Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry

Introduction: Refractory asthma represents a significant unmet clinical need where the evidence base for the assessment and therapeutic management is limited. The British Thoracic Society (BTS) Difficult Asthma Network has established an online National Registry to standardise specialist UK difficult asthma services and to facilitate research into the assessment and clinical management of difficult asthma.
Methods: Data from 382 well characterised patients, who fulfilled the American Thoracic Society definition for refractory asthma attending four specialist UK centres—Royal Brompton Hospital, London, Glenfield Hospital, Leicester, University Hospital of South Manchester and Belfast City Hospital—were used to compare patient demographics, disease characteristics and healthcare utilisation.
Results: Many demographic variables including gender, ethnicity and smoking prevalence were similar in UK centres and consistent with other published cohorts of refractory asthma. However, multiple demographic factors such as employment, family history, atopy prevalence, lung function, rates of hospital admission/unscheduled healthcare visits and medication usage were different from published data and significantly different between UK centres. General linear modelling with unscheduled healthcare visits, rescue oral steroids and hospital admissions as dependent variables all identified a significant association with clinical centre; different associations were identified when centre was not included as a factor.
Conclusion: Whilst there are similarities in UK patients with refractory asthma consistent with other comparable published cohorts, there are also differences, which may reflect different patient populations. These differences in important population characteristics were also identified within different UK specialist centres. Pooling multicentre data on subjects with refractory asthma may miss important differences and potentially confound attempts to phenotype this population.

Coxiella burnetii (Q fever) seroprevalence in cattle

Human cases of Q fever appear to be common in Northern Ireland compared to the rest of the British Isles. The purpose of this study was to describe the seroepidemiology of Coxiella burnetii infection in cattle in Northern Ireland in terms of seroprevalence and determinants of infection. A total of 5182 animals (from a stratified systematic random sample of 273 herds) were tested with a commercial C. burnetii phase 2 IgG ELISA. A total of 6.2% of animals and 48.4% of herds tested positively. Results from a multilevel logistic regression model indicated that the odds of cattle being infected with Q fever increased with age, Friesian breed, being from large herds and from dairy herds. Large dairy herd animal prevalence was 12.5% compared to 2.1% for small beef herds. Preliminary seroprevalence in sheep (12.3%), goats (9.3%), pigs (0%) rats (9.7%) and mice (3.2%) using indirect immunofluorescence is reported.

Glucose and citrate reduce the permeability changes caused by indomethacin in humans

Nonsteroidal anti-inflammatory drug (NSAID)-induced increased intestinal permeability appears to be a prerequisite for NSAID enteropathy. It has been suggested that early metabolic events leading to the permeability changes may involve inhibition of glycolysis and the tricarboxylic acid cycle, in which case the coadministration of glucose and citrate (the substrates for these metabolic pathways) with indomethacin may afford some protection. The present study, using a combined intestinal absorption-permeability test including 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and [51Cr]ethylene-diaminetetraacetic acid (EDTA) as test probes and the differential urine excretion ratio of [51Cr]-EDTA/L-rhamnose, showed that indomethacin (50 + 75 mg) increased intestinal permeability. A formulation of indomethacin containing 15 mg glucose and 15 mg citrate to each milligram of indomethacin did not increase intestinal permeability significantly above baseline values. When given alone with indomethacin, neither glucose nor citrate (45 mg to each milligram of indomethacin) had any protective effects. Pharmokinetic studies showed that the effects of glucose and citrate cannot be explained on the basis of altered drug absorption. These results suggest a new approach to reducing the small intestinal side effects of NSAIDs.

Clinical management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult Asthma Registry

Refractory asthma represents a significant unmet clinical need. Data from a national online registry audited clinical outcome in 349 adults with refractory asthma from four UK specialist centres in the British Thoracic Society Difficult Asthma Network. At follow-up, lung function improved, with a reduction in important healthcare outcomes, specifically hospital admission, unscheduled healthcare visits and rescue courses of oral steroids. The most frequent therapeutic intervention was maintenance oral corticosteroids and most steroid sparing agents (apart from omalizumab) demonstrated minimal steroid sparing benefit. A significant unmet clinical need remains in this group, specifically a requirement for therapies which reduce systemic steroid exposure.

