Simone Hashimoto

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

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

Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial

Background In patients with prednisone-dependent asthma the dose of oral corticosteroids should be adjusted to the lowest possible level to reduce long-term adverse effects. However, the optimal strategy for tapering oral corticosteroids is unknown. Objective To investigate whether an internet-based management tool including home monitoring of symptoms, lung function and fraction of exhaled nitric oxide (FENO) facilitates tapering of oral corticosteroids and leads to reduction of corticosteroid consumption without worsening asthma control or asthma-related quality of life. Methods In a 6-month pragmatic randomised prospective multicentre study, 95 adults with prednisone-dependent asthma from six pulmonary outpatient clinics were allocated to two tapering strategies: according to conventional treatment (n=43) or guided by a novel internet-based monitoring system (internet strategy) (n=52). Primary outcomes were cumulative sparing of prednisone, asthma control and asthma-related quality of life. Secondary outcomes were forced expiratory volume in 1 s (FEV1), exacerbations, hospitalisations and patients satisfaction with the tapering strategy. Results Median cumulative sparing of prednisone was 205 (25–75th percentile −221 to 777) mg in the internet strategy group compared with 0 (−497 to 282) mg in the conventional treatment group (p=0.02). Changes in prednisone dose (mixed effect regression model) from baseline were −4.79 mg/day and +1.59 mg/day, respectively (p<0.001). Asthma control, asthma-related quality of life, FEV1, exacerbations, hospitalisations and satisfaction with the strategy were not different between groups. Conclusions An internet-based management tool including home monitoring of symptoms, lung function and FENO in severe asthma is superior to conventional treatment in reducing total corticosteroid consumption without compromising asthma control or asthma-related quality of life. Clinical trial registration number Clinical trial registered with http://www.trialregister.nl (Netherlands Trial Register number 1146).

High-altitude treatment in atopic and nonatopic patients with severe asthma

The beneficial effects of high-altitude treatment in asthma have been attributed to allergen avoidance. Recent evidence shows that this treatment also improves airway inflammation in nonallergic patients. We hypothesised that high-altitude treatment is clinically equally effective in patients with severe refractory asthma, with or without allergic sensitisation. In a prospective observational cohort study, 137 adults with severe refractory asthma (92 with allergic sensitisation), referred for high-altitude (1,600 m) treatment in Davos, Switzerland, were consecutively included. We measured asthma control (Asthma Control Questionnaire (ACQ)), asthma-related quality of life (Asthma-Related Quality of Life Questionnaire (AQLQ)), sino-nasal symptoms (Sino-Nasal Outcome Test (SNOT-20)), medication requirement, postbronchodilator (post-BD) forced expiratory volume in 1 s (FEV1), 6-min walking distance (6MWD), total immunoglobulin (Ig)E, blood eosinophils and exhaled nitric oxide fraction (FeNO) at admission and after 12 weeks. Sensitised and nonsensitised patients showed similar improvements in ACQ (-1.4 and -1.5, respectively; p=0.79), AQLQ (1.6 and 1.5, respectively; p=0.94), SNOT-20 (-0.7 and -0.5, respectively; p=0.18), post-BD FEV1 (6.1% and 5.8% pred, respectively; p=0.87), 6MWD (+125 m and +147 m, respectively; p=0.43) and oral steroids (40% versus 44%, respectively; p=0.51). Sensitised patients showed a larger decrease in total IgE, blood eosinophils and FeNO. High-altitude treatment improves clinical and functional parameters, and decreases oral corticosteroid requirement in patients with severe refractory asthma, irrespective of allergic sensitisation.

Anxiety, depression and personality traits in severe, prednisone-dependent asthma

BACKGROUND Anxiety and depression are prevalent in patients with asthma, and associated with more exacerbations and increased health care utilization. Since psychiatric intervention might improve asthma control, we examined whether patients with severe, prednisone-dependent asthma are at higher risk of these disorders than patients with severe non-prednisone dependent asthma or mild-moderate asthma, and whether they exhibit different personality traits. METHODS Sixty-seven adults with severe prednisone-dependent asthma, 47 with severe non-prednisone dependent and 73 patients with mild-moderate asthma completed the HADS depression and anxiety subscale and the NEO-FFI for personality traits. In addition, asthma duration, body mass index and FEV1 were measured. RESULTS The prevalence of clinically significant depressive symptoms (9% vs. 0 vs. 0%; p = 0.009) and anxiety symptoms (19% vs. 6.4 vs. 5.5%; p = 0.01), was higher in patients with severe, prednisone-dependent asthma than in patients with severe non-prednisone dependent or mild-moderate asthma. Patients with prednisone-dependent asthma were respectively 3.4 (95%CI: 1.0-10.8 p = 0.04) and 3.5 (95%CI: 1.3-9.6 p = 0.01) times more likely to have significant depression symptoms and 1.6 (95%CI: 0.7-3.7, p = 0.2) and 2.5 (95%CI: 01.1-5.5, p = 0.02) times more likely to have symptoms of anxiety than patients with severe non-prednisone dependent or mild-moderate asthma. There were no differences found in personality traits between the 3 groups. CONCLUSION Patients with severe, prednisone-dependent asthma have more often psychological distress as compared to patients with severe non-prednisone dependent or mild-moderate asthma.

