Showing papers by "Ian D. Pavord published in 2009"

Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma

Abstract: BACKGROUND: Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS: Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS: Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)

An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.

Abstract: Background: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways.Purpose: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older.Methods: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures.Results: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge ...

Helicobacter pylori and lung function, asthma, atopy and allergic disease—A population-based cross-sectional study in adults

Abstract: Background Exposure to microbes may result in the polarization of the immune system and a decrease in the risk of asthma and associated allergic disease, whilst exposure to Helicobacter pylori has been hypothesized to increase the risk of obstructive airways disease. We tested the hypotheses that exposure to H. pylori reduces the risk of asthma and allergic disease and is associated with a decrease in lung function. Methods Data were collected on allergic disease symptoms, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), bronchial reactivity, allergen skin sensitization, serum IgE and H. pylori serological status in 2437 randomly selected adults. Results Individuals with serological evidence of exposure to H. pylori had lower lung function, FEV1 being lower by 53 ml (95% CI 1-106) and FVC 83 ml (95% CI 20-145) lower in the cross-sectional analysis. These differences ceased to be statistically significant after adjustment for height or socio-economic status. There was no association between H. pylori serological status and measures of asthma or atopy in the cross-sectional analysis, and there was no significant association between H. pylori serological status and decline in FEV1 and FVC over 9 years. Conclusion Although H. pylori exposure may be associated with lower cross-sectional FEV1 and FVC, this association was not independent of height or socio-economic status. There was no association between H. pylori exposure and either chronic obstructive pulmonary disease (COPD), measures of allergic disease or decline in lung function.

Airway inflammation in patients with asthma with high-fixed or low-fixed plus as-needed budesonide/formoterol

Abstract: Background Budesonide/formoterol maintenance and reliever therapy maintains asthma control and reduces exacerbation frequency compared with higher fixed-dose combination regimens. Its effects on eosinophilic airway inflammation and structure are unknown. Objective We sought to compare the effects of budesonide/formoterol 200/6 μg twice daily plus as-needed with budesonide/formoterol 800/12 μg twice daily on airway eosinophils and remodeling. Methods This 52-week, parallel-group, randomized, double-blind study of 127 asthma patients who were symptomatic despite therapy compared (1) the change between induced sputum percent eosinophils at baseline and the geometric mean of 4 on-treatment values and (2) the change in endobronchial biopsy eosinophil counts pre- and post-treatment. Results Mean daily doses of budesonide/formoterol were 604/18 μg in the maintenance and reliever therapy group and 1,600/24 μg in the high fixed-dose group. In the former, the geometric mean percent sputum eosinophils remained unchanged (1.6% to 1.9%), whereas biopsy specimen subepithelial eosinophils increased (6.2 to 12.3 cells/mm 2 ). Sputum and biopsy eosinophil counts decreased with high fixed-dose treatment (2.2% to 1.2% and 7.7 to 4.8 cells/mm 2 , respectively), resulting in significant treatment differences of 0.7% (ratio, 1.8; 95% CI, 1.2-2.8; P = .0038) and 7.5 cells/mm 2 (ratio, 2.9; 95% CI, 1.6-5.3; P 1 . Conclusion Compared with fixed-dose combination treatment containing a 4-fold higher maintenance dose of budesonide, budesonide/formoterol maintenance and reliever therapy is associated with higher eosinophil counts, but these remain within the range associated with stable clinical control.

Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD.

Abstract: Background: Airway inflammation in chronic obstructive pulmonary disease (COPD) is predominately neutrophilic, but some subjects demonstrate eosinophilic airway inflammation. Whethe

The A to E of airway disease

Abstract: The terms asthma and chronic obstructive pulmonary disease have evolved from their original very specific physiology-based definition to describe additional disease entities such as symptoms, airway inflammation and airway structure. We argue that as a result there is widespread confusion about what the terms mean. This has become a significant hurdle to optimal disease management and drug development. We propose that these disease labels should be replaced with a new alphabetical assessment tool for characterizing airway disease, which provides a checklist of five relatively independent factors potentially responsible for morbidity in patients with airway disease: Airway hyperresponsiveness, Bronchitis, Cough reflex hypersensitivity, Damage to the airway and surrounding lung and Extrapulmonary factors. We speculate that the use of this system to characterize airway disease will improve outcomes by promoting better targeting of new and existing treatments.

Bronchial thermoplasty for the treatment of asthma.

