Overnight variation in tidal expiratory flow limitation in COPD patients and its correction: an observational study.

BACKGROUND: Tidal expiratory flow limitation (EFLT) is common among COPD patients. Whether EFLT changes during sleep and can be abolished during home ventilation is not known. METHODS: COPD patients considered for noninvasive ventilation used a ventilator which measured within-breath reactance change at 5 Hz (∆Xrs) and adjusted EPAP settings to abolish EFLT. Participants flow limited (∆Xrs > 2.8) when supine underwent polysomnography (PSG) and were offered home ventilation for 2 weeks. The EPAP pressure that abolished EFLT was measured and compared to that during supine wakefulness. Ventilator adherence and subjective patient perceptions were obtained after home use. RESULTS: Of 26 patients with supine EFLT, 15 completed overnight PSG and 10 the home study. In single night and 2-week home studies, EFLT within and between participants was highly variable. This was unrelated to sleep stage or body position with only 14.6% of sleep time spent within 1 cmH2O of the awake screening pressure. Over 2 weeks, mean EPAP was almost half the mean maximum EPAP (11.7 vs 6.4 cmH2O respectively). Group mean ∆Xrs was ≤ 2.8 for 77.3% of their home use with a mean time to abolish new EFLT of 5.91 min. Adherence to the ventilator varied between 71 and 100% in prior NIV users and 36-100% for naïve users with most users rating therapy as comfortable. CONCLUSIONS: Tidal expiratory flow limitation varies significant during sleep in COPD patients. This can be controlled by auto-titrating the amount of EPAP delivered. This approach appears to be practical and well tolerated by patients. TRIAL REGISTRATION: The trial was retrospectively registered at CT.gov NCT04725500.

The effect of neoadjuvant chemotherapy and chemoradiotherapy on exercise capacity and outcome following upper gastrointestinal cancer surgery: an observational cohort study.

BACKGROUND: In 2014 approximately 21,200 patients were diagnosed with oesophageal and gastric cancer in England and Wales, of whom 37 % underwent planned curative treatments. Potentially curative surgical resection is associated with significant morbidity and mortality. For operable locally advanced disease, neoadjuvant chemotherapy (NAC) improves survival over surgery alone. However, NAC carries the risk of toxicity and is associated with a decrease in physical fitness, which may in turn influence subsequent clinical outcome. Lower levels of physical fitness are associated with worse outcome following major surgery in general and Upper Gastrointestinal Surgery (UGI) surgery in particular. Cardiopulmonary exercise testing (CPET) provides an objective assessment of physical fitness. The aim of this study is to test the hypothesis that NAC prior to upper gastrointestinal cancer surgery is associated with a decrease in physical fitness and that the magnitude of the change in physical fitness will predict mortality 1 year following surgery. METHODS: This study is a multi-centre, prospective, blinded, observational cohort study of participants with oesophageal and gastric cancer scheduled for neoadjuvant cancer treatment (chemo- and chemoradiotherapy) and surgery. The primary endpoints are physical fitness (oxygen uptake at lactate threshold measured using CPET) and 1-year mortality following surgery; secondary endpoints include post-operative morbidity (Post-Operative Morbidity Survey (POMS)) 5 days after surgery and patient related quality of life (EQ-5D-5 L). DISCUSSION: The principal benefits of this study, if the underlying hypothesis is correct, will be to facilitate better selection of treatments (e.g. NAC, Surgery) in patients with oesophageal or gastric cancer. It may also be possible to develop new treatments to reduce the effects of neoadjuvant cancer treatment on physical fitness. These results will contribute to the design of a large, multi-centre trial to determine whether an in-hospital exercise-training programme that increases physical fitness leads to improved overall survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT01325883 - 29(th) March 2011.

A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

The effect of neoadjuvant chemotherapy on physical fitness and survival in patients undergoing oesophagogastric cancer surgery.

