Dave Singh

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 report focuses primarily on the revised and novel parts of the document. The most significant changes include: (1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; (2) for each of the groups A to D, escalation strategies for pharmacologic treatments are proposed; (3) the concept of deescalation of therapy is introduced in the treatment assessment scheme; (4) nonpharmacologic therapies are comprehensively presented; and (5) the importance of comorbid conditions in managing chronic obstructive pulmonary disease is reviewed.

The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines

Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erbα expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERBα activity. Circadian gating of endotoxin response was lost in rev-erbα−/− mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erbα expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERBα as the key link between the clock and immune function. REV-ERBα may therefore represent a unique therapeutic target in human inflammatory disease.

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary.

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: 1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed. Read the executive summary of the new @GOLD_COPD 2017 report in the European Respiratory Journal http://ow.ly/XxfD308BDfc

Blood Eosinophils: A Biomarker of Response to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease

To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition (1). The identification of COPD phenotypes may allow stratified treatment approaches that modulate discrete disease mechanisms. Peripheral blood eosinophilia is both a common and repeatable finding in COPD (2). In addition, the presence of a blood/sputum eosinophilia is associated with a significant proportion of COPD exacerbations (3, 4) and a favorable response to systemic steroids (5). However, the role of blood eosinophils in stratifying treatment response to inhaled corticosteroid/long-acting β-agonist combinations is poorly understood. The FORWARD (Foster 48-Week Trial to Reduce Exacerbations in COPD) study was a randomized, double-blind, parallel group trial that compared 48 weeks of treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP/FF), 100/6 μg pressurized metered-dose inhaler, two inhalations twice a day, versus FF 12 μg pressurized metered-dose inhaler, one inhalation twice a day, in patients with severe COPD with a history of exacerbations (clinical trial registered with www.clinicaltrials.gov [NCT 00929851]). The results of the study have been reported (6) and showed a significant reduction in exacerbation rate (28%) and improvement in lung function with BDP/FF compared with FF treatment. Here we evaluate the hypothesis that these treatment differences differ according to the baseline blood eosinophil count by performing a post hoc analysis on the FORWARD study data. Methods The median (quartile 1; quartile 3) baseline blood eosinophil count was 181.6 (110.4; 279.8), and the distribution of counts is shown in Figure E1 in the online supplement. The patients (n = 1,184) were stratified into quartile groups on the basis of the baseline eosinophil count. The clinical characteristics of the study population across the quartiles of baseline blood eosinophils are reported in Table E1. The following endpoints were analyzed: COPD exacerbation rate over the course of 48 weeks, using a negative binomial model for adjusted exacerbation rates, Kaplan-Meier analysis, and Cox proportional hazard model for time to first exacerbation event; change from baseline in predose morning FEV1 at 48 weeks, using a linear mixed model for repeated measurements; and change from baseline in St. George’s Respiratory Questionnaire total score at 48 weeks, using an analysis of covariance model. Further details of the models are provided in the online supplement. Additional analyses using percentage eosinophil count thresholds and considering absolute counts as a continuous variable were also performed. A predictive model (see online supplement for details) for future COPD exacerbation rate was estimated, accounting for a variety of baseline factors that may influence exacerbations (7). The effect of baseline blood eosinophil count on adverse events, and in particular pneumonia, was also evaluated.

Superiority of “triple” therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD

Background: The combination of salmeterol and fluticasone propionate (SFC) and tiotropium bromide (TIO) are commonly used treatments in chronic obstructive pulmonary disease (COPD) but there are few data on their effectiveness when used together. We compared the effects of SFC 50/500 μg twice daily in addition to TIO 18 μg once daily with the individual treatments alone. Methods: 41 patients with COPD participated in a randomised, double blind, double dummy, three way crossover study with 2 week washout periods between treatments. Lung function assessment included plethysmography and spirometry. The primary end point was post-dose specific airways conductance (sGaw) area under the curve (AUC0–4 h) on day 14. Results: AUC0–4 h sGaw was significantly higher on day 14 after SFC+TIO compared with TIO (22%) or SFC alone (27%) (both p<0.001). SFC+TIO significantly improved trough forced expiratory volume in 1 s compared with TIO alone (212 ml, p<0.001) and SFC alone (110 ml, p = 0.017) on day 14. Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14. Subjects receiving SFC+TIO had clinically relevant improvements in Transition Dyspnoea Index (TDI) total score of 2.2 compared with TIO alone (p<0.001) (but not SFC alone, 0.7; NS) and used significantly less rescue medication (1.0 occasion less daily than TIO (p<0.001) and 0.6 less than SFC (p = 0.01)). Conclusion: SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone. The advantages of triple therapy are observed across a range of physiologically important parameters, including airway conductance and lung volumes. Triple therapy also led to patient related benefits by improving TDI and use of rescue medication. Trial registration number: NCT00325169.

Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study

The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 μg or 400 μg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included peak FEV1, health status (St Georges Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI). Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV1 (99 and 128 mL; both p<0.0001) and peak FEV1 (185 and 209 mL; both p<0.0001). Peak FEV1 improvements on day 1 were comparable with week 24. Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p<0.001 and p<0.0001) and TDI focal score (0.6 and 1.0 units; p<0.05 and p<0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo. Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD.

Sputum neutrophils as a biomarker in COPD: findings from the ECLIPSE study.

