Euan J. Cameron

Digital Asthma Self-Management Interventions: A Systematic Review

Background Many people with asthma tolerate symptoms and lifestyle limitations unnecessarily by not utilizing proven therapies. Better support for self-management is known to improve asthma control, and increasingly the Internet and other digital media are being used to deliver that support. Objective Our goal was to summarize current knowledge, evidenced through existing systematic reviews, of the effectiveness and implementation of digital self-management support for adults and children with asthma and to examine what features help or hinder the use of these programs. Methods A comprehensive search strategy combined 3 facets of search terms: (1) online technology, (2) asthma, and (3) self-management/behavior change/patient experience. We undertook searches of 14 databases, and reference and citation searching. We included qualitative and quantitative systematic reviews about online or computerized interventions facilitating self-management. Title, abstract, full paper screening, and quality appraisal were performed by two researchers independently. Data extraction was undertaken using standardized forms. Results A total of 3810 unique papers were identified. Twenty-nine systematic reviews met inclusion criteria: the majority were from the United States (n=12), the rest from United Kingdom (n=6), Canada (n=3), Portugal (n=2), and Australia, France, Spain, Norway, Taiwan, and Greece (1 each). Only 10 systematic reviews fulfilled pre-determined quality standards, describing 19 clinical trials. Interventions were heterogeneous: duration of interventions ranging from single use, to 24-hour access for 12 months, and incorporating varying degrees of health professional involvement. Dropout rates ranged from 5-23%. Four RCTs were aimed at adults (overall range 3-65 years). Participants were inadequately described: socioeconomic status 0/19, ethnicity 6/19, and gender 15/19. No qualitative systematic reviews were included. Meta-analysis was not attempted due to heterogeneity and inadequate information provision within reviews. There was no evidence of harm from digital interventions. All RCTs that examined knowledge (n=2) and activity limitation (n=2) showed improvement in the intervention group. Digital interventions improved markers of self care (5/6), quality of life (4/7), and medication use (2/3). Effects on symptoms (6/12) and school absences (2/4) were equivocal, with no evidence of overall benefits on lung function (2/6), or health service use (2/15). No specific data on economic analyses were provided. Intervention descriptions were generally brief making it impossible to identify which specific “ingredients” of interventions contribute most to improving outcomes. Conclusions Digital self-management interventions show promise, with evidence of beneficial effects on some outcomes. There is no evidence about utility in those over 65 years and no information about socioeconomic status of participants, making understanding the “reach” of such interventions difficult. Digital interventions are poorly described within reviews, with insufficient information about barriers and facilitators to their uptake and utilization. To address these gaps, a detailed quantitative systematic review of digital asthma interventions and an examination of the primary qualitative literature are warranted, as well as greater emphasis on economic analysis within trials.

Long‐term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments

Macrolide antibiotics were discovered over 50 years ago and following their use as antimicrobials it became apparent that this group of antibiotics also possessed anti‐inflammatory properties. Subsequent clinical trials showed benefits of macrolides as long‐term adjuncts in the treatment of a spectrum of chronic inflammatory respiratory diseases, particularly diffuse panbronchiolitis, cystic fibrosis, post‐transplant bronchiolitis obliterans and more recently chronic obstructive pulmonary disease (COPD). The evidence for efficacy of macrolides in the long‐term treatment of chronic asthma and bronchiectasis is less well established. The mechanism(s) of action of macrolides in the treatment of these diseases remains unexplained, but may be due to their antibacterial and/or anti‐inflammatory actions, which include reductions in interleukin‐8 production, neutrophil migration and/or function. Macrolides have additional potentially beneficial properties including anti‐viral actions and an ability to restore corticosteroid sensitivity. The increased prescribing of macrolides for long‐term treatment could result in the development of microbial resistance and adverse drug effects. New macrolides have been developed which do not possess any antimicrobial activity and hence lack the ability to produce microbial resistance, but which still retain immunomodulatory effects. Potentially novel macrolides may overcome a significant barrier to the use of this type of drug for the long‐term treatment of chronic inflammatory airway diseases.

Peripheral blood dendritic cell subtypes are significantly elevated in subjects with asthma

Background Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non‐smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles.

