Mike Thomas

Cluster Analysis and Clinical Asthma Phenotypes

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.

British guideline on the management of asthma: A national clinical guideline

These guidelines have been replaced by British Guideline on the Management of Asthma. A national clinical guideline. Superseded By 2012 Revision Of 2008 Guideline: British Guideline on the Management of Asthma. Thorax 2008 May; 63(Suppl 4): 1–121.

Phase III Study of Carboplatin and Paclitaxel Alone or With Sorafenib in Advanced Non–Small-Cell Lung Cancer

PURPOSE This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2) (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. RESULTS Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.

Phase III Trial of Vandetanib Compared With Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

PURPOSE Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This phase III study assessed the efficacy of vandetanib versus erlotinib in unselected patients with advanced non-small-cell lung cancer (NSCLC) after treatment failure with one to two prior cytotoxic chemotherapy regimens. PATIENTS AND METHODS One thousand two hundred forty patients were randomly assigned to receive vandetanib 300 mg/d (n = 623) or erlotinib 150 mg/d (n = 617). The primary objective was to show superiority in progression-free survival (PFS) for vandetanib versus erlotinib. If the difference did not reach statistical significance for superiority, a noninferiority analysis was conducted. RESULTS There was no significant improvement in PFS for patients treated with vandetanib versus erlotinib (hazard ratio [HR], 0.98; 95.22% CI, 0.87 to 1.10; P = .721); median PFS was 2.6 months for vandetanib and 2.0 months for erlotinib. There was also no significant difference for the secondary end points of overall survival (HR, 1.01; P = .830), objective response rate (both 12%), and time to deterioration of symptoms for pain (HR, 0.92; P = .289), dyspnea (HR, 1.07; P = .407), and cough (HR, 0.94; P = .455). Both agents showed equivalent PFS and overall survival in a preplanned noninferiority analysis. Adverse events (AEs; any grade) more frequent with vandetanib than erlotinib included diarrhea (50% v 38%, respectively) and hypertension (16% v 2%, respectively); rash was more frequent with erlotinib than vandetanib (38% v 28%, respectively). The overall incidence of grade ≥ 3 AEs was also higher with vandetanib than erlotinib (50% v 40%, respectively). CONCLUSION In patients with previously treated advanced NSCLC, vandetanib showed antitumor activity but did not demonstrate an efficacy advantage compared with erlotinib. There was a higher incidence of some AEs with vandetanib.

Treatable traits: toward precision medicine of chronic airway diseases

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. A discussion of the concept of “treatable traits” as a way towards precision medicine of chronic airway diseases http://ow.ly/UbJAm

Effect of a concomitant diagnosis of allergic rhinitis on asthma‐related health care use by adults

Background Asthma and allergic rhinitis (AR) frequently coexist, but have usually been studied separately in health economic analyses.

The asthma control test(TM) (ACT) as a predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey

AIMS To evaluate whether the Asthma Control Test (ACT) score is predictive of Global Initiative for Asthma (GINA) guideline-defined classification levels of asthma control. The ACT is a validated, 5-item, patient-completed measure of asthma control with a recall period of four weeks. METHODS Cross-sectional survey comparing ACT score and GINA classification of asthma control among 2949 patients attending primary care physicians and specialists in France, Germany, Italy, Spain, the UK, and the USA. RESULTS The area under the receiver operating characteristics curve for ACT score predicting GINA control was 0.84 (95% CI 0.82-0.85). An ACT score of <19 (not well-controlled asthma) correctly predicted GINA-defined partly controlled/uncontrolled asthma 94% of the time, while an ACT score of >20 predicted GINA-defined controlled asthma 51% of the time, with kappa statistic of 0.42, representing moderate agreement. CONCLUSIONS An ACT score <19 is useful for identifying patients with poorly controlled asthma as defined by GINA.

EPOS Primary Care Guidelines: European Position Paper on the Primary Care Diagnosis and Management of Rhinosinusitis and Nasal Polyps 2007 - a summary

This paper is a summary of the 2007 European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS)1 which was published in Rhinology in 2007. In order to widen dissemination of the EP3OS paper, the editors of Rhinology and the Primary Care Respiratory Journal (PCRJ) have agreed to publish this summary - which is focussed on the needs of general practitioners and community-based non-specialist clinicians - in the PCRJ. In the EP3OS process, an evidence-based methodology was used to identify evidence and to grade recommendations for clinical practice for the management of rhinosinusitis. The EP3OS Taskforce was commissioned by the European Academy of Allergology and Clinical Immunology (EAACI) with the aims of: * Presenting specialist and generalist clinicians with an updated summary of knowledge of rhinosinusitis and nasal polyposis * Providing clinicans with an evidence-based summary of diagnostic methods appropriate for specialist and generalist settings * Providing evidence-based recommendations for management in specialist and generalist settings * Proposing guidance for definitions and outcome measurements in clinical practice and in research in different settings. The current document aims to distil the information presented in the full EP3OS document1 into a shorter and more concise format suitable for use in primary care generalist settings. The summary recommendations for generalists are that clinicians should be aware that rhinitis and sinusitis usually co-exist, and that management strategies should encompass this. Acute rhinosinusitis is an inflammatory condition that may be diagnosed on the basis of acute symptoms of nasal blockage, obstruction, congestion with or without facial pain or reduced smell; many episodes are self-limiting, but where symptoms persist or increase after five days, topical nasal steroids may be considered, with addition of antibiotics in patients with more severe or increasing symptoms. Non-resolution in 14 days, or the presence of atypical symptoms, should prompt consideration of referral to specialist care. Chronic rhinosinusitis occurs when symptoms have been present for >12 weeks, and anterior rhinoscopy or more detailed endoscopy should be performed to identify polyps. Topical nasal corticosteroids, nasal douching, and use of antihistamines in allergic patients, may be used in patients without, or with less symptomatic, polyps; referral to specialist care is needed for patients whose symptoms do not respond or who have large polyps.

Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study

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.

Breathing exercises for asthma: a randomised controlled trial

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.