IntroductionThe percentage of neutrophils in sputum are increased in COPD patients, and may therefore be a biomarker of airway inflammation. We studied the relationships between sputum neutrophils and FEV1, health status, exacerbation rates, systemic inflammation and emphysema, and long term variability at 1 year.MethodsSputum samples were obtained from 488 COPD patients within the ECLIPSE cohort. 359 samples were obtained at baseline, and 297 after 1 year. 168 subjects provided samples at both visits. Serum interleukin-6 (IL-6), IL-8, surfactant protein D and C-reactive protein levels were measured by immunoassays. Low-dose CT scans evaluated emphysema.ResultsSputum neutrophil % increased with GOLD stage. There was a weak association between % sputum neutrophils and FEV1 % predicted (univariate r2 = 0.025 and 0.094 at baseline and year 1 respectively, p < 0.05 after multivariate regression). Similar weak but significant associations were observed between neutrophil % and health status measured using the St Georges Respiratory Questionairre. There were no associations between neutrophils and exacerbation rates or emphysema. Associations between sputum neutrophils and systemic biomarkers were non-significant or similarly weak. The mean change over 1 year in neutrophil % was an increase of 3.5%.ConclusionsSputum neutrophil measurements in COPD are associated weakly with FEV1 % predicted and health status. Sputum neutrophil measurements were dissociated from exacerbation rates, emphysema and systemic inflammation.

The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. A randomized trial.

RATIONALE Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-β. Exogenous IFN-β restores antiviral activity. OBJECTIVES To compare the efficacy and safety of inhaled IFN-β with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses. METHODS A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2-5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-β (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses. MEASUREMENTS AND MAIN RESULTS A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse (mean change in six-item Asthma Control Questionnaire <0.5) and IFN-β treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset of more difficult-to-treat, Step 4-5 people with asthma (n = 27 IFN-β; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-β (P = 0.004). CONCLUSIONS Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-β is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the need for further, adequately powered, trials in this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).

Eosinophilic inflammation in COPD: prevalence and clinical characteristics

To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, with patients displaying varying clinical and pathophysiological features. The identification of COPD phenotypes with distinct characteristics may allow targeted treatment strategies directed towards specific biological pathways. Eosinophilic inflammation is thought to be a characteristic feature of asthma rather than COPD. However, studies have shown that a subset of COPD patients with eosinophilic airway inflammation exists, even after the careful exclusion of patients with any features of asthma, such as β-agonist reversibility, bronchial hyperresponsiveness, atopy or a childhood history of asthma [1–4]. Interestingly, these patients exhibit the greatest response to corticosteroid treatment [1–4]. Likewise, sputum eosinophil numbers are increased in a subset of COPD exacerbations [5, 6], and titrating corticosteroid therapy according to sputum eosinophil counts reduces exacerbation rates [7]. Furthermore, there are similar increases in sputum and blood eosinophil numbers during COPD exacerbations [5]; using blood eosinophils as a surrogate maker for airway eosinophils to direct oral corticosteroid therapy for the treatment of COPD exacerbations enhances clinical recovery [8]. Taken together, these observations suggest that eosinophilic airway inflammation in COPD is a predictive biomarker of corticosteroid responsiveness during clinical stability and exacerbations. The prevalence of eosinophilic inflammation in COPD patients is unknown. We do not know whether patients with sputum or blood eosinophilia represent a stable COPD phenotype over time and, apart from corticosteroid responsiveness, little is known about the other clinical characteristics of this subset of patients. We analysed samples from the ECLIPSE (Evaluation of COPD Longitudinally to Identify …

Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management

Chronic obstructive pulmonary disease (COPD) is a common, complex, and heterogeneous disorder that is responsible for substantial and growing morbidity, mortality, and health-care expense worldwide. Of imperative importance to decipher the complexity of COPD is to identify groups of patients with similar clinical characteristics, prognosis, or therapeutic needs, the so-called clinical phenotypes. This strategy is logical for research but might be of little clinical value because clinical phenotypes can overlap in the same patient and the same clinical phenotype could result from different biological mechanisms. With the goal to match assessment with treatment choices, the latest iteration of guidelines from the Global Initiative for Chronic Obstructive Lung Disease reorganised treatment objectives into two categories: to improve symptoms (ie, dyspnoea and health status) and to decrease future risk (as predicted by forced expiratory volume in 1 s level and exacerbations history). This change thus moves treatment closer to individualised medicine with available bronchodilators and anti-inflammatory drugs. Yet, future treatment options are likely to include targeting endotypes that represent subtypes of patients defined by a distinct pathophysiological mechanism. Specific biomarkers of these endotypes would be particularly useful in clinical practice, especially in patients in which clinical phenotype alone is insufficient to identify the underlying endotype. A few series of potential COPD endotypes and biomarkers have been suggested. Empirical knowledge will be gained from proof-of-concept trials in COPD with emerging drugs that target specific inflammatory pathways. In every instance, specific endotype and biomarker efforts will probably be needed for the success of these trials, because the pathways are likely to be operative in only a subset of patients. Network analysis of human diseases offers the possibility to improve understanding of disease pathobiological complexity and to help with the development of new treatment alternatives and, importantly, a reclassification of complex diseases. All these developments should pave the way towards personalised treatment of patients with COPD in the clinic.