Randomised controlled trial of azithromycin in smokers with asthma

To the Editor: Smokers with asthma have poor symptom control, accelerated decline in lung function and an attenuated response to corticosteroids compared to nonsmokers with asthma [1]. There is an unmet need for alternative or additional drugs for smokers with asthma who are unable to stop smoking [2]. Macrolide antibiotics have anti-inflammatory activity [3] and in clinical studies there is good evidence for efficacy in the treatment of diffuse pan-bronchiolitis and cystic fibrosis, as well as in preventing chronic rejection after lung transplantation [4, 5]. In asthma, chronic treatment is associated with a reduction in bronchial hyperreactivity in mild-to-moderate asthma [6] and in exacerbation rates in non-eosinophilic severe asthma [7]. To date, no studies have examined the efficacy of macrolide antibiotics exclusively in current smokers with asthma. A randomised double-blind parallel-group trial compared azithromycin, 250 mg per day, with placebo for 12 weeks. All subjects were aged 18–70 years, were current smokers (≥5 pack-years history) with chronic asthma (>1 year duration; defined by international criteria [8]) and had to be free of exacerbation and respiratory tract infection for a minimum 6-week period prior to randomisation. A baseline visit was performed following a 4-week run-in period on inhaled corticosteroid (ICS) therapy equivalent to 400 μg beclometasone ± a long-acting β2-agonist (LABA). Ethical approval was obtained and all subjects provided written informed consent. Study visits were performed at 4, 8 and 12 weeks. Clinic visit peak expiratory flow (PEF) after 12 weeks treatment was the primary outcome measure. A sample size of 68 …

Challenges of treating asthma in people who smoke

Cigarette smoking is common in asthma and is associated with poor symptom control and a reduced therapeutic response to inhaled and oral corticosteroids as compared with nonsmokers with asthma. This review examines the range of adverse health effects of smoking in asthma, the inflammatory mechanisms that may influence the efficacy of current drugs and discusses potential future therapeutic directions.

Effects of a FLAP inhibitor, GSK2190915, in asthmatics with high sputum neutrophils

Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils. Patients received 14 (range 13-16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design (N = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits. GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: -0.9 [-12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB4 and urine LTE4, but did not alter clinical endpoints. There were no safety issues. Despite suppressing the target mediator LTB4, FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.

Effectiveness of bronchial thermoplasty in severe asthma in ‘real life’ patients compared with those recruited to clinical trials in the same centre:

Published information on the effectiveness of bronchial thermoplasty (BT) for severe asthma in ‘real life’ patients is limited. We compared safety and efficacy outcomes 12 months post procedure in 10 clinic patients and 15 patients recruited to clinical trials of BT at the same centre. Baseline asthma severity was greater in the clinic group. Adverse events were similar. Clinical improvements occurred in 50% of the clinic patients compared with 73% of the research patients.

Increased sputum endotoxin levels are associated with an impaired lung function response to oral steroids in asthmatic patients.

BACKGROUND Airway endotoxin might contribute to corticosteroid insensitivity in asthmatic patients. OBJECTIVE Because cigarette smoke contains endotoxin, we tested the hypothesis that sputum endotoxin concentrations are increased in cigarette smokers and that endotoxin concentrations are associated with corticosteroid insensitivity in asthmatic patients. METHODS Sixty-nine asthmatic patients (never smokers, smokers, and exsmokers) and 20 healthy subjects (never smokers and smokers) were recruited. Fifty-three asthmatic patients received a 2-week course of oral dexamethasone. Serum and induced sputum endotoxin and cytokine concentrations were quantified by using an enzyme immunoassay. RESULTS Median (interquartile range [IQR]) sputum endotoxin concentration were not significantly different between asthmatic never smokers (184 endotoxin units [EU]/mL; IQR, 91-310 EU/mL), exsmokers (123 EU/mL; IQR, 39-207 EU/mL), and smokers (177 EU/mL; IQR, 41-772 EU/mL; P = .703) and healthy subjects (164 EU/mL; IQR, 106-373 EU/mL). The lung function response to oral corticosteroids decreased with increasing sputum endotoxin concentrations in the never smokers (linear regression α = .05, Spearman r = -0.503, P = .009) but not in smokers (α = .587, r = -0.282, P = .257), as confirmed by using multiple regression analysis. Asthmatic smokers had higher concentrations of serum endotoxin than asthmatic nonsmokers (0.25 EU/mL [IQR, 0.09-0.39 EU/mL] vs 0.08 EU/mL [IQR, 0.05-0.19 EU/mL], P = .042) unrelated to steroid insensitivity or serum cytokine concentrations. In the asthmatic group sputum endotoxin concentrations correlated with sputum IL-1 receptor antagonist concentrations (r = 0.510, P < .001), and serum endotoxin concentrations significantly correlated with sputum IL-6, IL-8, and chemokine motif ligand 2 concentrations. CONCLUSION Asthmatic smokers have similar sputum endotoxin concentrations compared with those of asthmatic never smokers. The association between higher sputum endotoxin levels and an impaired lung function response to oral corticosteroids, particularly in asthmatic never smokers, suggests that airway endotoxin might contribute to corticosteroid insensitivity in asthmatic patients.