Obesity associated severe asthma represents a distinct clinical phenotype - Analysis of the British Thoracic Society Difficult Asthma Registry patient cohort according to body mass index

BACKGROUND: Obesity has emerged as a risk factor for the development of asthma and it may also influence asthma control and airways inflammation. However, the role of obesity in severe asthma remains unclear. OBJECTIVE: To explore the association between obesity (defined by BMI) and severe asthma. METHODS: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics and healthcare utilisation between three body mass index (BMI) categories (normal weight: 18.5 -24.99, overweight: 25 -29.99, obese: =30) in a well characterised group of severe asthmatic adults. RESULTS: The study population consisted of 666 severe asthmatics with a median BMI of 29.8 (interquartile range 22.5 -34.0). The obese group exhibited greater asthma medication requirements in terms of maintenance corticosteroid therapy (48.9% versus 40.4% and 34.5% in the overweight and normal weight groups, respectively), steroid burst therapy and short-acting ß2-agonist (SABA) use per day. Significant differences were seen with gastro-oesophageal reflux disease (GORD) (53.9% versus 48.1% and 39.7% in the overweight and normal weight groups, respectively) and proton pump inhibitor (PPI) use. Bone density scores were higher in the obese group, whilst pulmonary function testing revealed a reduced FVC and raised Kco. Serum IgE levels decreased with increasing BMI and the obese group were more likely to report eczema, but less likely to have a history of nasal polyps. CONCLUSIONS: Severe asthmatics display particular characteristics according to BMI that support the view that obesity associated severe asthma may represent a distinct clinical phenotype.1Royal Brompton Hospital, London, UK;2Department of Computing, Imperial College, UK3Airways Disease, National Heart & Lung Institute, Imperial College, UK;4Centre for infection and immunity, Queen's University of Belfast, UK;5University of Leicester, UK;6The University of Manchester and University Hospital of South Manchester, UK;7Birmingham Heartlands Hospital, University of Birmingham, UK;8Gartnavel General Hospital, University of Glasgow, UK;9Glasgow Royal Infirmary, Glasgow, UKCorrespondence: Dr Andrew N. Menzies-Gow, Royal Brompton Hospital, Fulham Road, London SW3 6HP.

A longitudinal analysis of estimation, counting skills, and mathematical ability across the first school year

In response to claims that the quality (and in particular linearity) of children's mental representation of number acts as a constraint on number development, we carried out a longitudinal assessment of the relationships between number line estimation, counting, and mathematical abilities. Ninety-nine 5-year-olds were tested on 4 occasions at 3 monthly intervals. Correlations between the 3 types of ability were evident, but while the quality of children's estimations changed over time and performance on the mathematical tasks improved over the same period, changes in one were not associated with changes in the other. In contrast to the earlier claims that the linearity of number representation is potentially a unique contributor to children's mathematical development, the data suggest that this variable is not significantly privileged in its impact over and above simple procedural number skills. We propose that both early arithmetic success and estimating skill are bound closely to developments in counting ability.

Clinical outcomes and inflammatory biomarkers in current smokers and exsmokers with severe asthma

Clinical outcomes are worse in current smokers and exsmokers with mild-to-moderate asthma compared with never smokers, but little is known about the influence of smoking status in patients with severe asthma.

Integrated care pathways for airway diseases (AIRWAYS-ICPs)

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).

Research in Progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

The UK Refractory Asthma Stratification Programme(RASP-UK) will explore novel biomarker stratificationstrategies in severe asthma to improve clinicalmanagement and accelerate development of newtherapies. Prior asthma mechanistic studies have notstratified on inflammatory phenotype and theunderstanding of pathophysiological mechanisms inasthma without Type 2 cytokine inflammation is limited.RASP-UK will objectively assess adherence tocorticosteroids (CS) and examine a novel compositebiomarker strategy to optimise CS dose; this will alsoaddress what proportion of patients with severe asthmahave persistent symptoms without eosinophilic airwaysinflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.

The cost of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma Registry

Severe refractory asthma poses a substantial burden in terms of healthcare costs but relatively little is known about the factors which drive these costs. This study uses data from the British Thoracic Society Difficult Asthma Registry (n=596) to estimate direct healthcare treatment costs from an National Health Service perspective and examines factors that explain variations in costs. Annual mean treatment costs among severe refractory asthma patients were £2912 (SD £2212) to £4217 (SD £2449). Significant predictors of costs were FEV1% predicted, location of care, maintenance oral corticosteroid treatment and body mass index. Treating individuals with severe refractory asthma presents a substantial cost to the health service.

Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry

Objective: To determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma.
Design: Cross-sectional observational study.Setting The primary care Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry.
Participants: Optimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)—severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control).
Main outcome measures: Prevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group.
Results: 748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified.

Conclusions: Oral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments.