Pavord Group Publications 2005-current

Hilvering B, Hinks TSC, Stöger L, Marchi E, Salimi M, Shrimanker R, Liu W, Chen W, Luo J, Go S et al. 2018. Correction: Synergistic activation of pro-inflammatory type-2 CD8 + T lymphocytes by lipid mediators in severe eosinophilic asthma. Mucosal Immunol, | Show Abstract | Read more

This article was originally published under standard licence, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.

Shrimanker R, Pavord ID, Yancey S, Heaney LG, Green RH, Bradding P, Hargadon B, Brightling CE, Wardlaw AJ, Haldar P. 2018. Exacerbations of severe asthma in patients treated with mepolizumab. Eur Respir J, 52 (6), pp. 1801127-1801127. | Read more

Criner GJ, Martinez FJ, Aaron S, Agusti A, Anzueto A, Bafadhel M, Barnes PJ, Bourbeau J, Chen R, Ewig J et al. 2018. Current Controversies in Chronic Obstructive Pulmonary Disease: A Report from the GOLD Scientific Committee. Ann Am Thorac Soc, | Read more

Agusti A, Pavord ID. 2018. Do we really need a new classification of airway diseases? Lancet Respir Med, 6 (12), pp. 891-893. | Read more

Heaney LG, Busby J, Bradding P, Chaudhuri R, Mansur AH, Niven R, Pavord I, Lindsay JT, Costello RW, Medical Research Council UK Refractory Asthma Stratification Programme (RASP-UK). 2018. Remotely Monitored Therapy and Nitric Oxide Suppression Identifies Non-Adherence in Severe Asthma. Am J Respir Crit Care Med, | Show Abstract | Read more

Rationale Poor adherence is common in difficult-to-control asthma. Distinguishing patients with difficult-to-control asthma who respond to inhaled corticosteroids (ICS) from refractory asthma is an important clinical challenge. Objectives Suppression of fractional exhaled nitric oxide (FeNO) with directly observed ICS therapy over 7 days can identify non-adherence to ICS treatment in difficult-to-control asthma. We examined the feasibility and utility of FeNO suppression testing in routine clinical care within UK severe asthma centres using remote monitoring technologies. Methods A web-based interface with integrated remote monitoring technology was developed to deliver FeNO suppression testing. We examined the utility of FeNO suppression testing to demonstrate ICS responsiveness and clinical benefit on electronically-monitored treatment with standard high dose ICS and long-acting β2-agonist (LABA) treatment. Measurements and Main Results Clinical response was assessed using the Asthma Control Questionnaire (ACQ-5), spirometry and biomarker measurements (FeNO and peripheral blood eosinophil count). Of 250 subjects, 201 completed the test with 130 positive suppression tests. Compared to a negative suppression test, a positive test identified a FeNO-low population when adherent with ICS/LABA (median 26ppb [IQR 16-36] v 43ppb [IQR 38-73]) with significantly greater FEV1% (mean 88.2±16.4 v 74.1±20.9], p<0.01). ACQ-5 improved significantly in both groups (positive test, mean difference 1.2, 95% CI -0.9, -1.5, negative test, mean difference 0.9, 95% CI -0.4, -1.3). Conclusions Remote FeNO suppression testing is an effective means of identifying non-adherence to ICS in subjects with difficult-to-control asthma and the substantial population of subjects who derive important clinical benefits from optimised ICS/LABA treatment.

Kerkhof M, Tran TN, van den Berge M, Brusselle GG, Gopalan G, Jones RCM, Kocks JWH, Menzies-Gow A, Nuevo J, Pavord ID et al. 2018. Association between blood eosinophil count and risk of readmission for patients with asthma: Historical cohort study. PLoS One, 13 (7), pp. e0201143. | Citations: 1 (Scopus) | Show Abstract | Read more

BACKGROUND: Recent studies have demonstrated an association between high blood eosinophil counts and greater risk of asthma exacerbations. We sought to determine whether patients hospitalized for an asthma exacerbation were at greater risk of readmission if they had a high blood eosinophil count documented before the first hospitalization. METHODS: This historical cohort study drew on 2 years of medical record data (Clinical Practice Research Datalink with Hospital Episode Statistics linkage) of patients (aged ≥5 years) admitted to hospital in England for asthma, with recorded blood eosinophil count within 1 baseline year before admission. We analyzed the association between high blood eosinophil count (≥0.35x109 cells/L) and readmission risk during 1 year of follow-up after hospital discharge, with adjustment for predefined, relevant confounders using forward selection. RESULTS: We identified 2,613 eligible patients with asthma-related admission, of median age 51 years (interquartile range, 36-69) and 76% women (1,997/2,613). Overall, 835/2,613 (32.0%) had a preadmission high blood eosinophil count. During the follow-up year, 130/2,613 patients (5.0%) were readmitted for asthma, including 55/835 (6.6%) with vs. 75/1,778 (4.2%) without high blood eosinophil count at baseline (adjusted hazard ratio [HR] 1.49; 95% CI 1.04-2.13, p = 0.029). The association was strongest in never-smokers (n = 1,296; HR 2.16, 95% CI 1.27-3.68, p = 0.005) and absent in current smokers (n = 547; HR 1.00, 95% CI 0.49-2.04, p = 0.997). CONCLUSIONS: A high blood eosinophil count in the year before an asthma-related hospitalization is associated with increased risk of readmission within the following year. These findings suggest that patients with asthma and preadmission high blood eosinophil count require careful follow-up, with treatment optimization, after discharge.

Pavord ID. 2018. GLUCOLD, eosinophils and chronic obstructive pulmonary disease. Respirology, 23 (11), pp. 966-967. | Read more

Shrimanker R, Pavord ID. 2018. Will precision medicine become an effective tool for airway disease? Per Med, 15 (4), pp. 243-245. | Read more

Hilvering B, Hinks TSC, Stöger L, Marchi E, Salimi M, Shrimanker R, Liu W, Chen W, Luo J, Go S et al. 2018. Synergistic activation of pro-inflammatory type-2 CD8+ T lymphocytes by lipid mediators in severe eosinophilic asthma. Mucosal Immunol, 11 (5), pp. 1408-1419. | Show Abstract | Read more

Human type-2 CD8+ T cells are a cell population with potentially important roles in allergic disease. We investigated this in the context of severe asthma with persistent airway eosinophilia-a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines, which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

Psallidas I, Kanellakis NI, Gerry S, Thézénas ML, Charles PD, Samsonova A, Schiller HB, Fischer R, Asciak R, Hallifax RJ et al. 2018. Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis. Lancet Oncol, 19 (7), pp. 930-939. | Citations: 2 (Scopus) | Show Abstract | Read more

BACKGROUND: The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. METHODS: In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. FINDINGS: 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score). INTERPRETATION: To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. FUNDING: European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.

Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, Busse WW, Ford L, Sher L, FitzGerald JM et al. 2018. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med, 378 (26), pp. 2486-2496. | Citations: 30 (Scopus) | Show Abstract | Read more

BACKGROUND: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma. METHODS: We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed. RESULTS: The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo. CONCLUSIONS: In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).

Pavord ID. 2018. Biologics and chronic obstructive pulmonary disease. J Allergy Clin Immunol, 141 (6), pp. 1983-1991. | Citations: 1 (Scopus) | Show Abstract | Read more

The presence of airway inflammation in patients with chronic obstructive pulmonary disease (COPD) provides a rationale for biological agents targeting specific inflammatory pathways. This approach has been strikingly effective in patients with other chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and asthma. However, there are important and unresolved challenges in COPD, including our incomplete understanding of heterogeneity of the lower airway inflammatory response and how these contribute to the clinical expression of disease. As a result, progress has been slow, and there have been many failures. One notable exception is the targeting of eosinophilic airway inflammation with anti-IL-5, which has an acknowledged and important role in the treatment of severe eosinophilic asthma. Recent phase III studies have shown a reduction in exacerbations of around 20% in patients with COPD and clear evidence of a blood eosinophil count-dependent beneficial effect. The demonstration of clinical efficacy linked to a clinically accessible biomarker raises the possibility of precision biomarker-directed use of biological agents in patients with COPD. The hope is that this will be an exemplar for the future development of biological agents in patients with COPD.

Busse WW, Maspero JF, Rabe KF, Papi A, Wenzel SE, Ford LB, Pavord ID, Zhang B, Staudinger H, Pirozzi G et al. 2018. Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma. Adv Ther, 35 (5), pp. 737-748. | Citations: 1 (Scopus) | Show Abstract | Read more

INTRODUCTION: Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma. METHODS: Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12. CONCLUSION: Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc. CLINICAL TRIALS. GOV IDENTIFIER: NCT02414854.

Ghebre MA, Pang PH, Diver S, Desai D, Bafadhel M, Haldar K, Kebadze T, Cohen S, Newbold P, Rapley L et al. 2018. Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles. J Allergy Clin Immunol, 141 (6), pp. 2027-2036.e12. | Citations: 4 (Scopus) | Show Abstract | Read more

BACKGROUND: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous. OBJECTIVE: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations. METHODS: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center. Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation. Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters. RESULTS: The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6 receptor, TNF-α, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN-γ) and proportions of the phyla Actinobacteria and Firmicutes. CONCLUSIONS: A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD. The sputum mediator and microbiome profiles were distinct between clusters.

Hancox RJ, Pavord ID, Sears MR. 2018. Associations between blood eosinophils and decline in lung function among adults with and without asthma. Eur Respir J, 51 (4), pp. 1702536-1702536. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

Eosinophilic inflammation and airway remodelling are characteristic features of asthma, but the association between them is unclear. We assessed associations between blood eosinophils and lung function decline in a population-based cohort of young adults.We used linear mixed models to analyse associations between blood eosinophils and spirometry at 21, 26, 32 and 38 years adjusting for sex, smoking, asthma and spirometry at age 18 years. We further analysed associations between mean eosinophil counts and changes in spirometry from ages 21 to 38 years.Higher eosinophils were associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratios and lower FEV1 % predicted values for both pre- and post-bronchodilator spirometry (all p-values ≤0.048). Although eosinophil counts were higher in participants with asthma, the associations between eosinophils and spirometry were similar among participants without asthma or wheeze. Participants with mean eosinophil counts >0.4×109 cells·L-1 between 21 and 38 years had greater declines in FEV1/FVC ratios (difference 1.8%, 95% CI 0.7-2.9%; p=0.001) and FEV1 values (difference 3.4% pred, 95% CI 1.5-5.4% pred); p=0.001) than those with lower counts.Blood eosinophils are associated with airflow obstruction and enhanced decline in lung function, independently of asthma and smoking. Eosinophilia is a risk factor for airflow obstruction even in those without symptoms.

Pascoe S, Pavord I, Hinds D, Locantore N, Barnes N. 2018. The association between blood eosinophils and risk and treatment outcome in COPD is not dichotomised. Lancet Respir Med, 6 (5), pp. e18. | Citations: 1 (European Pubmed Central) | Read more

Barker R, Shrimanker R, Russell R, Fenton-Woods J, Jones C, Smith L, Johnson M, Pavord I. 2018. P187 Seasonality of eosinophilic and non-eosinophilic exacerbations of copd (vol 72, pg A183, 2017) THORAX, 73 (4),

Brusselle G, Pavord ID, Landis S, Pascoe S, Lettis S, Morjaria N, Barnes N, Hilton E. 2018. Blood eosinophil levels as a biomarker in COPD. Respir Med, 138 pp. 21-31. | Citations: 3 (Scopus) | Show Abstract | Read more

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder and patients respond differently to treatment. Blood eosinophils are a potential biomarker to stratify patient subsets for COPD therapy. We reviewed the value of blood eosinophils in predicting exacerbation risk and response to corticosteroid treatment in the available literature (PubMed articles in English; keywords: "COPD" and "eosinophil"; published prior to May 2017). Overall, clinical data suggest that in patients with a history of COPD exacerbations, a higher blood eosinophil count predicts an increased risk of future exacerbations and is associated with improved response to treatment with inhaled corticosteroids (in combination with long-acting bronchodilator[s]). Blood eosinophils are therefore a promising biomarker for phenotyping patients with COPD, although prospective studies are needed to assess blood eosinophils as a biomarker of corticosteroid response for this.

McKeever T, Mortimer K, Wilson A, Walker S, Brightling C, Skeggs A, Pavord I, Price D, Duley L, Thomas M et al. 2018. Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations. N Engl J Med, 378 (10), pp. 902-910. | Citations: 11 (Scopus) | Show Abstract | Read more

BACKGROUND: Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma. METHODS: We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma. RESULTS: A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group. CONCLUSIONS: In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN15441965 .).

Pavord ID. 2018. COUNTERPOINT: Should an Attempt Be Made to Withdraw Inhaled Corticosteroids in All Patients With Stable GOLD 3 (30% ≤ FEV1 < 50% Predicted) COPD? No. Chest, 153 (4), pp. 782-784. | Citations: 2 (Web of Science Lite) | Read more

Pavord ID. 2018. Rebuttal From Dr Pavord. Chest, 153 (4), pp. 786-787. | Read more

Sciurba FC, Bradford ES, Pavord ID. 2018. Mepolizumab for Eosinophilic COPD. N Engl J Med, 378 (7), pp. 681-683. | Citations: 1 (European Pubmed Central) | Read more

Bush A, Pavord ID. 2018. 'We can't diagnose asthma until <insert arbitrary age>'. Arch Dis Child, 103 (8), pp. 729-731. | Citations: 1 (Scopus) | Read more

Hanratty CE, Matthews JG, Arron JR, Choy DF, Pavord ID, Bradding P, Brightling CE, Chaudhuri R, Cowan DC, Djukanovic R et al. 2018. A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial. Trials, 19 (1), pp. 5. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Patients with difficult-to-control asthma consume 50-60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called 'T2-low asthma' and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy. METHODS/DESIGN: Patients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers. DISCUSSION: Multi-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02717689 . Registered on 16 March 2016.

Bruton A, Lee A, Yardley L, Raftery J, Arden-Close E, Kirby S, Zhu S, Thiruvothiyur M, Webley F, Taylor L et al. 2018. Physiotherapy breathing retraining for asthma: a randomised controlled trial. Lancet Respir Med, 6 (1), pp. 19-28. | Citations: 5 (Scopus) | Show Abstract | Read more

BACKGROUND: Despite effective pharmacotherapy, asthma continues to impair quality of life for most patients. Non-pharmacological approaches, including breathing retraining, are therefore of great interest to patients. However, clinicians rarely advocate breathing retraining and access to this intervention is restricted for most patients due to the limited availability of suitable physiotherapists and poor integration of breathing retraining into standard care. We aimed to assess the effectiveness of a digital self-guided breathing retraining intervention. METHODS: In this randomised controlled trial, we recruited patients from 34 general practices in the UK. Eligibility criteria for patients with asthma were broad, comprising a physician diagnosis of asthma, age of 16-70 years, receipt of at least one anti-asthma medication in the previous year, and impaired asthma-related quality of life (Asthma Quality of Life Questionnaire [AQLQ] score of <5·5). We developed a self-guided intervention, which was delivered as a DVD plus a printed booklet (DVDB). Participants were randomly assigned to receive either the DVDB intervention, three face-to-face breathing retraining sessions, or standard care, in a 2:1:2 ratio, for 12 months. Randomisation was achieved using the Southampton Clinical Trials Unit telephone randomisation service by use of random number generators. The primary outcome was the AQLQ score in the intention-to-treat population at 12 months. The trial was powered to show equivalence between the two active intervention groups, and superiority of both intervention groups over usual care. Secondary outcomes included patient-reported and physiological measures of asthma control, patient acceptability, and health-care costs. This trial was registered with International Standard Randomised Controlled Trial Number registry, number ISRCTN88318003. FINDINGS: Between Nov 5, 2012 and Jan 28, 2014, invitations to participate in the study were sent to 15 203 patients with general practitioner-diagnosed asthma, of whom 655 were recruited into the study. AQLQ scores at 12 months were significantly higher in the DVDB group (mean 5·40, SD 1·14) than in the usual care group (5·12, SD 1·17; adjusted mean difference 0·28, 95% CI 0·11 to 0·44), and in the face-to-face group (5·33, SD 1·06) than in the usual care group (adjusted mean difference 0·24, 95% CI 0·04 to 0·44); AQLQ scores were similar between the DVDB group and the face-to-face group (0·04, 95% CI -0·16 to 0·24). There were no significant differences between the randomisation groups in FEV1 or fraction of exhaled nitric oxide. 744 adverse events occurred in 272 patients: 101 (39%) of 261 patients in the DVDB group, 55 (42%) of 132 patients in the face-to-face group, and 132 (50%) of 262 in the usual care group, with patients reporting one or more event. 11 (4%) patients in the DVDB group, four (3%) patients in the face-to-face group, and 20 (8%) patients in the usual care group had a serious adverse event. INTERPRETATION: Breathing retraining programmes improve quality of life in patients with incompletely controlled asthma despite having little effect on lung function or airway inflammation. Such programmes can be delivered conveniently and cost-effectively as a self-guided digital audiovisual programme, so might also reduce health-care costs. FUNDING: UK National Institute of Health Research.

Siddiqui SH, Pavord ID, Barnes NC, Guasconi A, Lettis S, Pascoe S, Petruzzelli S. 2018. Blood eosinophils: a biomarker of COPD exacerbation reduction with inhaled corticosteroids. Int J Chron Obstruct Pulmon Dis, 13 pp. 3669-3676. | Show Abstract | Read more

Background: Growing evidence suggests that blood eosinophil count is associated with patient responsiveness to inhaled corticosteroids (ICS). We performed post hoc predictive modeling on data from the FORWARD study and two replicate studies by Dransfield, to evaluate the relationships between baseline eosinophil count and the effect of ICS on exacerbations and lung function in patients with COPD. Methods: The studies assessed ICS/long-acting β2 agonist (LABA) combinations vs LABA alone. Using data from each study, we modeled COPD exacerbation rates, predose FEV1, and St George's Respiratory Questionnaire score ([FORWARD only]) over a continuous range of eosinophils (0-1,000 eosinophils/µL in FORWARD, 0-993 eosinophils/µL in Dransfield). Results: In all studies, ICS/LABA reduced exacerbations versus LABA alone across all eosinophil levels, with progressively greater reductions at increasing baseline blood eosinophil counts. In FORWARD, annual exacerbation rates ranged from 0.78 to 0.83 per year between 0 and 1,000 eosinophils/µL in the ICS/LABA arm, and from 0.81 to 1.54 per year in the LABA-only arm. In the Dransfield studies, exacerbation rates ranged from 0.54 to 1.02 per year in the ICS/LABA arm between 0 and 993 eosinophils/µL, and from 0.56 to 1.75 per year in the LABA-only arm. Change in FEV1 was not associated with eosinophil count in ICS-treated patients in FORWARD, whereas an increased treatment benefit in terms of FEV1 was observed at higher eosinophil levels in the Dransfield studies. ICS/LABA led to greater improvements in St George's Respiratory Questionnaire total scores compared to LABA alone in patients in FORWARD with ≥67 eosinophils/µL. Conclusion: Higher blood eosinophil count in patients with COPD is associated with an increased beneficial effect from ICS in terms of exacerbation reduction. Further prospective data are required to assess the role of blood eosinophils as a biomarker for therapeutic recommendations.

Gunsoy NB, Cockle SM, Yancey SW, Keene ON, Bradford ES, Albers FC, Pavord ID. 2018. Evaluation of Potential Continuation Rules for Mepolizumab Treatment of Severe Eosinophilic Asthma. J Allergy Clin Immunol Pract, 6 (3), pp. 874-882.e4. | Citations: 4 (Scopus) | Show Abstract | Read more

BACKGROUND: Mepolizumab significantly reduces exacerbations in patients with severe eosinophilic asthma. The early identification of patients likely to receive long-term benefit from treatment could ensure effective resource allocation. OBJECTIVE: To assess potential continuation rules for mepolizumab in addition to initiation criteria defined as 2 or more exacerbations in the previous year and blood eosinophil counts of 150 cells/μL or more at initiation or 300 cells/μL or more in the previous year. METHODS: This post hoc analysis included data from 2 randomized, double-blind, placebo-controlled studies (NCT01000506 and NCT01691521) of mepolizumab in patients with severe eosinophilic asthma (N = 1,192). Rules based on blood eosinophils, physician-rated response to treatment, FEV1, Asthma Control Questionnaire (ACQ-5) score, and exacerbation reduction were assessed at week 16. To assess these rules, 2 key metrics accounting for the effects observed in the placebo arm were developed. RESULTS: Patients not meeting continuation rules based on physician-rated response, FEV1, and the ACQ-5 score still derived long-term benefit from mepolizumab. Nearly all patients failing to reduce blood eosinophils had counts of 150 cells/μL or less at baseline. For exacerbations, assessment after 16 weeks was potentially premature for predicting future exacerbations. CONCLUSION: There was no evidence of a reliable physician-rated response, ACQ-5 score, or lung function-based continuation rule. The added value of changes in blood eosinophils at week 16 over baseline was marginal. Initiation criteria for mepolizumab treatment provide the best method for assessing patient benefit from mepolizumab treatment, and treatment continuation should be reviewed on the basis of a predefined reduction in long-term exacerbation frequency and/or oral corticosteroid dose.

Yancey SW, Keene ON, Albers FC, Ortega H, Bates S, Bleecker ER, Pavord I. 2017. Biomarkers for severe eosinophilic asthma. J Allergy Clin Immunol, 140 (6), pp. 1509-1518. | Citations: 17 (Scopus) | Show Abstract | Read more

The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment.

Haughney J, Morice A, Blyth KG, Lee AJ, Coutts A, McKnight E, Pavord I. 2018. A retrospective cohort study in severe asthma describing commonly measured biomarkers: Eosinophil count and IgE levels. Respir Med, 134 pp. 117-123. | Citations: 1 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Identifying asthma patients suitable for biologic therapy includes the assessment of blood biomarkers (IgE and eosinophils (EOS)). How they relate to each other is unclear. METHODS: This retrospective, database study used routinely collected clinical data to identify and evaluate an asthma cohort (classification code for asthma; ≥ 18 years; ≥1 prescription for asthma; ≥1 estimation of serum IgE, in 2 years prior to index date). Distribution into high and low IgE and EOS groups (IgE cut-point: > or ≤75 kU/L; EOS cut point: >or ≤400 μ/L), and characteristics by group are described. FINDINGS: In patients with severe asthma (British Thoracic Society Step (BTS) ≥4; N = 884), using maximum recorded IgE/EOS, 33% had high IgE/high EOS, 28% low IgE/low EOS and approximately a fifth each had high IgE/low EOS or low IgE/high EOS. Proportions were similar when EOS values measured 2 or 4 weeks before an exacerbation were excluded. Using EOS/IgE 'same day' measurements (N = 578) only identified half of the high EOS group. Patients in high IgE groups were more likely to be younger males without comorbid COPD; those in high EOS groups were more likely to be on BTS treatment Step 5 vs 4. The low IgE/low EOS group had the lowest incidence of asthma-related hospital attendances, the highest incidence was observed in the high EOS groups. CONCLUSION: Maximum available EOS measurement irrespective of exacerbations may be relevant when considering therapy. These data showed low IgE/Low EOS to be more benign and high EOS groups at increased risk of frequent, severe exacerbations.

Hinks TSC, Batty P, Klenerman P, Pavord ID, Xue L. 2017. Cytometric Gating Stringency Impacts Studies of Type 2 Innate Lymphoid Cells in Asthma. Am J Respir Cell Mol Biol, 57 (6), pp. 745-747. | Read more

Cooper CB, Brusselle G, Pascoe SJ, Pavord ID. 2018. The Significance of Eosinophilic Inflammation in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med, 197 (7), pp. 967-968. | Read more

Hull JH, Pavord ID. 2018. Treating asthma exacerbations in athletes: TUE or not TUE? Lancet Respir Med, 6 (1), pp. 8-10. | Read more

Spinou A, Lee KK, Sinha A, Elston C, Loebinger MR, Wilson R, Chung KF, Yousaf N, Pavord ID, Matos S et al. 2017. The Objective Assessment of Cough Frequency in Bronchiectasis. Lung, 195 (5), pp. 575-585. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

INTRODUCTION: Cough in bronchiectasis is associated with significant impairment in health status. This study aimed to quantify cough frequency objectively with a cough monitor and investigate its relationship with health status. A secondary aim was to identify clinical predictors of cough frequency. METHODS: Fifty-four patients with bronchiectasis were compared with thirty-five healthy controls. Objective 24-h cough, health status (cough-specific: Leicester Cough Questionnaire LCQ and bronchiectasis specific: Bronchiectasis Health Questionnaire BHQ), cough severity and lung function were measured. The clinical predictors of cough frequency in bronchiectasis were determined in a multivariate analysis. RESULTS: Objective cough frequency was significantly raised in patients with bronchiectasis compared to healthy controls [geometric mean (standard deviation)] 184.5 (4.0) vs. 20.6 (3.2) coughs/24-h; mean fold-difference (95% confidence interval) 8.9 (5.2, 15.2); p < 0.001 and they had impaired health status. There was a significant correlation between objective cough frequency and subjective measures; LCQ r = -0.52 and BHQ r = -0.62, both p < 0.001. Sputum production, exacerbations (between past 2 weeks to 12 months) and age were significantly associated with objective cough frequency in multivariate analysis, explaining 52% of the variance (p < 0.001). There was no statistically significant association between cough frequency and lung function. CONCLUSIONS: Cough is a common and significant symptom in patients with bronchiectasis. Sputum production, exacerbations and age, but not lung function, were independent predictors of cough frequency. Ambulatory objective cough monitoring provides novel insights and should be further investigated as an outcome measure in bronchiectasis.

Clark VL, Gibson PG, Genn G, Hiles SA, Pavord ID, McDonald VM. 2017. Multidimensional assessment of severe asthma: A systematic review and meta-analysis. Respirology, 22 (7), pp. 1262-1275. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

The management of severe asthma is complex. Multidimensional assessment (MDA) of specific traits has been proposed as an effective strategy to manage severe asthma, although it is supported by few prospective studies. We aimed to systematically review the literature published on MDA in severe asthma, to identify the traits included in MDA and to determine the effect of MDA on asthma-related outcomes. We identified 26 studies and classified these based on study type (cohort/cross-sectional studies; experimental/outcome studies; and severe asthma disease registries). Study type determined the comprehensiveness of the assessment. Assessed traits were classified into three domains (airways, co-morbidities and risk factors). The airway domain had the largest number of traits assessed (mean ± SD = 4.2 ± 1.7) compared with co-morbidities (3.6 ± 2.2) and risk factors (3.9 ± 2.1). Bronchodilator reversibility and airflow limitation were assessed in 92% of studies, whereas airway inflammation was only assessed in 50%. Commonly assessed co-morbidities were psychological dysfunction, sinusitis (both 73%) and gastro-oesophageal reflux disease (GORD; 69%). Atopic and smoking statuses were the most commonly assessed risk factors (85% and 86%, respectively). There were six outcome studies, of which five concluded that MDA is effective at improving asthma-related outcomes. Among these studies, significantly more traits were assessed than treated. MDA studies have assessed a variety of different traits and have shown evidence of improved outcomes. This promising model of care requires more research to inform which traits should be assessed, which traits should be treated and what effect MDA has on patient outcomes.

Pavord ID, Chanez P, Criner GJ, Kerstjens HAM, Korn S, Lugogo N, Martinot J-B, Sagara H, Albers FC, Bradford ES et al. 2017. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med, 377 (17), pp. 1613-1629. | Citations: 58 (Scopus) | Show Abstract | Read more

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5. METHODS: We performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed. RESULTS: In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .).

Agustí A, Bafadhel M, Beasley R, Bel EH, Faner R, Gibson PG, Louis R, McDonald VM, Sterk PJ, Thomas M et al. 2017. Precision medicine in airway diseases: moving to clinical practice. Eur Respir J, 50 (4), pp. 1701655-1701655. | Citations: 15 (Scopus) | Show Abstract | Read more

On February 21, 2017, a European Respiratory Society research seminar held in Barcelona discussed how to best apply precision medicine to chronic airway diseases such as asthma and chronic obstructive pulmonary disease. It is now clear that both are complex and heterogeneous diseases, that often overlap and that both require individualised assessment and treatment. This paper summarises the presentations and discussions that took place during the seminar. Specifically, we discussed the need for a new taxonomy of human diseases, the role of different players in this scenario (exposome, genes, endotypes, phenotypes, biomarkers and treatable traits) and a number of unanswered key questions in the field. We also addressed how to deploy airway precision medicine in clinical practice today, both in primary and specialised care. Finally, we debated the type of research needed to move the field forward.