P205 Managing the challenges of recruitment of patients with asthma to randomised controlled trials

Introduction Many trials do not recruit sufficient participants, particularly from primary care settings, making it difficult to get meaningful results. A recent Cochrane systematic review studying recruitment concluded there is still much to learn. Here we describe details of two MRC funded, primary care based, asthma randomised controlled trials, and their recruitment strategies and challenges. Methods Trial 1: Examined whether short-term treatment with atorvastatin improves lung function, asthma control and quality of life in smokers with asthma (completed 2009). Trial 2: examined the same question using azithromycin (completed July 2011). The participant flow charts and trial documents of both trials were examined to establish recruitment details. Results Trial 1: Target to randomise =80, target to complete =68, study extended by 3 months due to slow recruitment. Actual randomised =71, actual completed =60. 54/438 GP practices approached, participated. 2483 patients from practices and 356 from a database of previous trial participants received two mailings via GP surgeries, and then following an ethics amendment via telephone for a small number of surgeries. 331/2483 (11.7%) patients responded positively, and of these 286 were able to be contacted and telephone screened for eligibility, leaving 131 eligible participants. 129/131 attended a screening visit; 58/129 screen failed (eg, due to deterioration in peak flow, unable to wean off regular asthma medications) leaving 71 randomised (2.5%) of total patients invited. Trial 2: similar picture, completed July 2011, extended by 6 months due to slow recruitment. Target to randomise =80, target to complete =68. Actual completed: 71/8398 (<1%) of those invited. Conclusion Achieving the completion target in randomised controlled trials requires significant administrative support, and the capacity to increase support should difficulties in recruitment be encountered. Closer partnership with primary care practitioners, better access to primary care patient databases and direct contact with potential recruits can overcome this. Loss of potential recruits during the run-in phase needs exploration, and is of significant importance to improve the efficiency of screening to randomisation. Addressing these issues will mean fewer trials are underpowered and hence provide better return for grant awarding bodies.

S122 Sputum cytokine profiles in asthma and the impact of smoking-a factor analysis

Introduction Cigarette smokers with asthma have a distinct clinical phenotype from non-smokers with asthma. This may reflect altered airway inflammation although how cigarette smoking directs this is unclear. We employed exploratory factor analysis to examine the impact of smoking on airway inflammation. Methods 22 smokers (sm), 10 ex-smokers (ex-sm) and 21 never smokers (ns) with asthma performed spirometry, induced sputum and completed asthma control questionnaires pre and post an oral corticosteroid trial. Sputum fluid cytokines were quantified using a 25-plex bead system (Invitrogen, Paisley). Factor analysis was performed (SPSS V.17) using principal component analysis and Varimax rotation. Factors were identified according to; visual inspection of the scree plot, eigenvalues >1.1, minimum of three cytokines loading >0.4. Sequential removal of cytokines was performed in stages according to; moderate to strong (>0.4) loadings, followed by requirement for ‘strong’ loading (>0.6) to only one factor then removal of cytokines that reduced the reliability of the data set. In a final step cytokines with the lowest loadings were removed if a factor had >3. Results The subjects were well matched except for higher asthma control questionnaires scores and inhaled corticosteroid dose in sm. Sm failed to demonstrate a lung function response to oral corticosteroids in contrast to nsm. No sputum cell differential differences were evident between smokers and non-smokers with asthma. A number of pre-steroid sputum cytokines were elevated in sm compared to nsm. The greatest difference present for interleukin 6 (sm 34.4 pg/ml (IQR 14.1, 72.4), nsm 8.1 pg/ml (4.4, 11.1), p<0.001). Factor analysis of the pre-steroid cytokines demonstrated that three factors explained 90% of the variance in the data. Sequential processing revealed three cytokines per factor (Abstract S122 table 1).Abstract S122 Table 1 Factor loadings Rotated component matrix Factor 1 2 3 IFN-? 0.991 IL-4 0.986 IL-5 0.986 IL-6 0.864 CXCL9 0.964 CXCL10 0.908 CCL2 0.813 CCL3 0.889 CCL4 0.920 Discussion Sputum cytokine profiling of subjects with asthma with differing smoking histories reveals distinct groupings when examined by exploratory factor analysis providing insight into airway inflammation in asthma and the impact of smoking. Larger cohorts of patients with asthma should be examined to confirm these preliminary findings.