BACKGROUND: Neoadjuvant chemotherapy (NAC) followed by surgery for resectable oesophageal or gastric cancer improves outcome when compared with surgery alone. However NAC has adverse effects. We assess here whether NAC adversely affects physical fitness and whether such an effect is associated with impaired survival following surgery. METHODS: We prospectively studied 116 patients with oesophageal or gastric cancer to assess the effect of NAC on physical fitness, of whom 89 underwent cardiopulmonary exercise testing (CPET) before NAC and proceeded to surgery. 39 patients were tested after all cycles of NAC but prior to surgery. Physical fitness was assessed by measuring oxygen uptake (VO2 in ml kg(-1) min(-1)) at the estimated lactate threshold (θL) and at peak exercise (VO2 peak in ml kg(-1) min(-1)). RESULTS: VO2 at θL and at peak were significantly lower after NAC compared to pre-NAC values: VO2 at θL 14.5 ± 3.8 (baseline) vs. 12.3 ± 3.0 (post-NAC) ml kg(-1) min(-1); p ≤ 0.001; VO2 peak 20.8 ± 6.0 vs. 18.3 ± 5.1 ml kg(-1) min(-1); p ≤ 0.001; absolute VO2 (ml min(-1)) at θL and peak were also lower post-NAC; p ≤ 0.001. Decreased baseline VO2 at θL and peak were associated with increased one year mortality in patients who completed a full course of NAC and had surgery; p = 0.014. CONCLUSION: NAC before cancer surgery significantly reduced physical fitness in the overall cohort. Lower baseline fitness was associated with reduced one-year-survival in patients completing NAC and surgery, but not in patients who did not complete NAC. It is possible that in some patients the harms of NAC may outweigh the benefits. Trials Registry Number: NCT01335555.

Chronic obstructive pulmonary disease and exacerbations: clinician insights from the global Hidden Depths of COPD survey.

OBJECTIVE: This real-life, global study aimed to investigate current views of and clinical practice in the management of COPD and its exacerbations, among clinicians from both the primary and secondary care settings. METHODOLOGY: We devised an online questionnaire about COPD management and invited 13,613 general practitioners (GPs) and respiratory specialists to respond. Participating clinicians, recruited from an established research panel, treated a minimum of 10 (GPs) or 20 (respiratory specialists) patients with COPD per month. Completed responses were collected from 1400 clinicians from 14 countries. RESULTS: A third of GPs and respiratory specialists reported that the main goal of COPD management was to improve patients' quality of life; only 14% of GPs thought that the prevention of exacerbations was a priority. The study showed a strong preference for inhaled corticosteroids in combination with other treatments, rather than as sole therapy, in line with global guidelines. Fewer GPs than respiratory specialists routinely recommended anticholinergics, pulmonary rehabilitation or oxygen therapy. Clinicians reported that 55% (GPs) and 57% (respiratory specialists) of their COPD patients had experienced an exacerbation in the previous 12 months. Although higher than those reported in clinical trials, these rates were lower than patients' own estimates from a corresponding patient survey, even in mild COPD patients (62%; 80% in severe patients). Despite this, 74% of GPs and 67% of respiratory physicians reported satisfaction with therapies to prevent exacerbations. CONCLUSIONS: This global survey revealed that clinicians' main goal when managing COPD was to improve the lives of their patients, and that few viewed reducing exacerbations as a priority. Despite a relatively high level of adherence to treatment recommendations, it appears that clinicians, particularly GPs, underestimate the frequency and impact of exacerbations. These results suggest a need to raise awareness of exacerbations among both GPs and respiratory specialists.

Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study.

We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced expiratory volume in 1 s (FEV(1)) <60% predicted. COPD exacerbations were defined by worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate) or hospital admission (severe). Seasonality effect was calculated as the proportion of patients experiencing an exacerbation each month. Exacerbations in the northern and southern regions showed an almost two-fold increase in the winter months. No seasonal pattern occurred in the tropics. Overall, 38% of exacerbations were treated with antibiotics only, 19% with systemic corticosteroids only and 43% with both, while 20% required hospital admission irrespective of the season. Exacerbation frequency was associated with older age, lower body mass index, lower FEV(1) % pred and history of prior exacerbations. Females and patients with worse baseline breathlessness, assessed using the Medical Research Council (MRC) dyspnoea scale, exacerbated more often (rate ratio (RR) for male versus female 0.7, 95% CI 0.7-0.8 (p<0.001); RR for MRC dyspnoea score 3 versus 1 and 2 combined 1.1, 95% CI 1.1-1.2 (p<0.001)). The effect of season was independent of these risk factors. COPD exacerbations and hospitalisations were more frequent in winter.

Roflumilast with long-acting ß2-agonists for COPD: influence of exacerbation history.

The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting ß(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 µg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.

Candidate genes for COPD in two large data sets.

Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV1 % predicted and FEV1/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.

Beclomethasone/formoterol in the management of COPD: a randomised controlled trial.