Bush A, Pavord ID. 2017. After the asthmas: Star Wars and Star Trek. Eur Respir J, 50 (3), pp. 1701362-1701362. | Citations: 1 (Web of Science Lite) | Read more

Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, Cullinan P, Custovic A, Ducharme FM, Fahy JV et al. 2018. After asthma: redefining airways diseases. Lancet, 391 (10118), pp. 350-400. | Citations: 73 (Scopus) | Read more

Bafadhel M, Pavord ID, Russell REK. 2017. Eosinophils in COPD: just another biomarker? Lancet Respir Med, 5 (9), pp. 747-759. | Citations: 34 (Web of Science Lite) | Show Abstract | Read more

Eosinophils are innate immune cells that, under certain conditions, can be recruited to the lungs, where they have an incompletely understood role in health and disease. Eosinophils have been found in the airways, tissues, and circulation of patients with COPD, during both stable disease and exacerbations. Epidemiological studies and post-hoc analyses of clinical trials of corticosteroid treatment for COPD have shown that the blood eosinophil count is associated with the risk of COPD exacerbations, mortality, decline in FEV1, and response to both inhaled and systemic corticosteroids. Further studies are urgently needed to explore the contribution of eosinophils to the mechanism of disease in COPD and to identify their association with levels of clinical risk. In this review, we explore the role of the eosinophil as a biomarker and mediator of disease in COPD.

Brusselle G, Pavord I. 2017. Azithromycin in uncontrolled asthma. Lancet, 390 (10095), pp. 629-630. | Citations: 1 (Web of Science Lite) | Read more

Kerkhof M, Sonnappa S, Postma DS, Brusselle G, Agustí A, Anzueto A, Jones R, Papi A, Pavord I, Pizzichini E et al. 2017. Blood eosinophil count and exacerbation risk in patients with COPD. Eur Respir J, 50 (1), pp. 1700761-1700761. | Citations: 9 (Web of Science Lite) | Read more

Morice AH, McGarvey L, Pavord ID, Higgins B, Chung KF, Birring SS. 2017. Theobromine for the treatment of persistent cough: a randomised, multicentre, double-blind, placebo-controlled clinical trial. J Thorac Dis, 9 (7), pp. 1864-1872. | Citations: 2 (Scopus) | Show Abstract | Read more

BACKGROUND: To investigate the effect of BC1036 on health-related quality of life (QOL) in subjects with persistent cough. The secondary objective was to investigate the effect of BC1036 on subjective cough severity. METHODS: This was a randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 289 subjects with persistent cough. Subjects received BC1036 or placebo twice daily for 14 days. The primary endpoint comprised cough-related QOL assessed using the validated Leicester Cough Questionnaire (LCQ) at Day 14. Secondary endpoints comprised the LCQ scores at Day 7 and Day 28, cough severity VAS scores at each visit and pulmonary function tests. RESULTS: At baseline, mean total LCQ score in the BC1036 group was lower (i.e., worse QOL) than placebo (P<0.001), indicating significant between-group heterogeneity. Mean baseline-adjusted change in LCQ score at Day 14 was greater for BC1036 [mean (SD) 2.4±3.5] compared to placebo [mean (SD) score 2.2±3.0], but did not reach statistical significance (P=0.60). Mean cough severity VAS score decreased to a greater extent in the BC1036 group compared to placebo, but again the results were not statistically significant (-12.2±23.28 in BC1036 group and -11.0±21.34 in placebo group at Day 14, P=0.688). There was no significant change in pulmonary function measurements. The adverse event (AE) profile was similar in both groups. CONCLUSIONS: This study showed that BC1036 was well tolerated and, although the primary endpoint did not achieve statistical significance, the magnitude of improvement was greater with BC1036 compared to placebo with respect to improving QOL and reducing cough severity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01656668.

Bilocca D, Hargadon B, Pavord ID, Green RH, Brightling CE, Bradding P, Wardlaw AJ, Martin N, Murphy AC, Siddiqui S. 2018. The role of oral methotrexate as a steroid sparing agent in refractory eosinophilic asthma. Chron Respir Dis, 15 (1), pp. 85-87. | Citations: 1 (European Pubmed Central) | Show Abstract | Read more

The use of oral methotrexate for refractory eosinophilic asthma in a tertiary asthma referral centre, Glenfield Hospital, Leicester, was evaluated between January 2006 and December 2014. The patients ( n = 61) were carefully phenotyped at baseline with markers of airway inflammation. In addition, a structured oral methotrexate proforma was utilized to evaluate response to therapy and adverse events. Oral steroid withdrawal was attempted 3 months after commencing treatment. Several outcomes were evaluated at 12 months, including both efficacy and adverse effects; 15% ( n = 9/61) responded by achieving a decrease in daily oral corticosteroid dose (mean 8.43 (±8.76) mg), although we were unable to identify factors that predicted a treatment response. There were no other significant changes in any other clinical outcome measures. There was a high rate of adverse events (19/61 (31%)), primarily gastrointestinal/hepatitis. Our findings support the use of biological agents in preference to using oral methotrexate as a steroid sparing agent at the first instance. In the event of failure of these agents, oral methotrexate remains a therapeutic option, which can be considered in highly specialist severe asthma centres.

Buhl R, Humbert M, Bjermer L, Chanez P, Heaney LG, Pavord I, Quirce S, Virchow JC, Holgate S, expert group of the European Consensus Meeting for Severe Eosinophilic Asthma. 2017. Severe eosinophilic asthma: a roadmap to consensus. Eur Respir J, 49 (5), pp. 1700634-1700634. | Citations: 17 (Scopus) | Read more

Shrimanker R, Choo XN, Pavord ID. 2017. A new approach to the classification and management of airways diseases: identification of treatable traits. Clin Sci (Lond), 131 (10), pp. 1027-1043. | Citations: 9 (Scopus) | Show Abstract | Read more

This review outlines a new, personalized approach for the classification and management of airway diseases. The current approach to airways disease is, we believe, no longer fit for purpose. It is impractical, overgeneralizes complex and heterogeneous conditions and results in management that is imprecise and outcomes that are worse than they could be. Importantly, the assumptions we make when applying a diagnostic label have impeded new drug discovery and will continue to do so unless we change our approach. This review suggests a new mechanism-based approach where the emphasis is on identification of key causal mechanisms and targeted intervention with treatment based on possession of the relevant mechanism rather than an arbitrary label. We highlight several treatable traits and suggest how they can be identified and managed in different healthcare settings.

Pavord ID. 2017. Mepolizumab, quality of life, and severe eosinophilic asthma. Lancet Respir Med, 5 (5), pp. 362-363. | Citations: 1 (Web of Science Lite) | Read more

Shrimanker R, Pavord ID. 2017. Interleukin-5 Inhibitors for Severe Asthma: Rationale and Future Outlook. BioDrugs, 31 (2), pp. 93-103. | Citations: 10 (Scopus) | Show Abstract | Read more

In this review, we outline the pathophysiology of severe asthma and discuss the role of anti-interleukin (IL)-5 inhibitors for the treatment of asthma. Anti-IL-5 treatments have shown efficacy in reducing the rate of severe asthma attacks in eosinophilic asthma. We review the history of the development of these agents, lessons learnt about severe asthma along the way and key clinical trials supporting efficacy of the three anti-IL-5 treatments that are clinically available or undergoing clinical trials in asthma.

Pavord ID, Mathieson N, Scowcroft A, Pedersini R, Isherwood G, Price D. 2017. The impact of poor asthma control among asthma patients treated with inhaled corticosteroids plus long-acting β2-agonists in the United Kingdom: a cross-sectional analysis. NPJ Prim Care Respir Med, 27 (1), pp. 17. | Citations: 2 (European Pubmed Central) | Show Abstract | Read more

There are several new treatment options for patients whose asthma remains uncontrolled on free-dose and fixed-dose combinations of inhaled corticosteroids plus long-acting β2-agonists (ICS+LABA). In order to evaluate the likely impact of these treatments, we assessed the effect of uncontrolled asthma on healthcare and patient burden within the UK among adult patients treated with ICS+LABA. Data obtained from 2010-2011 UK National Health and Wellness Surveys identified 701 patients treated with ICS+LABA. Patients with not well-controlled asthma (Asthma Control Test™ score <20) were compared with well-controlled asthma (score ≥ 20) patients on multiple measures. Cost burden was calculated using healthcare resource utilisation models and work productivity and impairment questionnaire. Overall, 452 and 249 patients reported not well-controlled and well-controlled asthma, respectively. A greater proportion of not well-controlled patients visited the accident & emergency department (21 vs. 14%, P = 0.016), were hospitalised (13 vs. 8%, P = 0.022) and had lower mental and physical health-related quality of life (P < 0.001) and impaired work productivity and activity scores: presenteeism (23 vs. 11%, P < 0.001), work impairment (29 vs. 17%, P < 0.001) and activity impairment (46 vs. 24%, P < 0.001). Calculated direct and indirect yearly costs/person doubled among not well-controlled compared to well-controlled asthma patients (£6592 vs. £3220). Total cost to society was estimated at £6172 million/year (direct costs, £1307 million; indirect costs, £4865 million). In conclusion, not well-controlled asthma is common among UK adults treated with ICS+LABA, resulting in impairments across a number of important health outcomes and represents a significant unmet need and resource burden. ASTHMA: DRUG COMBO LEAVES MANY WITH UNCONTROLLED DISEASE: Many people who take inhaled steroids combined with long-acting β2-agonist drugs still have poorly controlled asthma. A team led by Ian Pavord from the University of Oxford, UK, identified 701 people from the 2010-2011 UK National Health and Wellness Surveys who were taking this drug combination for their asthma. The researchers found that nearly two-thirds of these individuals had poorly controlled asthma associated with more visits to the emergency room, worse quality of life (both mentally and physically), impaired productivity and other health problems. The calculated direct and indirect costs per person with poorly controlled asthma were about double that for someone whose asthma was under control. The authors conclude that better treatment and management is needed to reduce costs and address the unmet medical need for people with persistent uncontrolled asthma.

Bousquet J, Farrell J, Crooks G, Hellings P, Bel EH, Bewick M, Chavannes NH, de Sousa JC, Cruz AA, Haahtela T et al. 2017. Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5). Clin Transl Allergy, 7 (1), pp. 5. | Show Abstract | Read more

[This corrects the article DOI: 10.1186/s13601-016-0116-9.].

Pavord ID, Afzalnia S, Menzies-Gow A, Heaney LG. 2017. The current and future role of biomarkers in type 2 cytokine-mediated asthma management. Clin Exp Allergy, 47 (2), pp. 148-160. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

Assessment and management of asthma is complicated by the heterogeneous pathophysiological mechanisms that underlie its clinical presentation, which are not necessarily reflected in standardized management paradigms and which necessitate an individualized approach to treatment. This is particularly important with the emerging availability of a variety of targeted forms of therapy that may only be appropriate for use in particular patient subgroups. The identification of biomarkers can potentially aid diagnosis and inform prognosis, help guide treatment decisions and allow clinicians to predict and monitor response to treatment. Biomarkers for asthma have been identified from a variety of sources, including airway, exhaled breath and blood. Biomarkers from exhaled breath include fractional exhaled nitric oxide, measurement of which can help identify patients most likely to benefit from inhaled corticosteroids and targeted anti-immunoglobulin E therapy. Biomarkers measured in blood are relatively non-invasive and technically more straightforward than those measured from exhaled breath or directly from the airway. The most well established of these are the blood eosinophil count and serum periostin, both of which have demonstrated utility in identifying patients most likely to benefit from targeted anti-interleukin and anti-immunoglobulin E therapies, and in monitoring subsequent treatment response. For example, serum periostin appears to be a biomarker for responsiveness to inhaled corticosteroid therapy and may help identify patients as suitable candidates for anti-IL-13 treatment. The use of biomarkers can therefore potentially help avoid unnecessary morbidity from high-dose corticosteroid therapy and allow the most appropriate and cost-effective use of targeted therapies. Ongoing clinical trials are helping to further elucidate the role of established biomarkers in routine clinical practice, and a range of other circulating novel potential biomarkers are currently being investigated in the research setting.

Salimi M, Stöger L, Liu W, Go S, Pavord I, Klenerman P, Ogg G, Xue L. 2017. Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines. J Allergy Clin Immunol, 140 (4), pp. 1090-1100.e11. | Citations: 25 (Scopus) | Show Abstract | Read more

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D2 [PGD2]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C4, LTD4, and LTE4, are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. OBJECTIVES: We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. METHODS: For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD2, IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. RESULTS: Human ILC2s expressed the LT receptor CysLT1, levels of which were increased in atopic subjects. CysLTs, particularly LTE4, induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE4 enhanced the effect of PGD2, IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE4 was inhibited by montelukast, a CysLT1 antagonist. Interestingly, addition of IL-2 to LTE4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CONCLUSION: CysLTs, particularly LTE4, are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators.

Hilvering B, Vijverberg SJH, Jansen J, Houben L, Schweizer RC, Go S, Xue L, Pavord ID, Lammers J-WJ, Koenderman L. 2017. Diagnosing eosinophilic asthma using a multivariate prediction model based on blood granulocyte responsiveness. Allergy, 72 (8), pp. 1202-1211. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The identification of inflammatory asthma phenotypes, using sputum analysis, has proven its value in diagnosis and disease monitoring. However due to technical limitations of sputum analysis, there is a strong need for fast and noninvasive diagnostics. This study included the activation state of eosinophils and neutrophils in peripheral blood to phenotype and monitor asthma. OBJECTIVES: To (i) construct a multivariable model using the activation state of blood granulocytes, (ii) compare its diagnostic value with sputum eosinophilia as gold standard and (iii) validate the model in an independent patient cohort. METHODS: Clinical parameters, activation of blood granulocytes and sputum characteristics were assessed in 115 adult patients with asthma (training cohort/Utrecht) and 34 patients (validation cohort/Oxford). RESULTS: The combination of blood eosinophil count, fractional exhaled nitric oxide, Asthma Control Questionnaire, medication use, nasal polyposis, aspirin sensitivity and neutrophil/eosinophil responsiveness upon stimulation with formyl-methionyl-leucyl phenylalanine was found to identify sputum eosinophilia with 90.5% sensitivity and 91.5% specificity in the training cohort and with 77% sensitivity and 71% specificity in the validation cohort (relatively high percentage on oral corticosteroids [OCS]). CONCLUSIONS: The proposed prediction model identifies eosinophilic asthma without the need for sputum induction. The model forms a noninvasive and externally validated test to assess eosinophilic asthma in patients not on OCS.

Harnan SE, Essat M, Gomersall T, Tappenden P, Pavord I, Everard M, Lawson R. 2017. Exhaled nitric oxide in the diagnosis of asthma in adults: a systematic review. Clin Exp Allergy, 47 (3), pp. 410-429. | Citations: 4 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVES: To identify and synthesize evidence on the diagnostic accuracy of FE NO for asthma in adults. MATERIALS AND METHODS: Systematic searches (nine key biomedical databases and trial registers) were carried out on November 2014. Records were included if they recruited patients with the symptoms of asthma; used a single set of inclusion criteria; measured FE NO50 in accordance with American Thoracic Society guidelines, 2005 (off-line excluded); reported/allowed calculation of true-positive, true-negative, false-positive and false-negative patients as classified against any reference standard. Study quality was assessed using QUADAS II. Meta-analysis was planned where clinical study heterogeneity allowed. Rule-in and rule-out uses of FE NO were considered. RESULTS: A total of 4861 records were identified originally and 1312 in an update. Twenty-seven studies were included. Heterogeneity precluded meta-analysis. Results varied even within subgroups of studies. Cut-off values for the best sum of sensitivity and specificity varied from 12 to 55 p.p.b., but did not produce high accuracy. 100% sensitivity or 100% specificity was reported by some studies indicating potential use as a rule-in or rule-out strategy. CONCLUSIONS AND CLINICAL RELEVANCE: FE NO50 had variable diagnostic accuracy even within subgroups of studies with similar characteristics. Diagnostic accuracy, optimal cut-off values and best position for FE NO50 within a pathway remain poorly evidenced.

Hynes G, Pavord ID. 2016. Asthma-like Features and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med, 194 (11), pp. 1308-1309. | Citations: 4 (Scopus) | Read more

Price D, Miravitlles M, Pavord I, Thomas M, Wedzicha J, Haughney J, Bichel K, West D. 2016. First maintenance therapy for COPD in the UK between 2009 and 2012: a retrospective database analysis. NPJ Prim Care Respir Med, 26 (1), pp. 16061. | Citations: 8 (Scopus) | Show Abstract | Read more

Clinical guidelines recommend long-acting bronchodilators as first maintenance therapy for chronic obstructive pulmonary disease (COPD), with inhaled corticosteroids (ICS) reserved for patients with more severe disease and exacerbations. The aim of this analysis was to examine real-life prescribing of first maintenance therapy for COPD in the UK. Data were extracted from the UK Optimum Patient Care Research Database for patients with a first prescription for COPD maintenance therapy between 2009 and 2012 and a diagnosis of COPD at or before the date of the first prescription for COPD maintenance therapy. Routine clinical data including demographics, disease history and symptoms, comorbidities, therapy, hospitalisation rate and exacerbation rate were collected and used to characterise patients stratified by disease severity and Global Initiative for Chronic Obstructive Lung Disease (GOLD) group (A-D). The analysis population included 2,217 individuals (55.4% male, 45.2% smokers). Long-acting muscarinic antagonists (LAMA) as monotherapy were prescribed as first maintenance therapy for 40.2% of patients. ICS were prescribed as ICS/long-acting beta-agonists combination for 29.1% of patients or as monotherapy for 15.5%. ICS (alone or in combination) were prescribed to >40% of patients in each GOLD group. ICS-containing regimens were prescribed to patients with a history of pneumonia and comorbid conditions for whom the risks of ICS therapy may outweigh the benefits. The clinical reality of prescribing indicates that ICS are often prescribed outside current guideline recommendations for many patients newly diagnosed with COPD in the UK. Encouragingly, LAMAs are increasingly being prescribed as first maintenance therapy for these patients.

Skeggs A, McKeever T, Duley L, Mitchell E, Bradshaw L, Mortimer K, Walker S, Parrott S, Wilson A, Pavord I et al. 2016. FourFold Asthma Study (FAST): a study protocol for a randomised controlled trial evaluating the clinical cost-effectiveness of temporarily quadrupling the dose of inhaled steroid to prevent asthma exacerbations. Trials, 17 (1), pp. 499. | Citations: 2 (Scopus) | Show Abstract | Read more

BACKGROUND: Asthma is one of the commonest chronic diseases in the UK. Acute exacerbations of asthma are unpredictable, disruptive and frightening. They cause considerable morbidity and account for a large component of the health service costs of asthma. The widespread use of an asthma self-management plan, designed to encourage disease monitoring and timely intervention, can reduce exacerbations and is, therefore, recommended for all patients with asthma. Unfortunately, the majority of patients are not provided with such a plan. There are a variety of reasons for this but uncertainty about what to include in the plan when asthma control is deteriorating, but before the need for orally administered corticosteroids, is a contributing factor. The aim of this trial is to determine whether an asthma self-management plan, which includes a temporary quadrupling of the dose of inhaled corticosteroid when asthma control starts to deteriorate, reduces asthma exacerbations requiring orally administered corticosteroids or unscheduled health care consultation for asthma. METHODS: A multicentre, pragmatic, randomised trial in adults aged over 16 years with a clinical diagnosis of asthma, treated with a licensed dose of inhaled corticosteroid and at least one exacerbation in the previous 12 months requiring treatment with systemic corticosteroids. Participants will be randomised to either a self-management plan, which includes a temporary (maximum of 14 days) fourfold increase in inhaled corticosteroid or the same plan without an increase in inhaled corticosteroid. Participants will be followed up at 6 and 12 months and will attend the clinic for an additional visit if their asthma control deteriorates. The primary outcome is time to first asthma exacerbation, defined as the need for systemic corticosteroids and/or unscheduled health care consultation for asthma. The estimated sample size is 1800 participants. DISCUSSION: The FAST trial is an independent study that has been prioritised and commissioned by the National Institute for Health Research (NIHR) in the United Kingdom. It will provide high-quality evidence to inform clinical decision-making on the role of an asthma self-management plan, which includes a temporary fourfold increase of inhaled corticosteroid, when asthma control starts to deteriorate. The first participant was randomised on 17th May 2013 and recruitment will close on 31 January 2016 with the last patient last visit taking place in January 2017. TRIAL REGISTRATION: ISRCTN: 15441965 , registered on 25 April 2013.

Yancey SW, Ortega HG, Keene ON, Mayer B, Gunsoy NB, Brightling CE, Bleecker ER, Haldar P, Pavord ID. 2017. Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma. J Allergy Clin Immunol, 139 (4), pp. 1167-1175.e2. | Citations: 21 (Scopus) | Show Abstract | Read more

BACKGROUND: Studies show that mepolizumab can reduce the frequency of clinically significant exacerbations in patients with severe eosinophilic asthma, compared with placebo. However, important events such as hospitalizations and emergency room visits are rare and difficult to characterize in single studies. OBJECTIVE: We sought to compare hospitalization or hospitalization and/or emergency room visit rates in patients with severe eosinophilic asthma treated with mepolizumab or placebo in addition to standard of care for at least 24 weeks. METHODS: This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. PubMed and the GSK Clinical Study Register were searched for suitable studies. The primary end points were the rate of exacerbations requiring hospitalization and the rate of exacerbations requiring hospitalization/emergency room visit. The proportion of patients with 1 or more event was also assessed. All mepolizumab doses were combined and individual patient-level data were analyzed. RESULTS: Four studies (n = 1388) were eligible for inclusion. Mepolizumab significantly reduced the rate of exacerbations requiring hospitalization (relative rate, 0.49; 95% CI, 0.30-0.80; P = .004) and hospitalization/emergency room visit (relative rate, 0.49; 95% CI, 0.33-0.73; P < .001) versus placebo. Significant reductions of 45% and 38% were also observed for the proportion of patients experiencing 1 or more hospitalization and hospitalization and/or emergency room visit, respectively. CONCLUSIONS: Mepolizumab approximately halved exacerbations requiring hospitalization and/or emergency room visits compared with placebo in patients with severe eosinophilic asthma. This treatment addresses a key outcome in a patient population with a high unmet need (GSK Study 204664).

Pavord ID. 2016. Lessons from LAVOLTA. Lancet Respir Med, 4 (10), pp. 764-765. | Citations: 1 (European Pubmed Central) | Read more

Hambleton K, Pavord ID. 2016. What can we learn from blood granulocyte patterns in patients with asthma? Eur Respir J, 48 (4), pp. 976-978. | Citations: 2 (Scopus) | Read more

Slater MG, Pavord ID, Shaw DE. 2016. Step 4: stick or twist? A review of asthma therapy. BMJ Open Respir Res, 3 (1), pp. e000143. | Citations: 1 (European Pubmed Central) | Show Abstract | Read more

Many people with asthma do not achieve disease control, despite bronchodilators and inhaled corticosteroid therapy. People with uncontrolled asthma are at higher risk of an asthma attack and death, with mortality rates estimated at 1000 deaths/year in England and Wales. The recent National Review of Asthma Deaths (NRAD) report, 'Why asthma still kills', recommended that patients at step 4 or 5 of the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidance must be referred to a specialist asthma service. This article reviews the 2014 evidence base for therapy of asthma patients at BTS/SIGN step 4 of the treatment cascade, in response to key findings of the NRAD report and lack of preferred treatment option at this step.

Pavord ID, Lettis S, Anzueto A, Barnes N. 2016. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med, 4 (9), pp. 731-741. | Citations: 40 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Inhaled corticosteroids are important in the management of chronic obstructive pulmonary disease (COPD), but can slightly increase the risk of pneumonia in patients with moderate-to-severe COPD. Patients with circulating eosinophil counts of 2% or more of blood leucocytes respond better to inhaled corticosteroids than do those with counts of less than 2% and it was therefore postulated that blood eosinophil count might also have an effect on the risk of pneumonia in patients with COPD. In this post-hoc meta-analysis, we investigate whether a 2% threshold can identify patients who differ in their risk of pneumonia, irrespective of inhaled corticosteroid treatment. METHODS: From the GlaxoSmithKline trial registry, we selected randomised, double-blind, clinical trials of patients with COPD that had: inhaled corticosteroid arms (fluticasone propionate and salmeterol or fluticasone furoate and vilanterol); a control arm (not given inhaled fluticasone); and pre-randomisation measurements of blood eosinophil counts and were of at least 24 weeks in duration. With use of specified terms from the Medical Dictionary for Regulatory Activities we identified pneumonia adverse events in patient-level data. We calculated number of patients with pneumonia events, stratified by baseline blood eosinophil count (<2% vs ≥2% of blood leucocytes) and whether or not patients had received inhaled corticosteroids. FINDINGS: We identified ten trials (conducted between 1998 and 2011), with eosinophil count data available for 10 861 patients with COPD. 4043 patients had baseline blood eosinophil counts of less than 2% and 6818 patients had baseline blood eosinophil counts of 2% or more. 149 (3·7%) patients with counts less than 2% had one or more pneumonia adverse events compared with 215 (3·2%) with counts of 2% or more (hazard ratio [HR] 1·31; 95% CI 1·06-1·62). In patients not treated with inhaled corticosteroids, 40 (3·8%) patients with less than 2% blood eosinophil counts had a pneumonia event versus 48 (2·4%) with 2% or more blood eosinophils (HR 1·53; 95% CI 1·01-2·31). In patients treated with inhaled corticosteroids, events occurred in 107 (4·5%) versus 164 (3·9%; HR 1·25; 95% CI 0·98-1·60), respectively. INTERPRETATION: Using 2% baseline eosinophil count as a threshold, patients with COPD with lower blood eosinophil counts had more pneumonia events than did those with higher counts. The magnitude of this increased risk was small and should be further explored in large, prospective studies. These data should be considered when making treatment decisions, alongside existing evidence that patients with COPD and baseline blood eosinophil counts less than 2% have a poorer response to inhaled corticosteroids. FUNDING: GlaxoSmithKline.

Gonem S, Berair R, Singapuri A, Hartley R, Laurencin MFM, Bacher G, Holzhauer B, Bourne M, Mistry V, Pavord ID et al. 2016. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med, 4 (9), pp. 699-707. | Citations: 77 (Web of Science Lite) | Show Abstract | Read more

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.

Bafadhel M, Greening NJ, Harvey-Dunstan TC, Williams JEA, Morgan MD, Brightling CE, Hussain SF, Pavord ID, Singh SJ, Steiner MC. 2016. Blood Eosinophils and Outcomes in Severe Hospitalized Exacerbations of COPD. Chest, 150 (2), pp. 320-328. | Citations: 40 (Scopus) | Show Abstract | Read more

BACKGROUND: Patients with moderate exacerbations of COPD and the eosinophilic phenotype have better outcomes with prednisolone. Whether this outcome is similar in patients hospitalized with a severe exacerbation of COPD is unclear. We investigated the rate of recovery of eosinophilic and noneosinophilic exacerbations in patients participating in a multicenter randomized controlled trial assessing health outcomes in hospitalized exacerbations. METHODS: Patients were recruited at presentation to the hospital with an exacerbation of COPD. They were stratified into groups according to eosinophilic exacerbations if the peripheral blood eosinophil count on admission was ≥ 200 cells/μL and/or ≥ 2% of the total leukocyte count. Admission details, serum C-reactive protein levels, length of stay, and subsequent rehospitalization data were compared between groups. RESULTS: A total of 243 patients with COPD (117 men) with a mean age of 71 years (range, 45-93 years) were recruited. The inpatient mortality rate was 3% (median time to death, 12 days; range, 9-16 days). The median absolute eosinophil count was 100 cells/μL (range, 10-1,500 cells/μL), and 25% met our criteria for an eosinophilic exacerbation; in this population, the mean length of stay (in days) was shorter than in patients with noneosinophilic exacerbations (5.0 [range, 1-19] vs 6.5 [range, 1-33]; P = .015) following treatment with oral corticosteroids and independent of treatment prior to admission. Readmission rates at 12 months were similar between groups. CONCLUSIONS: The study patients presenting to the hospital with a severe eosinophilic exacerbation of COPD had a shorter length of stay. The exacerbations were usually not associated with elevated C-reactive protein levels, suggesting that better treatment stratification of exacerbations can be used. TRIAL REGISTRY: http://www.isrctn.com/ISRCTN05557928.

Pavord ID, Hilvering B, Shrimanker R. 2016. Emerging Biologics in Severe Asthma. Immunol Allergy Clin North Am, 36 (3), pp. 609-623. | Citations: 4 (European Pubmed Central) | Show Abstract | Read more

Asthma is a heterogeneous disease that can be classified into different clinical endotypes, depending on the type of airway inflammation, clinical severity, and response to treatment. This article focuses on the eosinophilic endotype of asthma, which is defined by the central role that eosinophils play in the pathophysiology of the condition. It is characterized by persistently elevated sputum and/or blood eosinophils and by a significant response to treatments that suppress eosinophilia. Eosinophil activity in the airway may be more important than their numbers and this needs to be investigated. Transcriplomic or Metabolomic signatures may also be useful to identify this endotype.

