Neil C. Thomson

Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma

Background: Although inhaled corticosteroids have an established role in the treatment of asthma, studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma. Methods: The effect of treatment with inhaled fluticasone propionate (1000 μg daily) or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled study of 38 steroid naïve adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning and evening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, and sputum eosinophil counts. Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients. Results: There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone (27 l/min v –5 l/min). Non-smokers had a statistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1 second (0.17 l), and geometric mean PC20 (2.6 doubling doses), and a significant decrease in the proportion of sputum eosinophils (–1.75%) after fluticasone compared with placebo. No significant changes were observed in the smoking asthmatic patients for any of these parameters. Conclusions: Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma. This finding has important implications for the management of patients with mild asthma who smoke.

Asthma and cigarette smoking

In most developed countries ∼25% of adults with asthma are current cigarette smokers. Asthma and active cigarette smoking interact to cause more severe symptoms, accelerated decline in lung function, and impaired short-term therapeutic response to corticosteroids. Cigarette smoking may modify inflammation that is associated with asthma, although there is limited published data on airway pathology in smokers with asthma. To date, the evidence points towards a combination of both heightened and suppressed inflammatory responses in smokers compared with nonsmokers with asthma. The mechanisms of corticosteroid resistance in asthmatic smokers are unexplained, but could be as a result of alterations in airway inflammatory cell phenotypes (e.g. increased neutrophils or reduced eosinophils), changes in the glucocorticoid receptor-α to -β ratio (e.g. overexpression of glucocorticoid receptor β), and increased activation of pro-inflammatory transcription factors (e.g. nuclear factor-κB) or reduced histone deacetylase activity. In conclusion, every effort should be made to encourage asthmatics who smoke to stop, although the effects of smoking cessation upon reversing the adverse effects of tobacco smoke on asthma control, therapeutic response to corticosteroids and airway pathology have yet to be fully elucidated. Alternative or additional therapies to inhaled corticosteroids are needed for asthmatic patients who are unable to quit smoking.

Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial.

RATIONALE Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. OBJECTIVES To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. METHODS A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). MEASUREMENTS AND MAIN RESULTS The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). CONCLUSIONS BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

A Novel Anti-Inflammatory Role of Simvastatin in a Murine Model of Allergic Asthma

Statins, the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, are effective serum cholesterol-lowering agents in clinical practice, and they may also have anti-inflammatory properties. Asthma is characterized by chronic eosinophilic inflammation in the airways, which is thought to be regulated by the activity of T lymphocytes. We therefore examined the anti-inflammatory activity of simvastatin in a murine model of allergic asthma. In mice previously sensitized to OVA, simvastatin treatment, either orally or i.p., reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid in response to inhaled OVA challenge. Simvastatin therapy i.p. was also associated with a reduction in IL-4 and IL-5 levels in bronchoalveolar lavage fluid and, at higher doses, a histological reduction in inflammatory infiltrates in the lungs. OVA-induced IL-4, IL-5, IL-6, and IFN-γ secretion was reduced in thoracic lymph node cultures from simvastatin-treated mice. Simvastatin treatment did not alter serum total IgE or OVA-specific IgG1 and IgG2a levels. These data demonstrate the therapeutic potential of statin-sensitive pathways in allergic airways disease.

Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma

Background: Cigarette smokers with asthma are insensitive to short term inhaled corticosteroid therapy, but efficacy when given for a longer duration at different doses is unknown. Methods: Ninety five individuals with mild asthma were recruited to a multicentre, randomised, double blind, parallel group study comparing inhaled beclomethasone in doses of 400 μg or 2000 μg daily for 12 weeks in smokers and non-smokers. The primary end point was the change in morning peak expiratory flow (PEF). Secondary end points included evening PEF, use of reliever inhaler, number of asthma exacerbations, spirometric parameters, and asthma control score. Results: After 12 weeks of inhaled beclomethasone there was a considerable difference between the morning PEF measurements of smokers and non-smokers with asthma (−18 (95% CI −35 to −1), adjusted p = 0.035). Among those receiving 400 μg daily there was a difference between the mean (95% CI) morning PEF (l/min) in smokers and non-smokers (−25 (95% CI −45 to −4), adjusted p = 0.019) and in the number of asthma exacerbations (6 v 1 in smokers and non-smokers, respectively, p = 0.007). These differences were reduced between smokers and non-smokers receiving 2000 μg inhaled beclomethasone daily. Conclusions: Compared with non-smokers, smokers with mild persistent asthma are insensitive to the therapeutic effect of low dose inhaled corticosteroid treatment administered for a 12 week period. The disparity of the response between smokers and non-smokers appears to be reduced with high dose inhaled corticosteroid. These findings have important implications for the management of individuals with mild asthma who smoke.