Telemanagement in asthma: an innovative and effective approach.

Purpose of reviewInformation and communication technology (ICT) could potentially help to reduce the considerable burden of asthma that still exists despite wide availability of effective therapies. Telemanagement is an interactive and proactive management approach consisting of an ongoing partnership of patients and professionals supported by ICT and focused on clinical outcomes and patient goals in the individual. This review highlights recent developments in telemanagement in the ongoing management of patients with asthma focused on the effectiveness, cost-effectiveness and implementation of telemanagement in asthma care. Recent findingsAn increasing number of studies address the effectiveness of components or a comprehensive telemanagement intervention in children and adults with mild to severe asthma. Telemanagement of asthma in the individual patient includes key components of asthma management, such as education, self-monitoring, goal setting, written action plans and regular medical review. Such a comprehensive telemanagement approach is effective in improving quality of life and clinical outcomes, especially in adult patients with moderate to severe asthma. ConclusionTelemanagement of asthma can be an effective and cost-effective approach tailored to the individual patient needs. More research is needed on the long-term effectiveness and cost-effectiveness of telemanagement of patients with asthma under real-world conditions and on effective implementation strategies.

Altered exhaled biomarker profiles in children during and after rhinovirus-induced wheeze

Preschool rhinovirus-induced wheeze is associated with an increased risk of asthma. In adult asthma, exhaled volatile organic compounds (VOC) are associated with inflammatory activity. We therefore hypothesised that acute preschool wheeze is accompanied by a differential profile of exhaled VOC, which is maintained after resolution of symptoms in those children with rhinovirus-induced wheeze. We included 178 children (mean±sd age 22±9 months) from the EUROPA cohort comparing asymptomatic and wheezing children during respiratory symptoms and after recovery. Naso- and oropharyngeal swabs were tested for rhinovirus by quantitative PCR. Breath was collected via a spacer and analysed using an electronic nose. Between-group discrimination was assessed by constructing a 1000-fold cross-validated receiver operating characteristic curve. Analyses were stratified by rhinovirus presence/absence. Wheezing children demonstrated a different VOC profile when compared with asymptomatic children (p<0.001), regardless of the presence (area under the curve (AUC) 0.77, 95% CI 0.07) or absence (AUC 0.81, 95% CI 0.05) of rhinovirus. After symptomatic recovery, discriminative accuracy was maintained in children with rhinovirus-induced wheeze (AUC 0.84, 95% CI 0.06), whereas it dropped significantly in infants with non-rhinovirus-induced wheeze (AUC 0.67, 95% CI 0.06). Exhaled molecular profiles differ between preschool children with and without acute respiratory wheeze. This appears to be sustained in children with rhinovirus-induced wheeze after resolution of symptoms. Therefore, exhaled VOC may qualify as candidate biomarkers for early signs of asthma. Children with rhinovirus-induced wheeze have altered exhaled biomarkers both during symptoms and after resolution http://ow.ly/C6vWT

Targeting IL-5 in severe asthma: a DREAM come true?