Pascoe SJ, Lipson DA, Locantore N, Barnacle H, Brealey N, Mohindra R, Dransfield MT, Pavord I, Barnes N. 2016. A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol. Eur Respir J, 48 (2), pp. 320-330. | Citations: 35 (Scopus) | Show Abstract | Read more

Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017.

Bousquet J, Schünemann HJ, Hellings PW, Arnavielhe S, Bachert C, Bedbrook A, Bergmann K-C, Bosnic-Anticevich S, Brozek J, Calderon M et al. 2016. MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis. J Allergy Clin Immunol, 138 (2), pp. 367-374.e2. | Citations: 42 (Scopus) | Show Abstract | Read more

The selection of pharmacotherapy for patients with allergic rhinitis (AR) depends on several factors, including age, prominent symptoms, symptom severity, control of AR, patient preferences, and cost. Allergen exposure and the resulting symptoms vary, and treatment adjustment is required. Clinical decision support systems (CDSSs) might be beneficial for the assessment of disease control. CDSSs should be based on the best evidence and algorithms to aid patients and health care professionals to jointly determine treatment and its step-up or step-down strategy depending on AR control. Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR [fighting chronic diseases for active and healthy ageing]), one of the reference sites of the European Innovation Partnership on Active and Healthy Ageing, has initiated an allergy sentinel network (the MACVIA-ARIA Sentinel Network). A CDSS is currently being developed to optimize AR control. An algorithm developed by consensus is presented in this article. This algorithm should be confirmed by appropriate trials.

Trivedi A, Pavord ID, Castro M. 2016. Bronchial thermoplasty and biological therapy as targeted treatments for severe uncontrolled asthma. Lancet Respir Med, 4 (7), pp. 585-592. | Citations: 25 (Scopus) | Show Abstract | Read more

Although a small proportion of patients with asthma have severe disease, it accounts for the majority of morbidity related to the illness. Severe asthma comprises a heterogeneous group of phenotypes. Targeted treatments for these phenotypes represent a major advancement in the management of severe asthma. Omalizumab, a monoclonal antibody to IgE, improves asthma control in patients with a predominant allergic phenotype. Monoclonal antibodies targeted to interleukin 4α and interleukin 5 have shown substantial benefit in patients with the eosinophilic asthma phenotype; so too have monoclonal antibodies targeted to interleukin 13 in patients with a type 2 allergic phenotype. Bronchial thermoplasty, a new technique to reduce airway smooth muscle mass, improves symptoms and reduces exacerbations in patients with severe uncontrolled asthma and the chronic airflow obstruction phenotype. While awaiting comparative trials, we can now use a targeted approach with these phenotypes, guiding our treatment selection with the best evidence. This Review will focus on the latest developments in these new treatments and inform the clinician on how to select the appropriate patient for these treatments.

Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, Brightling CE, Pavord ID. 2016. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med, 4 (7), pp. 549-556. | Citations: 106 (Scopus) | Show Abstract | Read more

BACKGROUND: Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds. METHODS: We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab ( DREAM: 75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per μL, ≥300 cells per μL, ≥400 cells per μL, and ≥500 cells per μL) and baseline blood eosinophil ranges (<150 cells per μL, ≥150 cells per μL to <300 cells per μL, ≥300 cells per μL to <500 cells per μL, and ≥500 cells per μL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis. FINDINGS: Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL, predicted efficacy of mepolizumab was reduced. INTERPRETATION: Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab. FUNDING: GlaxoSmithKline.

Pavord ID, Agusti A. 2016. Blood eosinophil count: a biomarker of an important treatable trait in patients with airway disease. Eur Respir J, 47 (5), pp. 1299-1303. | Citations: 11 (Web of Science Lite) | Read more

Bousquet J, Barbara C, Bateman E, Bel E, Bewick M, Chavannes NH, Cruz AA, Haahtela T, Hellings PW, Khaltaev N et al. 2016. AIRWAYS-ICPs (European Innovation Partnership on Active and Healthy Ageing) from concept to implementation. Eur Respir J, 47 (4), pp. 1028-1033. | Citations: 23 (Scopus) | Read more

Gomersal T, Harnan S, Essat M, Tappenden P, Wong R, Lawson R, Pavord I, Everard ML. 2016. A systematic review of fractional exhaled nitric oxide in the routine management of childhood asthma. Pediatr Pulmonol, 51 (3), pp. 316-328. | Citations: 14 (Scopus) | Show Abstract | Read more

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker of eosinophilic inflammation which may be used to guide the management of asthma in childhood. OBJECTIVES: To synthesise the available evidence on the efficacy of FeNO-guided management of childhood asthma. METHODS: Databases including MEDLINE and the Cochrane Library were searched, and randomised controlled trials (RCTs) comparing FeNO-guided management with any other monitoring strategy were included. Study quality was assessed using the Cochrane risk of bias tool for RCTs, and a number of outcomes were examined, including: exacerbations, medication use, quality of life, adverse events, and other markers of asthma control. Meta-analyses were planned if multiple studies with suitable heterogeneity were available. However, due to wide variations in study characteristics, meta-analysis was not possible. RESULTS: Seven RCTs were identified. There was some evidence that FeNO-guided monitoring results in improved asthma control during the first year of management, although few results attained statistical significance. The impact on severe exacerbations was unclear. Similarly, the impact on use of anti-asthmatic drugs was unclear, and appears to depend on the step up/down protocols, and the clinical characteristics of patients. CONCLUSIONS: The potential benefit of FeNO monitoring is equivocal. Trends toward reduced exacerbation and increased medication use were seen, but typically failed to reach statistical significance. There are a number of issues that complicate data interpretation, including differences in the likely severity of included cohorts and variations in treatment algorithms. Further work is needed to systematically explore the impact of these parameters.

Choo XN, Pavord ID. 2016. Morbidity associated with oral corticosteroids in patients with severe asthma. Thorax, 71 (4), pp. 302-304. | Citations: 3 (European Pubmed Central) | Read more

Sinha A, Lee KK, Rafferty GF, Yousaf N, Pavord ID, Galloway J, Birring SS. 2016. Predictors of objective cough frequency in pulmonary sarcoidosis. Eur Respir J, 47 (5), pp. 1461-1471. | Citations: 9 (Web of Science Lite) | Show Abstract | Read more

Cough is a common symptom of pulmonary sarcoidosis. This study aimed to quantify cough frequency, and investigate its relationship with cough reflex sensitivity, pulmonary function and health status.32 patients with pulmonary sarcoidosis were compared with 40 healthy controls. Cough reflex sensitivity to capsaicin, objective 24-h cough counts, cough-specific health status, cough severity and cough triggers were measured. The predictors of cough frequency in sarcoidosis were determined in a multivariate analysis.Objective cough frequency was significantly raised in patients with sarcoidosis compared with healthy controls (p<0.001) and patients with cough had an impaired health status. Patients with pulmonary sarcoidosis had a heightened cough reflex sensitivity compared with healthy controls (p<0.001). Only cough reflex sensitivity was significantly associated with objective cough frequency in multivariate analysis, explaining 42% of the variance (p<0.001). There was no association between cough frequency, lung function, number of organs involved, chest radiograph stage or serum angiotensin-converting enzyme levels.Cough is a common and significant symptom in patients with sarcoidosis. Ambulatory objective cough monitoring provides novel insights into the determinants of cough in sarcoidosis, suggesting that cough reflex sensitivity may be more important than lung function and other measures of disease severity, and this should be investigated further.

Beasley R, Pavord I, Papi A, Reddel HK, Harrison T, Marks GB, Hancox RJ, Weatherall M. 2016. Description of a randomised controlled trial of inhaled corticosteroid/fast-onset LABA reliever therapy in mild asthma. Eur Respir J, 47 (3), pp. 981-984. | Citations: 8 (Web of Science Lite) | Read more

Essat M, Harnan S, Gomersall T, Tappenden P, Wong R, Pavord I, Lawson R, Everard ML. 2016. Fractional exhaled nitric oxide for the management of asthma in adults: a systematic review. Eur Respir J, 47 (3), pp. 751-768. | Citations: 35 (Scopus) | Show Abstract | Read more

The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults.13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed.Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63-1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43-1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of -0.24 (95% CI -0.56-0.07). No statistically significant differences for health-related quality of life or asthma control were found.FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or inhaled corticosteroid use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most.

Agusti A, Bel E, Thomas M, Vogelmeier C, Brusselle G, Holgate S, Humbert M, Jones P, Gibson PG, Vestbo J et al. 2016. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J, 47 (2), pp. 410-419. | Citations: 177 (Web of Science Lite) | Show Abstract | Read more

Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airway diseases that have a high personal and social impact. They likely represent a continuum of different diseases that may share biological mechanisms (i.e. endotypes), and present similar clinical, functional, imaging and/or biological features that can be observed (i.e. phenotypes) which require individualised treatment. Precision medicine is defined as "treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations". In this Perspective, we propose a precision medicine strategy for chronic airway diseases in general, and asthma and COPD in particular.

Willson J, Bateman ED, Pavord I, Lloyd A, Krivasi T, Esser D. 2016. Erratum to: Cost Effectiveness of Tiotropium in Patients with Asthma Poorly Controlled on Inhaled Glucocorticosteroids and Long-Acting β-Agonists. Appl Health Econ Health Policy, 14 (1), pp. 119-125. | Citations: 4 (European Pubmed Central) | Read more

Price DB, Pavord ID, Thomas M, Corrigan CJ, Wilson AM, Hillyer EV, Kerkhof M. 2016. Inhaled corticosteroid dose-response on blood eosinophils in asthma - Authors' reply. Lancet Respir Med, 4 (1), pp. e1-e2. | Citations: 1 (European Pubmed Central) | Read more

Pavord ID, Jones PW, Burgel P-R, Rabe KF. 2016. Exacerbations of COPD. Int J Chron Obstruct Pulmon Dis, 11 Spec Iss pp. 21-30. | Citations: 26 (Scopus) | Show Abstract | Read more

Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as sustained worsening of a patient's condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization. Exacerbations have a significant and prolonged impact on health status and outcomes, and negative effects on pulmonary function. A significant proportion of exacerbations are unreported and therefore left untreated, leading to a poorer prognosis than those treated. COPD exacerbations are heterogeneous, and various phenotypes have been proposed which differ in biologic basis, prognosis, and response to therapy. Identification of biomarkers could enable phenotype-driven approaches for the management and prevention of exacerbations. For example, several biomarkers of inflammation can help to identify exacerbations most likely to respond to oral corticosteroids and antibiotics, and patients with a frequent exacerbator phenotype, for whom preventative treatment is appropriate. Reducing the frequency of exacerbations would have a beneficial impact on patient outcomes and prognosis. Preventative strategies include modification of risk factors, treatment of comorbid conditions, the use of bronchodilator therapy with long-acting β2-agonists or long-acting muscarinic antagonists, and inhaled corticosteroids. A better understanding of the mechanisms underlying COPD exacerbations will help to optimize use of the currently available and new interventions for preventing and treating exacerbations.

Slater MG, Pavord ID, Shaw DE. 2016. Step 4: stick or twist? A review of asthma therapy. BMJ Open Respiratory Research, 3 (1), | Show Abstract | Read more

Many people with asthma do not achieve disease control, despite bronchodilators and inhaled corticosteroid therapy. People with uncontrolled asthma are at higher risk of an asthma attack and death, with mortality rates estimated at 1000 deaths/year in England and Wales. The recent National Review of Asthma Deaths (NRAD) report, ‘Why asthma still kills’, recommended that patients at step 4 or 5 of the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidance must be referred to a specialist asthma service. This article reviews the 2014 evidence base for therapy of asthma patients at BTS/SIGN step 4 of the treatment cascade, in response to key findings of the NRAD report and lack of preferred treatment option at this step.

Samuelsen C, Bateman ED, Pavord I, Lloyd A, Baldwin M, Esser D. 2016. Comment on: "Cost Effectiveness of Tiotropium in Patients with Asthma Poorly Controlled on Inhaled Glucocorticosteroids and Long-Acting β-Agonists". Appl Health Econ Health Policy, 14 (1), pp. 117-118. | Citations: 2 (Scopus) | Read more

Forrester DL, Knox AJ, Smyth AR, Barr HL, Simms R, Pacey SJ, Pavord ID, Honeybourne D, Dewar J, Clayton A, Fogarty AW. 2016. Glutamine supplementation in cystic fibrosis: A randomized placebo-controlled trial. Pediatr Pulmonol, 51 (3), pp. 253-257. | Citations: 2 (European Pubmed Central) | Show Abstract | Read more

RATIONALE: Pulmonary infection and malnutrition in cystic fibrosis are associated with decreased survival. Glutamine has a possible anti-microbial effect, with a specific impact against Pseudomonas aeruginosa. We aimed to test the hypothesis that oral glutamine supplementation (21 g/day) for 8 weeks in adults with cystic fibrosis would decrease pulmonary inflammation and improve clinical status. METHODS: The study design was a randomized double-blind placebo-controlled study design with an iso-nitrogenous placebo. The primary analysis was intention to treat, and the primary outcome was change in induced sputum neutrophils. RESULTS: Thirty-nine individuals were recruited and thirty-six completed the study. Glutamine supplementation had no impact on any of the outcome measures in the intention-to-treat analysis. In the per protocol analysis, glutamine supplementation was associated with an increase in induced sputum neutrophils (P = 0.046), total cells (P = 0.03), and in Pseudomonas isolation agar colony forming units (P = 0.04) compared to placebo. CONCLUSIONS: There was no effect of glutamine supplementation on markers of pulmonary inflammation in the intention-to-treat analysis.

Soler Artigas M, Wain LV, Miller S, Kheirallah AK, Huffman JE, Ntalla I, Shrine N, Obeidat M, Trochet H, McArdle WL et al. 2015. Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation. Nat Commun, 6 (1), pp. 8658. | Citations: 31 (European Pubmed Central) | Show Abstract | Read more

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

Pavord ID, Lettis S, Locantore N, Pascoe S, Jones PW, Wedzicha JA, Barnes NC. 2016. Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD. Thorax, 71 (2), pp. 118-125. | Citations: 122 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy. METHODS: Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57-75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. RESULTS: For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. DISCUSSION: Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations.

Bousquet J, Schunemann HJ, Fonseca J, Samolinski B, Bachert C, Canonica GW, Casale T, Cruz AA, Demoly P, Hellings P et al. 2015. MACVIA-ARIA Sentinel NetworK for allergic rhinitis (MASK-rhinitis): The new generation guideline implementation Allergy: European Journal of Allergy and Clinical Immunology, 70 (11), pp. 1372-1392. | Citations: 86 (Scopus) | Show Abstract | Read more

© 2015 John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards.

Price DB, Rigazio A, Campbell JD, Bleecker ER, Corrigan CJ, Thomas M, Wenzel SE, Wilson AM, Small MB, Gopalan G et al. 2015. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med, 3 (11), pp. 849-858. | Citations: 103 (Scopus) | Show Abstract | Read more

BACKGROUND: Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood eosinophil count and prospective annual asthma outcomes for a large UK cohort. METHODS: This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12-80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per μL or less versus greater than 400 cells per μL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541. FINDINGS: Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per μL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio [RR] 1·42, 95% CI 1·36-1·47) and acute respiratory events (RR 1·28, 1·24-1·33) than those with counts of 400 cells per μL or less. They also had significantly lower odds of achieving overall asthma control (OR 0·74, 95% CI 0·72-0·77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per μL or less. INTERPRETATION: Patients with asthma and blood eosinophil counts greater than 400 cells per μL experience more severe exacerbations and have poorer asthma control. Furthermore, a count-response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment. FUNDING: Teva Pharmaceuticals.

Harnan S, Essat M, Gomersall T, Tappenden P, Wong R, Lawson R, Pavord I, Everard M. 2015. Exhaled Nitric Oxide For The Diagnosis Of Asthma In Adults And Children: A Systematic Review. Value Health, 18 (7), pp. A345. | Read more

Harnan SE, Tappenden P, Essat M, Gomersall T, Minton J, Wong R, Pavord I, Everard M, Lawson R. 2015. Measurement of exhaled nitric oxide concentration in asthma: a systematic review and economic evaluation of NIOX MINO, NIOX VERO and NObreath. Health Technol Assess, 19 (82), pp. 1-330. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: High fractions of exhaled nitric oxide (FeNO) in the breath of patients with symptoms of asthma are correlated with high levels of eosinophils and indicate that a patient is likely to respond to inhaled corticosteroids. This may have a role in the diagnosis and management of asthma. OBJECTIVE: To assess the diagnostic accuracy, clinical effectiveness and cost-effectiveness of the hand-held electrochemical devices NIOX MINO(®) (Aerocrine, Solna, Sweden), NIOX VERO(®) (Aerocrine) and NObreath(®) (Bedfont Scientific, Maidstone, UK) for the diagnosis and management of asthma. DATA SOURCES: Systematic searches were carried out between March 2013 and April 2013 from database inception. Databases searched included MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, Science Citation Index Expanded and Conference Proceedings Citation Index - Science. Trial registers such as ClinicalTrials.gov and the metaRegister of Controlled Trials were also searched in March 2013. All searches were updated in September 2013. REVIEW METHODS: A rapid review was conducted to assess the equivalence of hand-held and chemiluminescent FeNO monitors. Systematic reviews of diagnostic accuracy and management efficacy were conducted. A systematic review of economic analyses was also conducted and two de novo health economic models were developed. All three reviews were undertaken according to robust high-quality methodology. RESULTS: The rapid review (27 studies) found varying levels of agreement between monitors (Bland-Altman 95% limits of agreement up to ±10 parts per billion), with better agreement at lower FeNO values. Correlation was good (generally r > 0.9). The diagnostic accuracy review identified 22 studies in adults (all ages) and four in children. No studies used NObreath or NIOX VERO and seven used NIOX MINO. Estimates of diagnostic accuracy varied widely. FeNO used in combination with another test altered diagnostic accuracy only slightly. High levels of heterogeneity precluded meta-analysis. Limited observations included that FeNO may be more reliable and useful as a rule-in than as a rule-out test; lower cut-off values in children and in smokers may be appropriate; and FeNO may be less reliable in the elderly. The management review identified five randomised controlled trials in adults, one in pregnant asthmatics and seven in children. Despite clinical heterogeneity, exacerbation rates were lower in all studies but not generally statistically significantly so. Effects on inhaled corticosteroid (ICS) use were inconsistent, possibly because of differences in management protocols, differential effectiveness in adults and children and differences in population severity. One UK diagnostic model and one management model were identified. Aerocrine also submitted diagnostic and management models. All had significant limitations including short time horizons and the selective use of efficacy evidence. The de novo diagnostic model suggested that the expected difference in quality-adjusted life-year (QALY) gains between diagnostic options is likely to be very small. Airway hyper-responsiveness by methacholine challenge test is expected to produce the greatest QALY gain but with an expected incremental cost-effectiveness ratio (ICER) compared with FeNO (NObreath) in combination with bronchodilator reversibility of £1.125M per QALY gained. All remaining options are expected to be dominated. The de novo management model indicates that the ICER of guidelines plus FeNO monitoring using NObreath compared with guidelines alone in children is expected to be approximately £45,200 per QALY gained. Within the adult subgroup, FeNO monitoring using NObreath compared with guidelines alone is expected to have an ICER of approximately £2100 per QALY gained. The results are particularly sensitive to assumptions regarding changes in ICS use over time, the number of nurse visits for FeNO monitoring and duration of effect. CONCLUSIONS: Limitations of the evidence base impose considerable uncertainty on all analyses. Equivalence of devices was assumed but not assured. Evidence for diagnosis is difficult to interpret in the context of inserting FeNO monitoring into a diagnostic pathway. Evidence for management is also inconclusive, but largely consistent with FeNO monitoring resulting in fewer exacerbations, with a small or zero reduction in ICS use in adults and a possible increased ICS use in children or patients with more severe asthma. It is unclear which specific management protocol is likely to be most effective. The economic analysis indicates that FeNO monitoring could have value in diagnostic and management settings. The diagnostic model indicates that FeNO monitoring plus bronchodilator reversibility dominates many other diagnostic tests. FeNO-guided management has the potential to be cost-effective, although this is largely dependent on the duration of effect. The conclusions drawn from both models require strong technical value judgements with respect to several aspects of the decision problem in which little or no empirical evidence exists. There are many potential directions for further work, including investigations into which management protocol is best and long-term follow-up in both diagnosis and management studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004149. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

De Soyza A, Pavord I, Elborn JS, Smith D, Wray H, Puu M, Larsson B, Stockley R. 2015. A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis. Eur Respir J, 46 (4), pp. 1021-1032. | Citations: 31 (Web of Science Lite) | Show Abstract | Read more

This randomised double-blind placebo-controlled parallel-group multicentre phase IIa study evaluated the effect of the CXCR2 antagonist AZD5069 on sputum neutrophil counts in adults with bronchiectasis.Patients were randomised 1:1 to receive AZD5069 80 mg or placebo orally twice daily for 28 days. Assessments included blood cell counts, inflammatory markers in blood, morning spontaneous sputum, lung function, safety and tolerability and patients completed daily BronkoTest diary cards. The primary outcome measure was the change in absolute sputum neutrophil count.Of 52 randomised patients, 45 completed treatment, 20 (76.9%) out of 26 receiving AZD5069 and 25 (96.2%) out of 26 receiving placebo. AZD5069 reduced the absolute neutrophil cell count in morning sputum by 69% versus placebo (p=0.004); percentage sputum neutrophil count was reduced by 36% (p=0.008). The number of infections/exacerbations was similar with AZD5069 and placebo (nine versus eight), but these led to more study discontinuations with AZD5069 (four versus zero). Sputum interleukin (IL)-6 and growth-regulated oncogene (GRO)-α and serum GRO-α, IL-1ß and IL-8 levels increased with AZD5069 versus placebo (all p<0.001), while serum high-sensitivity C-reactive protein levels did not change. AZD5069 was well tolerated.AZD5069 markedly reduced absolute sputum neutrophil counts in bronchiectasis patients, although this was not associated with improvements in clinical outcomes in this exploratory study.

Wain LV, Shrine N, Miller S, Jackson VE, Ntalla I, Soler Artigas M, Billington CK, Kheirallah AK, Allen R, Cook JP et al. 2015. Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank. Lancet Respir Med, 3 (10), pp. 769-781. | Citations: 110 (Scopus) | Show Abstract | Read more

BACKGROUND: Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. METHODS: We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10(-8). FINDINGS: UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50,008 unique samples: 10,002 individuals with low FEV1, 10,000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2.29 × 10(-16)) and between individuals with and without doctor-diagnosed asthma (p=6.06 × 10(-11)). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. INTERPRETATION: By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. FUNDING: Medical Research Council.

Bush A, Pavord I. 2015. Look back with (some) anger, and a lot of pleasure. Thorax, 70 (9), pp. 819-821. | Read more

Hilvering B, Xue L, Pavord ID. 2015. Evidence for the efficacy and safety of anti-interleukin-5 treatment in the management of refractory eosinophilic asthma. Ther Adv Respir Dis, 9 (4), pp. 135-145. | Citations: 23 (Scopus) | Show Abstract | Read more

Two recent phase III trials in patients with severe eosinophilic asthma have shown that anti-interleukin 5 (IL-5) therapy with mepolizumab reduces the frequency of asthma attacks, improves symptoms and allows patients to reduce oral glucocorticoid use without loss of control of asthma. An earlier large 616 patient Dose Ranging Efficacy And safety with Mepolizumab in severe asthma (DREAM) study had shown that the only variables associated with treatment efficacy were a prior history of asthma attacks and the peripheral blood eosinophil count. The link between blood eosinophil counts and treatment efficacy is biologically obvious given that IL-5 has a pivotal role in eosinophil production, proliferation and chemotaxis. It is also clinically relevant as the blood eosinophil count is routinely measured and thus readily available in patients with asthma. Recognition of the link between airway or blood eosinophilia and treatment response was also important in the clinical testing of the alternative IL-5 blocker, such as reslizumab, which is currently being evaluated in a phase III randomized controlled trial (RCT) after having shown to improve lung function, improve symptom score and reduce sputum eosinophilia in a smaller phase IIb study. In addition, benralizumab, an IL-5α receptor blocker, has shown good effects in a phase IIb RCT with patients with severe asthma that had sputum eosinophilia and more recently in a phase IIa trial with patients with eosinophilic chronic obstructive pulmonary disease. Therefore anti-IL-5 treatment seems generally effective in eosinophilic asthma, either assessed by blood or airway eosinophilia. This factor together with the impressive clinical efficacy and good safety profile make anti-IL-5 (mepolizumab, reslizumab) and benralizumab (anti-IL-5 receptor α) very promising drugs for the treatment of patients with severe eosinophilic asthma, a subgroup that is in desperate need of better treatments.

Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord I. 2015. Blood eosinophil counts as markers of response to inhaled corticosteroids in COPD?--Authors' reply. Lancet Respir Med, 3 (8), pp. e27. | Citations: 3 (Web of Science Lite) | Read more

Heaney LG, Djukanovic R, Woodcock A, Walker S, Matthews JG, Pavord ID, Bradding P, Niven R, Brightling CE, Chaudhuri R et al. 2016. Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK). Thorax, 71 (2), pp. 187-189. | Citations: 35 (Scopus) | Show Abstract | Read more

The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.

Bousquet J, Schunemann HJ, Fonseca J, Samolinski B, Bachert C, Canonica GW, Casale T, Cruz AA, Demoly P, Hellings P et al. 2015. MACVIA-ARIA Sentinel NetworK for allergic rhinitis (MASK-rhinitis): the new generation guideline implementation. Allergy, 70 (11), pp. 1372-1392. | Citations: 78 (Web of Science Lite) | Show Abstract | Read more

Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards.

Bush A, Pavord I. 2015. Highlights from this issue Thorax, 70 (7), pp. i-i. | Read more

Pavord I, Bush A. 2015. Two Lovely Black Eyes; Oh, what a surprise! Thorax, 70 (7), pp. 609-610. | Citations: 10 (Scopus) | Read more

Bafadhel M, Haldar K, Barker B, Patel H, Mistry V, Barer MR, Pavord ID, Brightling CE. 2015. Airway bacteria measured by quantitative polymerase chain reaction and culture in patients with stable COPD: relationship with neutrophilic airway inflammation, exacerbation frequency, and lung function. Int J Chron Obstruct Pulmon Dis, 10 pp. 1075-1083. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: Potentially pathogenic microorganisms can be detected by quantitative real-time polymerase chain reaction (qPCR) in sputum from patients with COPD, although how this technique relates to culture and clinical measures of disease is unclear. We used cross-sectional and longitudinal data to test the hypotheses that qPCR is a more sensitive measure of bacterial presence and is associated with neutrophilic airway inflammation and adverse clinical outcomes. METHODS: Sputum was collected from 174 stable COPD subjects longitudinally over 12 months. Microbial sampling using culture and qPCR was performed. Spirometry and sputum measures of airway inflammation were assessed. FINDINGS: Sputum was qPCR-positive (>10(6) copies/mL) in 77/152 samples (Haemophilus influenzae [n=52], Moraxella catarrhalis [n=24], Streptococcus pneumoniae [n=19], and Staphylococcus aureus [n=7]). Sputum was culture-positive in 50/174 samples, with 49 out of 50 culture-positive samples having pathogen-specific qPCR bacterial loads >10(6) copies/mL. Samples that had qPCR copy numbers >10(6)/mL, whether culture-positive or not, had increased sputum neutrophil counts. H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P<0.001), were repeatable within subjects, and were >10(6)/mL three or more times in 19 patients, eight of whom were repeatedly sputum culture-positive. Persistence, whether defined by culture, qPCR, or both, was associated with a higher sputum neutrophil count, lower forced expiratory volume in 1 second (FEV1), and worsened quality of life. INTERPRETATION: qPCR identifies a significant number of patients with potentially bacteria-associated neutrophilic airway inflammation and disease that are not identified by traditional culture-based methods.

Moeller A, Carlsen K-H, Sly PD, Baraldi E, Piacentini G, Pavord I, Lex C, Saglani S, ERS Task Force Monitoring Asthma in Children. 2015. Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation. Eur Respir Rev, 24 (136), pp. 204-215. | Citations: 33 (Scopus) | Show Abstract | Read more

This review focuses on the methods available for measuring reversible airways obstruction, bronchial hyperresponsiveness (BHR) and inflammation as hallmarks of asthma, and their role in monitoring children with asthma. Persistent bronchial obstruction may occur in asymptomatic children and is considered a risk factor for severe asthma episodes and is associated with poor asthma outcome. Annual measurement of forced expiratory volume in 1 s using office based spirometry is considered useful. Other lung function measurements including the assessment of BHR may be reserved for children with possible exercise limitations, poor symptom perception and those not responding to their current treatment or with atypical asthma symptoms, and performed on a higher specialty level. To date, for most methods of measuring lung function there are no proper randomised controlled or large longitudinal studies available to establish their role in asthma management in children. Noninvasive biomarkers for monitoring inflammation in children are available, for example the measurement of exhaled nitric oxide fraction, and the assessment of induced sputum cytology or inflammatory mediators in the exhaled breath condensate. However, their role and usefulness in routine clinical practice to monitor and guide therapy remains unclear, and therefore, their use should be reserved for selected cases.