High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity

Background: In some patients chronic asthma results in irreversible airflow obstruction. High resolution computed tomography (HRCT) has been advocated for assessing the structural changes in the asthmatic lung and permits investigation of the relationships between airway wall thickening and clinical parameters in this condition. Methods: High resolution CT scanning was performed in 49 optimally controlled asthmatic patients and measurements of total airway and lumen diameter were made by two independent radiologists using electronic callipers. Wall area as % total airway cross sectional area (WA%) and wall thickness to airway diameter ratio (T/D) were calculated for all airways clearly visualised with a transverse diameter of more than 1.5 mm, with a mean value derived for each patient. Intra- and inter-observer variability was assessed for scope of agreement in a subgroup of patients. Measurements were related to optimum forced expiratory volume in 1 second (FEV1), forced mid expiratory flow, carbon monoxide gas transfer, two scores of asthma severity, airway inflammation as assessed with induced sputum, and exhaled nitric oxide. Results: Neither observer produced a statistically significant difference between measurements performed on two occasions but there was a significant difference between observers (limits of agreement –2.6 to 6.8 for WA%, p<0.0001). However, mean WA% measured on two occasions differed by no more than 5.4% (limits of agreement –4.0 to 5.4; mean (SD) 0.7 (2.4)). Statistically significant positive associations were observed between both WA% and T/D ratio and asthma severity (rS=0.29 and 0.30, respectively, for ATS score), and an inverse association with gas transfer coefficient was observed (rS=–0.43 for WA% and rS=–0.41 for T/D). No association was identified with FEV1 or airway inflammation. Conclusions: The airway wall is thickened in more severe asthma and is associated with gas transfer coefficient. This thickening does not relate directly to irreversible airflow obstruction as measured with FEV1.

TLR2 Agonist Ameliorates Established Allergic Airway Inflammation by Promoting Th1 Response and Not via Regulatory T Cells

TLRs are primary sensors of both innate and adaptive immune systems, where they play a pivotal role in the response directed against structurally conserved components of pathogens. Synthetic bacterial lipopeptide Pam3CSK4 is a TLR2 agonist capable of modulating Th1 and Th2 responses. This study examines the therapeutic effect of Pam3CSK4 in established airway inflammation in a murine model of asthma. In mice previously sensitized and challenged with OVA, Pam3CSK4 given i.p. markedly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid. Pam3CSK4 therapy was associated with a reduction in OVA-induced IL-4 and IL-5 secretion from thoracic lymph node culture, airways inflammation, bronchial hyperresponsiveness, and serum levels of IgE. Pam3CSK4 therapy was also associated with an increase in OVA-induced IFN-γ, IL-12, and IL-10 production. However, the anti-inflammatory effect of Pam3CSK4 was independent of IL-10 or TGF-β, but was critically dependent on IL-12, the production of which by dendritic cells was enhanced by Pam3CSK4 in vitro. Our results provide direct evidence that Pam3CSK4 could represent a novel therapeutic agent in allergic airways disease.

Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma

BACKGROUND Sputum eosinophil counts and exhaled nitric oxide (NO) levels are increased in asthma and both measurements fall in response to corticosteroids. METHODS Exhaled NO levels and sputum eosinophil counts were assessed as non-invasive markers of the response to an oral steroid in 37 patients (19 women) with stable chronic asthma (mean (SD) age 48.6 (12.2) years, asthma duration 25.9 (17.3) years, and baseline forced expiratory volume in one second (FEV1) 76.3 (21.9)% predicted). Spirometric tests, with reversibility to a β agonist (2.5 mg nebulised salbutamol), and induced sputum (using nebulised 3% saline) were performed at recruitment and following treatment with 30 mg prednisolone/day for 14 days. RESULTS Baseline NO levels correlated with the percentage improvement in FEV1from baseline to the post-steroid, post-bronchodilator value (r s = 0.47, p = 0.003), with an NO level of >10 ppb at baseline having a positive predictive value of 83% for an improvement in FEV1 of ⩾15% (sensitivity 59%, specificity 90%). Sputum eosinophilia (⩾4%) had a positive predictive value of 68% (sensitivity 54%, specificity 76%) for an increase in FEV1 of ⩾15%. A combination of sputum eosinophilia and increased NO levels resulted in a positive predictive value of 72% and a negative predictive value of 79% (sensitivity 76%, specificity 75%). CONCLUSION Exhaled NO levels and sputum eosinophilia may be useful in predicting the response to a trial of oral steroid in asthma.

Potential therapeutic role for statins in respiratory disease

Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and have an established role in the treatment of atherosclerotic disease. Recent research has identified anti-inflammatory properties of statins. Statins appear to reduce the stability of lipid raft formation with subsequent effects on immune activation and regulation, and also prevent the prenylation of signalling molecules with subsequent downregulation of gene expression. Both these effects result in reduced cytokine, chemokine, and adhesion molecule expression, with effects on cell apoptosis or proliferation. This review considers the evidence for the anti-inflammatory properties of statins in the lung, and how these effects are being applied to research into the role of statins as a novel treatment of respiratory diseases.

Smoking and asthma: dangerous liaisons.

Cigarette smoking and asthma interact to induce important adverse effects on clinical, prognostic and therapeutic outcomes. This review examines recent evidence on the harmful effects of smoking in asthma, possible underlying inflammatory mechanisms for this altered response, management options for these patients and potential future therapeutic directions. Active smokers, particularly females, are at risk of developing asthma. Prevalence rates for smoking in asthma are relatively close to those found in the general population. Smokers with asthma experience worse asthma control than nonsmokers with asthma. Mechanisms for the adverse effects of smoking in asthma include altered airway inflammation and corticosteroid insensitivity. Quitting smoking can improve symptoms and lung function, but the low rates of smoking cessation highlights the need for improved strategies for managing these patients. Clinical trials assessing new therapies for asthma need to enrol smokers to identify treatments that are effective in the asthma smoking phenotype.