OBJECTIVES: To evaluate the effect of beclomethasone/formoterol versus budesonide/formoterol (non-inferiority) and versus formoterol (superiority) in patients with severe stable chronic obstructive pulmonary disease (COPD). METHODS: A double-blind, double-dummy, randomised, active-controlled, parallel-group study. After 4 weeks run-in with ipratropium/salbutamol (40/200 µg, three times daily) patients were randomised to receive beclomethasone/formoterol (200/12 µg pressurised metered dose inhaler), budesonide/formoterol (400/12 µg dry powder inhaler) or formoterol (12 µg dry powder inhaler) twice daily for 48 weeks. Co-primary efficacy variables were change from baseline to 48 weeks in pre-dose morning forced expiratory volume in 1 s (FEV(1)) and mean rate of COPD exacerbations. RESULTS: Of 718 patients randomised, 703 (232 beclomethasone/formoterol, 238 budesonide/formoterol, 233 formoterol) were in the ITT analysis. Improvement in pre-dose morning FEV(1) was 0.077 L, 0.080 L and 0.026 L for beclomethasone/formoterol, budesonide/formoterol and formoterol respectively (LS mean from the ANCOVA model). Beclomethasone/formoterol was not inferior to budesonide/formoterol (95% CI of the difference -0.052, 0.048) and superior to formoterol (p = 0.046). The overall rate of COPD exacerbations/patient/year was similar and not statistically significantly different among treatments (beclomethasone/formoterol 0.414, budesonide/formoterol 0.423 and formoterol 0.431). Quality of life and COPD symptoms improved in all groups and use of rescue medication decreased. Safety profiles were as expected and treatments well-tolerated. CONCLUSIONS: Beclomethasone/formoterol (400/24 µg) treatment for 48 weeks improved pulmonary function, reduced symptoms compared to formoterol, was safe and well-tolerated in patients with severe stable COPD. Neither of the long-acting ß2-agonist/inhaled corticosteroid combinations affected the low exacerbation rate seen in this population.

Patterns of brain activity in response to respiratory stimulation in patients with idiopathic hyperventilation (IHV).

Dyspnoea, usually defined as an uncomfortable awareness of breathing, is one of the most frequent and distressing symptoms experienced by patients with lung disease. Idiopathic hyperventilation (IHV) has unknown aetiology and little is known about the mechanisms that cause the characteristic sustained hypocapnia and chronic dyspnoea. We have shown in IHV and other chronic respiratory disorders that air hunger is the dominant sensation during exercise, while resting breathlessness is characterised by an affective component. The increased drive to breathe in IHV, and indeed dyspnoea in all chronic respiratory disorders, might be better understood if the central mechanisms of dyspnoea were known. The aim of the present study was to characterise the cortical processing of respiratory-related sensory inputs in patients with IHV. Four patients with IHV were studied with ethical approval. Respiratory stimulation was produced using transient occlusion of inspiration (TIO) during spontaneous breathing (delivered in early inspiration with duration c. 300 ms; this is well tolerated) while BOLD fMRI was performed on a 3 Tesla Siemens Trio. TIO was associated with significant activation in sensorimotor and pre-motor cortical areas and the cerebellum, notably the anterior insula, an area previously associated with breathlessness in healthy volunteers. These preliminary observations on the pattern of brain activity in response to respiratory stimulation support the hypothesis that breathlessness in IHV may reflect inappropriate cortical processing of respiratory-related sensory inputs.

Is treatment with ICS and LABA cost-effective for COPD? Multinational economic analysis of the TORCH study.

The TOwards a Revolution in COPD Health (TORCH) study was a 3-yr multicentre trial of 6,112 patients randomised to salmeterol (Salm), fluticasone propionate (FP), a Salm/FP combination (SFC) or placebo (P). Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed. For four regions, 3-yr all-cause hospitalisation, medication and outpatient care costs were calculated. The sample was restricted to the 21 countries (n = 4,237) in which European quality of life five-dimension (EQ-5D) data were collected in order to estimate the number of quality-adjusted life years (QALYs). Regression models were fitted to survival, study medication cost, other medication cost and EQ-5D data in order to estimate total cost, number of QALYs and cost per QALY, adjusted for missing data and region. SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars (USD) compared with P (95% confidence interval 21,400-123,500 USD). Estimates for Salm versus P (197,000 USD) and FP versus P (78,000 USD) were less favourable. The US estimates were greater than those from other regions; for SFC versus P, the cost per QALY was 77,100 (46,200-241,700) USD compared to 24,200 (15,200-56,100) USD in Western Europe. Compared with P, SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone, and is, therefore, preferred to these monotherapies on the grounds of cost-effectiveness.

The evidence for the use of oral mucolytic agents in chronic obstructive pulmonary disease (COPD).