De Fonseka D, Lama-Lopez A, Batchelor T, Edey A, Maskell NA. 2015. The Harlequin sign Thorax, 70 (6), pp. 605-606. | Read more

Bush A, Pavord I. 2015. Highlights from this issue Thorax, 70 (6), pp. i-i. | Read more

Hodgson D, Anderson J, Reynolds C, Meakin G, Bailey H, Pavord I, Shaw D, Harrison T. 2015. A randomised controlled trial of small particle inhaled steroids in refractory eosinophilic asthma (SPIRA) Thorax, 70 (6), pp. 559-565. | Citations: 10 (Scopus) | Show Abstract | Read more

Background: Some patients with refractory asthma have evidence of uncontrolled eosinophilic inflammation in the distal airways. While traditional formulations of inhaled steroids settle predominantly in the large airways, newer formulations with an extra-fine particle size have a more peripheral pattern of deposition. Specifically treating distal airway inflammation may improve asthma control. Methods: 30 patients with refractory asthma despite high dose inhaled corticosteroids were identified as having persistent airway eosinophilia. Following 2 weeks of prednisolone 30 mg, patients demonstrating an improvement in asthma control were randomised to receive either ciclesonide 320 mg twice daily or placebo in addition to usual maintenance therapy for 8 weeks. The primary outcome measure was sputum eosinophil count at week 8. Alveolar nitric oxide was measured as a marker of distal airway inflammation. Results: There was continued suppression of differential sputum eosinophil counts with ciclesonide (median 2.3%) but not placebo (median 4.5%) though the between-group difference was not significant. When patients who had changed their maintenance prednisolone dose during the trial were excluded the difference between groups was significant (1.4% vs 4.5%, p=0.028). Though alveolar nitric oxide decreased with ciclesonide the value did not reach statistical significance. Conclusions: These data demonstrate that patients with ongoing eosinophilic inflammation are not truly refractory, and that suppression of airway eosinophilia may be maintained with additional inhaled corticosteroid. Further work is needed with a focus on patient-orientated outcome measures such as exacerbation rate, with additional tests of small airway function.

Lødrup Carlsen KC, Pijnenburg MW, ERS Task Force Monitoring Asthma in Children. 2015. Monitoring asthma in childhood. Eur Respir Rev, 24 (136), pp. 178-186. | Citations: 6 (Scopus) | Show Abstract | Read more

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. However, to date there is limited evidence on how to monitor patients with asthma. Childhood asthma introduces specific challenges in terms of deciding what, when, how often, by whom and in whom different assessments of asthma should be performed. The age of the child, the fluctuating course of asthma severity, variability in clinical presentation, exacerbations, comorbidities, socioeconomic and psychosocial factors, and environmental exposures may all influence disease activity and, hence, monitoring strategies. These factors will be addressed in herein. We identified large knowledge gaps in the effects of different monitoring strategies in children with asthma. Studies into monitoring strategies are urgently needed, preferably in collaborative paediatric studies across countries and healthcare systems.

Rottier BL, Eber E, Hedlin G, Turner S, Wooler E, Mantzourani E, Kulkarni N, ERS Task Force Monitoring Asthma in Children. 2015. Monitoring asthma in childhood: management-related issues. Eur Respir Rev, 24 (136), pp. 194-203. | Citations: 11 (Scopus) | Show Abstract | Read more

Management-related issues are an important aspect of monitoring asthma in children in clinical practice. This review summarises the literature on practical aspects of monitoring including adherence to treatment, inhalation technique, ongoing exposure to allergens and irritants, comorbid conditions and side-effects of treatment, as agreed by the European Respiratory Society Task Force on Monitoring Asthma in Childhood. The evidence indicates that it is important to discuss adherence to treatment in a non-confrontational way at every clinic visit, and take into account a patient's illness and medication beliefs. All task force members teach inhalation techniques at least twice when introducing a new inhalation device and then at least annually. Exposure to second-hand tobacco smoke, combustion-derived air pollutants, house dust mites, fungal spores, pollens and pet dander deserve regular attention during follow-up according to most task force members. In addition, allergic rhinitis should be considered as a cause for poor asthma control. Task force members do not screen for gastro-oesophageal reflux and food allergy. Height and weight are generally measured at least annually to identify individuals who are susceptible to adrenal suppression and to calculate body mass index, even though causality between obesity and asthma has not been established. In cases of poor asthma control, before stepping up treatment the above aspects of monitoring deserve closer attention.

Brand PLP, Mäkelä MJ, Szefler SJ, Frischer T, Price D, ERS Task Force Monitoring Asthma in Children. 2015. Monitoring asthma in childhood: symptoms, exacerbations and quality of life. Eur Respir Rev, 24 (136), pp. 187-193. | Citations: 15 (Scopus) | Show Abstract | Read more

Monitoring asthma in children in clinical practice is primarily performed by reviewing disease activity (daytime and night-time symptoms, use of reliever medication, exacerbations requiring frequent use of reliever medication and urgent visits to the healthcare professional) and the impact of the disease on children's daily activities, including sports and play, in a clinical interview. In such an interview, most task force members also discuss adherence to maintenance therapy and the patients' (and parents') views and beliefs on the goals of treatment and the amount of treatment required to achieve those goals. Composite asthma control and quality of life measures, although potentially useful in research, have limited value in clinical practice because they have a short recall window and do not cover the entire spectrum of asthma control. Telemonitoring of children with asthma cannot replace face-to-face follow-up and monitoring because there is no evidence that it is associated with improved health outcomes.

Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. 2015. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials (vol 3, pg 435, 2015) LANCET RESPIRATORY MEDICINE, 3 (6), pp. E19-E19. | Citations: 1 (Web of Science Lite) | Read more

Pavord I, Bush A. 2015. Two Lovely Black Eyes; Oh, what a surprise! Thorax, 70 (7), pp. 609-610. | Citations: 7 (Web of Science Lite) | Read more

Bush A, Pavord I. 2015. Ring in the new. Thorax, 70 (5), pp. 403. | Citations: 1 (Web of Science Lite) | Read more

Pavord ID, Bush A, Holgate S. 2015. Asthma diagnosis: addressing the challenges LANCET RESPIRATORY MEDICINE, 3 (5), pp. 339-341. | Citations: 7 (Web of Science Lite) | Read more

Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM. 2015. Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma (vol 371, pg 1198, 2014) NEW ENGLAND JOURNAL OF MEDICINE, 372 (18), pp. 1777-1777. | Read more

Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. 2015. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med, 3 (6), pp. 435-442. | Citations: 257 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are greater in patients with evidence of eosinophilic airway inflammation. We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency. METHODS: We did a post-hoc analysis of data from two replicate, randomised, double-blind trials of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg, 100 μg, or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year. We compared exacerbation rates according to two baseline eosinophil cell count strata (<2% and ≥2%), and according to four baseline percentage groupings. We also assessed lung function and incidence of pneumonia per strata in treatment groups. FINDINGS: We included 3177 patients in the analyses, with 2083 patients (66%) having an eosinophil count of 2% or higher at study entry. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0·91 vs 1·28 exacerbations per patient per year; p<0·0001) in patients with eosinophil counts of 2% or higher, and by 10% (0·79 vs 0·89; p=0·2827) in patients with eosinophil counts lower than 2%. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥2-<4%, 32% for those with counts of 4-<6%, and 42% for those with eosinophil counts of ≥6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category. Improvement in trough forced expiratory volume in 1 s (FEV1) and the increased risk of pneumonia with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count. INTERPRETATION: Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD. Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies. FUNDING: GlaxoSmithKline (study ID 201595).

Hodgson D, Anderson J, Reynolds C, Meakin G, Bailey H, Pavord I, Shaw D, Harrison T. 2015. A randomised controlled trial of small particle inhaled steroids in refractory eosinophilic asthma (SPIRA). Thorax, 70 (6), pp. 559-565. | Citations: 5 (European Pubmed Central) | Show Abstract | Read more

BACKGROUND: Some patients with refractory asthma have evidence of uncontrolled eosinophilic inflammation in the distal airways. While traditional formulations of inhaled steroids settle predominantly in the large airways, newer formulations with an extra-fine particle size have a more peripheral pattern of deposition. Specifically treating distal airway inflammation may improve asthma control. METHODS: 30 patients with refractory asthma despite high dose inhaled corticosteroids were identified as having persistent airway eosinophilia. Following 2 weeks of prednisolone 30 mg, patients demonstrating an improvement in asthma control were randomised to receive either ciclesonide 320 µg twice daily or placebo in addition to usual maintenance therapy for 8 weeks. The primary outcome measure was sputum eosinophil count at week 8. Alveolar nitric oxide was measured as a marker of distal airway inflammation. RESULTS: There was continued suppression of differential sputum eosinophil counts with ciclesonide (median 2.3%) but not placebo (median 4.5%) though the between-group difference was not significant. When patients who had changed their maintenance prednisolone dose during the trial were excluded the difference between groups was significant (1.4% vs 4.5%, p=0.028). Though alveolar nitric oxide decreased with ciclesonide the value did not reach statistical significance. CONCLUSIONS: These data demonstrate that patients with ongoing eosinophilic inflammation are not truly refractory, and that suppression of airway eosinophilia may be maintained with additional inhaled corticosteroid. Further work is needed with a focus on patient-orientated outcome measures such as exacerbation rate, with additional tests of small airway function. TRIAL REGISTRATION NUMBER: NCT01171365. Protocol available at http://www.clinicaltrials.gov.

Bush A, Pavord I. 2015. Highlights from this issue Thorax, 70 (4), pp. i-i. | Read more

Bush A, Pavord I. 2015. Year in review 2014. Paediatric and adult clinical studies. Thorax, 70 (4), pp. 368-372. | Show Abstract | Read more

Our prizes for best papers in the last year have become as eagerly awaited as the Oscars and are much more glamorous. As before, we have awarded GOLD, SILVER and BRONZE prizes in the following categories: paediatrics, adult clinical, basic science and epidemiology. This is the first of two reviews of manuscripts published in Thorax in 2014 dealing with manuscripts on the clinical aspects of paediatrics and adult respiratory medicine. Decisions are purely those of the editors and deputy editors. Our only restriction has been to not consider manuscripts exclusively from Imperial and Oxford because we have conflicts of interest. Next month we deal with basic science and epidemiology manuscripts and reveal the overall winner.

Pavord ID, Hilvering B. 2015. Biomarkers and inhaled corticosteroid responsiveness in asthmatic patients. J Allergy Clin Immunol, 135 (4), pp. 884-885. | Citations: 6 (Web of Science Lite) | Read more

Bush A, Kleinert S, Pavord ID. 2015. The asthmas in 2015 and beyond: a Lancet Commission. Lancet, 385 (9975), pp. 1273-1275. | Citations: 15 (Web of Science Lite) | Read more

Gaillard EA, McNamara PS, Murray CS, Pavord ID, Shields MD. 2015. Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial? Clin Exp Allergy, 45 (9), pp. 1384-1395. | Citations: 12 (Scopus) | Show Abstract | Read more

Childhood wheezing is common particularly in children under the age of 6 years and in this age group is generally referred to as preschool wheezing. Particular diagnostic and treatment uncertainties exist in these young children due to the difficulty in obtaining objective evidence of reversible airways narrowing and inflammation. A diagnosis of asthma depends on the presence of relevant clinical signs and symptoms and the demonstration of reversible airways narrowing on lung function testing, which is difficult to perform in young children. Few treatments are available and inhaled corticosteroids are the recommended preventer treatment in most international asthma guidelines. There is, however, considerable controversy about its effectiveness in children with preschool wheeze and a corticosteroid responder phenotype has not been established. These diagnostic and treatment uncertainties in conjunction with the knowledge of corticosteroid side effects, in particular the reduction of growth velocity, have resulted in a variable approach to inhaled corticosteroid prescribing by medical practitioners and a reluctance in carers to regularly administer the treatment. Identifying children who are likely responders to corticosteroid therapy would be a major benefit in the management of this condition. Eosinophils have emerged as a promising biomarker of corticosteroid responsive airways disease, and evaluation of this biomarker in sputum has successfully been employed to direct management in adults with asthma. Obtaining sputum from young children is time consuming and difficult, and it is hard to justify more invasive procedures such as a bronchoscopy in young children routinely. Recently, in children, interest has shifted to assessing the value of less invasive biomarkers of likely corticosteroid response and the biomarker 'blood eosinophils' has emerged as an attractive candidate. The aim of this review was to summarize the evidence for blood eosinophils as a predictive biomarker for corticosteroid responsive disease with a particular focus on the difficult area of preschool wheeze.

Pavord ID, Bush A, Holgate S. 2015. Asthma diagnosis: addressing the challenges. Lancet Respir Med, 3 (5), pp. 339-341. | Citations: 5 (European Pubmed Central) | Read more

Pijnenburg MW, Baraldi E, Brand PLP, Carlsen K-H, Eber E, Frischer T, Hedlin G, Kulkarni N, Lex C, Mäkelä MJ et al. 2015. Monitoring asthma in children. Eur Respir J, 45 (4), pp. 906-925. | Citations: 36 (Web of Science Lite) | Show Abstract | Read more

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence.

Bush A, Pavord I. 2015. Highlights from this issue Thorax, 70 (3), pp. i-i. | Read more

Bush A, Pavord I. 2015. Highlights from this issue: Thorax, 70 (2), pp. i-i. | Read more

Hilvering B, Pavord ID. 2015. What goes up must come down: biomarkers and novel biologicals in severe asthma. Clin Exp Allergy, 45 (7), pp. 1162-1169. | Citations: 17 (Scopus) | Show Abstract | Read more

Asthma is a heterogeneous airway disease characterized by typical symptoms in combination with variable airway obstruction. Most patients with asthma have well controlled symptoms and a low risk of asthma attacks with inhaled corticosteroid (ICS) treatment. However, a clinically important subgroup (~ 10%) remains symptomatic and/or at risk of asthma attacks despite maximum inhaled therapy. Patients with severe asthma are responsible for a significant proportion of healthcare costs attributable to asthma and have a large unmet need for better treatments. An important advance in recent years has been the recognition that severe asthma is heterogeneous with respect to clinical problems and the pattern of lower airway inflammation. Identification of eosinophilic inflammation in the airways has become an important priority as novel biologicals that target Th2 cytokines, such as anti-IL5, anti-IL-13 and combined anti-IL-4/13 are showing considerable promise as treatments for this subgroup. It has also become clear that anti-IgE (Omalizumab), the first monoclonal antibody registered for treatment of severe asthma, is only active in patients with active eosinophilic airway inflammation. The future will be identification of potentially responsive patients on the basis of raised biomarkers and, as suggested by the title of this review, targeted treatment with specific cytokine blockade that has a direct effect on the biomarkers. In this review, we outline an approach to the clinical assessment of patients potentially suitable for biological treatment and describe in detail the likely clinical impact of established and new biological treatments.

Hilvering B, Xue L, Pavord ID. 2015. IL-33-dependent Th2 response after rhinovirus infection in asthma: more information needed. Am J Respir Crit Care Med, 191 (2), pp. 237. | Citations: 2 (European Pubmed Central) | Read more

Brightling CE, Pavord ID, Bafadhel M. 2015. Inhaled glucocorticoids and COPD exacerbations. N Engl J Med, 372 (1), pp. 93. | Citations: 7 (Web of Science Lite) | Read more

Gupta S, Hartley R, Singapuri A, Hargadon B, Monteiro W, Pavord ID, Sousa AR, Marshall RP, Subramanian D, Parr D et al. 2015. Temporal assessment of airway remodeling in severe asthma using quantitative computed tomography. Am J Respir Crit Care Med, 191 (1), pp. 107-110. | Citations: 4 (Web of Science Lite) | Read more

Bush A, Pavord I. 2015. Thorax: the lean and slippered Pantaloon years. Thorax, 70 (1), pp. 11. | Read more

Ghebre MA, Bafadhel M, Desai D, Cohen SE, Newbold P, Rapley L, Woods J, Rugman P, Pavord ID, Newby C et al. 2015. Biological clustering supports both "dutch" and "british" hypotheses of asthma and chronic obstructive pulmonary disease Journal of Allergy and Clinical Immunology, 135 (1), pp. 63-72. | Citations: 66 (Scopus) | Show Abstract | Read more

© 2014 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma and Immunology. Conclusions Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.Results Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study.Background Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases.Objective We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis.Methods We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD).

Brightling CE, Pavord ID, Bafadhel M. 2015. Inhaled Glucocorticoids and COPD Exacerbations New England Journal of Medicine, 372 (1), pp. 92-94. | Read more

Pavord ID, Bush A, Holgate S. 2015. Asthma diagnosis: Addressing the challenges The Lancet Respiratory Medicine, 3 (5), pp. 339-341. | Citations: 9 (Scopus) | Read more

Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. 2015. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: A secondary analysis of data from two parallel randomised controlled trials The Lancet Respiratory Medicine, 3 (6), pp. 435-442. | Citations: 264 (Scopus) | Show Abstract | Read more

© 2015 Elsevier Ltd. Background: The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are greater in patients with evidence of eosinophilic airway inflammation. We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency. Methods: We did a post-hoc analysis of data from two replicate, randomised, double-blind trials of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg, 100 μg, or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year. We compared exacerbation rates according to two baseline eosinophil cell count strata (<2% and ≥2%), and according to four baseline percentage groupings. We also assessed lung function and incidence of pneumonia per strata in treatment groups. Findings: We included 3177 patients in the analyses, with 2083 patients (66%) having an eosinophil count of 2% or higher at study entry. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0·91 vs 1·28 exacerbations per patient per year; p<0·0001) in patients with eosinophil counts of 2% or higher, and by 10% (0·79 vs 0·89; p=0·2827) in patients with eosinophil counts lower than 2%. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥2-<4%, 32% for those with counts of 4-<6%, and 42% for those with eosinophil counts of ≥6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category. Improvement in trough forced expiratory volume in 1 s (FEV<inf>1</inf>) and the increased risk of pneumonia with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count. Interpretation: Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD. Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies. Funding: GlaxoSmithKline (study ID 201595).

Bel EH, Ortega HG, Pavord ID. 2014. Glucocorticoids and mepolizumab in eosinophilic asthma. N Engl J Med, 371 (25), pp. 2434. | Citations: 13 (Web of Science Lite) | Read more

Bel EH, Ortega HG, Pavord ID. 2014. Glucocorticoids and mepolizumab in eosinophilic asthma The New England journal of medicine, 371 (25), pp. 2434. | Citations: 8 (Scopus) | Read more

Lindsay JT, Heaney L. 2014. Glucocorticoids and mepolizumab in eosinophilic asthma. N Engl J Med, 371 (25), pp. 2433. | Citations: 13 (Web of Science Lite) | Read more

Iikura M, Hojo M, Sugiyama H. 2014. Glucocorticoids and Mepolizumab in Eosinophilic Asthma NEW ENGLAND JOURNAL OF MEDICINE, 371 (25), pp. 2433-2434. | Citations: 13 (Web of Science Lite)

Bush A, Pavord I. 2014. Highlights from this issue Thorax, 69 (12), pp. i-i. | Read more

Bush A, Pavord I. 2014. Highlights from this issue Thorax, 69 (11), pp. i-i. | Read more

Baines KJ, Pavord ID, Gibson PG. 2014. The role of biomarkers in the management of airways disease. Int J Tuberc Lung Dis, 18 (11), pp. 1264-1268. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease, are responsible for a large global disease burden. The recognition of airway disease phenotypes is important for the application of new therapies targeted at specific underlying biological mechanisms. Biomarkers are indicators of biological or pathogenic processes that are objectively measured. In airway disease, biomarkers will ideally provide predictive information regarding diagnosis, disease mechanisms, phenotypes, treatment responses and prognosis or future risk. Non-invasive biomarkers that aid phenotyping are crucial to the development of targeted and more efficacious treatment, leading to personalised approaches to airway disease management. Sputum and peripheral blood eosinophils and fractional exhaled nitric oxide (FeNO) are current examples of potential biomarkers. However, recent advances in technology have demonstrated the role for airway transcriptomics in biomarker discovery. This perspective piece discusses the need for biomarkers in airway disease, the use of eosinophil counts and FeNO as biomarkers, the use of transcriptomics for biomarker discovery, and the application of biomarkers in clinical and research settings. A combined approach incorporating clinical information with biological markers such as eosinophils, FeNO and inflammatory gene markers is likely to have the most success in predicting patient outcomes.

Bush A, Pavord I. 2014. Upping the impact: to (not quite!) infinity and beyond. Thorax, 69 (10), pp. 890. | Read more

Bush A, Pavord I. 2014. Highlights from this issue Thorax, 69 (10), pp. i-i. | Read more

Barker BL, McKenna S, Mistry V, Pancholi M, Patel H, Haldar K, Barer MR, Pavord ID, Steiner MC, Brightling CE, Bafadhel M. 2014. Systemic and pulmonary inflammation is independent of skeletal muscle changes in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 9 pp. 975-981. | Citations: 6 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. OBJECTIVES: To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. METHODS: Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m(2) and/or fat-free mass index (FFMI) less than 15 or 17 kg/m(2) in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. RESULTS: Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P<0.01). There were no differences in airway inflammation and bacterial colonization in patients with and without nutritional depletion. At baseline, BMI correlated positively with serum CRP (rs=0.14, P=0.04). Change in weight and change in FFM over time could not be predicted from baseline patient characteristics. CONCLUSION: Nutritional depletion and progressive muscle atrophy are not related to airway inflammation or bacterial colonization. Overspill of pulmonary inflammation is not a key driver of muscle atrophy in COPD.

Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID, SIRIUS Investigators. 2014. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med, 371 (13), pp. 1189-1197. | Citations: 457 (Scopus) | Show Abstract | Read more

BACKGROUND: Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. METHODS: In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment). Other outcomes included the rate of asthma exacerbations, asthma control, and safety. RESULTS: The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P=0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P=0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P=0.04) and a reduction of 0.52 points with respect to asthma symptoms (P=0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms. (Funded by GlaxoSmithKline; SIRIUS ClinicalTrials.gov number, NCT01691508.).

Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW et al. 2014. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med, 371 (13), pp. 1198-1207. | Citations: 621 (Scopus) | Show Abstract | Read more

BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, Smith JA, Parker SM, Chung KF, Lai K et al. 2014. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J, 44 (5), pp. 1149-1155. | Citations: 72 (Web of Science Lite) | Show Abstract | Read more

Reports from individual centres suggest a preponderance of females with chronic cough. Females also have heightened cough reflex sensitivity. Here we have reviewed the age and sex of unselected referrals to 11 cough clinics. To investigate the cause of any observed sex dimorphism, functional magnetic resonance imaging of putative cough centres was analysed in normal volunteers. The demographic profile of consecutive patients presenting with chronic cough was evaluated. Cough challenge with capsaicin was undertaken in normal volunteers to construct a concentration-response curve. Subsequent functional magnetic resonance imaging during repeated inhalation of sub-tussive concentrations of capsaicin observed areas of activation within the brain and differences in the sexes identified. Of the 10,032 patients presenting with chronic cough, two-thirds (6591) were female (mean age 55 years). The patient profile was largely uniform across centres. The most common age for presentation was 60-69 years. The maximum tolerable dose of inhaled capsaicin was lower in females; however, a significantly greater activation of the somatosensory cortex was observed. Patients presenting with chronic cough from diverse racial and geographic backgrounds have a strikingly homogeneous demographic profile, suggesting a distinct clinical entity. The preponderance of females may be explained by sex-related differences in the central processing of cough sensation.

Barnes PJ, Casale TB, Dahl R, Pavord ID, Wechsler ME. 2014. The Asthma Control Questionnaire as a clinical trial endpoint: past experience and recommendations for future use. Allergy, 69 (9), pp. 1119-1140. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

The goal of asthma treatment is to control the disease according to guidelines issued by bodies such as the Global Initiative for Asthma. Effective control is dependent upon evaluation of symptoms, initiation of appropriate treatment and minimization of the progressive adverse effects of the disease and its therapies. Although individual outcome measures have been shown to correlate with asthma control, composite endpoints are preferred to enable more accurate and robust monitoring of the health of the individual patient. A number of validated instruments are utilized to capture these component endpoints; however, there is no consensus on the optimal instrument for use in clinical trials. The Asthma Control Questionnaire (ACQ) has been shown to be a valid, reliable instrument that allows accurate and reproducible assessment of asthma control that compares favourably with other commonly used instruments. This analysis provides a summary of the use of ACQ in phase II, III and IV asthma trials. Comparisons between the ACQ and other instruments are also presented. Our analysis suggests that the ACQ is a valid and robust measure for use as a primary or secondary endpoint in future clinical trials.

Wilson E, McKeever T, Hargadon B, Hearson G, Anderson J, Hodgson D, Bailey H, Meakin G, Thomas M, Pavord ID et al. 2014. Exhaled nitric oxide and inhaled corticosteroid dose reduction in asthma: a cohort study. Eur Respir J, 44 (6), pp. 1705-1707. | Citations: 3 (Web of Science Lite) | Read more

Barker BL, Haldar K, Patel H, Pavord ID, Barer MR, Brightling CE, Bafadhel M. 2015. Association between pathogens detected using quantitative polymerase chain reaction with airway inflammation in COPD at stable state and exacerbations. Chest, 147 (1), pp. 46-55. | Citations: 18 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Relationships between airway inflammation and respiratory potentially pathogenic microorganisms (PPMs) quantified using quantitative polymerase chain reaction (qPCR) in subjects with COPD are unclear. Our aim was to evaluate mediators of airway inflammation and their association with PPMs in subjects with COPD at stable state and during exacerbations. METHODS: Sputum from 120 stable subjects with COPD was analyzed for bacteriology (colony-forming units; total 16S; and qPCR targeting Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae), differential cell counts, and inflammatory mediators using the Meso-Scale Discovery Platform. Subjects were classified as colonized if any PPM was identified above the threshold of detection by qPCR. Symptoms were quantified using the visual analog scale. RESULTS: At stable state, 60% of subjects were qPCR positive for H influenzae, 48% for M catarrhalis, and 28% for S pneumoniae. Elevated sputum concentrations of IL-1β, IL-10, and tumor necrosis factor (TNF)-α were detected in samples qPCR positive for either H influenzae or M catarrhalis. Bacterial loads of H influenzae positively correlated with IL-1β, IL-8, IL-10, TNF-α, and symptoms; and M catarrhalis correlated with IL-10 and TNF-α. H influenzae qPCR bacterial load was an independent predictor of sputum TNF-α and IL-1β. In 55 subjects with paired exacerbation data, qPCR bacterial load fold change at exacerbation in M catarrhalis but not H influenzae correlated to changes in sputum TNF-α and IL-1β concentrations. CONCLUSIONS: At stable state, H influenzae is associated with increased airway inflammation in COPD. The relationship between bacterial load changes of specific pathogens and airway inflammation at exacerbation and recovery warrants further investigation.

Bush A, Pavord I. 2014. Highlights from this issue Thorax, 69 (7), pp. i-i. | Read more

Willson J, Bateman ED, Pavord I, Lloyd A, Krivasi T, Esser D. 2014. Cost effectiveness of tiotropium in patients with asthma poorly controlled on inhaled glucocorticosteroids and long-acting β-agonists. Appl Health Econ Health Policy, 12 (4), pp. 447-459. | Citations: 19 (European Pubmed Central) | Show Abstract | Read more

BACKGROUND: A considerable proportion of patients with asthma remain uncontrolled or symptomatic despite treatment with a high dose of inhaled glucocorticosteroids (ICSs) and long-acting β2-agonists (LABAs). Tiotropium Respimat(®) added to usual care improves lung function, asthma control, and the frequency of non-severe and severe exacerbations, in a population of adult asthma patients who are uncontrolled despite treatment with ICS/LABA. OBJECTIVE: This study estimated the cost effectiveness of tiotropium therapy as add-on to usual care in asthma patients that are uncontrolled despite treatment with ICS/LABA combination from the perspective of the UK National Health Service (NHS). METHODS: A Markov model was developed which considers levels of asthma control and exacerbations. The model analysed cost and quality-adjusted life-years (QALYs); sensitivity and scenario analyses were also conducted to test the robustness of the base case outcomes. All costs are given at 2012 prices. RESULTS: The model found that in this category of asthma with unmet need, add-on tiotropium therapy generated an incremental 0.24 QALYs and £5,238 costs over a lifetime horizon, resulting in an incremental cost-effectiveness ratio of £21,906 per QALY gained. Sensitivity analysis suggested that findings were most dependent on the costs of managing uncontrolled asthma and the cost of treatment with tiotropium. CONCLUSION: In this modelled analysis of two clinical trials, tiotropium was found to be cost effective when added to usual care in patients who remain uncontrolled despite treatment with high-dose ICS/LABA. Further research should investigate the long-term treatment effectiveness of tiotropium.

