Mark Spears

Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 μg·day−1), theophylline (400 mg·day−1) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L·min−1, 95% confidence intervals (CI) 10.9–68.8) and ACQ score (-0.47, 95% CI -0.91– -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13–342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99– -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.

The influence of smoking on the treatment response in patients with asthma.

Purpose of reviewCigarette smoking and asthma are associated with poor symptom control and impaired therapeutic responses to corticosteroids. We summarize the clinical evidence for corticosteroid resistance, the mechanisms which could be responsible and potential management of this resistance. We also consider the effect smoking has on other drugs commonly used to treat patients with asthma. Recent findingsIn most developed countries the prevalence of active smoking in adults with asthma is about 25%. Compared with nonsmokers with asthma, active smokers have more severe asthma symptoms, accelerated decline in lung function and impaired short-term therapeutic responses to corticosteroids. The mechanism of corticosteroid resistance in smokers with asthma is currently unexplained but could be due to alterations in airway inflammatory cell phenotypes, changes in glucocorticoid receptor α to β ratio, and reduced histone deacetylase activity. Cigarette smoking also increases the clearance of drugs such as theophylline by induction of metabolizing enzymes. Alternative or additional treatment to inhaled corticosteroids may be required for individuals with asthma who are unable to stop smoking or who have persistent symptoms following smoking cessation. SummarySmokers with chronic asthma have a reduced response to short-term corticosteroid therapy. Every effort should be made to encourage individuals with asthma who smoke to stop. Alternative or additional therapies to inhaled corticosteroids are needed for individuals with asthma who are unable to quit smoking. Abbreviations COPD: chronic obstructive pulmonary disease; CYP: cytochrome P450; FEV1: forced expiratory volume in 1 s; HDAC: histone deacetylase; NF-κB: nuclear factor κB; PEF: peak expiratory flow.

Peroxisome proliferator‐activated receptor‐γ agonists as potential anti‐inflammatory agents in asthma and chronic obstructive pulmonary disease

Inhaled corticosteroids are the most effective therapy for chronic persistent asthma and have a role in the treatment of chronic obstructive pulmonary disease (COPD). However, corticosteroids have reduced efficacy in some patients with asthma and fail to halt the progressive deterioration in lung function characteristic of COPD. Additional or alternative drug treatments to corticosteroids are required to improve control of inflammation in patients with therapy resistant airway disease. Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) agonists have displayed potent anti‐inflammatory properties in experimental models of asthma and other airway diseases and as a result have the potential to become an additional treatment for asthma and COPD. We review the evidence from these experimental models and their applicability to asthma and COPD and the requirements for future clinical and experimental research.

Bronchodilatory Effect of the PPAR-γ Agonist Rosiglitazone in Smokers With Asthma

Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator–activated receptor‐γ (PPAR‐γ) agonist would be superior for the clinical treatment of these asthma patients. Forty‐six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 µg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV1) = 183 ml, P = 0.051; forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25–75) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR‐γ agonists in steroid‐resistant airway disease are indicated.

Role of symptoms and lung function in determining asthma control in smokers with asthma

Background:  Cigarette smoking in asthma increases the severity and accelerates the decline in lung function. The relative role of symptoms and lung function in determining asthma control in smokers with asthma is not known.

Effects of short-term treatment with atorvastatin in smokers with asthma - a randomized controlled trial

BackgroundThe immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control in smokers with asthma.MethodsSeventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 μg per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation.ResultsAt 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow [-10.67 L/min, 95% CI -38.70 to 17.37, p = 0.449], but there was an improvement with atorvastatin in asthma quality of life score [0.52, 95% CI 0.17 to 0.87 p = 0.005]. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks.ConclusionsShort-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma.Trial RegistrationClinicaltrials.gov identifier:NCT00463827

Corticosteroid Insensitivity in Smokers with Asthma: Clinical Evidence, Mechanisms, and Management

Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies considerably between individuals. Several clinical studies have found that smokers with asthma are insensitive to the beneficial effects of short- to medium-term inhaled corticosteroid treatment compared with non-smokers with asthma. It is estimated that 25% of adults in most industrialized countries smoke cigarettes, and similar surveys amongst asthmatic individuals suggest that the prevalence of smoking in this grouping mirrors that found in the general population. Therefore, cigarette smoking is probably the most common cause of corticosteroid insensitivity in asthma. Cigarette smoking and asthma are also associated with poor symptom control and an accelerated rate of decline in lung function. The mechanism of corticosteroid insensitivity in smokers with asthma is currently unexplained but could be due to alterations in airway inflammatory cell phenotypes, changes in glucocorticoid receptor α/β ratio, and/or reduced histone deacetylase activity. Smoking cessation should be encouraged in all smokers with asthma. Short-term benefits include improvements in lung function and asthma control. However, the numbers of sustained quitters is disappointingly small. Additional or alternative drugs need to be identified to treat those individuals who are unable to stop smoking or who have persistent symptoms following smoking cessation.

Emerging therapies for severe asthma

Many patients with asthma have poorly controlled symptoms, and particularly for those with severe disease, there is a clear need for improved treatments. Two recent therapies licensed for use in asthma are omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, and bronchial thermoplasty, which involves the delivery of radio frequency energy to the airways to reduce airway smooth muscle mass. In addition, there are new therapies under development for asthma that have good potential to reach the clinic in the next five years. These include biological agents targeting pro-inflammatory cytokines such as interleukin-5 and interleukin-13, inhaled ultra long-acting β2-agonists and once daily inhaled corticosteroids. In addition, drugs that block components of the arachidonic acid pathway that targets neutrophilic asthma and CRTH2 receptor antagonists that inhibit the proinflammatory actions of prostaglandin D2 may become available. We review the recent progress made in developing viable therapies for severe asthma and briefly discuss the idea that development of novel therapies for asthma is likely to increasingly involve the assessment of genotypic and/or phenotypic factors.

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 …