Jaymin B. Morjaria

EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as Tobacco Cigarettes Substitute: A Prospective 12-Month Randomized Control Design Study

Background Electronic cigarettes (e-cigarettes) are becoming increasingly popular with smokers worldwide. Users report buying them to help quit smoking, to reduce cigarette consumption, to relieve tobacco withdrawal symptoms, and to continue having a ‘smoking’ experience, but with reduced health risks. Research on e-cigarettes is urgently needed in order to ensure that the decisions of regulators, healthcare providers and consumers are based on science. Methods ECLAT is a prospective 12-month randomized, controlled trial that evaluates smoking reduction/abstinence in 300 smokers not intending to quit experimenting two different nicotine strengths of a popular e-cigarette model (‘Categoria’; Arbi Group Srl, Italy) compared to its non-nicotine choice. GroupA (n = 100) received 7.2 mg nicotine cartridges for 12 weeks; GroupB (n = 100), a 6-week 7.2 mg nicotine cartridges followed by a further 6-week 5.4 mg nicotine cartridges; GroupC (n = 100) received no-nicotine cartridges for 12 weeks. The study consisted of nine visits during which cig/day use and exhaled carbon monoxide (eCO) levels were measured. Smoking reduction and abstinence rates were calculated. Adverse events and product preferences were also reviewed. Results Declines in cig/day use and eCO levels were observed at each study visits in all three study groups (p<0.001 vs baseline), with no consistent differences among study groups. Smoking reduction was documented in 22.3% and 10.3% at week-12 and week-52 respectively. Complete abstinence from tobacco smoking was documented in 10.7% and 8.7% at week-12 and week-52 respectively. A substantial decrease in adverse events from baseline was observed and withdrawal symptoms were infrequently reported during the study. Participants’ perception and acceptance of the product under investigation was satisfactory. Conclusion In smokers not intending to quit, the use of e-cigarettes, with or without nicotine, decreased cigarette consumption and elicited enduring tobacco abstinence without causing significant side effects. Trial Registration ClinicalTrials.gov NCT01164072 NCT01164072

The Role Of A Soluble Tnf-Á Receptor Fusion Protein (Etanercept) In Corticosteroid-Refractory Asthma: A Double Blind, Randomised Placebo-Controlled Trial

Aim: Tumour necrosis factor α (TNFα) is a cytokine recognised as a therapeutic target in chronic inflammatory diseases. Methods: A randomised, double blind, placebo controlled parallel group trial is reported of etanercept (an IgG1-TNF p75 receptor fusion protein), administered once weekly for 12 weeks in 39 patients with severe corticosteroid refractory asthma. Efficacy was measured by change from the pretreatment baseline in Asthma Related Quality of Life (AQLQ) and Asthma Control (ACQ) Questionnaire scores (the primary endpoints), lung function, peak expiratory flow (PEF) and bronchial hyperresponsiveness (BHR). Sputum and serum inflammatory cells and cytokines, serum albumin and C reactive protein (CRP) as biomarkers of inflammation were also assessed. Results: There was a small but significant difference in reduction of ACQ scores between treatment and placebo (−1.11 (95% CI −1.56 to −0.75) and −0.52 (95% CI −0.97 to −0.07), respectively, p = 0.037). There was no significant difference in improvements in AQLQ scores, lung function, PEF, BHR or exacerbation rates between the groups. Minor adverse events, including injection site pain and skin rashes, were more frequent with etanercept. There was a significant reduction in sputum macrophages and CRP, and increases in serum TNFα and albumin following treatment, but not in other laboratory parameters. Conclusion: Etanercept therapy over 12 weeks demonstrated only a small but significant improvement in asthma control and systemic inflammation, as measured by serum albumin and CRP. Larger randomised, placebo controlled trials are required to clarify the role of TNFα antagonism in subjects with severe refractory asthma.

Chemokine Receptor 4 Plays a Key Role in T Cell Recruitment into the Airways of Asthmatic Patients

T lymphocytes of the Th2 type are central orchestrators of airway inflammation in asthma. The mechanisms that regulate their accumulation in the asthmatic airways remains poorly understood. We tested the hypothesis that CCR4, preferentially expressed on T lymphocytes of the Th2 type, plays a critical role in this process. We enumerated by flow cytometry the CCR4-expressing T cells from blood, induced sputum, and biopsy samples of patients with asthma and control subjects. We showed a positive correlation between the numbers of peripheral blood CCR4+ T cells and asthma severity, provided evidence of preferential accumulation of CCR4+ T cells in asthmatic airways, and demonstrated that CCR4+ but not CCR4− cells from patients with asthma produce Th2 cytokines. Explanted airway mucosal biopsy specimens, acquired by bronchoscopy from subjects with asthma, were challenged with allergen and the explant supernatants assayed for T cell chemotactic activity. Allergen-induced ex vivo production of the CCR4 ligand, CCL17 was raised in explants from patients with asthma when compared with healthy controls. Using chemotaxis assays, we showed that the T cell chemotactic activity generated by bronchial explants can be blocked with a selective CCR4 antagonist or by depleting CCR4+ cells from responder cells. These results provide evidence that CCR4 might play a role in allergen-driven Th2 cell accumulation in asthmatic airways. Targeting this chemokine receptor in patients with asthma might reduce Th2 cell-driven airway inflammation; therefore, CCR4 antagonists could be an effective new therapy for asthma. This study also provides wider proof of concept for using tissue explants to study immunomodulatory drugs for asthma.

Effect of Smoking Abstinence and Reduction in Asthmatic Smokers Switching to Electronic Cigarettes: Evidence for Harm Reversal

Electronic cigarettes (e-cigs) are marketed as safer alternatives to tobacco cigarettes and have shown to reduce their consumption. Here we report for the first time the effects of e-cigs on subjective and objective asthma parameters as well as tolerability in asthmatic smokers who quit or reduced their tobacco consumption by switching to these products. We retrospectively reviewed changes in spirometry data, airway hyper-responsiveness (AHR), asthma exacerbations and subjective asthma control in smoking asthmatics who switched to regular e-cig use. Measurements were taken prior to switching (baseline) and at two consecutive visits (Follow-up/1 at 6 (±1) and Follow-up/2 at 12 (±2) months). Eighteen smoking asthmatics (10 single users, eight dual users) were identified. Overall there were significant improvements in spirometry data, asthma control and AHR. These positive outcomes were noted in single and dual users. Reduction in exacerbation rates was reported, but was not significant. No severe adverse events were noted. This small retrospective study indicates that regular use of e-cigs to substitute smoking is associated with objective and subjective improvements in asthma outcomes. Considering that e-cig use is reportedly less harmful than conventional smoking and can lead to reduced cigarette consumption with subsequent improvements in asthma outcomes, this study shows that e-cigs can be a valid option for asthmatic patients who cannot quit smoking by other methods.

Anti-IgE – emerging opportunities for Omalizumab

Introduction: Omalizumab is a recombinant DNA-derived humanized IgG1 monoclonal antibody that selectively binds to free and membrane-bound immunoglobulin E (IgE) antibodies. Omalizumab has been licensed for use in severe allergic asthma. A search on the website clinicaltrials.gov reveals there are currently 109 clinical trials with Omalizumab of which 46 are for conditions other than asthma. Areas covered: In addition to asthma, Omalizumab has been investigated in various other conditions including perennial and seasonal allergic rhinitis (AR), peanut allergy, latex allergy, atopic dermatitis, chronic urticaria (CU), idiopathic anaphylaxis, mastocytosis, eosinophilic gastroenteritis and nasal polyposis. This review aims to look at the various randomised and non-randomised clinical trials, case series and case reports for the role of Omalizumab in conditions other than asthma. Numerous clinical trials have shown a positive light on the role of Omalizumab in conditions other than asthma. Expert opinion: We feel that the future of Omalizumab would include a more diverse range of clinical conditions, and future trials should not only look into the clinical usefulness but also the economic impact of using this interesting molecule.

Sputum IL-6 concentrations in severe asthma and its relationship with FEV1

As asthma becomes more severe it adopts additional characteristics including corticosteroid refractoriness and a neutrophil-predominant inflammatory response implicating Th1 or Th17 responses involving cytokines such as tumour necrosis factor α, interleukin (IL)-6 and IL-8. We have examined the role of IL-6 and IL-8 in severe asthma. Subjects with severe asthma (GINA stage IV) who were exacerbation-free for ≥4 weeks with a forced expiratory volume in 1 s (FEV1) >30% but <80% predicted were studied from the baseline parameters of a clinical trial.1 Cell counts and cytokines were measured in induced sputum (see online supplement for Methods). Eighteen subjects (9M, 9F) with severe asthma (mean±SD age 43.4±11.4 years (1SD), FEV1 59±14% predicted) were studied (see table 1 in online appendix). The median (IQR) levels of sputum IL-8, IL-6, neutrophils (%), macrophages (%) and eosinophils (%) were 1853.8 pg/ml (1376.8–2537.7), 70.0 pg/ml (28.55–127.5), 32.5% (24.1–42.6), 46.8% (39.8–54.8) and 4.4% (3.2–9.4), respectively. We observed significant negative correlations between FEV1 …

Evidence for harm reduction in COPD smokers who switch to electronic cigarettes

BackgroundElectronic cigarettes (ECs) are battery-operated devices designed to vaporise nicotine, which may help smokers quitting or reducing their tobacco consumption. There is a lack of data on the health effects of EC use among smokers with COPD and whether regular use results in improvement in subjective and objective COPD outcomes.We investigated long-term changes in objective and subjective respiratory outcomes in smokers with a diagnosis of COPD who quit or reduced substantially their tobacco consumption by supplementing with or converting only to ECs use.MethodsWe conducted a retrospective chart review of patients with COPD to identify those reporting regular daily use of ECs on at least two follow-up visits at 12- (F/up1) and 24-months (F/up2). Regularly smoking COPD patients were included as a reference group.ResultsA marked reduction in cigarette consumption was observed in ECs users. A significant reduction in COPD exacerbations was reported in the COPD EC user group, their mean (±SD) decreasing from 2.3 (±1) at baseline to 1.8 (±1; p = 0.002) and 1.4 (±0.9; p < 0.001) at F/up1 and F/up2 respectively. A significant reduction in COPD exacerbations was also observed in ECs users who also smoked conventional cigarettes (i.e. ‘dual users’). COPD symptoms and ability to perform physical activities improved statistically in the EC group at both visits, with no change in the control group.ConclusionsThese findings suggest that ECs use may aid smokers with COPD reduce their cigarette consumption or remain abstinent, which results in marked improvements in annual exacerbation rate as well as subjective and objective COPD outcomes.

Biologic and pharmacologic therapies in clinical development for the inflammatory response in COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating condition with declining lung function associated with airway inflammation, mucus hypersecretion and remodeling. Inflammatory cells contribute to the disease processes via the production of proteases, fibrotic or mitogenic growth factors, cytokines, chemokines and their receptors. Particularly newer agents that treat the underlying inflammation and remodeling. Here, we briefly review current understanding of the inflammatory mechanisms involved in the pathogenesis of COPD. This understanding has enabled the identification of several therapeutic targets that might have great potential for the development of novel anti-inflammatory and anti-remodeling biologic therapies with considerable clinical advantage for COPD. Some of these molecules have been assessed, and others are in the early stages of being assessed. This article gives an up-to-date summary of these novel therapies and their status of clinical development in targeting the various inflammatory pathways of COPD.

Role of long term antibiotics in chronic respiratory diseases.

Antibiotics are commonly used in the management of respiratory disorders such as cystic fibrosis (CF), non-CF bronchiectasis, asthma and COPD. In those conditions long-term antibiotics can be delivered as nebulised aerosols or administered orally. In CF, nebulised colomycin or tobramycin improve lung function, reduce number of exacerbations and improve quality of life (QoL). Oral antibiotics, such as macrolides, have acquired wide use not only as anti-microbial agents but also due to their anti-inflammatory and pro-kinetic properties. In CF, macrolides such as azithromycin have been shown to improve the lung function and reduce frequency of infective exacerbations. Similarly macrolides have been shown to have some benefits in COPD including reduction in a number of exacerbations. In asthma, macrolides have been reported to improve some subjective parameters, bronchial hyperresponsiveness and airway inflammation; however have no benefits on lung function or overall asthma control. Macrolides have also been used with beneficial effects in less common disorders such as diffuse panbronchiolitis or post-transplant bronchiolitis obliterans syndrome. In this review we describe our current knowledge the use of long-term antibiotics in conditions such as CF, non-CF bronchiectasis, asthma and COPD together with up-to-date clinical and scientific evidence to support our understanding of the use of antibiotics in those conditions.

Changes in breathomics from a 1‐year randomized smoking cessation trial of electronic cigarettes

Electronic cigarette (EC) use is an emerging behaviour that has been shown to help smokers to reduce cigarette consumption. The aim of this study was to illustrate long‐term changes in exhaled breath measurements and respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to ECs.