European Innovation Partnership on Active and Healthy Ageing, Action Plan B3, Mechanisms of the Development of Allergy, WP 10, Global Alliance against Chronic Respiratory Diseases, Bousquet J, Addis A, Adcock I, Agache I, Agusti A, Alonso A, Annesi-Maesano I et al. 2014. Integrated care pathways for airway diseases (AIRWAYS-ICPs). Eur Respir J, 44 (2), pp. 304-323. | Citations: 99 (Web of Science Lite) | Show Abstract | Read more

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Bafadhel M, Davies L, Calverley PMA, Aaron SD, Brightling CE, Pavord ID. 2014. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J, 44 (3), pp. 789-791. | Citations: 66 (Scopus) | Read more

Newby C, Agbetile J, Hargadon B, Monteiro W, Green R, Pavord I, Brightling C, Siddiqui S. 2014. Lung function decline and variable airway inflammatory pattern: longitudinal analysis of severe asthma. J Allergy Clin Immunol, 134 (2), pp. 287-294. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Eosinophilic airway inflammation measured by using induced sputum is an important treatment stratification tool in patients with severe asthma. In addition, sputum eosinophilia has been shown to be associated with severe exacerbations and airflow limitation. OBJECTIVES: We sought to identify whether eosinophilic inflammation in sputum is associated with FEV₁ decrease in patients with severe asthma and whether we could identify subgroups of decrease behavior based on the variation of eosinophilic airway inflammation over time. METHODS: Ninety-seven patients with severe asthma from the Glenfield Asthma Cohort were followed up with scheduled 3-month visits; the median duration of follow-up and number of visits was 6 years (interquartile range, 5.6-7.6 years) and 2.7 visits per year. Induced sputum was analyzed for eosinophilic inflammation at scheduled visits. Linear mixed-effects models were used to identify variables associated with lung function and overall decrease. In addition, using individual patients' mean and SD sputum eosinophil percentages over time, a 2-step cluster analysis was performed to identify patient clusters with different rates of decrease. RESULTS: FEV₁ decrease was -25.7 mL/y in the overall population. Postbronchodilator FEV₁ was also dependent on exacerbations, age of onset, height, age, sex, and log10 sputum eosinophil percentages (P < .001). Three decrease patient clusters were identified: (1) noneosinophilic with low variation (mean decrease, -14.0 mL/y), (2) eosinophilic with high variation (mean decrease, -40.9 mL/y), and (3) hypereosinophilic with low variation (mean decrease in lung function, -19.2 mL/y). CONCLUSION: The amplitude of sputum eosinophilia was associated with postbronchodilator FEV₁ in asthmatic patients. In contrast, high variability rather than the amplitude at baseline or over time of sputum eosinophils was associated with accelerated FEV₁ decrease.

Bush A, Pavord I. 2014. Highlights from this issue Thorax, 69 (6), pp. i-i. | Read more

Bjermer L, Alving K, Diamant Z, Magnussen H, Pavord I, Piacentini G, Price D, Roche N, Sastre J, Thomas M, Usmani O. 2014. Current evidence and future research needs for FeNO measurement in respiratory diseases Respiratory Medicine, 108 (6), pp. 830-841. | Citations: 76 (Scopus) | Show Abstract | Read more

Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases. © 2014 Elsevier Ltd. All rights reserved.

Gonem S, Scadding A, Soares M, Singapuri A, Gustafsson P, Ohri C, Range S, Brightling CE, Pavord I, Horsley A, Siddiqui S. 2014. Lung clearance index in adults with non-cystic fibrosis bronchiectasis. Respir Res, 15 (1), pp. 59. | Citations: 17 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Lung 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). METHODS: Forty-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. RESULTS: LCI 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. CONCLUSION: LCI 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.

Gonem S, Scadding A, Soares M, Singapuri A, Gustafsson P, Ohri C, Range S, Brightling CE, Pavord I, Horsley A, Siddiqui S. 2014. Lung clearance index in adults with non-cystic fibrosis bronchiectasis Respiratory Research, 15 (1), | Citations: 18 (Scopus) | Show Abstract | Read more

Background: Lung 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).Methods: Forty-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.Results: LCI 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.Conclusion: LCI 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. © 2014 Gonem et al.; licensee BioMed Central Ltd.

Bush A, Pavord I. 2014. Year in review 2013: paediatric and adult clinical studies. Thorax, 69 (4), pp. 309-311. | Citations: 2 (Scopus) | Read more

Bush A, Pavord I. 2014. Highlights from this issue Thorax, 69 (4), pp. i-i. | Read more

Jones RCM, Price D, Ryan D, Sims EJ, von Ziegenweidt J, Mascarenhas L, Burden A, Halpin DMG, Winter R, Hill S et al. 2014. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med, 2 (4), pp. 267-276. | Citations: 60 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Patterns of health-care use and comorbidities present in patients in the period before diagnosis of chronic obstructive pulmonary disease (COPD) are unknown. We investigated these factors to inform future case-finding strategies. METHODS: We did a retrospective analysis of a clinical cohort in the UK with data from Jan 1, 1990 to Dec 31, 2009 (General Practice Research Database and Optimum Patient Care Research Database). We assessed patients aged 40 years or older who had an electronically coded diagnosis of COPD in their primary care records and had a minimum of 3 years of continuous practice data for COPD (2 years before diagnosis up to a maximum of 20 years, and 1 year after diagnosis) and at least two prescriptions for COPD since diagnosis. We identified missed opportunites to diagnose COPD from routinely collected patient data by reviewing patterns of health-care use and comorbidities present before diagnosis. We assessed patterns of health-care use in terms of lower respiratory consultations (infective and non-infective), lower respiratory consultations with a course of antibiotics or oral steroids, and chest radiography. If these events did not lead to a diagnosis of COPD, they were deemed to be missed opportunities. This study is registered with ClinicalTrials.gov, number NCT01655667. FINDINGS: We assessed data for 38,859 patients. Opportunities for diagnosis were missed in 32,900 (85%) of 38,859 patients in the 5 years immediately preceding diagnosis of COPD; in 12,856 (58%) of 22,286 in the 6-10 years before diagnosis, in 3943 (42%) of 9351 in the 11-15 years before diagnosis; and in 95 (8%) of 1167 in the 16-20 years before diagnosis. Between 1990 and 2009, we noted decreases in the age at diagnosis (0·05 years of age per year, 95% CI 0·03-0·07) and yearly frequency of lower respiratory prescribing consultations (rate ratio 0·982 opportunities per year, 95% CI 0·979-0·985). Prevalence of all comorbidities present at COPD diagnosis increased except for asthma and bronchiectasis, which decreased between 1990 and 2007, from 281 (33·4%) of 842 patients to 451 of 1465 (30·8%) for asthma, and from 53 of 842 (6·3%) to 53 of 1465 (3·6%) for bronchiectasis. In the 2 years before diagnosis, of 6897 patients who had had a chest radiography, only 2296 (33%) also had spirometry. INTERPRETATION: Opportunities to diagnose COPD at an earlier stage are being missed, and could be improved by case-finding in patients with lower respiratory tract symptoms and concordant long-term comorbidities. FUNDING: UK Department of Health, Research in Real Life.

Bush A, Pavord I. 2014. A tale of two letters. Thorax, 69 (3), pp. 291. | Read more

Gupta S, Hartley R, Khan UT, Singapuri A, Hargadon B, Monteiro W, Pavord ID, Sousa AR, Marshall RP, Subramanian D et al. 2014. Quantitative computed tomography-derived clusters: redefining airway remodeling in asthmatic patients. J Allergy Clin Immunol, 133 (3), pp. 729-38.e18. | Citations: 44 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)-assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms. OBJECTIVES: The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes. METHODS: Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes. RESULTS: Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm(3) [SD, 112.6 mm(3)], 259.0 mm(3) [SD, 53.3 mm(3)], 366.4 mm(3) [SD, 195.3 mm(3)], respectively; P = .007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P = .04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P = .007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects. CONCLUSIONS: Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies.

Bush A, Pavord I. 2014. Highlights from this issue Thorax, 69 (3), pp. i-i. | Read more

Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W, Bradding P, Green RH, Wardlaw AJ, Ortega H, Pavord ID. 2014. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: A 12-month follow-up analysis Journal of Allergy and Clinical Immunology, 133 (3), pp. 921-923. | Read more

Gupta S, Hartley R, Khan UT, Singapuri A, Hargadon B, Monteiro W, Pavord ID, Siddiqui S, Brightling CE, Raj V et al. 2014. Quantitative computed tomography-derived clusters: Redefining airway remodeling in asthmatic patients Journal of Allergy and Clinical Immunology, 133 (3), | Citations: 1 (Scopus) | Show Abstract | Read more

Background Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)-assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms. Objectives The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes. Methods Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes. Results Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm [SD, 112.6 mm], 259.0 mm [SD, 53.3 mm], 366.4 mm [SD, 195.3 mm], respectively; P =.007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P =.04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P =.007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects. Conclusions Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies. © 2013 American Academy of Allergy, Asthma and Immunology.

Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W, Bradding P, Green RH, Wardlaw AJ, Ortega H, Pavord ID. 2014. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: A 12-month follow-up analysis Journal of Allergy and Clinical Immunology, 133 (3), pp. 921-923. | Citations: 70 (Scopus) | Read more

Gupta S, Hartley R, Khan UT, Singapuri A, Hargadon B, Monteiro W, Pavord ID, Sousa AR, Marshall RP, Subramanian D et al. 2014. Quantitative computed tomography-derived clusters: Redefining airway remodeling in asthmatic patients Journal of Allergy and Clinical Immunology, 133 (3), | Citations: 50 (Scopus) | Show Abstract | Read more

Background Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)-assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms. Objectives The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes. Methods Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes. Results Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm3[SD, 112.6 mm3], 259.0 mm3[SD, 53.3 mm3], 366.4 mm3[SD, 195.3 mm3], respectively; P =.007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P =.04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P =.007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects. Conclusions Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies. © 2013 American Academy of Allergy, Asthma and Immunology.

Bjermer L, Alving K, Diamant Z, Magnussen H, Pavord I, Piacentini G, Price D, Roche N, Sastre J, Thomas M, Usmani O. 2014. Current evidence and future research needs for FeNO measurement in respiratory diseases. Respir Med, 108 (6), pp. 830-841. | Citations: 69 (Web of Science Lite) | Show Abstract | Read more

Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases.

Siva R, Bafadhel M, Monteiro W, Brightling CE, Pavord ID. 2014. Effect of levofloxacin on neutrophilic airway inflammation in stable COPD: a randomized, double-blind, placebo-controlled trial. Int J Chron Obstruct Pulmon Dis, 9 pp. 179-186. | Citations: 7 (Web of Science Lite) | Show Abstract | Read more

RATIONALE: Airway inflammation persists after smoking cessation in established chronic obstructive pulmonary disease (COPD), suggesting that other factors drive the airway inflammatory response. OBJECTIVES: We tested the hypothesis that high levels of bacterial colonization are associated with increased levels of neutrophilic airway inflammation in stable COPD by examining the cross-sectional relationship between these measurements and by conducting a randomized, double-blind, placebo-controlled study of the effect of levofloxacin in patients with stable COPD. METHODS: Patients were randomized to receive either levofloxacin 500 mg daily or placebo for 7 days and underwent sputum induction for a differential cell count and quantitative bacterial analysis at baseline and at days 7, 14, and 28. RESULTS: Sputum percentage neutrophil count correlated with airway bacterial load at baseline (r=0.56; P=0.003). Levofloxacin reduced bacterial load compared with placebo by 4.9-fold (95% confidence interval, 1.4-25.7; P=0.02) at day 7 but had no effect at any point on any marker of neutrophilic airway inflammation. In patients with a baseline bacterial load of more than 10(6) cfu/mL, levofloxacin treatment was associated with a 26.5% (95% confidence interval, 1.8%-51.3%; P=0.04) greater reduction in the percentage neutrophil count compared with placebo at day 7. Change in percentage neutrophil count correlated significantly with baseline airway bacterial load and change in airway bacterial load. CONCLUSION: In stable COPD, levofloxacin treatment causes a short-term reduction in bacterial load. This is associated with a reduction in neutrophilic airway inflammation in patients with high bacterial loads. Further studies are required to investigate whether this effect is clinically advantageous.

Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W, Bradding P, Green RH, Wardlaw AJ, Ortega H, Pavord ID. 2014. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol, 133 (3), pp. 921-923. | Citations: 68 (Web of Science Lite) | Read more

Pavord ID, Bush A. 2014. Thorax: the prostate years. Thorax, 69 (1), pp. 3-4. | Citations: 1 (European Pubmed Central) | Read more

Vanfleteren LEGW, Kocks JWH, Stone IS, Breyer-Kohansal R, Greulich T, Lacedonia D, Buhl R, Fabbri LM, Pavord ID, Barnes N et al. 2014. Moving from the Oslerian paradigm to the postgenomic era: Are asthma and COPD outdated terms? Thorax, 69 (1), pp. 72-79. | Citations: 39 (Scopus) | Show Abstract | Read more

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms 'asthma' and 'COPD' as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory.

Agbetile J, Bourne M, Fairs A, Hargadon B, Desai D, Broad C, Morley J, Bradding P, Brightling CE, Green RH et al. 2014. Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study) Journal of Allergy and Clinical Immunology, 134 (1), pp. 33-39. | Citations: 38 (Scopus) | Show Abstract | Read more

Background IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment. Objectives We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. Methods Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. Results Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, -0.05 to -0.11), or any of our secondary outcome measures. Conclusion We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control. © 2014 American Academy of Allergy, Asthma and Immunology.

Willson J, Bateman ED, Pavord I, Lloyd A, Krivasi T, Esser D. 2014. Cost effectiveness of tiotropium in patients with asthma poorly controlled on inhaled glucocorticosteroids and long-acting β-agonists Applied Health Economics and Health Policy, 12 (4), pp. 447-459. | Citations: 21 (Scopus) | Show Abstract | Read more

Background: A considerable proportion of patients with asthma remain uncontrolled or symptomatic despite treatment with a high dose of inhaled glucocorticosteroids (ICSs) and long-acting β2-agonists (LABAs). Tiotropium Respimat® added to usual care improves lung function, asthma control, and the frequency of non-severe and severe exacerbations, in a population of adult asthma patients who are uncontrolled despite treatment with ICS/LABA. Objective: This study estimated the cost effectiveness of tiotropium therapy as add-on to usual care in asthma patients that are uncontrolled despite treatment with ICS/LABA combination from the perspective of the UK National Health Service (NHS). Methods: A Markov model was developed which considers levels of asthma control and exacerbations. The model analysed cost and quality-adjusted life-years (QALYs); sensitivity and scenario analyses were also conducted to test the robustness of the base case outcomes. All costs are given at 2012 prices. Results: The model found that in this category of asthma with unmet need, add-on tiotropium therapy generated an incremental 0.24 QALYs and £5,238 costs over a lifetime horizon, resulting in an incremental cost-effectiveness ratio of £21,906 per QALY gained. Sensitivity analysis suggested that findings were most dependent on the costs of managing uncontrolled asthma and the cost of treatment with tiotropium. Conclusion: In this modelled analysis of two clinical trials, tiotropium was found to be cost effective when added to usual care in patients who remain uncontrolled despite treatment with high-dose ICS/LABA. Further research should investigate the long-term treatment effectiveness of tiotropium. © 2014 Springer International Publishing.

Ghebre MA, Bafadhel M, Desai D, Cohen SE, Newbold P, Rapley L, Woods J, Rugman P, Pavord ID, Newby C et al. 2015. Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol, 135 (1), pp. 63-72. | Citations: 62 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. OBJECTIVE: We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis. METHODS: We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD). RESULTS: Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study. CONCLUSIONS: Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.

Barnes PJ, Casale TB, Dahl R, Pavord ID, Wechsler ME. 2014. The Asthma Control Questionnaire as a clinical trial endpoint: Past experience and recommendations for future use Allergy: European Journal of Allergy and Clinical Immunology, 69 (9), pp. 1119-1140. | Citations: 7 (Scopus) | Show Abstract | Read more

The goal of asthma treatment is to control the disease according to guidelines issued by bodies such as the Global Initiative for Asthma. Effective control is dependent upon evaluation of symptoms, initiation of appropriate treatment and minimization of the progressive adverse effects of the disease and its therapies. Although individual outcome measures have been shown to correlate with asthma control, composite endpoints are preferred to enable more accurate and robust monitoring of the health of the individual patient. A number of validated instruments are utilized to capture these component endpoints; however, there is no consensus on the optimal instrument for use in clinical trials. The Asthma Control Questionnaire (ACQ) has been shown to be a valid, reliable instrument that allows accurate and reproducible assessment of asthma control that compares favourably with other commonly used instruments. This analysis provides a summary of the use of ACQ in phase II, III and IV asthma trials. Comparisons between the ACQ and other instruments are also presented. Our analysis suggests that the ACQ is a valid and robust measure for use as a primary or secondary endpoint in future clinical trials. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Newby C, Agbetile J, Hargadon B, Monteiro W, Green R, Pavord I, Brightling C, Siddiqui S. 2014. Lung function decline and variable airway inflammatory pattern: Longitudinal analysis of severe asthma Journal of Allergy and Clinical Immunology, 134 (2), | Citations: 24 (Scopus) | Show Abstract | Read more

Background Eosinophilic airway inflammation measured by using induced sputum is an important treatment stratification tool in patients with severe asthma. In addition, sputum eosinophilia has been shown to be associated with severe exacerbations and airflow limitation. Objectives We sought to identify whether eosinophilic inflammation in sputum is associated with FEV1 decrease in patients with severe asthma and whether we could identify subgroups of decrease behavior based on the variation of eosinophilic airway inflammation over time. Methods Ninety-seven patients with severe asthma from the Glenfield Asthma Cohort were followed up with scheduled 3-month visits; the median duration of follow-up and number of visits was 6 years (interquartile range, 5.6-7.6 years) and 2.7 visits per year. Induced sputum was analyzed for eosinophilic inflammation at scheduled visits. Linear mixed-effects models were used to identify variables associated with lung function and overall decrease. In addition, using individual patients' mean and SD sputum eosinophil percentages over time, a 2-step cluster analysis was performed to identify patient clusters with different rates of decrease. Results FEV1 decrease was -25.7 mL/y in the overall population. Postbronchodilator FEV 1 was also dependent on exacerbations, age of onset, height, age, sex, and log10 sputum eosinophil percentages (P <.001). Three decrease patient clusters were identified: (1) noneosinophilic with low variation (mean decrease, -14.0 mL/y), (2) eosinophilic with high variation (mean decrease, -40.9 mL/y), and (3) hypereosinophilic with low variation (mean decrease in lung function, -19.2 mL/y). Conclusion The amplitude of sputum eosinophilia was associated with postbronchodilator FEV1 in asthmatic patients. In contrast, high variability rather than the amplitude at baseline or over time of sputum eosinophils was associated with accelerated FEV 1 decrease. © 2014 American Academy of Allergy, Asthma and Immunology.

Pavord I, Lassen C, Casale T, Beeh K-M. 2014. Exhaled Nitric Oxide And The Response To Cyt003-Qbg10 In Patients With Persistent Allergic Asthma AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189

Custovic A, Johnston SL, Pavord I, Gaga M, Fabbri L, Bel EH, Le Souëf P, Lötvall J, Demoly P, Akdis CA et al. 2013. EAACI position statement on asthma exacerbations and severe asthma. Allergy, 68 (12), pp. 1520-1531. | Citations: 65 (Scopus) | Show Abstract | Read more

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.

Pavord ID. 2013. Eosinophilic phenotypes of airway disease. Ann Am Thorac Soc, 10 Suppl (Supplement), pp. S143-S149. | Citations: 19 (Scopus) | Show Abstract | Read more

Our understanding of the clinical implications of eosinophilic airway inflammation has increased significantly over the last 20 years, aided by the development of noninvasive means to assess it. This pattern of airway inflammation can occur in a diverse range of airway diseases. It is associated with a positive response to corticosteroids and a high risk of preventable exacerbations. Our new understanding of the role of eosinophilic airway inflammation has paved the way for the clinical development of a number of more specific inhibitors that may become new treatment options. Different definitions, ideas of disease, and adoption of biomarkers that are not well known are necessary to fully realize the potential of these treatments.

Wechsler ME, Laviolette M, Rubin AS, Fiterman J, Lapa E Silva JR, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM et al. 2013. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma Journal of Allergy and Clinical Immunology, 132 (6), | Citations: 146 (Scopus) | Show Abstract | Read more

Background Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. Objective We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. Methods BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.gov NCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. Results One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV1 values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. Conclusions These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β2-agonists. © 2013 American Academy of Allergy, Asthma & Immunology.

Agbetile J, Bourne M, Fairs A, Hargadon B, Desai D, Broad C, Morley J, Bradding P, Brightling CE, Green RH et al. 2014. Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol, 134 (1), pp. 33-39. | Citations: 34 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment. OBJECTIVES: We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. METHODS: Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. RESULTS: Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, -0.05 to -0.11), or any of our secondary outcome measures. CONCLUSION: We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.

Pavord ID, Thomson NC, Niven RM, Corris PA, Chung KF, Cox G, Armstrong B, Shargill NS, Laviolette M, Research in Severe Asthma Trial Study Group. 2013. Safety of bronchial thermoplasty in patients with severe refractory asthma. Ann Allergy Asthma Immunol, 111 (5), pp. 402-407. | Citations: 48 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Patients with severe refractory asthma treated with bronchial thermoplasty (BT), a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle, were followed up for 5 years to evaluate long-term safety of this procedure. OBJECTIVES: To assess long-term safety of BT for 5 years. METHODS: Patients with asthma aged 18 to 65 years requiring high-dose inhaled corticosteroids (ICSs) (>750 μg/d of fluticasone propionate or equivalent) and long-acting β2-agonists (LABAs) (at least 100 μg/d of salmeterol or equivalent), with or without oral prednisone (≤30 mg/d), leukotriene modifiers, theophylline, or other asthma controller medications were enrolled in the Research in Severe Asthma (RISA) Trial. Patients had a prebronchodilator forced expiratory volume in 1 second of 50% or more of predicted, demonstrated methacholine airway hyperresponsiveness, had uncontrolled symptoms despite taking maintenance medication, abstained from smoking for 1 year or greater, and had a smoking history of less than 10 pack-years. RESULTS: Fourteen patients (of the 15 who received active treatment in the RISA Trial) participated in the long-term follow-up study for 5 years. The rate of respiratory adverse events (AEs per patient per year) was 1.4, 2.4, 1.7, and 2.4, respectively, in years 2 to 5 after BT. There was a decrease in hospitalizations and emergency department visits for respiratory symptoms in each of years 1, 2, 3, 4, and 5 compared with the year before BT treatment. Measures of lung function showed no deterioration for 5 years. CONCLUSION: Our findings suggest that BT is safe for 5 years after BT in patients with severe refractory asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00401986.

Bush A, Pavord I. 2013. Highlights from this issue Thorax, 68 (11), pp. i-i. | Read more

Pavord ID, Thomson NC, Niven RM, Corris PA, Chung KF, Cox G, Armstrong B, Shargill NS, Laviolette M. 2013. Safety of bronchial thermoplasty in patients with severe refractory asthma Annals of Allergy, Asthma and Immunology, 111 (5), pp. 402-407. | Citations: 55 (Scopus) | Show Abstract | Read more

Background: Patients with severe refractory asthma treated with bronchial thermoplasty (BT), a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle, were followed up for 5 years to evaluate long-term safety of this procedure. Objectives: To assess long-term safety of BT for 5 years. Methods: Patients with asthma aged 18 to 65 years requiring high-dose inhaled corticosteroids (ICSs) (>750 μg/d of fluticasone propionate or equivalent) and long-acting β2-agonists (LABAs) (at least 100 μg/d of salmeterol or equivalent), with or without oral prednisone (≤30 mg/d), leukotriene modifiers, theophylline, or other asthma controller medications were enrolled in the Research in Severe Asthma (RISA) Trial. Patients had a prebronchodilator forced expiratory volume in 1 second of 50% or more of predicted, demonstrated methacholine airway hyperresponsiveness, had uncontrolled symptoms despite taking maintenance medication, abstained from smoking for 1 year or greater, and had a smoking history of less than 10 pack-years. Results: Fourteen patients (of the 15 who received active treatment in the RISA Trial) participated in the long-term follow-up study for 5 years. The rate of respiratory adverse events (AEs per patient per year) was 1.4, 2.4, 1.7, and 2.4, respectively, in years 2 to 5 after BT. There was a decrease in hospitalizations and emergency department visits for respiratory symptoms in each of years 1, 2, 3, 4, and 5 compared with the year before BT treatment. Measures of lung function showed no deterioration for 5 years. Conclusion: Our findings suggest that BT is safe for 5 years after BT in patients with severe refractory asthma. Trial Registration: clinicaltrials.gov Identifier: NCT00401986. © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Godlee F, Malone R, Timmis A, Otto C, Bush A, Pavord I, Groves T. 2013. Journal policy on research funded by the tobacco industry BMJ, 347 (oct15 7), pp. f5193-f5193. | Citations: 25 (Scopus) | Read more

Godlee F, Malone R, Timmis A, Otto C, Bush A, Pavord I, Groves T. 2013. Journal policy on research funded by the tobacco industry. Thorax, 68 (12), pp. 1090-1091. | Citations: 3 (Web of Science Lite) | Read more

Godlee F, Malone R, Timmis A, Otto C, Bush A, Pavord I, Groves T. 2014. Journal policy on research funded by the tobacco industry. Heart, 100 (1), pp. 2-3. | Read more

Pavord ID, Bafadhel M. 2013. Exhaled nitric oxide and blood eosinophilia: independent markers of preventable risk. J Allergy Clin Immunol, 132 (4), pp. 828-829. | Citations: 21 (Web of Science Lite) | Read more

Berair R, Pavord ID. 2013. Rationale and clinical results of inhibiting interleukin-5 for the treatment of severe asthma. Curr Allergy Asthma Rep, 13 (5), pp. 469-476. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

Severe asthma is responsible for considerable morbidity and a high proportion of the healthcare costs attributable to asthma. Management is not straightforward as the clinical, pathological and physiological features are heterogeneous and the relationships between these features are poorly understood. In recent years significant progress has been made in understanding this heterogeneity and eosinophilic asthma has emerged as a potentially clinically important phenotype because treatment with monoclonal antibodies against IL-5 is effective. This has required a change in our understanding of the role of eosinophilic airway inflammation in airways disease and the developments of reliable biomarkers of eosinophilic airway inflammation. We will review these developments and describe the clinical experience so far with treatment with monoclonal antibiotics against IL-5.

Berair R, Pavord ID. 2013. Rationale and clinical results of inhibiting interleukin-5 for the treatment of severe asthma Current Allergy and Asthma Reports, 13 (5), pp. 469-476. | Citations: 10 (Scopus) | Show Abstract | Read more

Severe asthma is responsible for considerable morbidity and a high proportion of the healthcare costs attributable to asthma. Management is not straightforward as the clinical, pathological and physiological features are heterogeneous and the relationships between these features are poorly understood. In recent years significant progress has been made in understanding this heterogeneity and eosinophilic asthma has emerged as a potentially clinically important phenotype because treatment with monoclonal antibodies against IL-5 is effective. This has required a change in our understanding of the role of eosinophilic airway inflammation in airways disease and the developments of reliable biomarkers of eosinophilic airway inflammation. We will review these developments and describe the clinical experience so far with treatment with monoclonal antibiotics against IL-5. © 2013 Springer Science+Business Media New York.

Pavord ID, Bafadhel M. 2013. Exhaled nitric oxide and blood eosinophilia: Independent markers of preventable risk Journal of Allergy and Clinical Immunology, 132 (4), pp. 828-829. | Citations: 21 (Scopus) | Read more

Bush A, Pavord I. 2013. Eight o'clock ROCK! Thorax, 68 (9), pp. 802. | Read more

Blakey JD, Woolnough K, Fellows J, Walker S, Thomas M, Pavord ID. 2013. Assessing the risk of attack in the management of asthma: A review and proposal for revision of the current control-centred paradigm Primary Care Respiratory Journal, 22 (3), pp. 344-352. | Citations: 14 (Scopus) | Show Abstract | Read more

Asthma guidelines focus on day-to-day control of symptoms. However, asthma attacks remain common. They continue to cause mortality and considerable morbidity, and are a major financial burden to the UK National Health Service (NHS) and the wider community. Asthma attacks have chronic consequences, being associated with loss of lung function and significant psychological morbidity. In this article we argue that addressing daily symptom control is only one aspect of asthma treatment, and that there should be a more explicit focus on reducing the risk of asthma attacks. Management of future risk by general practitioners is already central to other conditions such as ischaemic heart disease and chronic renal impairment. We therefore propose a revised approach that separately considers the related domains of daily control and future risk of asthma attack. We believe this approach will have advantages over the current 'stepwise' approach to asthma management. It should encourage individualised treatment, including non-pharmacological measures, and thus may lead to more efficacious and less harmful management strategies. We speculate that this type of approach has the potential to reduce morbidity and healthcare costs related to asthma attacks. © 2013 Primary Care Respiratory Society UK. All rights reserved.

Bush A, Pavord I. 2013. Highlights from this issue THORAX, 68 (9), pp. i-i. | Read more

Wechsler ME, Laviolette M, Rubin AS, Fiterman J, Lapa e Silva JR, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM et al. 2013. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol, 132 (6), pp. 1295-1302. | Citations: 136 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE: We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS: BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS: One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV₁ values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS: These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β₂-agonists.

Straumann A, Haldar P, Pavord ID, Wardlaw AJ, Busse WW, Molfino NA, Kolbeck R, Shin MK, Bochner BS, Cools J. 2013. Antieosinophil Therapeutics pp. 577-605. | Read more

Blakey JD, Woolnough K, Fellows J, Walker S, Thomas M, Pavord ID. 2013. Assessing the risk of attack in the management of asthma: a review and proposal for revision of the current control-centred paradigm. Prim Care Respir J, 22 (3), pp. 344-352. | Citations: 14 (Web of Science Lite) | Show Abstract | Read more

Asthma guidelines focus on day-to-day control of symptoms. However, asthma attacks remain common. They continue to cause mortality and considerable morbidity, and are a major financial burden to the UK National Health Service (NHS) and the wider community. Asthma attacks have chronic consequences, being associated with loss of lung function and significant psychological morbidity. In this article we argue that addressing daily symptom control is only one aspect of asthma treatment, and that there should be a more explicit focus on reducing the risk of asthma attacks. Management of future risk by general practitioners is already central to other conditions such as ischaemic heart disease and chronic renal impairment. We therefore propose a revised approach that separately considers the related domains of daily control and future risk of asthma attack. We believe this approach will have advantages over the current 'stepwise' approach to asthma management. It should encourage individualised treatment, including non-pharmacological measures, and thus may lead to more efficacious and less harmful management strategies. We speculate that this type of approach has the potential to reduce morbidity and healthcare costs related to asthma attacks.

Quint JK, Bush A, Pavord I. 2013. Keeping 'a chest' of the literature. Thorax, 68 (7), pp. 610. | Read more

Vanfleteren LEGW, Kocks JWH, Stone IS, Breyer-Kohansal R, Greulich T, Lacedonia D, Buhl R, Fabbri LM, Pavord ID, Barnes N et al. 2014. Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms? Thorax, 69 (1), pp. 72-79. | Citations: 37 (Web of Science Lite) | Show Abstract | Read more

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms 'asthma' and 'COPD' as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory.

Bruton A, Kirby S, Arden-Close E, Taylor L, Webley F, George S, Yardley L, Price D, Moore M, Little P et al. 2013. The BREATHE study: Breathing REtraining for Asthma--Trial of Home Exercises. a protocol summary of a randomised controlled trial. Prim Care Respir J, 22 (2), pp. PS1-PS7. | Citations: 8 (European Pubmed Central) | Read more

Bush A, Pavord I. 2013. President elect kidnapped. Tsar very much. Thorax, 68 (5), pp. 409. | Read more

Nolte H, Pavord I, Backer V, Spector S, Shekar T, Gates D, Nair P, Hargreave F. 2013. Dose-dependent anti-inflammatory effect of inhaled mometasone furoate/formoterol in subjects with asthma. Respir Med, 107 (5), pp. 656-664. | Citations: 20 (Scopus) | Show Abstract | Read more

OBJECTIVE: A well-controlled study in patients with allergic asthma was warranted to assess dose-dependency between fractional concentration of exhaled nitric oxide (FeNO) and sputum eosinophils to a combination of an inhaled corticosteroid plus a long-acting β2-agonist. We sought to characterize the dose-dependency of mometasone furoate/formoterol (MF/F) using FeNO and sputum eosinophil percentage as surrogates of airway inflammation in subjects with allergic asthma. METHODS: Following a 2-week, open-label run-in, 93 subjects (≥12 y) using only short-acting beta agonist reliever medication as needed, were randomized to twice daily (BID) placebo; MF/F 100/10 μg, 200/10 μg, or 400/10 μg (via pressurized metered-dose inhaler [MDI]); MF-MDI 200 μg; or MF 200 μg via dry powder inhaler (DPI) during a 2-week, double-blind treatment period. RESULTS: All active treatments demonstrated significant percentage reductions from baseline in FeNO compared with placebo at all time points (P ≤ 0.034). At endpoint, mean MF/F treatment group FeNO reductions ranged from -35.3% to -61.4%. Sputum eosinophil percentage reductions from baseline were significant compared with placebo for the MF/F 200/10 μg, MF/F 400/10 μg, and MF-DPI 200 μg groups at endpoint (P ≤ 0.023). Escalating MF/F doses significantly reduced both FeNO (P ≤ 0.001) and sputum eosinophil (P ≤ 0.022) levels in a dose-dependent manner at all time points. All treatments were well tolerated; no serious adverse events were observed. CONCLUSION: All 3 MF/F doses demonstrated pronounced, clinically meaningful, dose-dependent reductions in FeNO, with reduced sputum eosinophil levels for MF/F 200/10 μg and MF/F 400/10 μg. These findings suggest both inflammatory markers may be useful in assessing corticosteroid responsiveness in asthma patients, and perhaps identifying the same asthma subphenotype. Clinical Trials.gov: NCT00635882.

Siva R, Birring SS, Berry M, Rowbottom A, Pavord ID. 2013. Peptic ulceration, Helicobacter pylori seropositivity and chronic obstructive pulmonary disease. Respirology, 18 (4), pp. 728-731. | Citations: 19 (Scopus) | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: We have suggested that chronic inflammation of other foregut derivatives might be associated with airway inflammation and amplification of the response to inhaled stimuli such as cigarette smoke leading to chronic obstructive pulmonary disease (COPD). One of the commonest causes of chronic foregut inflammation is gastritis secondary to Helicobacter Pylori infection. We tested the hypothesis that peptic ulceration and H. Pylori seropositivity are associated with COPD independently of other shared risk factors. METHODS: We reviewed primary care medical records and performed full lung function tests on 329 miners seen over 2 years as part of a compensation scheme. We also performed H. Pylori serology in patients with varying degrees of severity of COPD compared with a matched control population. RESULTS: The prevalence of peptic ulcer disease in the groups classed as normal, chronic bronchitis, mild, moderate and severe COPD was 3.2%, 16.2%, 21.4%, 42.4% and 56.2%, respectively. There was a strong and independent relationship between the presence of peptic ulcer disease and percent of predicted forced expiratory volume in 1 s (-13.3%; 95% confidence interval: 6.7-19.9; P < 0.001) and forced expiratory volume in 1 s/forced vital capacity ratio (-5.06%; 95% confidence interval: 1.8-8.2; P < 0.001). Positive H. pylori serology was present in 54.7% of 58 patients with COPD and 23.5% of 17 controls (P = 0.026). CONCLUSIONS: Our findings suggest a relationship between peptic ulcer disease and COPD that is more that just a shared susceptibility to different environmental stimuli.

Lee KK, Matos S, Evans DH, White P, Pavord ID, Birring SS. 2013. A longitudinal assessment of acute cough. Am J Respir Crit Care Med, 187 (9), pp. 991-997. | Citations: 24 (Scopus) | Show Abstract | Read more

RATIONALE: Cough can be assessed with visual analog scales (VAS), health status measures, and 24-hour cough frequency monitors (CF(24)). Evidence for their measurement properties in acute cough caused by upper respiratory tract infection (URTI) and longitudinal data is limited. OBJECTIVES: To assess cough longitudinally in URTI with subjective and objective outcome measures and determine sample size for future studies. METHODS: Thirty-three previously healthy subjects with URTI completed cough VAS, Leicester Cough Questionnaire (LCQ-acute), and CF(24) monitoring (Leicester Cough Monitor) on three occasions, 4 days apart. Changes in subjects' condition were assessed with a global rating of change questionnaire. The potential for baseline first-hour cough frequency (CF(1)), VAS, and LCQ to identify low CF(24) was assessed. MEASUREMENTS AND MAIN RESULTS: Mean ± SD duration of cough at visit 1 was 4.1 ± 2.5 days. Geometric mean ± log SD baseline CF(24) and median (interquartile range) cough bouts were high (14.9 ± 0.4 coughs/h and 85 [39-195] bouts/24 h). Health status was severely impaired. There was a significant reduction in CF(24) and VAS, and improvement in LCQ, from visits 1-3. At visit 3, CF(24) remained above normal limits in 52% of subjects. The smallest changes in CF(24), LCQ, and VAS that subjects perceived important were 54%, 2- and 17-mm change from baseline, respectively. The sample sizes required for parallel group studies to detect these changes are 27, 51, and 25 subjects per group, respectively. CF(1) (<20.5 coughs/h) was predictive of low CF(24). CONCLUSIONS: CF(24), VAS, and LCQ are responsive outcome tools for the assessment of acute cough. The smallest change in cough frequency perceived important by subjects is 54%. The sample sizes required for future studies are modest and achievable.

Desai D, Newby C, Symon FA, Haldar P, Shah S, Gupta S, Bafadhel M, Singapuri A, Siddiqui S, Woods J et al. 2013. Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Am J Respir Crit Care Med, 188 (6), pp. 657-663. | Citations: 90 (Scopus) | Show Abstract | Read more

RATIONALE: The relationship between airway inflammation and obesity in severe asthma is poorly understood. OBJECTIVES: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma. METHODS: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index. MEASUREMENTS AND MAIN RESULTS: Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2-2.6]) compared with overweight (1.1 [0.8-1.3]; P = 0.025) and lean (0.9 [0.6-1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8-31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4-14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index. CONCLUSIONS: Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.

Yousaf N, Montinero W, Birring SS, Pavord ID. 2013. The long term outcome of patients with unexplained chronic cough. Respir Med, 107 (3), pp. 408-412. | Citations: 9 (Scopus) | Show Abstract | Read more

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.

Pavord ID. 2013. Complex airway disease: an approach to assessment and management. Lancet Respir Med, 1 (1), pp. 84-90. | Citations: 15 (Web of Science Lite) | Show Abstract | Read more

Research into new treatments for airway disease focuses on severe disease because morbidity, mortality, and health-care costs are substantial and the unmet need is greatest. One reason why outcomes are poor in these patients could be that the clinical expression of disease is heterogeneous and difficult to classify. As a result, guideline-based management algorithms fail. Additionally, difficulties with disease classification and misconceptions about the relation between different aspects of severe airway disease have hindered new drug development. A potential solution is to use a new approach to assess severe airway disease, which moves the diagnostic focus from categorisation of patients to identification and characterisation of the main drivers of disease. This approach will help rather than hinder identification of clinically important phenotypes of disease and will facilitate the development of new phenotype-specific treatment options.

Bush A, Pavord ID. 2013. Omalizumab: NICE to USE you, to LOSE you NICE. Thorax, 68 (1), pp. 7-8. | Citations: 7 (European Pubmed Central) | Read more

Bush A, Pavord ID. 2013. Thorax: the Cappuccino years. Thorax, 68 (1), pp. 1-4. | Citations: 8 (European Pubmed Central) | Read more

Yousaf N, Monteiro W, Matos S, Birring SS, Pavord ID. 2013. Cough frequency in health and disease. Eur Respir J, 41 (1), pp. 241-243. | Citations: 17 (Scopus) | Read more

Godlee F, Malone R, Timmis A, Otto C, Bush A, Pavord I, Groves T. 2013. Journal policy on research funded by the tobacco industry. BMJ, 347 pp. f5193. | Citations: 17 (Web of Science Lite) | Read more

Gonem S, Raj V, Wardlaw AJ, Pavord ID, Green R, Siddiqui S. 2012. Phenotyping airways disease: an A to E approach. Clin Exp Allergy, 42 (12), pp. 1664-1683. | Citations: 28 (Scopus) | Show Abstract | Read more

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.

Lee KK, Savani A, Matos S, Evans DH, Pavord ID, Birring SS. 2012. Four-hour cough frequency monitoring in chronic cough. Chest, 142 (5), pp. 1237-1243. | Citations: 10 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: The recent development of automated cough monitors has enabled objective assessment of cough frequency. A study was undertaken to determine whether short-duration recordings( < 6 h) accurately reflect 24-h cough frequency and to investigate their responsiveness. METHODS: One hundred adults with chronic cough underwent 24-h cough frequency monitoring with the Leicester Cough Monitor and completed cough visual analog scales (VASs) and the Leicester Cough Questionnaire (LCQ). Cough recordings were analyzed using customized software to derive cough frequencies from 1 to 6 h and 24-h recordings. Responsiveness was assessed with repeat assessments following therapeutic trials. RESULTS: The median (interquartile range) 24-h cough frequency was 11.5 (5.8-26.6) coughs/h. Four hours was considered the shortest recording duration that represented 24-h cough frequency( ρ= 0.9, P ≤ .001). Median 4-h cough frequency was 16.6 (7.3-36.8) coughs/h. Both 4-h and 24-h cough frequency correlated moderately with cough VAS ( ρ= 0.49, P ≤ .01 and ρ= 0.44, P ≤ .01)and LCQ ( ρ = - 0.48, P ≤ .01; ρ = - 0.50, P ≤ .01). Four-hour cough frequency was responsive to improvements in cough severity following trials of therapy. CONCLUSIONS: Four-hour cough frequency correlates highly with 24-h cough frequency recordings and relates equally well with subjective measures in chronic cough. Short-duration cough monitoring could be a practical tool to validate the presence of cough and assess response to trials of therapy in the clinic setting.

Pavord ID. 2012. Asthma phenotypes. Semin Respir Crit Care Med, 33 (6), pp. 645-652. | Citations: 3 (European Pubmed Central) | Show Abstract | Read more

The identification of phenotypes of asthma has a long history, but previous classifications have not identified clinically important differences in pathology, natural history, or treatment response. Progress has accelerated recently, fueled by the development of new techniques to assess airway disease, particularly noninvasive techniques to assess airway inflammation. This article discusses evidence that a simple subdivision of patients into eosinophilic and noneosinophilic asthma is clinically important because it identifies groups with markedly different responses to corticosteroids and other drugs that manipulate the Th-2 (T-helper) pathway. All classification systems suffer from potential bias given that different disease variables are subjectively weighted. There has been increasing interest in the application of mathematical techniques such as factor analysis and cluster analysis to organize and group large amounts of interrelated data in an unbiased way. This article discusses attempts to do this in asthma and speculates on the clinical implications of this new information.

Shaw D, Green R, Berry M, Mellor S, Hargadon B, Shelley M, McKenna S, Thomas M, Pavord I. 2012. A cross-sectional study of patterns of airway dysfunction, symptoms and morbidity in primary care asthma. Prim Care Respir J, 21 (3), pp. 283-287. | Citations: 20 (Scopus) | Show Abstract | Read more

BACKGROUND: Most patients with asthma are managed exclusively in primary care. Little is known about the patterns of airway dysfunction in these patients and how these relate to other aspects of the disease. AIMS: We set out to assess this in a cross-sectional study of 262 patients. METHODS: Symptoms, spirometry, airway responsiveness, reversibility, and airway inflammation were all assessed. Exacerbations requiring oral corticosteroids in the preceding year were enumerated. RESULTS: Patients had heterogeneous patterns of airway dysfunction. Those with a post-bronchodilator forced expiratory volume in 1 sec/ forced vital capacity ratio of <0.7 had more exacerbations in the previous year (2.2 vs. 0.8; mean difference 1.4; 95% CI 0.4 to 2.4; p=0.007). Patients with normal results had less inflammation (proportion with a sputum eosinophil count of >1.9%, 20% vs. 48%, χ²=14.8, df=3; p<0.001) and fewer exacerbations (0.5 vs. 1.4; mean difference -0.9; 95% CI -1.4 to -0.4; p=0.001) but similar symptom scores (6.2 vs. 6.9; p=0.2) compared with patients with any abnormality. CONCLUSIONS: Patients with a diagnosis of asthma have mixed patterns of physiological impairment; many have no airflow obstruction or airway hyper-responsiveness. The physiological characterisation of asthma is not related to symptoms and is of little value in predicting exacerbations or eosinophilic airway inflammation.

Martin N, Ruddick A, Arthur GK, Wan H, Woodman L, Brightling CE, Jones DJL, Pavord ID, Bradding P. 2012. Primary human airway epithelial cell-dependent inhibition of human lung mast cell degranulation. PLoS One, 7 (8), pp. e43545. | Citations: 21 (Scopus) | Show Abstract | Read more

INTRODUCTION: Chronic mast cell activation is a characteristic feature of asthma. BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. The aim of this study was to examine the regulation of HLMC degranulation by primary AEC from healthy and asthmatic subjects, and investigate further the inhibitory mechanism. METHODS: HLMC were co-cultured with both BEAS-2B and primary AEC grown as monolayers or air-liquid interface (ALI) cultures. RESULTS: Both constitutive and IgE-dependent HLMC histamine release were attenuated by BEAS-2B, primary AEC monolayers and ALI cultures. This occurred in the absence of HLMC-AEC contact indicating the presence of a soluble factor. Unlike healthy ALI AEC, asthmatic ALI-AEC did not significantly reduce constitutive histamine release. AEC inhibitory activity was transferable in primary AEC monolayer supernatant, but less active than with Transwell co-culture, suggesting that the inhibitory factor was labile. The AEC inhibitory effects were attenuated by both AEC wounding and pertussis toxin, indicating the involvement of a G(0)/G(i) receptor coupled mechanism. Solid phase extraction of lipids (<10 kDa) removed the AEC inhibitory activity. The lipid derivatives resolving D1 and D2 and lipoxin A(4) attenuated HLMC histamine release in a dose-dependent fashion but were not detectable in co-culture supernatants. CONCLUSIONS: Primary AEC suppress HLMC constitutive and IgE-dependent histamine secretion through the release of a soluble, labile lipid mediator(s) that signals through the G(0)/G(i) receptor coupled mechanism. Manipulation of this interaction may have a significant therapeutic role in asthma.

Green RH, Pavord I. 2012. Stability of inflammatory phenotypes in asthma. Thorax, 67 (8), pp. 665-667. | Citations: 14 (Web of Science Lite) | Read more

Murphy AC, Proeschal A, Brightling CE, Wardlaw AJ, Pavord I, Bradding P, Green RH. 2012. The relationship between clinical outcomes and medication adherence in difficult-to-control asthma. Thorax, 67 (8), pp. 751-753. | Citations: 92 (Scopus) | Show Abstract | Read more

Medication non-adherence and the clinical implications in difficult-to-control asthma were audited. Prescription issue data from 115 patients identified sub-optimal adherence (<80%) in 65% of patients on inhaled corticosteroids (ICS) or combined ICS/long-acting β2 agonist (LABA). In those using separate ICS and LABA, adherence to LABA (50%) was significantly better than to ICS (14.3%). Patients with sub-optimal ICS adherence had reduced FEV(1) and higher sputum eosinophil counts. Adherence ratio was an independent predictor of previous ventilation for acute severe asthma (p=0.008). The majority of patients with difficult-to-control asthma are non-adherent with their asthma medication. Non-adherence is correlated with poor clinical outcomes.

Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. 2012. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet, 380 (9842), pp. 651-659. | Citations: 828 (Scopus) | Show Abstract | Read more

BACKGROUND: Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. METHODS: We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. FINDINGS: 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. INTERPRETATION: Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. FUNDING: GlaxoSmithKline.

Martin N, Lindley MR, Hargadon B, Monteiro WR, Pavord ID. 2012. Airway dysfunction and inflammation in pool- and non-pool-based elite athletes. Med Sci Sports Exerc, 44 (8), pp. 1433-1439. | Citations: 9 (Scopus) | Show Abstract | Read more

PURPOSE: This study sought to determine and compare the levels of airway dysfunction and inflammation in a large cohort of symptomatic international athletes from pool- and non-pool-based sporting backgrounds. In total, 118 athletes were recruited. METHODS: All subjects had symptoms of exercise asthma and were steroid naïve. They completed baseline spirometry, a symptom score, exhaled nitric oxide, a eucapnic voluntary hyperventilation (EVH) test, and a postchallenge induced sputum and urine test. RESULTS: Pool-based athletes had better lung function (FEV1 = 110% vs 102% predicted, mean difference = 8.200 ± 2.339, P = 0.0006 and FVC = 5.64 vs 4.75 L, mean difference = 0.8855 ± 0.1951, P < 0.0001) and more marked airways hyper-reactivity (AHR) (percent drop in FEV1 after EVH = 18.14 vs 11.47, mean difference = 6.67, 95% confidence interval = 2.89-10.53, P = 0.0009). More pool-based athletes had a positive EVH test (72% pool vs 39% nonpool), but there was no difference between groups with respect to eosinophilic inflammation (sputum eosinophil percentage: pool = 2.07, nonpool = 2.28, P = 0.77; exhaled nitric oxide: pool = 32.54, nonpool = 35.77, P = 0.60). Athletes with a positive EVH test had less neutrophilic inflammation (P = 0.01) and more epithelial cells (P = 0.03) in their sputum. CONCLUSIONS: Pool-based endurance athletes have greater evidence of AHR than non-pool-based athletes but no evidence of greater eosinophilic airway inflammation. Athletes who test positive on EVH are more likely to be eosinophilic and have higher levels of epithelial cells in their sputum.

Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. 2012. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med, 186 (1), pp. 48-55. | Citations: 225 (Web of Science Lite) | Show Abstract | Read more

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. OBJECTIVES: Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. METHODS: Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. MEASUREMENTS AND MAIN RESULTS: There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). CONCLUSIONS: The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

Pavord ID, Green RH, Haldar P. 2012. Diagnosis and Management of Asthma in Adults pp. 501-520. | Read more

Birring SS, Pavord ID. 2012. Cough pp. 242-249. | Read more

Haldar P, Pavord ID. 2012. Diagnosis and management of adult asthma Medicine, 40 (5), pp. 243-251. | Citations: 1 (Scopus) | Show Abstract | Read more

Asthma is a disorder of the airways that is characterized by typical symptoms arising from a complex interplay between chronic inflammation and disordered airway function. Worldwide disease prevalence continues to rise steadily and the condition contributes to significant morbidity and preventable mortality. The goals of treatment in asthma are to achieve control of symptoms and to prevent exacerbations. Important non-pharmacological measures include patient education, avoidance of triggers and smoking cessation. Pharmacological management involves the stepwise titration of β-agonist bronchodilators and inhaled corticosteroids according to symptoms. Although satisfactory control of asthma is achieved in primary care for a large proportion of patients, between 5 and 10%, with so-called 'refractory asthma', remain poorly controlled and contribute disproportionately to asthma-related morbidity and mortality. The reasons for this are complex and multifactorial and many patients with refractory asthma require referral to specialist centres. © 2012 Elsevier Ltd. All rights reserved.

Agbetile J, Fairs A, Desai D, Hargadon B, Bourne M, Mutalithas K, Edwards R, Morley JP, Monteiro WR, Kulkarni NS et al. 2012. Isolation of filamentous fungi from sputum in asthma is associated with reduced post-bronchodilator FEV1. Clin Exp Allergy, 42 (5), pp. 782-791. | Citations: 50 (Scopus) | Show Abstract | Read more

BACKGROUND: Fungal sensitization is common in severe asthma, but the clinical relevance of this and the relationship with airway colonization by fungi remain unclear. The range of fungi that may colonize the airways in asthma is unknown. OBJECTIVE: To provide a comprehensive analysis on the range of filamentous fungi isolated in sputum from people with asthma and report the relationship with their clinico-immunological features of their disease. METHODS: We recruited 126 subjects with a diagnosis of asthma, 94% with moderate-severe disease, and 18 healthy volunteers. At a single stable visit, subjects underwent spirometry; sputum fungal culture and a sputum cell differential count; skin prick testing to both common aeroallergens and an extended fungal panel; specific IgE to Aspergillus fumigatus. Fungi were identified by morphology and species identity was confirmed by sequencing. Four patients had allergic bronchopulmonary aspergillosis. RESULTS: Forty-eight percent of asthma subjects were IgE-sensitized to one fungal allergen and 22% to ≥ 2. Twenty-seven different taxa of filamentous fungi were isolated from 54% of their sputa, more than one species being detected in 17%. This compared with 3 (17%) healthy controls culturing any fungus (P < 0.01). Aspergillus species were most frequently cultured in isolation followed by Penicillium species. Post-bronchodilator FEV (1) (% predicted) in the subjects with asthma was 71(± 25) in those with a positive fungal culture vs. 83 (± 25) in those culture-negative, (P < 0.01). CONCLUSION AND CLINICAL RELEVANCE: Numerous thermotolerant fungi other than A. fumigatus can be cultured from sputum of people with moderate-to-severe asthma; a positive culture is associated with an impaired post-bronchodilator FEV (1) , which might be partly responsible for the development of fixed airflow obstruction in asthma. Sensitization to these fungi is also common.

Pavord ID, Gibson PG. 2012. Inflammometry: the current state of play. Thorax, 67 (3), pp. 191-192. | Citations: 24 (Scopus) | Read more

Thomas M, Pavord I. 2012. Single inhaler maintenance and reliever therapy (SMART) in general practice asthma management: where are we? Prim Care Respir J, 21 (1), pp. 8-10. | Citations: 4 (Web of Science Lite) | Read more

Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T, Parker D, Payton M, Collins LP, Pettipher R et al. 2012. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy, 42 (1), pp. 38-48. | Citations: 135 (Scopus) | Show Abstract | Read more

BACKGROUND: CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D(2) and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma. OBJECTIVE: To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma. METHODS: Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end-point was the change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV(1) ); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927). RESULTS: Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non-compliant subjects. In the FA population, the mean change in FEV(1) was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment. CONCLUSION AND CLINICAL RELEVANCE: This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.

Bush A, Pavord I. 2012. Thorax: the teenage years. Thorax, 67 (1), pp. 1-2. | Citations: 2 (European Pubmed Central) | Read more

Patel AS, Watkin G, Willig B, Mutalithas K, Bellas H, Garrod R, Pavord ID, Birring SS. 2011. Improvement in health status following cough-suppression physiotherapy for patients with chronic cough. Chron Respir Dis, 8 (4), pp. 253-258. | Citations: 18 (Scopus) | Show Abstract | Read more

Cough-suppression physiotherapy is a novel self-help therapy for chronic cough. We evaluated the effectiveness of cough physiotherapy in a pilot prospective observational study. We assessed cough-specific health-related quality of life (HRQOL) with the Leicester Cough Questionnaire (LCQ) and subjectively reported cough frequency and sleep disturbance in 23 patients with chronic cough refractory to medical therapy, before and after outpatient-based cough-suppression physiotherapy. Cough-suppression physiotherapy consisted of education, counselling, cough control, breathing retraining, and vocal hygiene. There was a significant improvement in cough-specific HRQOL after cough physiotherapy; mean (standard error of mean [SEM]) LCQ total score before 12.4 (0.9) versus after 15.1 (0.9); 95% confidence interval of difference -4.1 to -1.3; p < 0.001. The improvement in cough-specific HRQOL was greater than the LCQ minimal clinically important difference of 1.3. A significant improvement was seen in all LCQ domains: physical (p = 0.001), psychological (p < 0.001) and social (p < 0.04). There was a significant reduction in cough frequency scores (p = 0.002) and sleep disturbance scores (p = 0.02). Our findings suggest cough-suppression physiotherapy may lead to a clinically significant improvement in cough-specific HRQOL in patients with chronic cough.

Soler Artigas M, Wain LV, Repapi E, Obeidat M, Sayers I, Burton PR, Johnson T, Zhao JH, Albrecht E, Dominiczak AF et al. 2011. Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function. Am J Respir Crit Care Med, 184 (7), pp. 786-795. | Citations: 85 (Scopus) | Show Abstract | Read more

RATIONALE: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. OBJECTIVES: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. METHODS: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. MEASUREMENTS AND MAIN RESULTS: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV1 (β = -72.21 ml, P = 3.90 × 10(-4)) and FEV1/FVC (β = -1.53%, P = 6.35 × 10(-6)), and with COPD (odds ratio = 1.63, P = 1.46 × 10(-5)). CONCLUSIONS: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick M, Haldar K, Kebadze T, Duvoix A et al. 2011. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med, 184 (6), pp. 662-671. | Citations: 371 (Scopus) | Show Abstract | Read more

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. OBJECTIVES: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. METHODS: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. MEASUREMENTS AND MAIN RESULTS: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed “pauciinflammatory.” Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1β, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83–0.95); serum CXCL10, 0.83 (95% CI, 0.70–0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78–0.93), respectively. CONCLUSIONS: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1β, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.

