Dominick Shaw

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These guidelines have been replaced by British Guideline on the Management of Asthma.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 Superseded By 2012 Revision Of 2008 Guideline: British Guideline on the Management of Asthma.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.

Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma

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 μg 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/mm2 vs 23 cells/mm2 in eosinophilic asthma and 0 cells/mm2 in normal controls; p = 0.03) and normal subepithelial layer thickness (5.8 μm vs 10.3 μm in eosinophilic asthma and 5.1 μm 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/mm2, p = 0.016). Compared with placebo, 8 weeks of treatment with inhaled mometasone led to less improvement in methacholine PC20 (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.

The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma.

Background Assessment of eosinophilic airway inflammation may be helpful in the management of asthma. Nitric oxide (NO) has potential advantages as a tool to monitor airway inflammation although little is known about the relationship between NO and eosinophilic airway inflammation and the factors which influence it.

Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma.

Recent studies have suggested that alveolar nitric oxide (NO) concentration is a noninvasive test of distal lung inflammation. The current study determined whether alveolar NO concentration can be measured in patients with asthma of varying severity, tested the hypothesis that there is an association between alveolar NO and bronchoalveolar lavage (BAL) eosinophil count and determined whether refractory asthma is characterised by a raised alveolar NO concentration. Finally, the present authors assessed the effect of 2 weeks of prednisolone (30 mg q.d.) on alveolar NO concentration. Alveolar NO concentration was both measurable and repeatable in patients with refractory asthma. A positive correlation was found between alveolar NO concentration and BAL eosinophil count but not with bronchial wash or sputum eosinophil count. Alveolar NO concentration was increased in patients with refractory asthma (7.1 ppb) compared with mild-to-moderate asthma (3.4 ppb) and normal controls (3.4 ppb) and reduced by treatment with prednisolone. In conclusion, these findings support the hypothesis that alveolar nitric oxide is a measure of distal airway inflammation and suggest that distal lung inflammation is present in refractory asthma.

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach. This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements. Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids. Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach. Severe asthma results in more airway inflammation, worse symptoms and lower lung function, despite increased therapy http://ow.ly/QznR3

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.

Observational study of the natural history of eosinophilic bronchitis

Background Eosinophilic bronchitis is an important cause of chronic cough. Treatment with inhaled corticosteroids is associated with a short‐term improvement in cough and reduced sputum eosinophil count but the long‐term outcome is uncertain.

Efficacy and safety of maintenance and reliever combination budesonide–formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial

BACKGROUND The Single combination budesonide-formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations in patients, but whether the high doses of corticosteroid and β agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain. Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of β agonist, reduce the likelihood of patients to seek medical review when such episodes occurred, and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid. METHODS In this 24-week trial undertaken at four primary health-care practices and one hospital in New Zealand, patients (aged 16-65 years) with a recent asthma exacerbation were randomly assigned in a 1:1 ratio to the SMART or standard fixed-dose regimen. Treatment in the SMART group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily, delivered through a combination metered dose inhaler (MDI), with one extra actuation as needed for relief of symptoms; treatment in the standard group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily through a combination MDI with one to two actuations of salbutamol (100 μg per actuation) by MDI as needed for relief of symptoms. MDIs were monitored electronically to measure actual use of medication. The allocation sequence for randomisation was computer generated, with a block size of eight per site. Participants, investigators, and the statistician were not masked to group assignment. The primary outcome was the proportion of participants with at least one high-use episode of β agonist (more than eight actuations per day of budesonide-formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the standard group). Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000515099. FINDINGS 303 patients were randomly assigned to the SMART (n=151) or standard group (n=152). No significant difference was noted between the SMART and standard groups in the proportion of participants with at least one high-use episode of β agonist (84 [56%] vs 68 [45%], respectively, relative risk 1·24 [95% CI 0·99-1·56]; p=0·058). There were fewer days of high use in the SMART group (mean 5·1 days [SD 14·3] vs 8·9 days [20·9], relative rate 0·58 [0·39-0·88]; p=0·01). Of the patients who had at least one high-use episode, those in the SMART group had fewer days of high use without medical review (8·5 days [17·8] vs 18·3 days [24·8], 0·49 [0·31-0·75]; p=0·001). The SMART regimen resulted in higher inhaled corticosteroid exposure (943·5 μg budesonide per day [1502·5] vs 684·3 μg budesonide per day [390·5], respectively; ratio of means 1·22 [1·06-1·41]; p=0·006), but reduced oral corticosteroid exposure (77·5 mg prednisone [240·5] vs 126·6 mg prednisone [382·1], respectively; p=0·011), with no significant difference in composite systemic corticosteroid exposure (793·7 mg prednisone equivalent per year [893·1] vs 772·1 mg prednisone equivalent per year [1062·7], respectively; 1·03 [0·86-1·22]; p=0·76). Participants in the SMART group had fewer severe asthma exacerbations (35 [weighted mean rate per year 0·53] vs 66 [0·97]; relative rate 0·54 [0·36-0·82]; p=0·004). INTERPRETATION The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations. FUNDING Health Research Council of New Zealand.

Inhaled Corticosteroids and the Risk of Pneumonia in People With Asthma: A Case-Control Study

BACKGROUND In clinical trials, the use of inhaled corticosteroids is associated with an increased risk of pneumonia in people with COPD, but whether the same is true for people with asthma is not known. METHODS With the use of primary care data from The Health Improvement Network, we identified people with asthma, and from this cohort, we identified patients with pneumonia or lower respiratory tract infection and age- and sex-matched control subjects. Conditional logistic regression was used to determine the association between the dose and type of inhaled corticosteroid and the risk of pneumonia or lower respiratory tract infection. RESULTS A dose-response relationship was found between the strength of inhaled corticosteroid dose and risk of pneumonia or lower respiratory tract infection (P < .001 for trend) such that after adjusting for confounders, people receiving the highest strength of inhaled corticosteroid (≥ 1,000 μg) had a 2.04 (95% CI, 1.59-2.64) increased risk of pneumonia or lower respiratory tract infection compared with those with asthma who did not have a prescription for inhaled corticosteroids within the previous 90 days. CONCLUSIONS People with asthma receiving inhaled corticosteroids are at an increased risk of pneumonia or lower respiratory infection, with those receiving higher doses being at greater risk. Pneumonia should be considered as a possible side effect of inhaled corticosteroids, and the lowest possible dose of inhaled corticosteroids should be used in the management of asthma.

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts

U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life http://ow.ly/RrrGE