Abstract: Asthma is an increasingly prevalent disease, particularly in industrialized countries. With modern treatment, many patients can expect good asthma control; however, a significant minority continue to have excessive symptoms. Bronchial thermoplasty is a novel approach to treating asthma in which the hypertrophied airway smooth muscle present in the asthmatic airway is specifically targeted and depleted using thermal energy. In this article, we review the early animal and human development of the technique, summarize the randomized trials carried out in patients to date, discuss proposed mechanisms of action, and suggest directions for future work.

Assessment of gender differences in health status with the Leicester Cough Questionnaire (LCQ)

Abstract: Kelsall et al were surprised that there were no differences in Leicester Cough Questionaire (LCQ)1 scores in men and women with chronic cough and suggest that this was because the LCQ did not capture gender-specific differences in health status.2 We disagree. We have previously reported significantly worse health status in a larger group of females with chronic cough (see table 1).3 4 Furthermore, Polley et al investigated the gender differences in health status in 147 patients with chronic …

Asthma control, airway responsiveness and airway inflammation.

Abstract: Asthma control can be defined as the extent to which the various manifestations of asthma have been reduced or removed by treatment [1]. The manifestations of asthma have two important components: day-to-day symptoms and risk of future adverse events such as asthma exacerbations and the development of fixed airflow obstruction. Day-to-day symptoms can be assessed relatively simply by questionnaire. The Juniper Asthma Control Questionnaire (ACQ) is one of the most commonly used and best validated [1, 2]. The questionnaire is scored as the mean of the response to seven questions scored on a seven-point scale, with lower values representing better control. Five questions relate to day and nighttime symptoms over the previous 7 days, one to rescue b2-agonist use over the last 7 days and one on the % predicted pre-bronchodilator forced expiratory volume in 1 s. There is an emerging consensus that scores o 0.75 represent well-controlled asthma and 41.5 not well-controlled asthma [1, 3]. A shortened five-question symptom only questionnaire has been developed [4]. It performs almost as well as the longer questionnaire and may be a more suitable tool for clinical practice. Airway inflammation and airway hyperresponsiveness are acknowledged to be key features of asthma but there is uncertainty as to how they contribute to asthma control and whether incorporating measures of these features might add to an overall assessment. The first of these questions has been addressed by Quaedvilieg et al. in this issue of the journal [5]. In a cross-sectional study of 134 patients attending a local asthma clinic, the authors assessed the relationship between the ACQ score, methacholine airway responsiveness and eosinophilic airway inflammation assessed using induced sputum and exhaled nitric oxide concentration (FENO). The ACQ score was modified from the original seven-item questionnaire by excluding the lung function question. Airway responsiveness and the sputum eosinophil count were significantly increased in patients with an ACQ score 41.5 compared with those with a score o 0.75 whereas FENO was not. Although marginally better than simple spirometric indices, none of the measures reliably discriminated patients in different control categories. What are we to make of this data? What are the implications for use of these investigations in the clinic? The clinical manifestations of airway diseases can be viewed as the consequence of different patterns of airway inflammation and a limited number of abnormal physiological responses which can be conveniently summarized using an A to E checklist. These include: Airway hyperresponsiveness, responsible for short-term variable bronchodilator responsive airflow obstruction; Bronchitis, which may be eosinophilic and corticosteroid responsive or neutrophilic and corticosteroid resistant; Cough reflex hypersensitivity; Damage to the airway and lung resulting in bronchodilator and corticosteroid resistant airflow obstruction, bronchiectasis and impaired gas transfer; and Extra-pulmonary conditions such as dysfunctional breathing, adherence to medication, deconditioning, rhinitis and obesity. These abnormalities can, and often do, occur independently and they are controlled by distinct pathogenic pathways. The weak relationship between symptoms, eosinophilic airway inflammation and airway responsiveness noted by Quaedvilieg et al. implies that C, D and E make a large contribution to symptoms, at least in a population of patients attending a hospital clinic. Is there any evidence that measuring A (airway responsiveness) and B (bronchitis or airway inflammation) adds to an assessment of asthma control? Evidence suggests that both are particularly associated with risk. B can be clinically silent but it may also contribute to more gradual Correspondence: Prof. I. D. Pavord, Department of Respiratory Medicine, Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Groby Road, Leicester, LE3 9QP, UK. E-mail: ian.pavord@uhl-tr.nhs.uk Cite this as: I. D. Pavord, Clinical & Experimental Allergy, 2009 (39) 1780–1782. doi: 10.1111/j.1365-2222.2009.03395.x Clinical & Experimental Allergy, 39, 1780–1782

Will exhaled nitric oxide monitoring become routine in managing asthma

Abstract: In this editorial, we outline the rationale for a new approach to the assessment of airway disease based on measurement of airway inflammation using noninvasive markers (inflammometry). Our focus is on measurement of exhaled nitric oxide (FE(NO)), as this technique is simple and affordable, and is applicable in a wide variety of clinical settings. Studies have shown that raised FE(NO) is a useful marker of corticosteroid-responsive airway disease; low FE(NO) may identify patients who can safely reduce or withdraw corticosteroids. However, the optimum use of FE(NO) in clinical practice remains to be established.

The long-term outcome of patients with unexplained chronic cough

Abstract: INTRODUCTION Up to 40% of patients seen in a cough clinic have unexplained chronic cough. The long term outcome of these patients is uncertain. OBJECTIVE To determine the long-term outcome in patients diagnosed with unexplained chronic cough. METHODS We have performed a longitudinal study of symptoms, airway inflammation and spirometry in a cohort of patients with unexplained chronic cough diagnosed over 7 years ago. Cough was assessed using a 100 mm visual analogue scale (VAS). At the first and final visit cough reflex sensitivity was assessed as the concentration of inhaled capsaicin at which the volunteer coughed 2 (C2) and 5 times (C5). RESULTS We identified 42 patients (32 females) with unexplained chronic cough who had been assessed at least 7 years previously and agreed to a further assessment. The mean (SD) duration of cough was 11.5 (4.5) years at the time of their final assessment. Nine patients (21%) had organ specific autoimmune disease and twenty (48%) had a peripheral blood lymphopaenia. Six (14%) patients had complete resolution of symptoms and 11 (26%) had a significant >10 mm improvement in their cough VAS during follow up. Longitudinal spirometry data was available in 30 patients. The median rate of FEV(1) decline was 44 ml/year and four (13%) patients developed a post-bronchodilator forced expiratory volume in 1 s (FEV(1))/forced vital capacity of less than 0.7. FEV(1) decline was similar in patients with persistent cough and those whose cough improved. No other independent predictors of FEV(1) decline were identified. There were no independent predictors of improvement in cough. CONCLUSIONS Cough persists over time in the majority of patients with unexplained chronic cough. Patients have an increased rate of decline in FEV(1) and a significant minority develop fixed airflow obstruction.

The relationship between Aspergillus Fumigatus sensitisation and sputum culture

Abstract: This paper was published as Clinical and Experimental Allergy, 2009, 39 (12), p. 1937: British Society for Allergy and Clinical Immunology Annual Conference 2009 Abstracts, S2. It is available from http://www3.interscience.wiley.com/journal/122683542/issue. Doi: 10.1111/j.1365-2222.2009.03389.x

Non-invasive assessment of airway inflammation

Abstract: This chapter reviews the methodology and validation of induced sputum and FENO and outlines other more experimental approaches to the assessment of airway inflammation. There has been an explosion of interest in the assessment of airway inflammation using non-invasive means and there are now a large number of different techniques to assess airway inflammation, each with its own strengths and weaknesses. Two techniques are particularly well developed and are already widely used in clinical trials and impacting on clinical practice: induced sputum, where a sputum differential and total cell count is used to determine the characteristics and intensity of the lower airway inflammatory response; and exhaled nitric oxide (FENO), where the concentration of nitric oxide (NO) in exhaled air is used to provide information about the presence of eosinophilic, corticosteroid responsive airway inflammation. The different strengths and weaknesses of the techniques suggests that they may find different roles, with FENO being used mainly in primary care to facilitate diagnosis and to titrate corticosteroid therapy and induced sputum used in secondary and tertiary care, where more detailed information on the type of lower airway inflammation is necessary. The chapter finishes by discussing how the widespread application of induced sputum to large and heterogeneous populations of patients with airway disease has furthered our understanding of the complex relationship between airway inflammation and the clinical expression of airway disease and opened the way to a new approach to the management of airway disease based on assessment of airway inflammation. © 2009 Elsevier Ltd All rights reserved.

Role of breathing exercises in hyperventilating subjects

Abstract: If this ‘‘alternative form’’ was mentioned during the invitation to take part in the study (which is not stated in the article), then all the subjects could have been self-motivated, which is not representative of the general population and hence the results cannot be generalised. Last, the subjects who underwent breathing training were encouraged to do the breathing exercises throughout the 6-month period whereas the control group had three sessions of asthma education with no such ongoing ‘‘controlling effect’’. A significant improvement in forced expiratory volume in 1 s and a significant fall in exhaled nitric oxide 1 month after the intervention in the control group shows the beneficial effect of patient education. Hence, effective pharmacotherapy with asthma education continues to be the core of asthma treatment. The role of breathing training is possibly present in subjects who have a tendency to hyperventilate, which need not be due just to asthma but to any cause.