Arrigoni FI, Matarin M, Thompson PJ, Michaelides M, McClements ME, Redmond E, Clarke L, Ellins E, Mohamed S, Pavord I et al. 2011. Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy. European journal of human genetics : EJHG, 19 (9), pp. 1018-1018. | Read more

Bafadhel M, Umar I, Gupta S, Raj JV, Vara DD, Entwisle JJ, Pavord ID, Brightling CE, Siddiqui S. 2011. The role of CT scanning in multidimensional phenotyping of COPD. Chest, 140 (3), pp. 634-642. | Citations: 59 (Scopus) | Show Abstract | Read more

BACKGROUND: COPD is a heterogeneous disease characterized by airflow obstruction and diagnosed by lung function. CT imaging is emerging as an important, noninvasive tool in phenotyping COPD. However, the use of CT imaging in defining the disease heterogeneity above lung function is not fully known. METHODS: Seventy-five patients with COPD (58 men, 17 women) were studied with CT imaging and with measures of airway inflammation. Airway physiology and health status were also determined. RESULTS: The presence of emphysema (EM), bronchiectasis (BE), and bronchial wall thickening (BWT) was found in 67%, 27%, and 27% of subjects, respectively. The presence of EM was associated with lower lung function (mean difference % FEV(1), -20%; 95% CI, -28 to -11; P < .001). There was no difference in airway inflammation, exacerbation frequency, or bacterial load in patients with EM alone or with BE and/or BWT ± EM. The diffusing capacity of the lung for carbon monoxide/alveolar volume ratio was the most sensitive and specific parameter in identifying EM (area under the receiver operator characteristic curve, 0.87; 95% CI, 0.79-0.96). Physiologic cluster analysis identified three clusters, two of which were EM predominant and the third characterized by a heterogeneous combination of EM and BE. CONCLUSIONS: The application of CT imaging can be useful as a tool in the multidimensional approach to phenotyping patients with COPD.

Arrigoni FI, Matarin M, Thompson PJ, Michaelides M, McClements ME, Redmond E, Clarke L, Ellins E, Mohamed S, Pavord I et al. 2011. An updated tree of Y-chromosome Haplogroup O and revised phylogenetic positions of mutations P164 and PK4 (vol 19, pg 1018, 2011) EUROPEAN JOURNAL OF HUMAN GENETICS, 19 (9), pp. 1018-1018. | Read more

Birring SS, Pavord ID. 2011. COPD: an autoimmune disease? Eur Respir J, 38 (2), pp. 484. | Citations: 2 (Web of Science Lite) | Read more

Yousaf N, Lee KK, Jayaraman B, Pavord ID, Birring SS. 2011. The assessment of quality of life in acute cough with the Leicester Cough Questionnaire (LCQ-acute). Cough, 7 (1), pp. 4. | Citations: 28 (Scopus) | Show Abstract | Read more

INTRODUCTION: Acute cough has a significant impact on physical and psychosocial health and is associated with an impaired quality of life (QOL). The Leicester Cough Questionnaire (LCQ) is a validated cough-related health status questionnaire designed for patients with chronic cough. The purpose of this study was to validate the LCQ for the assessment of health related QOL in patients with acute cough and determine the clinical minimal important difference (MID). METHODS: 10 subjects with cough due to acute upper respiratory tract infection underwent focused interviews to investigate the face validity of the LCQ. The LCQ was also evaluated by a multidisciplinary team. 30 subjects completed the revised LCQ-acute and a cough visual analogue score (VAS: 0-100 mm) within one week of onset of cough and again <2 weeks later and at resolution of cough. The concurrent validity, internal reliability, repeatability and responsiveness of the LCQ-acute were also assessed. Patients also completed a Global Rating of Change Questionnaire that assessed the change in cough severity between visits. The MID was calculated as the change in LCQ-acute score for patients responding to GRCQ category representing the smallest change in health status that patients found worthwhile. RESULTS: Health status was severely impaired at baseline affecting all domains; median (interquartile range) total LCQ-acute score 13.0 (3.4). All subjects found the LCQ-acute questionnaire acceptable for assessing their cough. Internal reliability of the LCQ-acute was good for all domains and total score, Cronbach's α coefficients >0.9. There was a significant correlation between LCQ-acute and VAS (ρ = -0.48, p = 0.007). The LCQ-acute and its domains were highly responsive to change; effect sizes 1.7-2.3. The MID for total LCQ and VAS were 2.5 and 13 mm respectively. CONCLUSION: The LCQ-acute is a brief, simple and valid instrument to assess cough specific health related QOL in patients with acute cough. It is a highly responsive tool suggesting that it will be particularly useful to assess the effect of antitussive therapy.

Castro M, Rubin A, Laviolette M, Hanania NA, Armstrong B, Cox G, AIR2 Trial Study Group. 2011. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. Ann Allergy Asthma Immunol, 107 (1), pp. 65-70. | Citations: 54 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Bronchial thermoplasty (BT) has been demonstrated to be safe and effective in the treatment of severe persistent asthma out to at least 1 year. Preclinical studies have demonstrated that the reduction in airway smooth muscle after bronchial thermoplasty persists out to at least 3 years. OBJECTIVES: To examine the persistence of effectiveness of BT 2 years posttreatment in subjects with severe asthma. METHODS: Subjects participating in the long-term safety follow-up phase of the Asthma Intervention Research 2 (AIR2) Trial were evaluated by comparing the proportion of subjects who experienced exacerbations, adverse events, or healthcare utilization during the first year (year 1) after BT treatment with the proportion of subjects who experienced the same during the subsequent 12 months (year 2). RESULTS: Severe exacerbations, respiratory adverse events, emergency department visits for respiratory symptoms, and hospitalizations for respiratory symptoms (proportion of subjects experiencing and rates of events), and stability of pre- and post-bronchodilator forced expiratory volume in 1 second (FEV(1)), were comparable between years 1 and 2. The proportion of subjects experiencing severe exacerbations in year 2 after BT was 23.0%, compared with 30.9% in year 1. CONCLUSIONS: The reduction in the proportion of subjects experiencing severe exacerbations after BT is maintained for at least 2 years. Bronchial thermoplasty provides beneficial long-term effects on asthma outcomes in patients with severe asthma. TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT00231114.

Pavord ID, Bush A. 2011. Anti-IgE for Asthma in Inner-City Children NEW ENGLAND JOURNAL OF MEDICINE, 364 (26), pp. 2556-2557. | Citations: 10 (Web of Science Lite) | Read more

Pavord ID, Bush A. 2011. Anti-IgE for asthma in inner-city children. N Engl J Med, 364 (26), pp. 2556-2557. | Citations: 4 (European Pubmed Central) | Read more

Geraci C, Longo G. 2011. Anti-IgE for Asthma in Inner-City Children NEW ENGLAND JOURNAL OF MEDICINE, 364 (26), pp. 2557-2557. | Citations: 10 (Web of Science Lite)

Holgate ST, Noonan M, Chanez P, Busse W, Dupont L, Pavord I, Hakulinen A, Paolozzi L, Wajdula J, Zang C et al. 2011. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J, 37 (6), pp. 1352-1359. | Citations: 100 (Scopus) | Show Abstract | Read more

Increased tumour necrosis factor-α levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma. In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n=132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1)% predicted. Secondary end-points included morning peak expiratory flow, FEV1% pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire. No significant differences were observed between ETN and placebo for any of the efficacy end-points. ETN treatment was well tolerated, with no unexpected safety findings observed during the study. Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.

Bush A, Pavord I. 2011. Following Nero: fiddle while Rome burns, or is there a better way? Thorax, 66 (5), pp. 367. | Citations: 16 (Scopus) | Read more

Wardlaw A, Fairs A, Agbetile J, Pavord I, Pashley C. 2011. ABPA or AFAA: That Is the Question AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 183 (9), pp. 1281-1282. | Read more

Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC, Olivenstein R, Pavord ID, McCormack D, Laviolette M, Shargill NS et al. 2011. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med, 11 (1), pp. 8. | Citations: 112 (Scopus) | Show Abstract | Read more

BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure. METHODS: Patients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids ≥200 μg beclomethasone or equivalent + long-acting-beta2-agonists and demonstrated worsening of asthma on long-acting-β2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT. RESULTS: 45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group. CONCLUSIONS: The absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post-BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years.

Arrigoni FI, Matarin M, Thompson PJ, Michaelides M, McClements ME, Redmond E, Clarke L, Ellins E, Mohamed S, Pavord I et al. 2011. Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy. Eur J Hum Genet, 19 (2), pp. 131-137. | Citations: 16 (Scopus) | Show Abstract | Read more

Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.

Bush A, Pavord I. 2011. New year resolutions. Thorax, 66 (2), pp. 91-92. | Citations: 2 (Web of Science Lite) | Read more

Yousaf N, Monteiro W, Parker D, Matos S, Birring S, Pavord ID. 2010. Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial. Thorax, 65 (12), pp. 1107-1110. | Citations: 24 (Scopus) | Show Abstract | Read more

AIMS: Unexplained chronic cough is a common condition with no satisfactory treatments. Previous work has suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with unexplained chronic cough. METHODS: 30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take 250 mg erythromycin once daily (n=15) or placebo (n=15) for 12 weeks in a double-blind parallel group study. Cough frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary outcome measure was change in 24 h cough frequency at 12 weeks. RESULTS: There was no difference in the change in cough frequency between the erythromycin and placebo groups at 12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p=0.585) or at other times. There was a statistically significant between-treatment difference in the change in sputum neutrophils at 12 weeks (−10.2% vs +6.6% with erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p=0.03) but not at other times. There was no difference in the change in other measures of cough between treatments. CONCLUSIONS: Treatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but not cough frequency or severity in patients with unexplained chronic cough.

Fairs A, Agbetile J, Hargadon B, Bourne M, Monteiro WR, Brightling CE, Bradding P, Green RH, Mutalithas K, Desai D et al. 2010. IgE sensitization to Aspergillus fumigatus is associated with reduced lung function in asthma. Am J Respir Crit Care Med, 182 (11), pp. 1362-1368. | Citations: 130 (Scopus) | Show Abstract | Read more

RATIONALE: The importance of Aspergillus fumigatus sensitization and colonization of the airways in patients with asthma is unclear. OBJECTIVES: To define the relationship between the clinical and laboratory features of A. fumigatus-associated asthma. METHODS: We studied 79 patients with asthma (89% classed as GINA 4 or 5) classified into 3 groups according to A. fumigatus sensitization: (1) IgE-sensitized (immediate cutaneous reactivity > 3 mm and/or IgE > 0.35 kU/L); (2) IgG-only-sensitized (IgG > 40 mg/L); and (3) nonsensitized. These were compared with 14 healthy control subjects. Sputum culture was focused toward detection of A. fumigatus and compared with clinical assessment data. MEASUREMENTS AND MAIN RESULTS: A. fumigatus was cultured from 63% of IgE-sensitized patients with asthma (n = 40), 39% of IgG-only-sensitized patients with asthma (n = 13), 31% of nonsensitized patients with asthma (n = 26) and 7% of healthy control subjects (n = 14). Patients sensitized to A. fumigatus compared with nonsensitized patients with asthma had lower lung function (postbronchodilator FEV₁ % predicted, mean [SEM]: 68 [±5]% versus 88 [±5]%; P < 0.05), more bronchiectasis (68% versus 35%; P < 0.05), and more sputum neutrophils (median [interquartile range]: 80.9 [50.1-94.1]% versus 49.5 [21.2-71.4]%; P < 0.01). In a multilinear regression model, A. fumigatus-IgE sensitization and sputum neutrophil differential cell count were important predictors of lung function (P = 0.016), supported by culture of A. fumigatus (P = 0.046) and eosinophil differential cell count (P = 0.024). CONCLUSIONS: A. fumigatus detection in sputum is associated with A. fumigatus-IgE sensitization, neutrophilic airway inflammation, and reduced lung function. This supports the concept that development of fixed airflow obstruction in asthma is consequent upon the damaging effects of airway colonization with A. fumigatus.

Pavord ID, Bush A. 2010. On the shoulders of (real) giants. Thorax, 65 (11), pp. 943-944. | Read more

Barnes PJ, Dweik RA, Gelb AF, Gibson PG, George SC, Grasemann H, Pavord ID, Ratjen F, Silkoff PE, Taylor DR, Zamel N. 2010. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest, 138 (3), pp. 682-692. | Citations: 250 (Scopus) | Show Abstract | Read more

The upregulation of nitric oxide (NO) by inflammatory cytokines and mediators in central and peripheral airway sites can be monitored easily in exhaled air. It is now possible to estimate the predominant site of increased fraction of exhaled NO (FeNO) and its potential pathologic and physiologic role in various pulmonary diseases. In asthma, increased FeNO reflects eosinophilic-mediated inflammatory pathways moderately well in central and/or peripheral airway sites and implies increased inhaled and systemic corticosteroid responsiveness. Recently, five randomized controlled algorithm asthma trials reported only equivocal benefits of adding measurements of FeNO to usual clinical guideline management including spirometry; however, significant design issues may exist. Overall, FeNO measurement at a single expiratory flow rate of 50 mL/s may be an important adjunct for diagnosis and management in selected cases of asthma. This may supplement standard clinical asthma care guidelines, including spirometry, providing a noninvasive window into predominantly large-airway-presumed eosinophilic inflammation. In COPD, large/central airway maximal NO flux and peripheral/small airway/alveolar NO concentration may be normal and the role of FeNO monitoring is less clear and therefore less established than in asthma. Furthermore, concurrent smoking reduces FeNO. Monitoring FeNO in pulmonary hypertension and cystic fibrosis has opened up a window to the role NO may play in their pathogenesis and possible clinical benefits in the management of these diseases.

Gupta S, Siddiqui S, Haldar P, Entwisle JJ, Mawby D, Wardlaw AJ, Bradding P, Pavord ID, Green RH, Brightling CE. 2010. Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes. Thorax, 65 (9), pp. 775-781. | Citations: 61 (Scopus) | Show Abstract | Read more

BACKGROUND: Severe asthma is a heterogeneous condition. Airway remodelling is a feature of severe asthma and can be determined by the assessment of high-resolution computed tomography (HRCT) scans. The aim of this study was to assess whether airway remodelling is restricted to specific subphenotypes of severe asthma. METHODS: A retrospective analysis was performed of HRCT scans from subjects who had attended a single-centre severe asthma clinic between 2003 and 2008. The right upper lobe apical segmental bronchus (RB1) dimensions were measured and the clinical and sputum inflammatory characteristics associated with RB1 geometry were assessed by univariate and multivariate regression analyses. Longitudinal sputum data were available and were described as area under the time curve (AUC). Comparisons were made in RB1 geometry across subjects in four subphenotypes determined by cluster analysis, smokers and non-smokers, and subjects with and without persistent airflow obstruction. RESULTS: Ninety-nine subjects with severe asthma and 16 healthy controls were recruited. In the subjects with severe asthma the RB1 percentage wall area (%WA) was increased (p=0.009) and lumen area (LA)/body surface area (BSA) was decreased (p=0.008) compared with controls but was not different across the four subphenotypes. Airway geometry was not different between smokers and non-smokers and RB1 %WA was increased in those with persistent airflow obstruction. RB1 %WA in severe asthma was best associated with airflow limitation and persistent neutrophilic airway inflammation (model R(2)=0.27, p=0.001). CONCLUSIONS: Airway remodelling of proximal airways occurs in severe asthma and is associated with impaired lung function and neutrophilic airway inflammation.

Mutalithas K, Guillen C, Raport C, Kolbeck R, Soler D, Brightling CE, Pavord ID, Wardlaw AJ. 2010. Expression of CCR8 is increased in asthma. Clin Exp Allergy, 40 (8), pp. 1175-1185. | Citations: 26 (Scopus) | Show Abstract | Read more

BACKGROUND: Chemokines and their receptors could play key roles in the recruitment of T cells to the asthmatic lung. CCR8 is preferentially expressed on T-helper type 2 cells, and is thought to play a role in the pathogenesis of human asthma. OBJECTIVE: Determine the expression of CCR8 on T cells in blood, bronchoalveolar lavage (BAL) and bronchial mucosa from asthmatics and normal subjects. METHODS: CCR8 expression in blood and BAL from asthma and normal subjects was studied using flow cytometry. CCR8 expression on IFN-gamma+ and IL-4+/IL-13+ blood and BAL T cells was studied following stimulation with Phorbol-Myristate-Acetate and Calcium Ionophore. Paraffin-embedded bronchial biopsies were used to study CCR8 in bronchial epithelium. RESULTS: The percentage of CD3+ cells expressing CCR8 in the blood was higher in asthmatics (4.7+/-0.4%) compared with normal subjects (3.0+/-0.4%; P<0.01). There was an approximately sixfold enrichment of CCR8 on IL-4+/IL-13+ cells compared with IFN-gamma+ T cells (P<0.001) in both asthmatic and normal subjects in both blood and BAL. Significantly more BAL T cells expressed CCR8 in asthmatic (8.6+/-0.8%) compared with normal subjects (3.9+/-0.7%) (P<0.01). In paired blood-BAL samples from asthmatics, significantly more CCR8+CD3+ T cells were present in BAL (9.0+/-0.9%) than in blood (5.6+/-0.9%; P<0.05). There were more CCR8-positive cells in bronchial biopsies from asthmatic (93+/-11 cells/mm2) compared with normal subjects (30+/-16 cells/mm2) (P<0.05). The ligand CCL1 was increased in the BAL of asthmatics compared with normal subjects (35+/-6 vs. 12.9+/-7 pg/mL; P<0.05). CONCLUSION: There may be a role for CCR8 in the recruitment of T cells to the lung in asthmatics.

Kulkarni NS, Hollins F, Sutcliffe A, Saunders R, Shah S, Siddiqui S, Gupta S, Haldar P, Green R, Pavord I et al. 2010. Eosinophil protein in airway macrophages: a novel biomarker of eosinophilic inflammation in patients with asthma. J Allergy Clin Immunol, 126 (1), pp. 61-9.e3. | Citations: 41 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Noneosinophilic asthma is common across asthma severities. However, in patients with moderate-to-severe disease, the absence of sputum eosinophilia cannot distinguish between asthmatic subjects with eosinophilic inflammation controlled by corticosteroids versus those in whom eosinophilic inflammation is not a component of the disease. OBJECTIVES: We sought to develop a method to quantify eosinophil proteins in airway macrophages as a novel biomarker of eosinophilic airway inflammation. METHODS: Eosinophil proteins in airway macrophages were assessed by means of flow cytometry, immunofluorescence, and cytoplasmic hue change after ingestion of apoptotic eosinophils. Airway macrophage median percentage of red-hued area in stained sputum cytospin preparations was assessed by means of image analysis from (1) subjects with mild-to-severe asthma, subjects with nonasthmatic eosinophilic bronchitis, and healthy control subjects; (2) subjects with eosinophilic severe asthma after treatment with prednisolone; and (3) subject with noneosinophilic asthma before corticosteroid withdrawal. RESULTS: Eosinophil proteins were detected in airway macrophages, and cytoplasmic red hue increased after ingestion of apoptotic eosinophils. Airway macrophage percentage redhued area was increased in subjects with moderate-to-severe asthma compared with that seen in subjects with mild asthma and healthy control subjects, was similar in those with or without a sputum eosinophilia, and was increased after corticosteroid therapy. In asthmatic subjects without sputum eosinophilia, the airway macrophage percentage red-hued area was increased in subjects who did versus those who did not have sputum eosinophilia after corticosteroid withdrawal. CONCLUSIONS: Eosinophil proteins can be reliably measured in airway macrophages. In combination with sputum eosinophilia, the macrophage eosinophil protein content might further define the asthma phenotype and provide an additional tool to direct therapy.

Mutalithas K, Guillen C, Day C, Brightling CE, Pavord ID, Wardlaw AJ. 2010. CRTH2 expression on T cells in asthma. Clin Exp Immunol, 161 (1), pp. 34-40. | Citations: 32 (Scopus) | Show Abstract | Read more

Mast cell-derived prostaglandin D2 (PGD2) is the major prostanoid found within the airway of asthmatics immediately following allergen challenge. PGD2 has been shown to have chemokinetic effects on eosinophils and T helper type 2 (Th2) cells in vitro. This occurs through the interaction of PGD2 with the G-protein-coupled chemokine receptor homologous molecule expressed on Th2 lymphocytes (CRTH2). The expression of CRTH2 has been shown to be highly selective for Th2 cells. Using flow cytometry we have studied the expression of CRTH2 on T cells in blood and bronchoalveolar lavage fluid in asthmatics and normal subjects. CRTH2 expression was confined to a small percentage of blood T cells in asthmatics (1.8%+/-0.2) and normal (1.6%+/-0.2) subjects. CRTH2 was enriched significantly on interleukin (IL)-4+/IL-13+ T cells compared to interferon (IFN)-gamma+ T cells (P<0.001). There was a small population of CRTH2+ T cells in the bronchoalveolar lavage (BAL) of asthmatics (2.3%+/-0.6) and normal subjects (0.3%+/-0.1), and there was a significant difference between the two groups (P<0.05). There were similar amounts of PGD2 in the BAL of asthma and normal subjects. Within paired blood-BAL samples from the same subject there was no increase in CRTH2+ T cells in the BAL compared to blood in asthmatics. Enrichment of CRTH2 on IL-4+ and IL-13+ T cells compared to IFN-gamma+ T cells was also seen in BAL from asthmatics (P<0.001). CRTH2 is expressed preferentially by IL-4+/IL-13+ T cells compared to IFN-gamma+ T cells. However, given their small numbers they are unlikely to have a significant involvement in the pathogenesis of asthma. CRTH2 antagonism may not diminish T cell accumulation in the asthmatic lung.

Martin N, Pavord ID. 2010. Asthma in Elite Athletes Clinical Pulmonary Medicine, 17 (4), pp. 155-161. | Show Abstract | Read more

There is a high prevalence of asthma among elite performance athletes, particularly those who train and compete with high ventilation rates in austere environments, such as cross country skiers and swimmers. How best to assess, diagnose, and treat asthma or exercise-induced bronchoconstriction (EIB) in athletes remains controversial. The underlying high cardiorespiratory fitness levels of athletes make the diagnostic process more complex as do a variety of both common and rare alternative diagnoses that must be considered. To add to this, the pathophysiology of EIB in athletes is believed to differ significantly from the exercise-induced asthma seen in clinical patients, with less allergic inflammation and less steroid responsive airways pathology. This review aims to examine the underlying differences in EIB and exercise-induced asthma, to discuss diagnostic testing, and to look at the evidence that suggests how we should direct management and therapy. This discussion raises a number of questions about the diagnosis and treatment of airways symptoms in athletes, and it also suggests how future research should be targeted to answer these questions. Copyright © 2010 by Lippincott Williams & Wilkins.

Pavord ID, Haldar P, Bradding P, Wardlaw AJ. 2010. Mepolizumab in refractory eosinophilic asthma. Thorax, 65 (4), pp. 370. | Citations: 25 (Web of Science Lite) | Read more

Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM et al. 2010. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med, 181 (2), pp. 116-124. | Citations: 381 (Scopus) | Show Abstract | Read more

RATIONALE: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES: To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS: A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS: The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS: BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M, Zhao JH, Ramasamy A, Zhai G, Vitart V et al. 2010. Genome-wide association study identifies five loci associated with lung function. Nat Genet, 42 (1), pp. 36-44. | Citations: 350 (Scopus) | Show Abstract | Read more

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

Pavord ID, Wardlaw AJ. 2010. The A to E of airway disease. Clin Exp Allergy, 40 (1), pp. 62-67. | Citations: 33 (Web of Science Lite) | Show Abstract | Read more

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.

Bafadhel M, Singapuri A, Terry S, Hargadon B, Monteiro W, Green RH, Bradding PH, Wardlaw AJ, Pavord ID, Brightling CE. 2010. Body mass and fat mass in refractory asthma: an observational 1 year follow-up study. J Allergy (Cairo), 2010 pp. 251758. | Citations: 3 (European Pubmed Central) | Show Abstract | Read more

Background. Asthma and obesity are common; however the impact of obesity upon asthma remains uncertain. Objectives. To assess relationships between obesity and fat mass with airway inflammation, lung function, and disease control in patients with refractory asthma. Methods. 151 refractory asthma patients were characterised for measures of airway inflammation, lung function, Juniper asthma control questionnaire (JACQ), body mass index (BMI), and fat mass index (FMI) derived from dual energy X-ray absorptiometry. Patients were reassessed over 12 months. Results. 74% of patients had an elevated BMI. BMI and FMI correlated (r = 0.9, P < .001). FMI and JACQ correlated in men (r = 0.3, P = .01). After 12 months 23% lost weight. Weight change over 12 months correlated with FEV(1) change (r = -0.3, P = .03), but not with change in JACQ or exacerbations. Conclusion. Increased fat mass is common in refractory asthma and is associated with asthma symptom control in men. Loss of weight is associated with improvement in lung function in refractory asthma.

Gupta S, Siddiqui S, Haldar P, Raj JV, Entwisle JJ, Wardlaw AJ, Bradding P, Pavord ID, Green RH, Brightling CE. 2009. Qualitative analysis of high-resolution CT scans in severe asthma. Chest, 136 (6), pp. 1521-1528. | Citations: 110 (Scopus) | Show Abstract | Read more

BACKGROUND: High-resolution CT (HRCT) scanning is part of the management of severe asthma, but its application varies between centers. We sought to describe the HRCT scan abnormalities of a large severe asthma cohort and to determine the utility of clinical features to direct the use of HRCT scanning in this group of patients. METHODS: Subjects attending our Difficult Asthma Clinic (DAC) between February 2000 and November 2006 (n = 463) were extensively re-characterized and 185 underwent HRCT scan. The HRCT scans were analyzed qualitatively and the interobserver variability was assessed. Using logistic regression we defined clinical parameters that were associated with bronchiectasis (BE) and bronchial wall thickening (BWT) alone or in combination. RESULTS: HRCT scan abnormalities were present in 80% of subjects and often coexisted with BWT (62%), BE (40%), and emphysema (8%). The interobserver agreement for BE (kappa = 0.76) and BWT (kappa = 0.63) was substantial. DAC patients who underwent HRCT scanning compared with those who did not were older, had longer disease duration, had poorer lung function, were receiving higher doses of corticosteroids, and had increased neutrophilic airway inflammation. The sensitivity and specificity of detecting BE clinically were 74% and 45%, respectively. FEV(1)/FVC ratio emerged as an important predictor for both BE and BWT but had poor discriminatory utility for subjects who did not have airway structural changes (FEV(1)/FVC ratio, >or= 75%; sensitivity, 67%; specificity, 65%). CONCLUSION: HRCT scan abnormalities are common in patients with severe asthma. Nonradiologic assessments fail to reliably predict important bronchial wall changes; therefore, CT scan acquisition may be required in all patients with severe asthma.

Pavord ID. 2009. Asthma control, airway responsiveness and airway inflammation. Clin Exp Allergy, 39 (12), pp. 1780-1782. | Citations: 5 (Web of Science Lite) | Read more

Birring SS, Pavord ID. 2009. Assessment of gender differences in health status with the Leicester Cough Questionnaire (LCQ). Thorax, 64 (11), pp. 1008-1009. | Citations: 10 (Scopus) | Read more

Thomas M, Pavord ID. 2009. Role of breathing exercises in hyperventilating subjects Reply THORAX, 64 (9), pp. 824-824. | Read more

Pavord ID, Wardlaw AJ, Haldar P. 2009. Dr. Pavord and colleagues reply New England Journal of Medicine, 360 (24), pp. 2577.

Pavord ID, Wardlaw AJ, Haldar P. 2009. Anti-Interleukin-5 Therapy and Severe Asthma REPLY NEW ENGLAND JOURNAL OF MEDICINE, 360 (24), pp. 2577-2577.

Pavord ID, Jeffery PK, Qiu Y, Zhu J, Parker D, Carlsheimer A, Naya I, Barnes NC. 2009. Airway inflammation in patients with asthma with high-fixed or low-fixed plus as-needed budesonide/formoterol. J Allergy Clin Immunol, 123 (5), pp. 1083-1089.e7. | Citations: 45 (Scopus) | Show Abstract | Read more

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 microg twice daily plus as-needed with budesonide/formoterol 800/12 microg 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 microg in the maintenance and reliever therapy group and 1,600/24 microg 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 < .001), respectively. There were no between-treatment differences in reticular basement membrane thickness, exhaled nitric oxide, exacerbation frequency, or FEV(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.

Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. 2009. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med, 360 (10), pp. 973-984. | Citations: 1135 (Scopus) | Show Abstract | Read more

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.)

Pavord ID, Shaw DE. 2009. Measurement of Markers of Inflammation in Induced Sputum and Exhaled Air 2 pp. 1368-1380. | Show Abstract | Read more

Induced sputum is safe in both children (Venge et al. 1977) and adults (Gibson et al. 2002; Green et al. 2002a), repeatable, inexpensive, and provides a clinically relevant marker of airway inflammation in the assessment and treatment of asthma. It can also be used to measure a variety of cells, effector mediators, cellular markers, and cytokines and its use has led to new insights into the pathophysiology and management of asthma and other airways disease. FENO is a reasonably reliable marker of eosinophilic airway inflammation that can be measured simply and noninvasively. The clinical value of measuring FENO has not been explored extensively but it could be a valuable tool for diagnosis and monitoring of corticosteroid-responsive airways disease in primary care. © 2008 Blackwell Publishing.