626 www.thelancet.com Vol 380 August 18, 2012 It is now accepted that severe asthma is not one phenotype but a heterogeneous mixture of syndromes in which various clinical, physiological, and infl ammatory markers determine disease severity. In the past few years, several attempts have been made to categorise severe asthma into subphenotypes by application of unsupervised cluster analyses. The most prominent phenotype that has emerged is characterised by eosinophilic airway infl ammation despite the use of high-intensity anti-infl ammatory treatment. About a third of patients with severe asthma have this refractory eosinophilic asthma phenotype, which is associated with frequent asthma exacerbations, fi xed airfl ow limitation, air trapping, and nasal polyposis. Patients with this phenotype require frequent bursts of, or even depend on, daily oral corticosteroids, which lead to serious adverse eff ects and a poor quality of life. The importance of eosinophils in the pathogenesis of severe asthma was confi rmed after introduction of antibodies against interleukin 5 (IL-5) as a possible treatment for patients with refractory eosinophilic asthma. IL-5 is a key factor in regulation of the growth, diff erentiation, recruitment, activation, and survival of eosinophils. Findings from two proof-of-concept studies with mepolizumab—a humanised monoclonal antibody against IL-5—suggested that this drug is eff ective as a steroid-sparing agent, reduces the frequency of severe exacerbations, and improves quality of life in patients with severe refractory eosinophilic asthma. In The Lancet, Ian Pavord and colleagues provide further convincing evidence for mepolizumab as an eff ective, well tolerated, and safe treatment in severe eosinophilic asthma. In the multicentre, double-blind DREAM trial, they gave 616 patients with poorly controlled asthma and evidence of eosinophilic infl ammation one of three diff erent doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo every 4 weeks for 12 months. Compared with placebo, mepolizumab reduced the rate of clinically signifi cant asthma exacerbations, the primary outcome measure (48% reduction with 75 mg, 95% CI 31–61%; 39% with 250 mg, 19–54%; and 52% with 750 mg, 36–64%). Visits to emergency departments and admissions also fell, although with varying statistical support (60% reduction with 75 mg, 19–81%; 42% with 250 mg, –12% to 70%; 48% with 750 mg, –2% to 73%). These eff ects are very promising and give hope to many patients for whom no eff ective drugs are available without signifi cant adverse eff ects. However, several questions remain unanswered. First, mepolizumab reduced the rate of exacerbations, as in earlier studies, but did not produce consistent improvements in symptoms or lung function. This striking dissociation between clinical and functional measurements on the one hand and exacerbations on the other suggests that they represent diff erent aspects of the disease, with separate underlying pathophysiology. Lung function and asthma symptoms could be closely related to variations in airway calibre because of contraction of hyper-responsive smooth muscles, whereas severe exacerbations are elicited by recurrences of eosinophilic infl ammation in large and small airways. As a result, for comprehensive treatment of patients with severe refractory eosinophilic asthma, combination treatment should target both IL-5 and smooth muscle. Second, to whom should mepolizumab be prescribed? After Pavord and colleagues’ study, the best candidates for successful treatment are patients with asthma and active eosinophilic infl ammation despite adequate intake of high doses of inhaled corticosteroids, particularly those with frequent exacerbations and a good response to oral corticosteroids. Therefore, targeted treatment against IL-5 is not suitable for patients with other subphenotypes of severe asthma, such as the non-eosinophilic obese or β2-agonistdependent phenotypes. Mepolizumab could also play a part in eosinophilic diseases other than severe asthma. Individuals with refractory eosinophilia represent a substantial proportion of non-smoking patients with severe asthma, but eosinophilia is also common in patients with asthma who are past or present smokers and in those with chronic obstructive pulmonary disease and frequent exacerbations. Therefore, investigation of the eff ects of treatment targeting IL-5 in these patient populations could be interesting. Another category of patients to consider is those with refractory eosinophilic nasal polyposis and only mild to moderate asthma. Nasal polyposis is a known risk factor of late-onset asthma and often precedes progression to severe forms Targeting IL-5 in severe asthma: a DREAM come true?

Prevalence of rhinoviruses in young children of an unselected birth cohort from the Netherlands

Abstract Rhinovirus (RV) is a frequent pathogen in young children, eliciting symptoms ranging from common colds to wheezing illnesses and lower respiratory tract infections. The recently identified RV-C seems to be associated with asthma exacerbations and more severe disease, but results vary. We studied the prevalence and severity of infection with RV in an unselected birth cohort. Children with respiratory symptoms entered the symptomatic arm of the cohort and were compared with asymptomatic children. Severity of wheezing and other respiratory symptoms was registered. Respiratory viruses were evaluated using throat and nasopharyngeal swabs on first presentation and after recovery (wheezing children). RV genotyping was performed on RV-PCR positive samples. RV was the most prevalent respiratory virus and was found in 58/140 symptomatic children (41%), 24/96 (25%) control children and 19/74 (26%) wheezing symptomatic children after recovery (p <0.05) and did not differ between wheezing and non-wheezing symptomatic children—respectively, 42% (38/90) and 40% (20/50). RV-A was the most commonly detected species (40/68, 59%), followed by RV-C (22/68, 32%) and RV-B (6/68, 9%). RV-B was more frequently detected in asymptomatic children (5/6, p <0.05). There was no significant difference in the frequency of RV species between wheezing and non-wheezing symptomatic children. Children with RV mono-infection had more severe symptoms, but no association between RV species and severity of disease was seen. In an unselected birth cohort from the Netherlands with mild respiratory disease RV was the most prevalent respiratory virus. RV(-C) infection was not associated with more severe disease or wheezing.