance index in adults with non-cystic fibrosis bronchiectasis

BackgroundLung clearance index (LCI) is a measure of abnormal ventilation distribution derived from the multiple breath inert gas washout (MBW) technique. We aimed to determine the clinical utility of LCI in non-CF bronchiectasis, and to assess two novel MBW parameters that distinguish between increases in LCI due to specific ventilation inequality (LCIvent) and increased respiratory dead space (LCIds).MethodsForty-three patients with non-CF bronchiectasis and 18 healthy control subjects underwent MBW using the sulphur hexafluoride wash-in technique, and data from 40 adults with CF were re-analysed. LCIvent and LCIds were calculated using a theoretical two-compartment lung model, and represent the proportional increase in LCI above its ideal value due to specific ventilation inequality and increased respiratory dead space, respectively.ResultsLCI was significantly raised in patients with non-CF bronchiectasis compared to healthy controls (9.99 versus 7.28, p < 0.01), and discriminated well between these two groups (area under receiver operating curve = 0.90, versus 0.83 for forced expiratory volume in one second [% predicted]). LCI, LCIvent and LCIds were repeatable (intraclass correlation coefficient > 0.75), and correlated significantly with measures of spirometric airflow obstruction.ConclusionLCI is repeatable, discriminatory, and is associated with spirometric airflow obstruction in patients with non-CF bronchiectasis. LCIvent and LCIds are a practical and repeatable alternative to phase III slope analysis and may allow a further level of mechanistic information to be extracted from the MBW test in patients with severe ventilation heterogeneity.

Clinical significance of small airway obstruction markers in patients with asthma.

The role of small airway obstruction in the clinical expression of asthma is incompletely understood.

Evidence for phenotype-driven treatment in asthmatic patients.

Purpose of review Asthma is a complex inflammatory disease and current therapy remains inadequate in many sufferers. There is phenotypic heterogeneity in its clinical expression as a consequence of gene–environment interactions and heterogeneity in response to therapy. This review summarizes the current state of knowledge on phenotype-driven treatment of asthma. Recent findings Evidence is accumulating that even standard therapies such as inhaled corticosteroids benefit some groups of asthmatic patients more than others. Macrolide antibiotics and antifungal agents are examples of drugs that have established indications outside the field of airways disease but which may benefit a subset of patients with asthma. Finally, new and expensive biological therapies for asthma are emerging that may be highly efficacious, but only for a selected group of patients. Summary The emergence of novel therapies, in particular highly specific treatments, bring the promise of improving healthcare in asthma but present the challenge of choosing the right therapy for the right patient. Phenotype-driven treatment of asthma is emerging as a potential reality and will pave the way for personalized healthcare.

Validation of a photoacoustic gas analyser for the measurement of functional residual capacity using multiple-breath inert gas washout.

Background: The respiratory mass spectrometer is the current gold-standard technique for performing multiple-breath inert gas washout (MBW), but is expensive and lacks portability. A number of alternative techniques have recently been described. Objectives: We aimed to validate, using an in vitro lung model, an open-circuit MBW system that utilises a portable photoacoustic gas analyser, with sulphur hexafluoride (SF6) as the inert tracer gas. Methods: An acrylic glass lung model was utilised to assess the accuracy of functional residual capacity (FRC) measurements derived from MBW. Measurements were performed in triplicate at 20 combinations of simulated FRC, tidal volume and respiratory rate. FRC measured using MBW (FRCmbw) was compared to FRC calculated from the known dimensions of the model (FRCcalc). MBW was also performed in 10 healthy subjects and 14 patients with asthma. Results: The MBW system measured FRC with high precision. The mean bias of FRCmbw with respect to FRCcalc was -0.4% (95% limits of agreement of -4.6 and 3.9%). The mean coefficient of variation of triplicate FRC measurements was 4.0% in vivo and 1.0% in vitro. MBW slightly underestimated low lung volumes and overestimated high lung volumes, but this did not cause a significant error in lung clearance index except at lung volumes below 1,500 ml. Conclusions: The open-circuit MBW system utilising SF6 as the inert tracer gas and a photoacoustic gas analyser is both accurate and repeatable within the adult range of lung volumes. Further modifications would be required before its use in young children or infants.