INTRODUCTION: Oral mucolytics are now recommended in some treatment guidelines for the management of chronic obstructive pulmonary disease (COPD). This article reviews the evidence for their use and their possible benefits. SOURCES OF DATA: The review is based upon peer reviewed publications relating to the use of mucolytics in COPD cited in PubMed. AREAS OF AGREEMENT: Much of the published evidence is of somewhat poor quality and many studies include patients with both chronic bronchitis and COPD. Mucolytics reduce exacerbations by up to 0.8 exacerbations per year, but have little additional benefit in those on standard maximum therapy. AREAS OF CONTROVERSY: Data that mucolytics improve symptoms, alter mucus or impact health-related quality of life in COPD patients receiving other standard therapy are unconvincing. In those on little or no other treatment, they may reduce exacerbation rate. GROWING POINTS: The use of mucolytics to treat acute exacerbations is promising. AREAS TIMELY FOR DEVELOPING RESEARCH: Head-to-head trials of mucolytics versus long-acting bronchodilators and/or inhaled corticosteroids are lacking. Even in patients with severe COPD who remain symptomatic despite maximal inhaled therapy the role of mucolytics remains unproven.

Methods for therapeutic trials in COPD: lessons from the TORCH trial.

The TORCH (Towards a Revolution in COPD Health) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease. These include collection of off-treatment exacerbation data, analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids (ICS) prior to randomisation. When effective medications are available to patients who withdraw, inclusion of off-treatment data can mask important treatment effects on exacerbation rates. Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments. The negative binomial model is currently the best approach to statistical analysis of exacerbation rates, while analysis of time to exacerbation can supplement this approach. In the TORCH trial, exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments. Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo, regardless of prior use of ICS before entry to the study. Factorial analysis provides an alternative analysis for trials with combinations of treatments, but assumes no interaction between treatments, an assumption which cannot be verified by a significance test. No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality.

Adherence to inhaled therapy, mortality and hospital admission in COPD.

BACKGROUND: Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease (COPD) and the impact on mortality and morbidity. METHODS: Data on drug adherence from a randomised double-blind trial comparing inhaled salmeterol 50 microg + fluticasone propionate 500 microg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used. All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points. The study of adherence was not specified a priori as an ancillary study. RESULTS: Of the 4880 patients (79.8%) with good adherence defined as >80% use of study medication, 11.3% died compared with 26.4% of the 1232 patients (20.2%) with poor adherence. The annual rates of hospital admission for exacerbations were 0.15 and 0.27, respectively. The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis (hazard ratio 0.40 (95% CI 0.35 to 0.46), p<0.001). The association was even stronger when analysing on-treatment deaths only. Similarly, the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis (rate ratio 0.58 (95% CI 0.44 to 0.73, p<0.001). The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment. The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence. CONCLUSION: Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD. Further research is needed to understand these strong associations.

Hyperglycaemia as a predictor of outcome during non-invasive ventilation in decompensated COPD.

RATIONALE: Hyperglycaemia predicts a poor outcome in Intensive Care Unit (ICU) patients. Whether this is true for respiratory failure necessitating non-invasive ventilation (NIV) is not known. OBJECTIVES: To determine whether hyperglycaemia within 24 h of admission independently predicts outcome of NIV during acute decompensated ventilatory failure complicating chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: Patients with COPD presenting with acute hypercapnic respiratory failure at University Hospital Aintree between June 2006 and September 2007 and receiving NIV within 24 h of admission were studied prospectively. Random blood glucose levels were measured before NIV administration. RESULTS: 88 patients (mean baseline pH 7.25, PaCO(2) 10.20 kPa, and PaO(2) 8.19 kPa) met the inclusion criteria, with NIV normalising arterial pH off therapy in 79 (90%). After multivariate logistic regression, the following predicted outcome: baseline respiratory rate (OR 0.91; 95% CI 0.84 to 0.99), random glucose > or = 7 mmol/l (OR 0.07; 95% CI 0.007 to 0.63) and admission APACHE II (Acute Physiology and Chronic Health Evaluation II) score (OR 0.75; 95% CI 0.62 to 0.90). The combination of baseline respiratory rate (RR) <30 breaths/min and random glucose <7 mmol/l increased prediction of NIV success to 97%, whilst use of all three factors was 100% predictive. CONCLUSIONS: In acute decompensated ventilatory failure complicating COPD, hyperglycaemia upon presentation was associated with a poor outcome. Baseline RR and hyperglycaemia are as good at predicting clinical outcomes as the APACHE II score. Combining these variables increases predictive accuracy, providing a simple method of early risk stratification.

Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results.

Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.