Reddel HK, Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG et al. 2009. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med, 180 (1), pp. 59-99. | Citations: 963 (Scopus) | Show Abstract | Read more

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 about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. CONCLUSIONS: The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

Thomas M, McKinley RK, Mellor S, Watkin G, Holloway E, Scullion J, Shaw DE, Wardlaw A, Price D, Pavord I. 2009. Breathing exercises for asthma: a randomised controlled trial. Thorax, 64 (1), pp. 55-61. | Citations: 81 (Scopus) | Show Abstract | Read more

BACKGROUND: The effect of breathing modification techniques on asthma symptoms and objective disease control is uncertain. METHODS: A prospective, parallel group, single-blind, randomised controlled trial comparing breathing training with asthma education (to control for non-specific effects of clinician attention) was performed. Subjects with asthma with impaired health status managed in primary care were randomised to receive three sessions of either physiotherapist-supervised breathing training (n = 94) or asthma nurse-delivered asthma education (n = 89). The main outcome was Asthma Quality of Life Questionnaire (AQLQ) score, with secondary outcomes including spirometry, bronchial hyper-responsiveness, exhaled nitric oxide, induced sputum eosinophil count and Asthma Control Questionnaire (ACQ), Hospital Anxiety and Depression (HAD) and hyperventilation (Nijmegen) questionnaire scores. RESULTS: One month after the intervention there were similar improvements in AQLQ scores from baseline in both groups but at 6 months there was a significant between-group difference favouring breathing training (0.38 units, 95% CI 0.08 to 0.68). At the 6-month assessment there were significant between-group differences favouring breathing training in HAD anxiety (1.1, 95% CI 0.2 to 1.9), HAD depression (0.8, 95% CI 0.1 to 1.4) and Nijmegen (3.2, 95% CI 1.0 to 5.4) scores, with trends to improved ACQ (0.2, 95% CI 0.0 to 0.4). No significant between-group differences were seen at 1 month. Breathing training was not associated with significant changes in airways physiology, inflammation or hyper-responsiveness. CONCLUSION: Breathing training resulted in improvements in asthma-specific health status and other patient-centred measures but not in asthma pathophysiology. Such exercises may help patients whose quality of life is impaired by asthma, but they are unlikely to reduce the need for anti-inflammatory medication.

Pavord ID, Yousaf N, Birring SS. 2009. Chronic obstructive pulmonary disease in non-smokers. Lancet, 374 (9706), pp. 1964. | Citations: 2 (Web of Science Lite) | Read more

Pavord ID, Kharitonov SA. 2009. Non-invasive Assessment of Airway Inflammation pp. 543-557. | Citations: 1 (Scopus) | Show Abstract | Read more

This chapter reviews the methodology and validation of induced sputum and FENOand 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 FENObeing 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.

Pavord ID, Martin N. 2009. Will exhaled nitric oxide monitoring become routine in managing asthma? Expert Rev Respir Med, 3 (2), pp. 107-111. | Citations: 3 (European Pubmed Central) | Show Abstract | Read more

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.

Bafadhel M, Saha S, Siva R, McCormick M, Monteiro W, Rugman P, Dodson P, Pavord ID, Newbold P, Brightling CE. 2009. Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD. Respiration, 78 (3), pp. 256-262. | Citations: 32 (Scopus) | Show Abstract | Read more

BACKGROUND: Airway inflammation in chronic obstructive pulmonary disease (COPD) is predominately neutrophilic, but some subjects demonstrate eosinophilic airway inflammation. Whether these inflammatory phenotypes have differential cytokine and chemokine expression is unknown. OBJECTIVES: To assess the sputum concentrations of cytokines and chemokines and their response to oral corticosteroid therapy in COPD subjects with or without a sputum eosinophilia. METHODS: Cytokine and chemokine concentrations were measured using the meso-scale device platform. To assess validity, recovery of exogenous spikes was examined. The concentrations of the validated mediators were measured in COPD sputum from subjects with or without a sputum eosinophilia. In a subgroup with a sputum eosinophilia, the response to oral prednisolone 10 mg for 1 month was examined. RESULTS: The recovery in sputum of exogenous spiked mediators was >80% in 11/26 cytokines and chemokines. In supernatants from eosinophilic (n = 39) versus non-eosinophilic (n = 59) sputa, the geometric mean (95% CI) concentration was increased for IL-5 [9.0 (4.5-18) pg/ml vs. 3.6 (2.7-6.3) pg/ml, p = 0.03]. IL-5 alone was correlated with sputum eosinophil counts (r = 0.33, p = 0.001), and was attenuated following treatment with prednisolone [n = 9; mean difference 2.3 pg/ml (0.2-4.3), p = 0.032]. CONCLUSION: We have validated the use of the meso-scale device platform for cytokine and chemokine measurements in the sputum supernatants in COPD. Sputum IL-5 was associated with a sputum eosinophilia and was attenuated following oral corticosteroid therapy. Whether this cytokine is important in the pathogenesis of COPD in a subgroup of patients warrants further investigation.

Fullerton D, Britton JR, Lewis SA, Pavord ID, McKeever TM, Fogarty AW. 2009. Helicobacter pylori and lung function, asthma, atopy and allergic disease--a population-based cross-sectional study in adults. Int J Epidemiol, 38 (2), pp. 419-426. | Citations: 44 (Scopus) | Show Abstract | Read more

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.

Martin N, Pavord ID. 2009. Bronchial thermoplasty for the treatment of asthma. Curr Allergy Asthma Rep, 9 (1), pp. 88-95. | Citations: 5 (Web of Science Lite) | Show Abstract | Read more

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.

Taylor DR, Pavord ID. 2008. Biomarkers in the assessment and management of airways diseases. Postgrad Med J, 84 (998), pp. 628-634. | Citations: 24 (Scopus) | Show Abstract | Read more

A plethora of biomarkers are becoming available in the field of respiratory medicine, but their application in clinical practice has been limited. This is changing. There is increasing scope for biomarkers to be used to define pathological as well as treatment responder phenotypes in asthma and chronic obstructive pulmonary disease. In some situations, conventional diagnostic labelling is being superseded by this approach and clinical outcomes are improved. Biomarkers are potentially very important in the development and assessment of new therapeutic agents, particularly for the treatment of severe asthma. They also have a potential role in monitoring disease activity and predicting future clinical outcomes for asthma and chronic obstructive pulmonary disease. Current evidence in relation to these issues is explored in this review.

Pavord ID, Shaw D. 2008. The use of exhaled nitric oxide in the management of asthma. J Asthma, 45 (7), pp. 523-531. | Citations: 22 (Web of Science Lite) | Show Abstract | Read more

It has recently become clear that airways disease associated with eosinophilic airway inflammation, but not other patterns of inflammation, is closely associated with favourable short-and long-term responses to corticosteroid therapy, irrespective of the clinical context in which it occurs. Moreover, a raised exhaled nitric oxide (FE(NO)) is a reasonable marker of eosinophilic airway inflammation, which has a number of advantages as a diagnostic and monitoring tool. In this review we outline essential background information on the use of FE(NO) in clinical practice and discuss some recent work evaluating the clinical value of this technique.

Saha S, Mistry V, Siva R, Parker D, May R, Bradding P, Pavord ID, Brightling CE. 2008. Induced sputum and bronchial mucosal expression of interleukin-13 is not increased in chronic obstructive pulmonary disease. Allergy, 63 (9), pp. 1239-1243. | Citations: 16 (Scopus) | Show Abstract | Read more

BACKGROUND: The Th2 cytokine interleukin-13 (IL-13) has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We sought to examine IL-13 expression in COPD subjects in induced sputum and bronchus specimens. We hypothesized that inflammatory cells expressing IL-13 localize to the airway smooth muscle bundle and bronchial glands. METHODS: Interleukin-13 was measured in sputum samples from subjects with COPD (n = 34) across a range of severity (Global initiative for chronic Obstructive Lung Disease 2-4) and controls (n = 14) using ELISA. IL-13+ cells and inflammatory cells were enumerated within surgically resected proximal airway using immunohistochemical techniques from subjects with COPD (n = 10), smoking (n = 10) and nonsmoking controls (n = 8). RESULTS: Sputum IL-13 was measurable in only 6/34 subjects with COPD and was not found in the smoking or nonsmoking control subjects. In subjects with COPD and controls there was a paucity of IL-13+ cells. The distribution of inflammatory cells within different airway compartments was similar in COPD and controls except for an increase in CD3(+) lymphocytes within bronchial glands in COPD (P = 0.04). CONCLUSIONS: Our findings do not support a role for IL-13 in COPD. However, the tissue localization of inflammatory cells to airway compartments, particularly the increase of T cells in glands in COPD may be important in disease.

Siddiqui S, Mistry V, Doe C, Roach K, Morgan A, Wardlaw A, Pavord I, Bradding P, Brightling C. 2008. Airway hyperresponsiveness is dissociated from airway wall structural remodeling. J Allergy Clin Immunol, 122 (2), pp. 335-341.e3. | Citations: 92 (Scopus) | Show Abstract | Read more

BACKGROUND: Nonasthmatic eosinophilic bronchitis (EB) has emerged as a useful tool to study the structural and inflammatory mechanisms of airway hyperresponsiveness (AHR) in asthma. We have previously shown that vascular remodeling and reticular basement membrane (RBM) thickening are present in EB. However, it is not known whether other features of structural remodeling including increased airway smooth muscle (ASM) mass, matrix deposition, and glandular hyperplasia are also present in EB. OBJECTIVES: We sought to determine whether structural remodeling occurs in EB and is associated with AHR and airflow limitation. METHODS: Forty-two patients with asthma, 21 patients with EB, and 19 healthy volunteers were recruited. ASM area, RBM thickness, collagen 3 deposition, glandular area, mast cells, and granulocytes were assessed in bronchial biopsy samples. RESULTS: Nonasthmatic eosinophilic bronchitis and asthma were associated with a significant increase in ASM mass and RBM thickness compared with healthy subjects. In contrast, we did not observe any significant differences in collagen 3 deposition in the lamina propria and ASM or the % area of glands in the lamina propria. Univariate analysis demonstrated that mast cell numbers in the ASM were the only feature of remodeling associated with AHR (beta = -0.51; P = .004). Stepwise linear regression revealed that a combination of mast cell numbers in the ASM (beta = -0.43) and disease duration (beta = -0.25; model-adjusted R(2) = 0.26; P = .027) best modeled AHR. CONCLUSION: Mast cell localization to the ASM bundle, but not structural remodeling of the airway wall, is associated with AHR in asthma.

Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. 2008. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med, 178 (3), pp. 218-224. | Citations: 1023 (Scopus) | Show Abstract | Read more

RATIONALE: Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model. OBJECTIVES: To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups. METHODS: We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care. MEASUREMENTS AND MAIN RESULTS: Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 mug beclomethasone equivalent/d [95% confidence interval, 307-3,349 mug]; P = 0.02). CONCLUSIONS: Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.

Mutalithas K, Watkin G, Willig B, Wardlaw A, Pavord ID, Birring SS. 2008. Improvement in health status following bronchopulmonary hygiene physical therapy in patients with bronchiectasis. Respir Med, 102 (8), pp. 1140-1144. | Citations: 34 (Scopus) | Show Abstract | Read more

Chronic productive cough is a common symptom in patients with bronchiectasis that is associated with a reduction in health-related quality of life (QOL). Bronchopulmonary hygiene physical therapy (BHPT) is widely prescribed for patients with bronchiectasis, although the evidence for its efficacy is limited. We set out to prospectively evaluate the impact of BHPT on health-related QOL in patients with non-cystic fibrosis bronchiectasis. We assessed cough symptoms (0-100mm visual analogue scale; VAS) and cough-related QOL in 53 patients with stable non-cystic fibrosis bronchiectasis at baseline and >4 weeks after outpatient-based BHPT. Cough specific health status was assessed with the Leicester Cough Questionnaire (LCQ; total score range 3-21, higher scores representing better QOL). All patients with bronchiectasis complained of cough as the major symptom and had mean (SEM) FEV(1) of 2.1 (0.1)L. Cough-related health status was reduced at baseline; mean (SEM) LCQ score 14.3 (0.6). There were significant improvements in cough symptoms (mean cough VAS before 43.3 (3.6) vs after 27.5 (3.1); mean difference 15.8; 95% CI of difference 9.6-22; p<0.0001) and cough-related health status after BHPT (mean LCQ total score before 14.2 vs after 17.3; mean difference 3.1; 95% confidence interval of difference 2.4-3.9; p<0.001). A significant improvement was seen in all LCQ health-related domains (physical, psychological and social; all p<0.001). Our findings suggest that bronchopulmonary hygiene physical therapy can lead to a significant improvement in cough-related quality of life.

Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AI, Green RH. 2008. Cluster analysis and clinical asthma phenotypes AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 178 (3), pp. 218-224. | Citations: 932 (Web of Science Lite) | Read more

Berry MA, Pavord ID. 2008. Antagonism of tumour necrosis factor alpha in refractory asthma. Thorax, 63 (7), pp. 571-572. | Citations: 4 (Scopus) | Read more

Green RH, Pavord ID. 2008. Use of long-acting beta2 agonists in arginine-16 homozygous patients with asthma. Thorax, 63 (6), pp. 568-569. | Read more

British Thoracic Society Scottish Intercollegiate Guidelines Network. 2008. British Guideline on the Management of Asthma. Thorax, 63 Suppl 4 (Supplement 4), pp. iv1-121. | Citations: 335 (Scopus) | Read more

Birring SS, Fleming T, Matos S, Raj AA, Evans DH, Pavord ID. 2008. The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough. Eur Respir J, 31 (5), pp. 1013-1018. | Citations: 109 (Scopus) | Show Abstract | Read more

Chronic cough is a common condition that presents to both primary and secondary care. Assessment and management are hampered by the absence of well-validated outcome measures. The present study comprises the validation of the Leicester Cough Monitor (LCM), an automated sound-based ambulatory cough monitor. Cough frequency was measured with the LCM and compared with coughs and other sounds counted manually over 2 h of a 6-h recording by two observers in nine patients with chronic cough in order to determine the sensitivity and specificity of the LCM. Automated cough frequency was also compared with manual counts from one observer in 15 patients with chronic cough and eight healthy subjects. All subjects underwent 6-h recordings. A subgroup consisting of six control and five patients with stable chronic cough underwent repeat automated measurements > or = 3 months apart. A further 50 patients with chronic cough underwent 24-h automated cough monitoring. The LCM had a sensitivity and specificity of 91 and 99%, respectively, for detecting cough and a false-positive rate of 2.5 events x h(-1). Mean+/-SEM automated cough counts x patient x h(-1) was 48+/-9 in patients with chronic cough and 2+/-1 in the control group (mean difference 46 counts x patient x h(-1); 95% confidence interval (CI) 20-71). The automated cough counts were repeatable (intra-subject SD 11.4 coughs x patient x h(-1); intra-class correlation coefficient 0.9). The cough frequency in patients undergoing 24-h automated monitoring was 19 coughs x patient x h(-1); daytime (08:00-22:00 h) cough frequency was significantly greater than overnight cough frequency (25 versus 10 coughs x patient x h(-1); mean difference 15 coughs x patient x h(-1), 95% CI 8-22). The Leicester Cough Monitor is a valid and reliable tool that can be used to assess 24-h cough frequency in patients with cough. It should be a useful tool to assess patients with cough in clinical trials and longitudinal studies.

Raj AA, Birring SS, Green R, Grant A, de Caestecker J, Pavord ID. 2008. Prevalence of inflammatory bowel disease in patients with airways disease. Respir Med, 102 (5), pp. 780-785. | Citations: 40 (Scopus) | Show Abstract | Read more

BACKGROUND: Case reports and case series have suggested an association between inflammatory bowel disease (IBD) and airways disease, but there are no data demonstrating a higher prevalence of IBD among patients with airways disease. Furthermore, no consistent radiological, pulmonary or pathological abnormalities have been demonstrated in patients with both conditions. AIMS: To determine the prevalence of IBD among patients with airways disease and to evaluate clinical and pathophysiological features. METHODS: A retrospective analysis of outpatients with airways disease over a 10-year period. RESULTS: IBD was four times more prevalent among patients with airways disease compared with published local IBD prevalence [Odds Ratio 4.26, 95% CI 1.48, 11.71, p=0.006; Crohn's disease OR 5.96, 95% CI 1.94, 18.31, p=0.002 and ulcerative colitis OR 4.21, 95% CI 1.71, 10.41, p=0.001]. IBD was more frequent in all types of airways disease except asthma; the association was particularly strong for conditions associated with productive cough. All except 1 patient had established IBD before the onset of respiratory symptoms. There were no obvious radiological differences between ulcerative colitis and Crohn's disease cases. There was a trend for a higher lymphocyte count (despite a tendency to lower blood lymphocyte count) but lower sputum neutrophil count in patients with Crohn's disease compared with ulcerative colitis. There were no significant differences in physiological measurements of pulmonary function between the two types of IBD. CONCLUSION: Our findings support an association between airways disease and inflammatory bowel disease, particularly non-asthmatic airways disease with productive cough.

Haldar P, Pavord ID. 2008. Diagnosis and management of adult asthma Medicine, 36 (4), pp. 201-208. | Citations: 1 (Scopus) | Show Abstract | Read more

Asthma is a disorder of the airways that is characterized by typical symptoms arising from a complex interplay between chronic inflammation and disordered airway function. Worldwide disease prevalence continues to rise steadily and the condition contributes to significant morbidity and preventable mortality. The goals of treatment in asthma are to achieve control of symptoms and to prevent exacerbations. Important non-pharmacological measures include patient education, avoidance of triggers and smoking cessation. Pharmacological management involves the stepwise titration of β-agonist bronchodilators and inhaled corticosteroids according to symptoms. Although satisfactory control of asthma is achieved in primary care for a large proportion of patients, between 5 and 10% with so-called 'refractory asthma' remain poorly controlled and contribute disproportionately to asthma-related morbidity and mortality. The reasons for this are complex and multifactorial, and many patients with refractory asthma require referral to specialist centres. © 2008 Elsevier Ltd. All rights reserved.

Saha SK, Berry MA, Parker D, Siddiqui S, Morgan A, May R, Monk P, Bradding P, Wardlaw AJ, Pavord ID, Brightling CE. 2008. Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J Allergy Clin Immunol, 121 (3), pp. 685-691. | Citations: 185 (Scopus) | Show Abstract | Read more

BACKGROUND: The importance of IL-13 in the asthma paradigm is supported by increased expression in human subjects, particularly in patients with mild-to-moderate asthma. However, the role of IL-13 in severe asthma needs to be further defined. OBJECTIVE: We sought to assess IL-13 expression in sputum and bronchial biopsy specimens from subjects with mild-to-severe asthma. METHODS: Sputum IL-13 concentrations were measured in 32 control subjects, 34 subjects with mild asthma, 21 subjects with moderate asthma, and 26 subjects with severe asthma. Enumeration of mast cells, eosinophils, and IL-13+ cells in the bronchial submucosa and airway smooth muscle (ASM) bundle was performed in 7 control subjects, 14 subjects with mild asthma, 7 subjects with moderate asthma, and 7 subjects with severe asthma. RESULTS: The proportion of subjects with measurable IL-13 in the sputum was increased in the mild asthma group (15/34) and severe asthma group (10/26) compared with that seen in the control group (4/32; P = .004). IL-13+ cells were increased within the submucosa in all asthma severity groups compared with control subjects (P = .006). The number of IL-13+ cells were increased within the ASM bundle in the severe asthma group compared with that seen in the other groups (P < .05). Asthma control questionnaire scores positively correlated with sputum IL-13 concentrations (R(s) = 0.35, P = .04) and mast cells in the ASM bundle (R(s) = 0.7, P = .007). IL-13+ cells within the submucosa and ASM correlated with sputum eosinophilia (R(s) = 0.4, P < or = .05). CONCLUSIONS: IL-13 overexpression in sputum and bronchial biopsy specimens is a feature of severe asthma.

Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, de Jongste JC et al. 2008. A new perspective on concepts of asthma severity and control. Eur Respir J, 32 (3), pp. 545-554. | Citations: 273 (Scopus) | Show Abstract | Read more

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. "Asthma control" refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patient's phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.

Birring SS, Pavord ID. 2008. Cough pp. 285-291. | Read more

Pavord ID, Shaw DE, Gibson PG, Taylor DR. 2008. Inflammometry to assess airway diseases. Lancet, 372 (9643), pp. 1017-1019. | Citations: 51 (Web of Science Lite) | Read more

Pavord ID, Chung KF. 2008. Management of chronic cough. Lancet, 371 (9621), pp. 1375-1384. | Citations: 98 (Scopus) | Show Abstract | Read more

Cough that remains unexplained after basic clinical assessment is a common reason for referral to secondary care. Much of the evidence about management of isolated chronic cough is derived from case series; this evidence suggests that isolated chronic cough is usually due to asthma, gastro-oesophageal reflux disease, and upper airway conditions, and that it can be cured in most people by treatment of these conditions. However, there is increasing recognition that satisfactory control of chronic cough is not achieved in a substantial number of patients seen in secondary care. Moreover, there is a concern that perpetuation of the belief that chronic cough is solely due to the effects of comorbid conditions is inhibiting research into the pathophysiology of an abnormally heightened cough reflex, and jeopardising development of improved treatments. We advocate a change in emphasis, which makes a clear distinction between cough due to corticosteroid-responsive eosinophilic airway diseases and corticosteroid-resistant non-eosinophilic cough. We recommend that some factors with weak evidence of an association with cough are best viewed as potential aggravating factors of an intrinsic abnormality of the cough reflex, rather than the cause. We call for more research into the basic mechanisms and pharmacological control of an abnormally heightened cough reflex, and recommend ways to assess the effects of potentially antitussive treatments.

Chung KF, Pavord ID. 2008. Prevalence, pathogenesis, and causes of chronic cough. Lancet, 371 (9621), pp. 1364-1374. | Citations: 286 (Scopus) | Show Abstract | Read more

Cough is a reflex action of the respiratory tract that is used to clear the upper airways. Chronic cough lasting for more than 8 weeks is common in the community. The causes include cigarette smoking, exposure to cigarette smoke, and exposure to environmental pollution, especially particulates. Diseases causing chronic cough include asthma, eosinophilic bronchitis, gastro-oesophageal reflux disease, postnasal drip syndrome or rhinosinusitis, chronic obstructive pulmonary disease, pulmonary fibrosis, and bronchiectasis. Doctors should always work towards a clear diagnosis, considering common and rare illnesses. In some patients, no cause is identified, leading to the diagnosis of idiopathic cough. Chronic cough is often associated with an increased response to tussive agents such as capsaicin. Plastic changes in intrinsic and synaptic excitability in the brainstem, spine, or airway nerves can enhance the cough reflex, and can persist in the absence of the initiating cough event. Structural and inflammatory airway mucosal changes in non-asthmatic chronic cough could represent the cause or the traumatic response to repetitive coughing. Effective control of cough requires not only controlling the disease causing the cough but also desensitisation of cough pathways.

Pavord ID, Cox G, Thomson NC, Rubin AS, Corris PA, Niven RM, Chung KF, Laviolette M, RISA Trial Study Group. 2007. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med, 176 (12), pp. 1185-1191. | Citations: 243 (Scopus) | Show Abstract | Read more

RATIONALE: Bronchial thermoplasty (BT) is designed to reduce airway smooth muscle and improve asthma control. OBJECTIVES: This study was conducted to determine the safety and efficacy of this procedure in subjects with symptomatic, severe asthma. METHODS: Adults who were symptomatic despite treatment with fluticasone or equivalent at more than 750 mug/day, a long-acting beta(2)-agonist, and other medications, which could include 30 mg or less of oral prednisolone/day, were randomized to BT or to a control group. After treatment, subjects entered a 16-week steroid stable phase (Weeks 6-22), a 14-week steroid wean phase (Weeks 22-36), and a 16-week reduced steroid phase (Weeks 36-52). MEASUREMENTS AND MAIN RESULTS: BT resulted in a transient worsening of asthma symptoms. Seven hospitalizations for respiratory symptoms occurred in 4 of 15 BT subjects during the treatment period. Five hospitalizations were within 3 days of treatment. Two subjects had segmental collapse involving the most recently treated lobe; one required bronchoscopy and aspiration of a mucus plug. There were no hospitalizations during this period in the 17 control subjects. The rate of hospitalizations was similar in both groups in the post-treatment period. At 22 weeks, BT subjects had significant improvements versus control subjects in rescue medication use (-26.6 +/- 40.1 vs. -1.5 +/- 11.7 puffs/7 d, P < 0.05), prebronchodilator FEV(1)% predicted (14.9 +/- 17.4 vs. -0.94 +/- 22.3%, P = 0.04), and Asthma Control Questionnaire scores (-1.04 +/- 1.03 vs. -0.13 +/- 1.00, P = 0.02). Improvements in rescue medication use and Asthma Control Questionnaire scores remained significantly different from those of controls at 52 weeks. CONCLUSIONS: BT is associated with a short-term increase in asthma-related morbidity. However, there is preliminary evidence of long-lasting improvement in asthma control. Clinical trial registered with www.clinicaltrials.gov (NCT 00214539).

Pavord ID. 2007. Monitoring of exhaled nitric oxide in primary care. Prim Care Respir J, 16 (6), pp. 331-334. | Citations: 3 (Scopus) | Read more

Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. 2007. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest, 132 (6), pp. 1871-1875. | Citations: 132 (Scopus) | Show Abstract | Read more

BACKGROUND: There is debate about the mechanisms of persistent airflow limitation in patients with asthma. Chronic inflammation is assumed to be important, although there is limited and contradictory information about the relationship between airway inflammation and postbronchodilator FEV1. METHODS: We have assessed the cross-sectional relationship between prebronchodilator and postbronchodilator FEV1 and measures of airway inflammation after allowing for the effects of potential confounding factors. Multivariate analysis was performed on data collected from 1,197 consecutive patients with asthma seen at the respiratory outpatient clinic at Glenfield Hospital between 1997 and 2004. Relationships between induced sputum total neutrophil and differential eosinophil cell counts, and prebronchodilator and postbronchodilator lung function were examined. RESULTS: Sputum total neutrophil but not differential eosinophil count was associated with lower postbronchodilator FEV1. Both differential eosinophil and total neutrophil count were associated with lower prebronchodilator FEV1. These effects were independent after adjustment for age, smoking, ethnicity, asthma duration, and inhaled corticosteroid use. A 10-fold increase in neutrophil count was associated with a 92 mL reduction (95% confidence interval, 29 to 158; p = 0.007) in postbronchodilator FEV1. CONCLUSIONS: In this large heterogeneous population of adults with asthma, we have shown that prebronchodilator FEV1 is associated with neutrophilic and eosinophilic airway inflammation, whereas sputum total neutrophil counts alone are associated with postbronchodilator FEV1. This supports the hypothesis that neutrophilic airway inflammation has a role in the progression of persistent airflow limitation in asthma and raises the possibility that this progression and the development of COPD share a common mechanism.

Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C, Bradding P, Wardlaw AJ, Pavord ID. 2007. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax, 62 (12), pp. 1043-1049. | Citations: 266 (Scopus) | Show Abstract | Read more

BACKGROUND: Non-eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and there are no data from placebo-controlled studies examining the effect of inhaled corticosteroids. METHODS: Airway immunopathology was investigated using induced sputum, bronchial biopsies, bronchial wash and bronchoalveolar lavage in 12 patients with symptomatic eosinophilic asthma, 11 patients with non-eosinophilic asthma and 10 healthy controls. The patients with non-eosinophilic asthma and 6 different patients with eosinophilic asthma entered a randomised, double-blind, placebo-controlled crossover study in which the effects of inhaled mometasone 400 microg once daily for 8 weeks on airway responsiveness and asthma quality of life were investigated. RESULTS: Patients with non-eosinophilic asthma had absence of eosinophils in the mucosa (median 4.4 cells/mm(2) vs 23 cells/mm(2) in eosinophilic asthma and 0 cells/mm(2) in normal controls; p = 0.03) and normal subepithelial layer thickness (5.8 microm vs 10.3 microm in eosinophilic asthma and 5.1 microm in controls, p = 0.002). Non-eosinophilic and eosinophilic asthma groups had increased mast cell numbers in the airway smooth muscle compared with normal controls (9 vs 8 vs 0 cells/mm(2), p = 0.016). Compared with placebo, 8 weeks of treatment with inhaled mometasone led to less improvement in methacholine PC(20) (0.5 vs 5.5 doubling concentrations, 95% CI of difference 1.1 to 9.1; p = 0.018) and asthma quality of life (0.2 vs 1.0 points, 95% CI of difference 0.27 to 1.43; p = 0.008). CONCLUSIONS: Non-eosinophilic asthma represents a pathologically distinct disease phenotype which is characterised by the absence of airway eosinophilia, normal subepithelial layer thickness and a poor short-term response to treatment with inhaled corticosteroids.

Total publications on this page: 300

Total citations for publications on this page: 15894