Airway impedance entropy and exacerbations in severe asthma

Variability of peak flow measurements has been related to clinical outcomes in asthma. We hypothesised that the entropy, or information content, of airway impedance over short time scales may predict asthma exacerbation frequency. 66 patients with severe asthma and 30 healthy control subjects underwent impulse oscillometry at baseline and following bronchodilator administration. On each occasion, airway impedance parameters were measured at 0.2-s intervals for 150 s, yielding a time series that was then subjected to sample entropy (SampEn) analysis. Airway impedance and SampEn of impedance were increased in asthmatic patients compared with healthy controls. In a logistic regression model, SampEn of the resistance at 5 Hz minus the resistance at 20 Hz, a marker of the fluctuation of the heterogeneity of airway constriction over time, was the variable most strongly associated with the frequent exacerbation phenotype (OR 3.23 for every 0.1 increase in SampEn). Increased airway impedance and SampEn of impedance are associated with the frequent exacerbation phenotype. Prospective studies are required to assess their predictive value.

Advances in the management of severe asthma.

Severe asthma affects 5 to 10% of the asthma population but consumes a disproportionate amount of the global asthma budget (~50%) due to unscheduled health care utilization in primary care, hospitalizations due to severe exacerbations, and the costs of pharmacotherapy. A key challenge in managing severe asthma is to identify appropriate groups of patients that will respond best to existing and evolving therapies. Recent advances in our understanding of how to classify severe asthma using multivariate taxonomical approaches have provided a unique model of a stratified medicines approach. For example, patients with inflammation-predominant asthma with eosinophils benefit from both inhaled and oral corticosteroids as well as targeted biologics such as anti-interleukin (IL)-5, all of which significantly reduce asthma exacerbations. On the other hand, patients with noneosinophilic neutrophilic asthma may be more suitable for steroid down-titration and therapeutic trials of antineutrophilic agents such as macrolide antibiotics. A similar paradigm can be applied to other domains in severe asthma such as airway hyperresponsiveness, which may now be treated with the first mechanical therapy in airways disease (bronchial thermoplasty). At the same time it is important for the clinician to recognize and treat comorbid factors that make asthma difficult to manage such as poor adherence to medication, rhinosinusitis, and psychological comorbidity. Therefore it is of vital importance to develop a multidisciplinary approach to the management of severe asthma that is best applied within specialist centers with experience and wider access to national and international severe asthma networks.

Between-visit variability of small airway obstruction markers in patients with asthma

To the Editor: Clinical trials in patients with airway diseases often use forced expiratory volume in 1 s (FEV1) as the sole physiological outcome measure. However, FEV1 is thought to be insensitive to obstruction of the smaller airways, which may be particularly relevant in asthma [1]. Putative markers of small airway obstruction include measures of airway resistance using impulse oscillometry (IOS) [2] and indices of ventilation heterogeneity derived from multiple-breath inert gas washout (MBW) [3]. We recently showed that increased airway resistance at 5 Hz ( R 5) and 20 Hz ( R 20) is associated with worse asthma control and more frequent exacerbations [4], and Farah et al. [5] demonstrated that MBW parameters may be responsive to asthma therapy. In order to conduct clinical trials using these alternative outcome measures, it is necessary to be assured of their repeatability and stability over time. Moreover, an estimate of between-visit variability in the stable state is required so that sample size calculations can be performed. We therefore aimed to determine the between-visit variability of a range of IOS and MBW indices in a group of patients with asthma in the stable state. We investigated between-visit variability over two time intervals, namely 2 weeks and 3 months, in order to encompass the typical lengths of treatment period that are used in clinical trials. We recruited 18 adults (age >18 years) with moderate-to-severe asthma (Global Initiative for Asthma treatment steps 3–5 [6]), diagnosed by a specialist asthma physician in a secondary care setting, according to British Thoracic Society guidelines [ …